piperidines and piperine

Translation of traditional knowledge of herbs into a viable product for clinical use is still an uphill task. Piperine, a pungent alkaloid molecule derived from

Topics: Alkaloids; Benzodioxoles; COVID-19; Humans; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Natural products are an invaluable source for the discovery of drug and pesticide candidates. Piperine, a simple and pungent alkaloid, is isolated from several plants of Piperaceae. Piperine and its derivatives displayed a wide range of biological properties, such as antitumor activity, anti-inflammatory activity, antioxidant activity, neuroprotective activity, insecticidal activity, etc. In recent years, lots of works focused on the biological activities, mechanisms of action, total synthesis, and structural modifications of piperine and its derivatives have been conducted. To the best of our knowledge, however, few review articles related to the biological activities, mechanisms of action, total synthesis, and structural modifications of piperine and its derivatives have been reported to date. Therefore, this review summarizes the research advances (from 2014 to 2020) of piperine and its derivatives regarding bioactivity, mechanisms of action, total synthesis, and structural modifications. Meanwhile, the structure-activity relationships of piperine and its derivatives are also discussed.

Topics: Alkaloids; Benzodioxoles; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship

Piperine is a fascinating substance since it can be used as a biomarker in combination with other bioactive compounds or their analogues, as well as therapeutic molecules used for the healing of a variety of diseases. It displays a plentiful therapeutic potential and various health benefits when administered alone or in combination with several other drugs and/or phytochemicals. It has also been used to enhance the pharmacokinetic profile of many nutraceutical compounds like curcumin, resveratrol, quercetin, beta-carotene, barbiturates, propranolol, metformin, theophylline etc. The present review discloses the synergistic effect of piperine and its derivatives, clinical studies, and patent studies of piperine.

Topics: Alkaloids; Humans; Piperidines; Polyunsaturated Alkamides; Theophylline

Piperine (PIP) is an alkaloid found primarily in Piper longum, and this natural compound has been shown to exert effects on proliferation and survival against various types of cancer. In particular, PIP has potent inhibitory effects on breast cancer (BC), the most prevalent type of cancer in women worldwide. PIP targets numerous signaling pathways associated with the therapy of BC cells through the following mechanisms: (a) induction of arrest of the cell cycle and apoptosis; (b) alteration of the signaling protein expression; (c) reduction in transcription factors; and (d) inhibition of tumor growth. BC cells have the ability to resist conventional drugs, so one of the strategies is the combination of PIP with other phytochemicals such as paclitaxel, thymoquinone, hesperidin, bee venom, tamoxifen, mitoxantrone, piperlongumin, and curcumin. Nanotechnology-based drug encapsulation systems are currently used to enhance the release of PIP. This includes polymer nanoparticles, carbon nanotubes, and liposomes. In the present review, the chemistry and bioavailability of PIP, its molecular targets in BC, and nanotechnological strategies are discussed. Future research directions are also discussed to further understand this promising natural product.

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Breast Neoplasms; Female; Humans; Nanotubes, Carbon; Piperidines; Polyunsaturated Alkamides

As the major naturally occurring alkaloid in pepper with a pungent taste, piperine is known for its beneficial biological functions and therapeutic effects. In this work, the bioavailability and biological activities of piperine were presented and discussed. Novel delivery systems for enhancing the bioavailability of piperine were also reviewed. This study could provide a better understanding of the physiological and biochemical aspects of piperine to be further developed in the food and nutraceutical industries.

Topics: Alkaloids; Benzodioxoles; Biological Availability; Dietary Supplements; Humans; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Currently, black pepper commands the leading position among all the spices as a spice of great commercial importance in all the world trade and finds its way into the dietary habits of millions of people worldwide. Black pepper is biologically known as Piper nigrum and contains piperine as the main active chemical constituent. This paper highlights various general methods for extracting piperine from the crude drug such as maceration extraction, hydrotropic extraction, accelerated solvent extraction, thin-layer chromatography, and extraction with ethanol & dichloromethane Ionic fluid-based ultrasonic-assisted extraction, etc. In this review, piperine and its analogs exhibit numerous pharmacological activities and synthetic schemes of insecticidal activity, anti-cancer activity, anti-inflammatory activity, anti-diabetic activity, anti-hyperlipidemic activity, antifungal activity, narcotic activity, etc. and its structure-activity relationship. The biochemistry of piperine has also been summarized in the presented article. This very exhaustive review details the complete information about piperine, its derivatives, and further processing. Furthermore, the current study summarises recent research that has linked piperine to its use as a treatment for a variety of ailments.

Topics: Alkaloids; Benzodioxoles; Humans; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship

Piperine is a key bioactive alkaloid found in plants of piperaceae family. The compound possesses various medicinal and pharmacological activities (cholesterol-lowering, anti-cancer, Alzheimer's disease etc.). Owing to its various target receptors (TRPV1, P-gp, CYP3A4 etc.) and several mechanisms, piperine has been studied as bio-enhancer for other drugs and its role has been evidenced in the literature. When administered with other drugs, it increases the absorption of other drugs, thereby reducing the dose and dose-related toxic potential. There are various mechanisms of piperine as a bio-enhancer and the common ones are i) prevention of efflux of drug molecules out of the cells; ii) decreased metabolism of drugs, thereby prolonging the halflife of drugs resulting in reduced urinary excretion. The detailed mechanism indicating the bio-enhancing role of piperine along with various target receptors has not been comprehensively summarised to date.. Literature related to the molecular, enzymatic and receptor targets of piperine were studied, and database was collected using various search engines such as j-gate, google scholar, scihub, pubmed, sciencedirect, etc. The literature related to therapeutic activities of piperine and its bio-enhancer role for other drugs has been thoroughly studied and compiled in brief.. A detailed summary of piperine targets, along with related mechanisms, has been stated. A brief therapeutic profile of piperine alone has been produced with supporting literature. Piperine role as a potential bio-enhancer for other drugs has been summarized.. Piperine is a fascinating molecule of natural origin with several modes of its action, not only possesses its own therapeutic activity but also enhances the therapeutic efficacy of other synthetic and natural drug molecules. Combination dosage forms of various API incorporating piperine as a bio-enhancer can be a potential area of thrust for upcoming drug design and development.

Topics: Alkaloids; Benzodioxoles; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Medicinal plants have been used for years as a source of food, spices, and, in traditional medicine, as a remedy to numerous diseases. Piper nigrum, belonging to the family Piperaceae is one of the most widely used spices all over the world. It has a distinct sharp flavor attributed to the presence of the phytochemical, piperine. Apart from its use as a spice, P. nigrum is frequently used for medicinal, preservation, and perfumery purposes. Black pepper contains 2-7.4% of piperine, varying in content is associated with the pepper plant. Piperine displays numerous pharmacological effects such as antiproliferative, antitumor, antiangiogenesis, antioxidant, antidiabetic, anti-obesity, cardioprotective, antimicrobial, antiaging, and immunomodulatory effects in various in vitro and in vivo experimental trials. Furthermore, piperine has also been documented for its hepatoprotective, anti-allergic, anti-inflammatory, and neuroprotective properties. This review highlights and discusses the medicinal and health-promoting effects of piperine, along with possible mechanisms of its action in health promotion and disease prevention. In addition, the present review summarizes the recent literature related to piperine as a therapeutic agent against several diseases.

Topics: Alkaloids; Animals; Benzodioxoles; Drug Therapy, Combination; Humans; Piperidines; Polyunsaturated Alkamides

Piperine (PIP) is an alkaloid present in several species of piper, mainly Piper nigrum Linn. and P. longum, among other species. The present article provides a comprehensive review of PIP research in the last years concerning its chemical properties, synthesis, absorption, metabolism, bioavailability and toxicity. The reviewed PIP literature has shown many pharmacological properties, such as antidiabetic, antidiarrheal, antioxidant, antibacterial, and anti-parasitic activity of PIP. However, its low solubility and absorption make its application challenging. This review also includes advances in the development of nanosystems containing PIP, including liposomes, micelles, metal nanoparticles, nanofibers, polymeric nanoparticles, and solid-lipid nanoparticles. Finally, we discuss different in vitro and in vivo studies to evaluate the biological activity of this drug, as well as some methods for the synthesis of nanosystems and their physical characteristics.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Humans; Liposomes; Micelles; Nanoparticles; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Solubility

The continued spread of 2019-nCoV has prompted widespread concern around the world. WHO formally named COVID-19 and International Committee on Taxonomy called it Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Due to this viral attack, the whole world is in lockdown. Presently, there is no effective way to control it, except social distancing and hygienic activity. World class scientists and researchers are trying to make vaccine and discover the medicine against the control and cure to this deadly viral disease. Our aim to presenting this article is kick-off deadly viral disease i.e COVID-19 by an easy way with minimum intervention and effort. Different ayurvedic therapeutic agents (Curcuma Longa L, Green tea and Piper nigrum) inhabit entry of virus in host cell, transmission of pathogen and improve the immunity. Curcumin and piperine (1-piperoylpiperidine) interact to each other and form a π-π intermolecular complex which enhance the bioavailability of curcumin by inhibition of glucuronidation of curcumin in liver. Both the molecules curcumin and catechin get bound directly to receptors binding domain of S-protein and ACE-2 receptors of host cell, due to which these molecules inhibit the entry of virus in host cell i. e. animal survives from being infected.

Topics: Alkaloids; Angiotensin-Converting Enzyme 2; Animals; Antiviral Agents; Benzodioxoles; COVID-19; COVID-19 Drug Treatment; Curcumin; Humans; Piperidines; Polyunsaturated Alkamides; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Virus Internalization

Piper chaba Hunter, called Chui Jhal or Choi Jhal, is commonly used as a culinary (spice) herb in India and Bangladesh. It exhibits numerous important biological activities and has been widely used in traditional medicine.. This review focuses on the chemical and pharmacological activities of a culinary ingredient P. chaba based on information extracted from the literature to highlight its use in traditional medicine.. A literature search in known databases was conducted (till September 2019) for published articles using the relevant keywords.. Findings suggest that, to date, a number of important phytoconstituents such as dimeric alkaloids, and alkamides have been isolated from various parts of P. chaba. Extracts from P. chaba or derived compounds exhibit diverse biological activities, such as anti-microbial, anti-leishmanial, anti-malarial, anti-parasitic, cytotoxic/anticancer, adipogenic, hepato- and gastro-protective, anti-diabetic, analgesic, anti-diarrheal, depressive, anti-inflammatory, diuretic, anti-hypertensive, antipyretic, anti-ulcer, and immunomodulatory effect. Among the isolated compounds, chabamides, piperine, piplartine, retrofractamides A/B, methylenedioxyphenyl)-nona-2E,4E,8E-trienoic acid, n-butyl or n-pentyl amine, piperlonguminine, pipernonaline, dehydropipernonaline, N-isobutyl-(2E,4E)-octadecadienamide, and N-isobutyl-(2E,4E,14Z)-eicosatrienamide have documented important biological effects in various test systems.. Taken together, P. chaba may be a potential source of plant-based therapeutic lead compounds, which justify its uses in traditional medicine.

Topics: Adipogenesis; Alkaloids; Animals; Antifungal Agents; Antimalarials; Antiparasitic Agents; Bangladesh; Benzodioxoles; Dioxolanes; Humans; Hypoglycemic Agents; India; Medicine, Traditional; Phytotherapy; Piper; Piperidines; Plant Extracts; Polyunsaturated Alkamides

Black pepper (

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Dietary Supplements; Exercise; Humans; Iron; Phytochemicals; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats

The main limits of current anticancer therapy are relapses, chemoresistance, and toxic effects resulting from its poor selectivity towards cancer cells that severely impair a patient's quality of life. Therefore, the discovery of new anticancer drugs remains an urgent challenge. Natural products represent an excellent opportunity due to their ability to target heterogenous populations of cancer cells and regulate several key pathways involved in cancer development, and their favorable toxicological profile.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Benzodioxoles; Cell Line, Tumor; Dioxolanes; Drug Synergism; Fatty Acids, Unsaturated; Humans; Mice; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Quality of Life; Rats; Seeds

Piperine (PIP) is a natural alkaloid isolated from

Topics: Alkaloids; Benzodioxoles; Biological Availability; Brain; Chromatography, High Pressure Liquid; Drug Carriers; Drug Compounding; Drug Liberation; Humans; Piperidines; Polyunsaturated Alkamides; Solubility; Tandem Mass Spectrometry; Water

Topics: Alkaloids; Animals; Benzodioxoles; Central Nervous System Agents; Central Nervous System Diseases; Dose-Response Relationship, Drug; Drug Interactions; Humans; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Oral lichen planus (OLP) is a common T cell-mediated chronic inflammatory disease with malignant potential and unclear etiology. The present study suggests that antigen-specific mechanisms in which dentritic cells, T lymphocytes and NF-κB signaling pathway play critical roles, are involved in the pathogenesis of OLP. Additionally, it has been indicated that altered expression of cyclooxygenase 2 (COX-2) and imbalanced oxidant-antioxidant status as well as psychological issue may act as promoters to the development of OLP. Therapies for OLP are primarily aimed to control symptoms and a specific cure is not yet available. Black pepper and its principle bioactive compound piperine have been reported to possess remarkable pharmacological activities. Not only has piperine been evidenced to exhibit repressive effects on the maturation of dentritic cells, the proliferation, activation and function of T lymphocytes as well as the NF-κB signaling pathway, but also to suppress the overproduction of COX-2 and weaken the oxidative stress. Furthermore, piperine might be a possible agent for alleviating psychological disorders and preventing carcinogenesis. Given all these into consideration, piperine may be a novel and effective therapeutic strategy for OLP.

Topics: Alkaloids; Animals; Benzodioxoles; Cyclooxygenase 2; Humans; Lichen Planus, Oral; NF-kappa B; Phytochemicals; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Signal Transduction; T-Lymphocytes

Despite the significant advances in screening methods for early diagnosis, breast cancer remains a global threat and continues to be the leading cancer diagnosed in women, requiring effective therapy. Currently, combination therapy has become the hallmark of breast cancer treatment due to the high incidence of tumor recurrence and disease progression after monotherapeutic treatments, including surgery, radiotherapy, endocrine therapy, and chemotherapy. Over the past decades, there has been considerable interest in studying the anticancer effect of bioactive phytochemicals from medicinal plants combined with these conventional therapies. The rationale for this type of therapy is to use combinations of drugs that work by different mechanisms, thereby decreasing the likelihood that cancer cells will develop resistance, and also reduce the therapeutic dose and toxicity of single treatments. Three agents have received great attention with regard to their anticancer properties: 1) piperine, a dietary phytochemical isolated from black pepper (Piper nigrum L.) and long pepper (Piper longum L.); 2) sulforaphane, an isothiocyanate mainly derived from cruciferous vegetables; and 3) thymoquinone, the active compound from black seed (Nigella sativa L.). This review focused on the combined effect of these 3 compounds on conventional cancer therapy with the objective of observing enhanced efficacy compared with single treatments. This review also highlights the importance of the nanoformulation of such bioactive phytochemicals that could enhance their bioavailability by providing an efficient targeted delivery system with a reduced systemic dose while resulting in a more efficient dosing at the target site.

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Benzoquinones; Breast Neoplasms; Cell Line, Tumor; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Humans; In Vitro Techniques; Isothiocyanates; Patient Selection; Phytochemicals; Phytotherapy; Piperidines; Polyunsaturated Alkamides; Radiotherapy, Adjuvant; Sensitivity and Specificity; Sulfoxides

Plants are vital for the wellbeing of humankind in a variety of ways. Some plant extracts contain antimicrobial properties that can treat different pathogens. Most of the world's population relies on medicinal plants and natural products for their primary health care needs. Therefore, there is a growing interest in natural products, medicinal plants, and traditional medicine along with a desire to design and develop novel plant-based pharmaceuticals. These plant-based pharmaceuticals may address the concerns of reduced efficacy of synthetic antibiotics due to the emergence of drug-resistant pathogens. In this regard, some plant extracts from black pepper (Piper nigrum) with antimicrobial properties, including piperine, have the potential to be used as natural dietary supplements together with modern therapeutic approaches. This review highlights possible applications of piperine as the active compound in the fields of rational drug design and discovery, pharmaceutical chemistry, and biomedicine. We discuss different extraction methods and pharmacological effects of the analyzed substance to pave the way for further research strategies and perspectives towards the development of novel herbal products for better healthcare solutions.

Topics: Alkaloids; Animals; Benzodioxoles; Cell Line, Tumor; Humans; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Many of the activities associated with pepper fruits have been attributed to piperine, the most active compound present in these spices.. This paper aims to provide an overview of the known properties of piperine, i.e. piperine's chemistry, its physiological activity, documented interactions as a bioenhancer and reported data concerning its toxicity, antioxidant properties and anticancer activity.. It is known that piperine possesses several properties. In its interaction with other drugs, it can act as a bioavailability enhancer; this effect is also manifested in combination with other nutraceuticals, e.g. with curcumin, i.e. piperine can modify curcumin's antioxidant, anti-inflammatory, antimicrobial and anticancer effects. Piperine displays significant immunomodulating, antioxidant, chemopreventive and anticancer activity; these effects have been shown to be dose-dependent and tissue-specific. However, the main limitation associated with piperine seems to be its low bioavailability, a disadvantage that innovative formulations are overcoming.. It is predicted that an increasing number of studies will focus on piperine, especially those directed towards unraveling its properties at molecular level. The current knowledge about the action of piperine will form a foundation for ways to improve piperine's bioavailability e.g. exploitation of different carrier systems. The therapeutical applications of this compound will be clarified, and piperine will be recognized as an important nutraceutical.

Topics: Alkaloids; Benzodioxoles; Biological Availability; Dietary Supplements; Piperidines; Polyunsaturated Alkamides; Spices

Cancer is among the leading causes of death worldwide. Several pharmacological protocols have been developed in order to block tumor progression often showing partial efficacy and severe counterproductive effects. It is now conceived that a healthy lifestyle coupled with the consumption of certain phytochemicals can play a protective role against tumor development and progression. According to this vision, it has been introduced the concept of "chemoprevention". This term refers to natural agents with the capability to interfere with the tumorigenesis and metastasis, or at least, attenuate the cancer-related symptoms. Piperine (1-Piperoylpiperidine), a main extract of Piper longum and Piper nigrum, is an alkaloid with a long history of medicinal use. In fact, it exhibits a variety of biochemical and pharmaceutical properties, including chemopreventive activities without significant cytotoxic effects on normal cells, at least at doses < of 250 µg/ml. The aim of this review is to discuss the relevant molecular and cellular mechanisms underlying the chemopreventive action of this natural alkaloid.

Topics: Alkaloids; Apoptosis; Benzodioxoles; Cell Proliferation; Chemoprevention; Disease Progression; Humans; Neoplasm Metastasis; Neoplasms; Piperidines; Plant Extracts; Polyunsaturated Alkamides

Recently many studies showed anticancer activities of piperine, a pungent alkaloid found in black pepper and some other Piper species. We attempted to summarize acquired data that support anticancer potential of this natural agent. Piperine has been reported to possess effective chemopreventive activity. It has been studied to affect via several mechanisms of action, in brief enhancing antioxidant system, increasing level and activity of detoxifying enzymes and suppressing stem cell self-renewal. Moreover, piperine has been found to inhibit proliferation and survival of various cancerous cell lines via modulating cell cycle progression and exhibiting anti-apoptotic activity, respectively. This compound has been shown to modify activity of various enzymes and transcription factors to inhibit invasion, metastasis and angiogenesis. Interestingly, piperine has exhibited antimutagenic activity and also inhibited activity and expression of multidrug resistance transporters such as P-gp and MRP-1. Besides, about all reviewed studies have reported selective cytotoxic activity of piperine on cancerous cells in compared with normal cells. Altogether, the studies completely underline promising candidacy of piperine for further development. The collected preclinical data we provided in this article can be useful in the design of future researches especially clinical trials with piperine.

Topics: Alkaloids; Animals; Anticarcinogenic Agents; Antimutagenic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Benzodioxoles; Biological Availability; Cell Proliferation; Cell Survival; Drug Evaluation, Preclinical; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Inactivation, Metabolic; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Piper; Piperidines; Polyunsaturated Alkamides; Stem Cells

Piperine has various pharmacological effects and can modulate the functional activity of metabolic enzymes and drug transporters. Consequently, there is a great interest in the application of piperine as an alternative medicine or bioavailability enhancer. Areas covered: This review deals with the effects of piperine on metabolizing enzymes and drug transporters. It provides the readers with an update on transporter-mediated and also metabolic enzyme-mediated piperine-drug interactions, with emphasis on its in vivo implications. This article also encompasses recent advances in the formulation approaches and technologies for optimizing the delivery of piperine. Expert opinion: Piperine can influence the pharmacokinetics of coadministered drugs, which may result in a therapeutically beneficial or adverse effect. Given that piperine inhibits or stimulates the activity of metabolic enzymes and transporters depending on the treatment conditions, the clinical significance of piperine-drug interactions should be assessed by varying the dose, dosing frequency, and the duration of treatment. In particular, better understanding the clinical relevance of piperine-drug interactions based on long-term assessments will provide a strong basis for the feasibility and applicability of piperine as a bioenhancer or a health-promoting agent. The development of effective formulations is also critical to facilitate the therapeutic applications of piperine.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Chemistry, Pharmaceutical; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Interactions; Humans; Membrane Transport Proteins; Piperidines; Polyunsaturated Alkamides

Piperine is a simple and pungent alkaloid found in the seeds of black pepper (Piper nigrum). Following its isolation and full characterization, the biological properties of piperine have been extensively studied, and piperine-like derivatives have shown an interesting range of pharmacological activities. In this context, significant advances have been made in the discovery of new chemical entities based on the piperine scaffold endowed with therapeutic potential.. The aim of this review is to provide a thorough inquiry on the therapeutic potential of piperine and related derivatives. It provides an overview of recent developments in patented processes and applications thereof between 2000 and 2015.. Cumulative evidence shows that piperine is currently paving its way to become a privileged scaffold for the development of bioactive compounds with therapeutic application in multiple human diseases. In particular, piperine derivatives were shown to modulate the activity of several targets related to neurological disorders, including epilepsy, Parkinson's disease, depression and pain related disorders. Moreover, the efflux pump inhibitory ability of piperine and its analogues tackles important drug resistance mechanisms and may improve the clinical efficacy of antibiotic and anticancer drugs. Although the use of piperine as a scaffold for bioactive compounds is still in its early stages, the continuous exploration of this structure may lead to remarkable advances in drug discovery programs.

Topics: Alkaloids; Animals; Benzodioxoles; Drug Design; Drug Discovery; Drug Resistance; Humans; Nervous System Diseases; Patents as Topic; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Seeds

Spices have been widely used as food flavorings and folk medicines for thousands of years. Numerous studies have documented the antioxidant, anti-inflammatory and immunomodulatory effects of spices, which might be related to prevention and treatment of several cancers, including lung, liver, breast, stomach, colorectum, cervix, and prostate cancers. Several spices are potential sources for prevention and treatment of cancers, such as Curcuma longa (tumeric), Nigella sativa (black cumin), Zingiber officinale (ginger), Allium sativum (garlic), Crocus sativus (saffron), Piper nigrum (black pepper) and Capsicum annum (chili pepper), which contained several important bioactive compounds, such as curcumin, thymoquinone, piperine and capsaicin. The main mechanisms of action include inducing apoptosis, inhibiting proliferation, migration and invasion of tumors, and sensitizing tumors to radiotherapy and chemotherapy. This review summarized recent studies on some spices for prevention and treatment of cancers, and special attention was paid to bioactive components and mechanisms of action.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Apoptosis; Benzodioxoles; Benzoquinones; Capsaicin; Capsicum; Cell Proliferation; Crocus; Curcuma; Curcumin; Garlic; Humans; Neoplasms; Nigella sativa; Phytotherapy; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Spices; Zingiber officinale

Multidrug resistance is a principal mechanism by which tumors become resistant to structurally and functionally unrelated anticancer drugs. Resistance to chemotherapy has been correlated with overexpression of p-glycoprotein (p-gp), a member of the ATP-binding cassette (ABC) superfamily of membrane transporters. P-gp mediates resistance to a broad-spectrum of anticancer drugs including doxorubicin, taxol, and vinca alkaloids by actively expelling the drugs from cells. Use of specific inhibitors/blocker of p-gp in combination with clinically important anticancer drugs has emerged as a new paradigm for overcoming multidrug resistance. The aim of this paper is to review p-gp regulation by dietary nutraceuticals and to correlate this dietary nutraceutical induced-modulation of p-gp with activity of anticancer drugs.

Topics: Abietanes; Alkaloids; Allyl Compounds; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Benzodioxoles; beta Carotene; Biflavonoids; Capsaicin; Catechin; Catechols; Curcumin; Dietary Supplements; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Fatty Alcohols; Furocoumarins; Humans; Indoles; Limonins; Neoplasms; Phytotherapy; Piperidines; Polyunsaturated Alkamides; Proanthocyanidins; Quercetin; Resveratrol; Stilbenes; Sulfides; Tea; Triterpenes; Xanthophylls

Excessive free radical generation overbalancing the rate of their removal leads to oxidative stress. Oxidative stress has been implicated in the etiology of cardiovascular disease, inflammatory diseases, cancer, and other chronic diseases. Antioxidants are compounds that hinder the oxidative processes and thereby delay or suppress oxidative stress. There is a growing interest in natural antioxidants found in plants. Herbs and spices are most important targets to search for natural antioxidants from the point of view of safety. A wide variety of phenolic compounds present in spices that are extensively used as food adjuncts possess potent antioxidant, anti-inflammatory, antimutagenic, and cancer preventive activities. This paper reviews a host of spice compounds as exogenous antioxidants that are experimentally evidenced to control cellular oxidative stress, both in vitro and in vivo, and their beneficial role in preventing or ameliorating oxidative-stress-mediated diseases, from atherosclerosis to diabetes to cataract to cancer. The antioxidative effects of turmeric/curcumin, clove/eugenol, red pepper/capsaicin, black pepper/piperine, ginger/gingerol, garlic, onion, and fenugreek, which have been extensively studied and evidenced as potential antioxidants, are specifically reviewed in this treatise.

Topics: Alkaloids; Anti-Inflammatory Agents; Antimutagenic Agents; Antioxidants; Benzodioxoles; Capsaicin; Cardiotonic Agents; Catechols; Curcumin; Eugenol; Fatty Alcohols; Garlic; Humans; Neoplasms; Onions; Oxidative Stress; Phenols; Piperidines; Polyunsaturated Alkamides; Spices; Trigonella

The current review emphasizes on the herbal bioenhancers which themselves do not possess inherent pharmacological activity of their own but when co-administered with Active Pharmaceutical Ingredients (API), enhances their bioavailability and efficacy. Herbal bioenhancers play a crucial role in enhancing the bioavailability and bioefficacy of different classes of drugs, such as antihypertensives, anticancer, antiviral, antitubercular and antifungal drugs at low doses. This paper highlights various natural compounds that can be utilized as an efficient bioenhancer. Several herbal compounds including piperine, quercetin, genistein, naringin, sinomenine, curcumin, and glycyrrhizin have demonstrated capability to improve the pharmacokinetic parameters of several potent API. This article also focuses on various United States patents on herbal bioenhancers, which has proved to be beneficial in improving oral absorption of nutraceuticals like vitamins, minerals, amino acids and certain herbal compounds. The present paper also describes proposed mechanism of action, which mainly includes absorption process, drug metabolism, and action on drug target. The herbal bioenhancers are easily available, safe, free from side effects, minimizes drug toxicity, shortens the duration of treatment, lowers the drug resistance problems and minimizes the cost of treatment. Inspite of the fact that herbal bioenhancers provide an innovative concept for enhancing the bioavailability of several potent drugs, there are numerous bioenhancers of herbal origin that are yet to be explored in several vital areas. These bioenhancers must also be implied to enhance the bioavailability and bioefficacy through routes other than the oral route of drug delivery. There is a vast array of unexploited plants which can be investigated for their drug bioenhancing potency. The toxicity profiles of these herbal bioenhancers must not be overlooked. Researches must be carried out to solve these issues and to deliver a safe and effective dose of drugs to attain desired pharmacological response.

Topics: Adjuvants, Pharmaceutic; Alkaloids; Benzodioxoles; Biological Availability; Carum; Cuminum; Curcumin; Ergolines; Flavanones; Genistein; Glycyrrhizic Acid; Humans; Morphinans; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Quercetin; Zingiber officinale

Black pepper (Piper nigrum L.) is a very widely used spice, known for its pungent constituent piperine. However, in addition to its culinary uses, pepper has important medicinal and preservative properties, and, more recently, piperine has been shown to have fundamental effects on p-glycoprotein and many enzyme systems, leading to biotransformative effects including chemoprevention, detoxification, and enhancement of the absorption and bioavailability of herbal and conventional drugs. Based on modern cell, animal, and human studies, piperine has been found to have immunomodulatory, anti-oxidant, anti-asthmatic, anti-carcinogenic, anti-inflammatory, anti-ulcer, and anti-amoebic properties. In this review, the chemical constituents, biological activities, effects of processing, and future potential of black pepper and piperine have been discussed thoroughly.

Topics: Alkaloids; Animals; Benzodioxoles; Humans; Piper nigrum; Piperidines; Polyunsaturated Alkamides

For millennia, spices have been an integral part of human diets and commerce. Recently, the widespread recognition of diet-health linkages bolsters their dietary importance. The bioactive components present in them are of considerable significance owing to their therapeutic potential against various ailments. They provide physiological benefits or prevent chronic ailment in addition to the fundamental nutrition and often included in the category of functional foods. Black pepper (Piper Nigrum L.) is an important healthy food owing to its antioxidant, antimicrobial potential and gastro-protective modules. Black pepper, with piperine as an active ingredient, holds rich phytochemistry that also includes volatile oil, oleoresins, and alkaloids. More recently, cell-culture studies and animal modeling predicted the role of black pepper against number of maladies. The free-radical scavenging activity of black pepper and its active ingredients might be helpful in chemoprevention and controlling progression of tumor growth. Additionally, the key alkaloid components of Piper Nigrum, that is, piperine assist in cognitive brain functioning, boost nutrient's absorption and improve gastrointestinal functionality. In this comprehensive treatise, efforts are made to elucidate the antioxidant, antimicrobial, anti-inflammatory, gastro-protective, and antidepressant activities of black pepper. Moreover, the synergistic interaction of black pepper with different drugs and nutrients is the limelight of the manuscript. However, the aforementioned health-promoting benefits associated with black pepper are proven in animal modeling. Thus, there is a need to conduct controlled randomized trials in human subjects, cohort studies, and meta-analyses. Such future studies would be helpful in recommending its application in diet-based regimens to prevent various ailments.

Topics: Alkaloids; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antioxidants; Benzodioxoles; Diet; Dietary Supplements; Food, Organic; Humans; Oils, Volatile; Phytochemicals; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Spices

Cancer stem cells often have phenotypic and functional characteristics similar to normal stem cells including the properties of self-renewal and differentiation. Recent findings suggest that uncontrolled self-renewal may explain cancer relapses and may represent a critical target for cancer prevention. It is conceivable that the loss of regulatory molecules resulting from inappropriate consumption of specific foods and their constituents may foster the aberrant self-renewal of cancer stem cells. In fact, increasing evidence points to the network delivering signals for self-renewal from extracellular compartments to the nucleus including changes in stem cell environments, inducible expression of microRNAs, hyperplastic nuclear chromatin structures, and the on/off of differentiation process as possible sites of action for bioactive food components. Diverse dietary constituents such as vitamins A and D, genistein, (-)-epigallocatechin-3-gallate (EGCG), sulforaphane, curcumin, piperine, theanine and choline have been shown to modify self-renewal properties of cancer stem cells. The ability of these bioactive food components to influence the balance between proliferative and quiescent cells by regulating critical feedback molecules in the network including dickkopf 1 (DKK-1), secreted frizzled-related protein 2 (sFRP2), B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and cyclin-dependent kinase 6 (CDK6) may account for their biological response. Overall, the response to food components does not appear to be tissue or organ specific, suggesting there may be common cellular mechanisms. Unquestionably, additional studies are needed to clarify the physiological role of these dietary components in preventing the resistance of tumor cells to traditional drugs and cancer recurrence.

Topics: Alkaloids; Benzodioxoles; Catechin; Cell Differentiation; Cell Proliferation; Choline; Curcumin; Cyclin-Dependent Kinase 6; Diet; Epigenesis, Genetic; Gene Expression Regulation; Genistein; Glutamates; Humans; Intercellular Signaling Peptides and Proteins; Isothiocyanates; Membrane Proteins; Mesenchymal Stem Cells; Neoplastic Stem Cells; Nuclear Proteins; Piperidines; Plant Extracts; Polycomb Repressive Complex 1; Polyunsaturated Alkamides; Proto-Oncogene Proteins; Repressor Proteins; STAT1 Transcription Factor; Sulfoxides; Thiocyanates; Vitamin A; Vitamin D; Wnt Proteins

In India, Ayurveda has made a major contribution to the drug discovery process with new means of identifying active compounds. Recent advancement in bioavailability enhancement of drugs by compounds of herbal origin has produced a revolutionary shift in the way of therapeutics. Thus, bibliographic investigation was carried out by analyzing classical text books and peer-reviewed papers, consulting worldwide-accepted scientific databases from last 30 years. Herbal bioenhancers have been shown to enhance bioavailability and bioefficacy of different classes of drugs, such as antibiotics, antituberculosis, antiviral, antifungal, and anticancerous drugs at low doses. They have also improved oral absorption of nutraceuticals like vitamins, minerals, amino acids, and certain herbal compounds. Their mechanism of action is mainly through absorption process, drug metabolism, and action on drug target. This paper clearly indicates that scientific researchers and pharmaceutical industries have to give emphasis on experimental studies to find out novel active principles from such a vast array of unexploited plants having a role as a bioavailability and bioefficacy enhancer. Also, the mechanisms of action by which bioenhancer compounds exert bioenhancing effects remain to be explored.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Benzodioxoles; Biological Availability; Curcumin; Databases, Factual; Dietary Supplements; Drug Compounding; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Herb-Drug Interactions; Humans; Phenytoin; Piperidines; Plant Preparations; Plants, Medicinal; Polyunsaturated Alkamides

The emergence of cancer stem cell theory has profound implications for cancer chemoprevention and therapy. Cancer stem cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of anticancer drugs targeting cancer stem cells. Naturally occurring dietary compounds have received increasing attention in cancer chemoprevention. The anticancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect cancer stem cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against cancer stem cells. Three pathways (Wnt/β-catenin, Hedgehog and Notch) are summarized for their functions in self-renewal of cancer stem cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine and vitamin D(3), are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast cancer stem cells. Sulforaphane has been reported to inhibit pancreatic tumor-initiating cells and breast cancer stem cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of cancer stem cells. This may enable us to discover more preventive strategies for cancer management by reducing cancer resistance and recurrence and improving patient survival.

Topics: Alkaloids; Animals; Anticarcinogenic Agents; Benzodioxoles; beta Catenin; Carotenoids; Catechin; Cell Differentiation; Cell Proliferation; Cholecalciferol; Curcumin; Diet; Humans; Isoflavones; Isothiocyanates; Lycopene; Neoplasms; Neoplastic Stem Cells; Piperidines; Polyunsaturated Alkamides; Resveratrol; Signal Transduction; Stilbenes; Sulfoxides; Thiocyanates; Wnt Proteins

There is currently a need for a better understanding of the mechanisms of food-drug interaction as well as the clinical implication to maximize the effectiveness and applicability of black pepper or its active component, piperine, as a bioavailability enhancer in the clinical arena.. This review deals with the effects of black pepper and piperine on drug metabolizing enzymes as well as on intestinal drug absorption. The review provides the reader with a comprehensive update on the potential mechanisms and pharmacokinetic interactions of black pepper and piperine with co-administered medicines. The article also provides a comprehensive update on the current known issues with black pepper and piperine. The information provided is used to assess the clinical significance of black pepper and piperine and optimize their effectiveness as a bioavailability enhancer.. For black pepper or piperine to be widely applicable in current medical practice, as a combination therapy, the clinical significance of food-drug interactions caused by concurrent use of black pepper or piperine should be carefully assessed with consideration for many compounding factors affecting the clinical outcome of pharmacokinetic interactions (e.g., dose, dosing regimen, genetic variation and species). Furthermore, the effective formulation strategy for the optimization of the pharmacokinetic characteristics of dietary components is crucial to improve their in vivo performance and ultimately maximize their effectiveness as a bioavailability enhancer.

Topics: Alkaloids; ATP Binding Cassette Transporter, Subfamily B; Benzodioxoles; Biological Availability; Food-Drug Interactions; Humans; Intestinal Absorption; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Eighty percent (80%) aqueous acetone extract from fruit of Piper chaba (Piperaceae) was found to have a hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. Among the isolates, several amide constituents inhibited D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes, and the following structural requirements were suggested: i) the amide moiety was essential for strong activity; ii) the 1,9-decadiene structure between the benzene ring and the amide moiety tended to enhance the activity. Moreover, a principal constituent, piperine, exhibited strong in vivo hepatoprotective effect at a dose of 5 mg/kg, p.o. and its mode of action was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.

Topics: Alkaloids; Amides; Animals; Benzodioxoles; Cells, Cultured; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Dose-Response Relationship, Drug; Galactosamine; Hepatocytes; Lipopolysaccharides; Mice; Piper; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

Black pepper (Piper nigrum) is one of the most widely used among spices. It is valued for its distinct biting quality attributed to the alkaloid, piperine. Black pepper is used not only in human dietaries but also for a variety of other purposes such as medicinal, as a preservative, and in perfumery. Many physiological effects of black pepper, its extracts, or its major active principle, piperine, have been reported in recent decades. Dietary piperine, by favorably stimulating the digestive enzymes of pancreas, enhances the digestive capacity and significantly reduces the gastrointestinal food transit time. Piperine has been demonstrated in in vitro studies to protect against oxidative damage by inhibiting or quenching free radicals and reactive oxygen species. Black pepper or piperine treatment has also been evidenced to lower lipid peroxidation in vivo and beneficially influence cellular thiol status, antioxidant molecules and antioxidant enzymes in a number of experimental situations of oxidative stress. The most far-reaching attribute of piperine has been its inhibitory influence on enzymatic drug biotransforming reactions in the liver. It strongly inhibits hepatic and intestinal aryl hydrocarbon hydroxylase and UDP-glucuronyl transferase. Piperine has been documented to enhance the bioavailability of a number of therapeutic drugs as well as phytochemicals by this very property. Piperine's bioavailability enhancing property is also partly attributed to increased absorption as a result of its effect on the ultrastructure of intestinal brush border. Although initially there were a few controversial reports regarding its safety as a food additive, such evidence has been questionable, and later studies have established the safety of black pepper or its active principle, piperine, in several animal studies. Piperine, while it is non-genotoxic, has in fact been found to possess anti-mutagenic and anti-tumor influences.

Topics: Alkaloids; Animals; Anticarcinogenic Agents; Antimutagenic Agents; Antioxidants; Benzodioxoles; Biological Availability; Cytochrome P-450 Enzyme Inhibitors; Diet; Digestion; Enzyme Inhibitors; Female; Fertility; Fruit; Gastrointestinal Tract; Humans; Lipid Metabolism; Male; Piper nigrum; Piperidines; Polyunsaturated Alkamides

The pipeline for new antibacterials is bleak despite the fact that infectious diseases account for a quarter of all worldwide deaths due to disease. Bacteria are ideal organisms for a systems biology approach to understanding pathogenesis by combined use of genomic technologies and computer algorithms. This approach can be applied to identify control points in molecular networks, which could be targets for novel drugs.

Topics: Alkaloids; Animals; Anti-Bacterial Agents; Bacterial Infections; Benzodioxoles; Drug Design; Genome, Bacterial; Humans; Piperidines; Polyunsaturated Alkamides; Systems Biology

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Benzodioxoles; Oils, Volatile; Piper; Piper nigrum; Piperidines; Plants, Medicinal; Polyunsaturated Alkamides

COVID-19 pandemic has made the disease a major global problem by creating a significant burden on health, economic, and social status. To date, there are no effective and approved medications for this disease. Curcumin as an anti-inflammatory agent can have a positive effect on the control of COVID-19 complications. This study aimed to assess the efficacy of curcumin-piperine supplementation on clinical symptoms, duration, severity, and inflammatory factors in patients with COVID-19.. Forty-six outpatients with COVID-19 disease were randomly allocated to receive two capsules of curcumin-piperine; each capsule contained 500 mg curcumin plus 5 mg piperine or placebo for 14 days.. Mean changes in complete blood count, liver enzymes, blood glucose levels, lipid parameters, kidney function, and c-reactive protein (CRP) were not significantly different between the two groups. There was a significant improvement in health status, including dry cough, sputum cough, ague, sore throat, weakness, muscular pain, headache, and dyspnea at week 2 in both curcumin-piperine and placebo groups (P value < 0.05); however, the improvement in weakness was more in the curcumin-piperine group than with placebo group (P value 025).. The present study results showed that curcumin-piperine co-supplementation in outpatients with COVID-19 could significantly reduce weakness. However, in this study, curcumin-piperine co-supplementation could not significantly affect the other indices, including biochemical and clinical indices.. Iranian Registry of Clinical Trials IRCT20121216011763N46 . 2020-10-31.

Topics: Alkaloids; Benzodioxoles; Cough; COVID-19 Drug Treatment; Curcumin; Dietary Supplements; Double-Blind Method; Humans; Iran; Outpatients; Pandemics; Piperidines; Polyunsaturated Alkamides

Experimental and clinical studies have revealed that curcumin may be an effective therapy for non-alcoholic fatty liver disease (NAFLD). Hence, the aim of this study was to assess the effect of curcumin plus piperine administration on NAFLD.. Adults 18-65 years-old diagnosed with NAFLD by liver sonography were randomly allocated to curcumin (500 mg/day) or placebo groups for 2 months. All participants received both dietary and exercise advice. Anthropometric and biochemical measurements as well as hepatic ultrasound were performed at baseline and final conditions.. Seventy-nine participants were recruited and randomly allocated into the curcumin (n = 39) or placebo (n = 40) groups. There were no significant differences between placebo and curcumin groups for demographic and clinical characteristics and NAFLD grade at baseline. After the treatment period, the curcumin group exhibited lower alkaline phosphatase (-16.2 ± 22.8 versus -6.0 ± 22.5 mg/dL, p = 0.04) concentrations and severity of NAFLD compared with the placebo group (p = 0.04).. Results of this clinical trial suggest that short-term treatment with curcumin plus piperine administration improves NAFLD severity.

Topics: Adolescent; Adult; Aged; Alkaloids; Benzodioxoles; Curcumin; Dietary Supplements; Double-Blind Method; Humans; Liver; Middle Aged; Non-alcoholic Fatty Liver Disease; Piperidines; Polyunsaturated Alkamides; Young Adult

Acute myocardial infarction (AMI) is a leading cause of death and disability worldwide. Previous investigations have demonstrated that curcumin has a cardioprotective effect and may improve myocardial injury. So this study was performed to assess whether supplementation with curcumin could diminish myocardial injury following AMI.. To conduct this randomized, double-blinded, and placebo-controlled clinical trial, seventy-two patients with acute myocardial infarction, aged 18-75 years, were enrolled and randomly divided into the active intervention and control groups. The active intervention group (n = 38) received curcumin capsules with piperine supplement (500 mg/day, 95% curcuminoids) for 8 weeks, whereas the control group (n = 34) received a placebo capsule. At the baseline and end of the study, ejection fraction was assessed, and blood samples were taken from all patients to measure the levels of cardiac troponin I(cTnI), lipid profile, FBG, HbA1C, liver enzymes, renal function parameters, and electrolytes.. In this trial, curcumin supplementation significantly reduced the levels of HbA1C (-0.3 ± 2.2 vs. +1.1 ± 1.3, P = 0.002), LDL (-10.3 ± 20.7 vs. +0.2 ± 22.5, P = 0.039), ALT (-10.2 ± 28.5 vs. +7.3 ± 39.2, P = 0.029), and ALP (+6.4 ± 39.5 vs. +38.0 ± 69.0, P = 0.018) compared to the placebo group. Moreover, the serum concentration of HDL significantly improved in comparison with the placebo group (+4.5 ± 8.9 vs. -1.6 ± 7.7, P = 0.002). However, no substantial difference was perceived between the groups regarding the ejection fraction and serum levels of cTnI, FBG, renal function parameters, and electrolytes.. Our results indicated that daily intake of 500 mg of curcumin capsules with piperine supplement for 8 weeks modified lipid profile, liver enzymes, and glycemic status, but did not have any effect on ejection fraction and serum concentration of cardiac troponin I, renal function parameters, and electrolytes in acute myocardial infarction patients.

Topics: Alkaloids; Benzodioxoles; Curcumin; Dietary Supplements; Double-Blind Method; Humans; Myocardial Infarction; Piperidines; Polyunsaturated Alkamides

Resveratrol (3,4,5-trihydroxystilbene) is a naturally occurring phytoalexin with purported health-promoting effects, but with limited oral bioavailability. Our prior murine modeling research observed enhanced resveratrol bioavailability with piperine co-administration. In this study, single-dose pharmacokinetics of resveratrol with or without piperine and the associated toxicities were studied on a cohort of healthy volunteers. We performed a double-blind, randomized, three-arm pilot study. Participants were randomized to receive a single dose of resveratrol 2.5 g, with piperine in 0 mg, 5 mg, or 25 mg dose. An improved liquid chromatography/mass spectrometry assay was used to determine serum levels of resveratrol and resveratrol-glucuronide. Baseline through 24 h post-study drug serum analyses were performed and adverse events were followed for 30 days. Twenty-four participants were enroled. No significant relationship between dose and pharmacokinetic values were found. In the sex stratified analysis, Cmax for resveratrol in women showed a trend (P = 0.057) toward an increase with piperine. Pharmacokinetic values for resveratrol were: Cmax - 18.5 ± 16 ng/mL resveratrol alone, 29 ± 29 resveratrol + 5 mg piperine, 16 ± 13 resveratrol + 25 mg piperine; area under the concentration × time curve - 1270 ± 852 ng/h/mL resveratrol alone, 2083 ± 2284 resveratrol + 5 mg piperine, 1132 ± 222 resveratrol + 25 mg piperine. All subjects tolerated their protocol therapy with minimal to no toxicity and no evidence of differences between the three groups. The co-administration of resveratrol with piperine at 5 and 25 mg doses did not sufficiently alter the pharmacokinetics of resveratrol or resveratrol-glucuronide to demonstrate the significant enhancement observed in murine modeling.

Topics: Alkaloids; Animals; Benzodioxoles; Dose-Response Relationship, Drug; Female; Glucuronides; Humans; Mice; Pilot Projects; Piperidines; Polyunsaturated Alkamides; Resveratrol

Processed meat intake has been associated with adverse health outcomes. However, little is known about the type of processed meat more particularly responsible for these effects. This study aims to identify novel biomarkers for processed meat intake.. In a controlled randomized cross-over dietary intervention study, 12 healthy volunteers consume different processed and non-processed meats for 3 consecutive days each. Metabolomics analyses are applied on post-intervention fasting blood and urine samples to identify discriminating molecular features of processed meat intake. Nine and five pepper alkaloid metabolites, including piperine, are identified as major discriminants of salami intake in urine and plasma, respectively. The associations with processed meat intake are tested for replication in a cross-sectional study (n = 418) embedded within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Three of the serum metabolites including piperine are associated with habitual intake of sausages and to a lesser extent of total processed meat.. Pepper alkaloids are major discriminants of intake for sausages that contain high levels of pepper used as ingredient. Further work is needed to assess if pepper alkaloids in combination with other metabolites may serve as biomarkers of processed meat intake.

Topics: Alkaloids; Benzodioxoles; Cross-Sectional Studies; Female; Food Handling; Humans; Male; Meat; Metabolomics; Middle Aged; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Nonalcoholic fatty liver diseases (NAFLD) is a highly prevalent disease that is closely associated with several cardiometabolic complications. The potential anti-inflammatory role of curcuminoids that have already been reported to reduce hepatic steatosis, in patients with NAFLD was explored in this study.. This double-blind, randomized placebo-controlled trial was conducted for a period of 8 weeks in patients with NAFLD. Subjects (n = 55) were randomly allocated to receive either curcuminoids or placebo. The curcuminoids group received one capsule containing 500 mg curcuminoids (plus 5 mg piperine to increase intestinal absorption) per day for 8 weeks and the control group received matched placebo capsules for the same period. Liver ultrasonography was performed to assess the severity of hepatic steatosis at baseline and the study end. Serum levels of cytokines including interleukin-1α, interleukin-1β, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-α, monocyte chemoattractant protein-1, interferon γ, vascular endothelial growth factor and epidermal growth factor were measured before and after the intervention.. The two groups were comparable in demographic features at baseline. The results showed that supplementation with curcuminoids could decrease weight compared to the placebo group (p = 0.016) in patients with NAFLD. Curcuminoids supplementation improved the severity of NAFLD according to the ultrasound results (p = 0.002). Moreover, serum concentrations of TNF-α (p = 0.024), MCP-1 (p = 0.008) and EGF (p = 0.0001) were improved by curcuminoids in NAFLD patients.. The results of our study showed that curcumin supplementation can improve serum levels of inflammatory cytokines in subjects with NAFLD and this might be at least partly responsible for the anti-steatotic effects of curcuminoids.

Topics: Adolescent; Adult; Aged; Alkaloids; Benzodioxoles; Curcumin; Diarylheptanoids; Double-Blind Method; Female; Humans; Inflammation; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Piperidines; Polyunsaturated Alkamides; Young Adult

Previous studies have shown a beneficial effect of curcuminoids supplementation on serum concentrations of adipokines; however, there are no published studies that have examined this effect among critically ill patients. We aimed to assess the effects of supplementation with curcuminoids on serum concentrations of leptin and adiponectin in critically ill patients with traumatic brain injury (TBI). In this trial, 62 critically ill patients with TBI, aged 18-65 years, were randomly allocated to receive either 500 mg/day curcuminoids (co-administered with 5 mg/day piperine) or matched placebo for 7 days. Patients in both intervention groups received routine treatments for TBI as well as enteral nutrition. Serum concentrations of leptin and adiponectin were measured at baseline and at the end of trial. We found a significant reduction in serum levels of leptin in both curcuminoids (47.1%) and placebo (22.8%) groups; though the magnitude of reduction was greater in the former (p < .05). Supplementation with curcumioinds was not found to alter serum concentrations of adiponectin (p > .05). Supplementation with curcumioinds significantly reduced serum levels of leptin but had no significant effect on adiponectin levels in critically ill patients with TBI. Further clinical trials, particularly those with a long-term period, are needed to confirm our findings.

Topics: Adipokines; Adiponectin; Adolescent; Adult; Aged; Alkaloids; Benzodioxoles; Critical Illness; Curcumin; Diarylheptanoids; Dietary Supplements; Double-Blind Method; Female; Humans; Iran; Leptin; Male; Middle Aged; Piperidines; Placebos; Polyunsaturated Alkamides; Young Adult

This study aims to investigate the efficacy of curcumin-piperine co-supplementation on disease duration, severity and clinical symptoms, and inflammatory mediators in patients with coronavirus (COVID-19).. This is a randomized, placebo-controlled, double-blind, parallel arm clinical trial.. All patients aged 20-75 years with the diagnosis of Covid-19 based on the PCR test. The exclusion criteria will include an age less than 20 and more than 75 years, current use of warfarin or other anticoagulant drugs, and the presence of sensitivity to herbal products such as turmeric and pepper. This study will be conducted in academic hospitals affiliated to Isfahan University of Medical Sciences, Isfahan, Iran.. Fifty outpatients will be randomly allocated in a ratio of 1:1 to receive a capsule of curcumin-piperine containing 500 mg curcumin plus 5 mg piperine or matching placebo containing 505 mg maltodextrin twice a daily, after lunch and dinner, over a period of 2 weeks. Similarly, 50 inpatients who are admitted to hospital wards excluding intensive care unit (ICU) will be randomly assigned in a ratio of 1:1 to receive a capsule curcumin-piperine or matching placebo (provided by the Sami Labs company) twice a daily, after lunch and dinner, over a period of 2 weeks.. The main outcomes of this study are the efficacy of curcumin-piperine on coronavirus disease's clinical symptoms, duration, severity, and inflammatory mediators after 2 weeks of curcumin-piperine co-supplementation.. Randomization sequences will be generated with the use of a random-number table with a permuted block design (block size of 4) and stratification according to the gender variable (male vs. female). These sequences will be prepared by an independent statistician and will be kept in opaque, sealed, numbered envelopes which will be opened only at the time of enrollment. The allocation ratio in intervention and control groups is 1:1. Researchers and all patients will be unaware of the study-group assignment until the completion of data analyses.. This study is a double-blind clinical trial (participant, researcher). The curcumin-piperine and placebo supplements are packaged in similar numbered drug containers, and the researcher and all patients will be unaware of the study assignment until the end of the study.. The calculated total sample size is 100 patients, with 25 patients in each group.. The protocol is Version 2.0, May 24, 2020. Recruitment began May 4, 2020, and is anticipated to be completed by April 19, 2021.. This trial has been registered by the title of "Effect of curcumin-piperine co-supplementation on disease duration, severity and clinical signs, and inflammatory factors in patients with coronavirus (COVID-19): A randomized, double-blind, placebo-controlled clinical trial study" in the Iranian Registry of Clinical Trials (IRCT) with code "IRCT20121216011763N46", https://www.irct.ir/trial/47529 . The registration date is May 4, 2020.. The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Topics: Alkaloids; Benzodioxoles; COVID-19 Drug Treatment; Curcumin; Dietary Supplements; Double-Blind Method; Hospitalization; Humans; Iran; Piperidines; Polyunsaturated Alkamides; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome

Background The main causes of the progression of non-alcoholic fatty liver disease (NAFLD) are enhanced levels of reactive oxygen species and lipid peroxidation products. Therefore, the usage of antioxidant agents for the prevention and remedy of this disorder was recommended. Curcumin is proposed to treat NAFLD due to its high antioxidative activity. The aim of this study was to examine the effect of curcumin with piperine supplementation on oxidative stress in subjects with NAFLD. Methods In this double-blind, placebo-controlled trial, 55 subjects were randomly divided into two groups (curcumin with piperine and placebo). The participants received administrations of curcumin (500 mg) in combination with piperine (5 mg) and placebo daily for 8 weeks. Oxidative stress was assessed by measuring serum pro-oxidant and antioxidant balance (PAB) assay before and after the intervention. Results The serum PAB values did not significantly change between the treatment group vs. age and gender-matched placebo group after 8 weeks of supplementation. Also, curcumin in combination with piperine did not show a significant decrease (p = 0.06) in PAB levels compared to baseline. Conclusions The present study demonstrated that a dose of curcumin, co-supplied with piperine might be less than a dose in which curcumin can significantly decrease PAB values in these patients.

Topics: Adolescent; Adult; Aged; Alkaloids; Antioxidants; Benzodioxoles; Curcumin; Dietary Supplements; Double-Blind Method; Female; Humans; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Young Adult

Nonalcoholic fatty liver disease (NAFLD) as a prevalent hepatic disease is associated with an increased risk of morbidity and mortality related to the liver and cardiovascular disease (CVD). Lifestyle modification and good metabolic control is the first line of treatment, but not always efficacious in reversing NAFLD pathogenesis. Curcumin is a dietary phytochemical with hepatoprotective activities, though its low bioavailability is considered as a major challenge for clinical applications. Therefore, in this study, in order to improve the bioavailability of curcumin, it was coadministered with piperine and we investigated the effects of this bioavailability-enhanced curcumin on serum hepatic enzymes, lipid profile, and glycemic indices in patients with NAFLD.. In this randomized controlled parallel-group trial, 70 subjects with ultrasound-determined NAFLD were randomized to either 500 mg curcuminoids coadministered with 5 mg piperine daily or placebo for 12 weeks. NAFLD severity (on the basis of sonography) and hepatic function was assessed at baseline and at the study end.. Seventy subjects completed the study. Supplementation with curcuminoids plus piperine significantly reduced the hematocrit (P = 0.027), erythrocyte sedimentation rate (P = 0.048) and the serum concentrations of alanine aminotransferase (P = 0.035), aspartate aminotransferase (P = 0.042), alkaline phosphatase (P = 0.004), cholesterol (P < 0.016), low-density lipoprotein cholesterol (P < 0.017), Iron (P = 0.026), and Hemoglobin (P = 0.025) and increased total iron-binding capacity (P = 0.003). However, except albumin, changes in other parameters were not statistically different between groups. In addition, administration of curcuminoids plus piperine significantly improved NAFLD severity (P < 0.001), which was statistically different compared with the placebo group (P = 0.022). Also, the percentage of improved patients was marginally higher in the curcuminoids plus piperine group when compared with the placebo group (P = 0.058).. This study suggested beneficial effects of combined curcuminoids and piperine supplementation on disease severity in patients with NAFLD.

Topics: Adult; Alkaloids; Benzodioxoles; Biological Availability; Diarylheptanoids; Dietary Supplements; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Piperidines; Polyunsaturated Alkamides; Treatment Outcome; Ultrasonography

Curcuminoids have been shown to reduce glycemia and related complications in diabetes. In the present study, we evaluated the impact of curcuminoids plus piperine administration on glycemic, hepatic and inflammatory biomarkers in type 2 diabetes (T2D) patients.. T2D patients aged 18-65 years were enrolled in a randomized double-blind placebo-controlled trial and randomly allocated to standard-of-care treatment and dietary advises plus either curcuminoids (daily dose of 500 mg/day co-administered with piperine 5 mg/day) or placebo for a period of 3 months. Glycemic, hepatic and inflammatory parameters were measured at baseline and final conditions.. A total of 100 subjects (50 in each group) completed the 3-month period of trial. A significant reduction was found in serum levels of glucose (-9±16 mg/dL vs. -3±11 mg/dL in curcuminoids and placebo groups, respectively; p=0.048), C-peptide (-0.6±0.8 ng/mL vs. 0.02±0.6 ng/mL; p<0.001) and HbA1c (-0.9±1.1% vs. -0.2±0.5%; p<0.001) after curcuminoids supplementation versus placebo group. Additionally, participants in the intervention group showed lower serum alanine aminotransferase (-2±6 vs. -1±5; p=0.032) and aspartate aminotransferase (-3±5 vs. -0.3±4; p=0.002) levels compared with the placebo group. Finally, no significant differences in high-sensitivity C-reactive protein (hs-CRP) concentrations were observed between curcuminoids and placebo groups (p>0.05).. The results of the present trial revealed a beneficial effect of curcuminoids plus piperine supplementation on glycemic and hepatic parameters but not on hs-CRP levels in T2D patients.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Alkaloids; Antioxidants; Aspartate Aminotransferases; Benzodioxoles; Biomarkers; Blood Glucose; C-Reactive Protein; Curcumin; Diabetes Mellitus, Type 2; Dietary Supplements; Double-Blind Method; Female; Humans; Inflammation; Male; Middle Aged; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Young Adult

Vitiligo is the most common acquired hypopigmentary disease in the community. Piperine as an herbal extract derived from black pepper has strong impact on the melanocyte proliferation and adverse side effects less than synthetic drugs such as corticosteroids. For the first time, this study was aimed to evaluate the effect of topical piperine combined with narrowband ultraviolet B (NB-UVB) on vitiligo treatment. In this double-blind clinical trial, 63 patients with facial vitiligo were randomly divided into 2 groups: treated with piperine (case) and placebo (control). Also, both groups received NB-UVB phototherapy every other day for 3 months. In the case group, 10 patients have burning sensation on their skin areas (p value = .002). Also, redness of the treated areas was observed in 6 patients (p value = .028). Both side effects were temporary. Regarding repigmentation at time intervals of 1, 2, and 3 months after treatment, its level in the case group was significantly higher than the control group (p value < .001). Based on our findings, the combination therapy with NB-UVB/topical piperine has more influence on facial vitiligo than that of NB-UVB alone. It could be concluded that the simultaneous use of NB-UVB and topical piperine has a remarkable effect on treatment of vitiligo.

Topics: Administration, Cutaneous; Adolescent; Adult; Alkaloids; Benzodioxoles; Combined Modality Therapy; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Polyunsaturated Alkamides; Treatment Outcome; Ultraviolet Therapy; Vitiligo; Young Adult

Recently, resveratrol showed induction of γ-globin mRNA synthesis in human erythroid precursors and reducing oxidative stress in red cells of thalassemia patients in many in vitro studies. We aimed to investigate the efficacy and safety of resveratrol, for the first time, in non-transfusion-dependent beta-thalassemia intermedia (B-TI) in Southern Iran. In this double-blind randomized clinical trial, 54 patients with B-TI were investigated during 6 months between October 2016 and March 2017. Patients were randomly allocated into three groups by simple randomization method. Group 1 (hydroxyurea (HU) and placebo, 18 patients), group 2 (resveratrol/piperine and placebo, 16 patients), and group 3(HU and resveratrol/piperine, 20 patients). Primary end point was considered as change in hemoglobin (Hb) levels and need for blood transfusion. Drug safety was considered as a secondary end point. Mean age of the patients was 28.2 ± 5.6 (18-42) years. Response rate was not significantly different among the three groups (P > 0.05). Higher percentages of adverse events were detected in groups 2 (31.3%) and 3 (25%) compared to group 1 (5.6%). However, the difference was not statistically significant (P > 0.05). All reported adverse events were gastrointestinal symptoms. Resveratrol showed a similar efficacy with HU in the small population of non-transfusion B-TI patients during a 6-month follow-up. Complications, mostly gastrointestinal, were observed more frequently in resveratrol groups compared to the HU group. Although it was not statistically significant, more attention should be given to safety and efficacy of resveratrol as an oral HbF-augmenting agent.

Topics: Administration, Oral; Adolescent; Adult; Alkaloids; Benzodioxoles; beta-Thalassemia; Double-Blind Method; Female; Fetal Hemoglobin; Humans; Iran; Male; Piperidines; Polyunsaturated Alkamides; Resveratrol; Stilbenes; Treatment Outcome; Up-Regulation; Young Adult

Type 2 diabetes (T2D) is an established risk factor for cardiovascular disease (CVD) and is associated with disturbed metabolism of lipids and lipoproteins. Curcuminoids are natural products with anti-diabetic and lipid-modifying actions but their efficacy in improving dyslipidemia in diabetic individuals has not been sufficiently studied.. To investigate the efficacy of supplementation with curcuminoids, plus piperine as an absorption enhancer, in improving serum lipids in patients with T2D.. In this 12-week randomized double-blind placebo-controlled trial, subjects with T2D (n=118) were assigned to curcuminoids (1000mg/day plus piperine 10mg/day) or placebo plus standard of care for T2D. Serum concentrations of lipids including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), lipoprotein(a) [Lp(a)], and non-HDL-C were determined at baseline and at the end of trial.. Between-group comparison of change in the study parameters revealed significant reductions in serum levels of TC (-21.86±25.78 versus -17.06±41.51, respectively; p=0.023), non-HDL-C (-23.42±25.13 versus -16.84±41.42, respectively; p=0.014) and Lp(a) (-1.50±1.61 versus -0.34±1.73, respectively; p=0.001) and elevations in serum HDL-C levels (1.56±4.25 versus -0.22±4.62, respectively; p=0.048) in the curcuminoids group as compared with the placebo group (p<0.05). Serum TG and LDL-C changes did not show any significant difference between the study groups (p>0.05).. Curcuminoids supplementation can reduce serum levels of atherogenic lipid indices including non-HDL-C and Lp(a). Therefore, curcuminoids supplementation could contribute to a reduced risk of cardiovascular events in dyslipidemic patients with T2D.

Topics: Adult; Alkaloids; Benzodioxoles; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Curcuma; Curcumin; Diabetes Mellitus, Type 2; Dietary Supplements; Double-Blind Method; Dyslipidemias; Female; Humans; Lipids; Lipoprotein(a); Male; Middle Aged; Phytotherapy; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Triglycerides

Nowadays, therapeutic indications for cannabinoids, specifically Δ

Topics: Administration, Buccal; Administration, Oral; Adult; Alkaloids; Benzodioxoles; Biological Availability; Cannabidiol; Cross-Over Studies; Dronabinol; Drug Delivery Systems; Fasting; Healthy Volunteers; Humans; Male; Nanospheres; Piperidines; Polyunsaturated Alkamides; Young Adult

Curcumin is a naturally occurring polyphenol derived from tumeric that has been reported to have anti-inflammatory properties with effects on adipokine and ghrelin levels. Adiponectin, leptin and ghrelin modulate energy homeostasis but each has modulatory effects on inflammatory cytokines and the immune system. Therefore, this analysis was performed to investigate the effect of curcumin on adiponectin, leptin and ghrelin.. A double blind randomised control trial comparing curcumin 1000mg with 10mg of piperine daily to placebo over a 12 week period. 118 patients with type 2 diabetes were recruited out of which 50 control and 50 active subjects completed the trial. Adiponectin, leptin, ghrelin and tumor necrosis factor-α (TNF-α) were measured at baseline and 12 weeks.. Between group comparison of the magnitude of changes showed serum levels of leptin (p<0.001), TNF-α (p<0.001) and leptin:adiponectin ratio (p<0.001) to be significantly reduced while serum adiponectin levels were elevated in the curcuminoids versus placebo group (p=0.032). Changes in serum ghrelin levels did not differ between the study groups (p=0.135).. Curcumin supplementation increased adiponectin, whilst the the leptin:adiponectin ratio (a measure of atherosclerosis) and leptin levels were decreased independent of weight change and reflected a decrease in the inflammatory TNF-α levels.

Topics: Adipokines; Adiponectin; Adult; Alkaloids; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Curcumin; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Piperidines; Polyunsaturated Alkamides; Tumor Necrosis Factor-alpha

The overall goals for treatment of Tuberculosis (TB) are to cure individual patient and to minimize the transmission of Mycobacterium tuberculosis. At the time of study conduction, the standard treatment for newly diagnosed tuberculosis patients consisted of an intensive phase for two months with four drugs (HRZE), followed by continuation phase for four months with two drugs (HR). Rifampicin, which is very effective against Mycobacterium tuberculosis, in both the phases of treatment, has certain concerns, which includes, decreased bioavailability with chronic use and hepatotoxicity. To overcome these concerns a new boosted formulation of Rifampicin (Risorine) with bio-enhancer Piperine was developed. Piperine has been found to increase bioavailability of several drugs including Amoxicillin, Cefotaxime, Theophylline and Propranolol. Risorine is a fixed dose combination that contains Rifampicin 200 mg + Isoniazid 300 mg + Piperine 10 mg.. The aim of the present study was to validate the therapeutic efficacy and tolerability of Risorine formulation containing regimen with a conventional regimen in the management of patients with newly diagnosed pulmonary tuberculosis.. Total 216 patients with sputum positive and treatment naïve pulmonary tuberculosis were enrolled in the study after fulfillment of inclusion / exclusion criteria. These patients were randomized to receive either a conventional anti-TB therapy (n = 117) or a similar regimen containing Risorine (n = 99) for 6 months. During the study period, symptomatic improvement, sputum conversion and radiological improvement were monitored at regular intervals.. Of the 216 enrolled patients, 75% in the Risorine group and 79% in the control group completed the study. At 4 weeks the sputum conversion rate was significantly superior in Risorine group (93%) than the control group (84%), which was consistence throughout the study. Cure rate at the end of 24 weeks, was higher in Risorine group (92%) than in the control group (82%). Elevation of liver enzymes were observed in 3 patients in the Risorine group and in 9 patients in control group.. Risorine, a novel formulation of low dose Rifampicin (200 mg), a bio enhancer Piperine (10 mg) and standard dose Isoniazid (300 mg) when given along with Ethambutol and Pyrazinamide was comparable in efficacy with standard WHO therapy using conventional formulation. Risorine provides more Rifampicin in blood compare to GI tract as well as maintaining higher blood levels on chronic therapy compared to conventional Rifampicin with better safety profile. Risorine gives higher sputum conversion rate during the Intensive Phase which is maintained till the end of study. Further a trend was also noticed towards better tolerability with newer formulation, Risorine. H = Isoniazid, R = Rifampicin, Z = Pyrazinamide and E = Ethambutol.

Topics: Adult; Alkaloids; Antibiotics, Antitubercular; Benzodioxoles; Drug Combinations; Female; Humans; Isoniazid; Male; Piperidines; Polyunsaturated Alkamides; Rifampin; Sputum; Tuberculosis, Pulmonary

Oxidative stress plays a key role in the development of chronic pulmonary complications of sulfur mustard (SM). Curcuminoids are polyphenols with documented safety and antioxidant activity. The present study aimed to investigate the efficacy of short-term supplementation with curcuminoids (co-administered with piperine to enhance the bioavailability of curcuminoids) in alleviating systemic oxidative stress and clinical symptoms, and improvement of health-related quality of life (HRQoL) in subjects suffering from chronic pulmonary complications due to SM exposure who are receiving standard respiratory treatments. Eighty-nine subjects were recruited to this randomized double-blind placebo-controlled trial, being randomly allocated to either curcuminoids (1500 mg/day) + piperine (15 mg/day) combination (n = 45) or placebo (n = 44) for a period of 4 weeks. High-resolution computed tomography suggested the diagnosis of bronchiolitis obliterans in all subjects. Efficacy measures were changes in serum levels of reduced glutathione (GSH) and malonedialdehyde (MDA). The severity and frequency of respiratory symptoms and HRQoL were also assessed using St. George respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) indices. Serum levels of GSH were increased whilst those of MDA decreased by the end of trial in both groups. Likewise, there were significant improvements in the total as well as subscale (symptoms, activity and impact) SGRQ and CAT scores in both groups. However, comparison of magnitude of changes revealed a greater effect of curcuminoids-piperine combination compared to placebo in elevating GSH, reducing MDA and improving CAT and SGRQ (total and subscale) scores (p < 0.001). Regarding the promising effects of curcuminoids on the measures of systemic oxidative stress, clinical symptoms and HRQoL, these phytochemicals may be used as safe adjuvants in patients suffering from chronic SM-induced pulmonary complications who are receiving standard treatments.

Topics: Adult; Alkaloids; Antioxidants; Benzodioxoles; Bronchiolitis; Chronic Disease; Curcuma; Curcumin; Double-Blind Method; Glutathione; Humans; Male; Malondialdehyde; Middle Aged; Mustard Gas; Oxidative Stress; Phytotherapy; Piper; Piperidines; Plant Extracts; Polyphenols; Polyunsaturated Alkamides; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests

Oxidative stress is implicated in the pathogenesis of osteoarthritis. Curcuminoids are natural polyphenols with strong antioxidant capacity and may thus be helpful in the treatment of osteoarthritis. The present randomized double-blind placebo-controlled trial investigated the efficacy of curcuminoids in reducing systemic oxidative burden in patients suffering from knee osteoarthritis. Forty patients with mild-to-moderate primary knee osteoarthritis were given curcuminoid capsules (1500 mg/day in 3 divided doses; n = 19) or matched placebo capsules (n = 21) for a period of 6 weeks. Curcuminoids were co-administered with piperine (15 mg/day) in order to improve the bioavailability. Serum activities of superoxide dismutase (SOD) and concentrations of reduced glutathione (GSH) and malonedialdehyde (MDA) were determined spectrophotometrically at baseline and at the end of the treatment period in both groups. Serum activities of SOD as well as GSH and MDA concentrations were comparable between the study groups at baseline (p > 0.05). There was a significant elevation in serum SOD activities (mean change: 2.94 ± 3.73 vs. -0.38 ± 1.33; p < 0.001), a borderline significant elevation in GSH concentrations (mean change: 1.39 ± 2.78 vs. -0.02 ± 1.62; p = 0.064) and a significant reduction in MDA concentrations (mean change: -5.26 ± 4.46 vs. -2.49 ± 3.81; p = 0.044) in the curcuminoids compared with the placebo group. Changes in serum activities of SOD and concentrations of GSH and MDA during the course of trial were significantly correlated. Short-term supplementation with curcuminoids attenuates systemic oxidative stress in patients with osteoarthritis. These antioxidant effects may account for the reported therapeutic effects of curcuminoids in relieving osteoarthritis symptoms.

Topics: Aged; Alkaloids; Antioxidants; Benzodioxoles; Biological Availability; Body Mass Index; Curcumin; Double-Blind Method; Female; Glutathione; Humans; Male; Malondialdehyde; Middle Aged; Osteoarthritis, Knee; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Superoxide Dismutase

Physical inactivity reduces, and exercise training increases, mitochondrial capacity. In rodents, exercise training effects can be augmented by large doses of resveratrol supplementation but whether this can occur in humans with a smaller dose is unclear. This study sought to determine the effects of resveratrol supplementation in combination with exercise training on skeletal muscle mitochondrial capacity. Sixteen healthy young adults were randomly assigned in a double-blind fashion to consume either placebo or 500 mg of resveratrol plus 10 mg of piperine, a bioenhancer to increase bioavailibilty and bioefficacy of resveratrol. Participants ingested the pills daily for 4 weeks and completed 3 sessions per week of submaximal endurance training of the wrist flexor muscles of the nondominant arm. The contralateral arm served as an untrained control. Skeletal muscle mitochondrial capacity was measured using near-infrared spectroscopy. Changes in mitochondrial capacity from baseline to post-testing indicated significant differences between the resveratrol+piperine-trained arm and the placebo-trained arm (p = 0.02), with the resveratrol+piperine group increasing about 40% from baseline (Δk = 0.58), while the placebo group increased about 10% from baseline (Δk = 0.13). Neither the placebo group nor the resveratrol+piperine group exhibited changes in mitochondrial capacity in the untrained arm. In conclusion, low-intensity exercise training can increase forearm skeletal muscle mitochondrial capacity when combined with resveratrol and piperine supplementation.

Topics: Adolescent; Alkaloids; Benzodioxoles; Dietary Supplements; Double-Blind Method; Exercise; Female; Humans; Linear Models; Longitudinal Studies; Male; Mitochondria; Muscle, Skeletal; Physical Endurance; Piperidines; Polyunsaturated Alkamides; Resveratrol; Spectroscopy, Near-Infrared; Stilbenes; Young Adult

Current medications have limited efficacy in controlling the symptoms of major depressive disorder (MDD), and are associated with several adverse events on long-term use. Curcuminoids are extremely safe and multifunctional phytopharmaceuticals that have been shown to alleviate depressive symptoms in a variety of experimental models. The present study aimed to investigate the efficacy of curcuminoids as an add-on to standard antidepressants in patients with MDD. One hundred and eleven subjects were assigned to standard antidepressive therapy plus curcuminoids-piperine combination (1000-10 mg/day; n=61) or standard antidepressive therapy alone (n=50) for a period of 6 weeks. Efficacy measures were changes in the psychological status on the basis of the Hospital Anxiety and Depression Scale (HADS) and Beck Depression Inventory II (BDI-II). The BDI-II and HADS total and subscale scores were reduced by the end of trial in both study groups. There were significantly greater reductions in total HADS score and subscales of anxiety and depression in the curcuminoids versus control group (p<0.001). Likewise, reductions in BDI-II total score and scores of somatic and cognitive subscales were found to be greater in the curcuminoids compared with control group (p<0.001). Co-administration of curcuminoids with piperine may be used as a safe and effective add-on to standard antidepressants in patients with MDD.

Topics: Adult; Alkaloids; Antidepressive Agents; Anxiety; Benzodioxoles; Biological Availability; Curcumin; Depressive Disorder, Major; Female; Humans; Male; Middle Aged; Piperidines; Polyunsaturated Alkamides; Psychiatric Status Rating Scales

Oxidative stress and inflammation have been proposed as emerging components of metabolic syndrome (MetS). Curcuminoids are natural polyphenols with strong antioxidant and anti-inflammatory properties.. To study the effectiveness of supplementation with a bioavailable curcuminoid preparation on measures of oxidative stress and inflammation in patients with MetS. Our secondary aim was to perform a meta-analysis of data from all randomized controlled trials in order to estimate the effect size of curcuminoids on plasma C-reactive protein (CRP) concentrations.. In this randomized double-blind placebo-controlled trial, 117 subjects with MetS (according to the NCEP-ATPIII diagnostic criteria) were randomly assigned to curcuminoids (n = 59; drop-outs = 9) or placebo (n = 58; drop-outs = 8) for eight weeks. Curcuminoids were administered at a daily dose of 1 g, and were co-supplemented with piperine (10 mg/day) in order to boost oral bioavailability. Serum activities of superoxide dismutase (SOD) and concentrations of malondialdehyde (MDA) and CRP were measured at baseline and at study end. Regarding the importance of CRP as a risk marker and risk factor of cardiovascular disease, a random-effects meta-analysis of clinical trials was performed to estimate the overall impact of curcuminoid therapy on circulating concentrations of CRP. The robustness of estimated effect size was evaluated using leave-one-out sensitivity analysis.. Supplementation with curcuminoid-piperine combination significantly improved serum SOD activities (p < 0.001) and reduced MDA (p < 0.001) and CRP (p < 0.001) concentrations compared with placebo. Quantitative data synthesis revealed a significant effect of curcuminoids vs. placebo in reducing circulating CRP concentrations (weighed mean difference: -2.20 mg/L; 95% confidence interval [CI]: -3.96, -0.44; p = 0.01). This effect was robust in sensitivity analysis.. Short-term supplementation with curcuminoid-piperine combination significantly improves oxidative and inflammatory status in patients with MetS. Curcuminoids could be regarded as natural, safe and effective CRP-lowering agents.

Topics: Adult; Alkaloids; Anti-Inflammatory Agents; Antioxidants; Benzodioxoles; Biological Availability; Blood Pressure; Body Mass Index; C-Reactive Protein; Curcumin; Databases, Factual; Dietary Supplements; Double-Blind Method; Female; Humans; Inflammation; Male; Malondialdehyde; Meta-Analysis as Topic; Metabolic Syndrome; Middle Aged; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Superoxide Dismutase

Oropharyngeal dysphagia (OD) is a major gastrointestinal motility disorder that causes severe nutritional and respiratory complications in elderly and neurological patients. In an earlier study, we found that stimulation of pharyngeal sensory neurons by capsaicinoids acting on transient receptor potential vanilloid 1 (TRPV1) improved the swallow response of dysphagic patients. The aim of this study was to explore the effect of piperine, a dual TRPV1/TRPA1 agonist, on the swallow response of dysphagic patients.. A videofluoroscopic study was performed to assess the signs of impaired safety and efficacy of swallow and the swallow response of 40 dysphagic patients while swallowing one series of nectar control boluses and two series of nectar boluses supplemented with piperine. Patients were randomized into two groups: one group received 150 μM piperine and the other group received 1 mM.. Piperine improved the safety of swallow by: (a) reducing the prevalence of unsafe swallows by -34.48% (P = 0.004) at 150 μM and -57.19% (P < 0.001) at 1 mM, and the severity score of the penetration-aspiration scale from 3.25 ± 0.51 to 1.85 ± 0.27 (P = 0.003, 1 mM); and (b) shortening the time to laryngeal vestibule closure from 0.366 ± 0.024 to 0.270 ± 0.022 s with 150 μM piperine (P < 0.001) and from 0.380 ± 0.032 to 0.306 ± 0.028 s with 1 mM piperine (P < 0.05).. Supplementing the alimentary bolus with piperine speeds swallow response and strongly improves safety of swallow in patients with OD, with a maximal therapeutic effect at 1 mM. Our results suggest that activation of TRPV1/A1 in oropharyngeal sensory neurons is a very promising neurostimulation strategy for dysphagic patients.

Topics: Administration, Oral; Aged; Alkaloids; Benzodioxoles; Calcium Channels; Deglutition; Deglutition Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluoroscopy; Humans; Male; Nerve Tissue Proteins; Piperidines; Polyunsaturated Alkamides; Sensory Receptor Cells; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels; Video Recording

Previous research has shown that resveratrol can increase cerebral blood flow (CBF) in the absence of improved cognitive performance in healthy, young human subjects during the performance of cognitively demanding tasks. This lack of cognitive effects may be due to low bioavailability and, in turn, reduced bioefficacy of resveratrol in vivo. Piperine can alter polyphenol pharmacokinetics, but previous studies have not investigated whether this affects the efficacy of the target compound. Therefore, the objective of the present study was to ascertain whether co-supplementation of piperine with resveratrol affects the bioavailability and efficacy of resveratrol with regard to cognition and CBF. The present study utilised a randomised, double-blind, placebo-controlled, within-subjects design, where twenty-three adults were given placebo, trans-resveratrol (250 mg) and trans-resveratrol with 20 mg piperine on separate days at least a week apart. After a 40 min rest/absorption period, the participants performed a selection of cognitive tasks and CBF was assessed throughout the period, in the frontal cortex, using near-IR spectroscopy. The presence of resveratrol and its conjugates in the plasma was confirmed by liquid chromatography-MS analysis carried out following the administration of the same doses in a separate cohort (n 6). The results indicated that when co-supplemented, piperine and resveratrol significantly augmented CBF during task performance in comparison with placebo and resveratrol alone. Cognitive function, mood and blood pressure were not affected. The plasma concentrations of resveratrol and its metabolites were not significantly different between the treatments, which indicates that co-supplementation of piperine with resveratrol enhances the bioefficacy of resveratrol with regard to CBF effects, but not cognitive performance, and does this without altering bioavailability.

Topics: Adult; Alkaloids; Benzodioxoles; Cerebrovascular Circulation; Cognition; Cognition Disorders; Cohort Studies; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Female; Frontal Lobe; Humans; Intestinal Absorption; Male; Nootropic Agents; Pilot Projects; Piperidines; Polyunsaturated Alkamides; Resveratrol; Spectroscopy, Near-Infrared; Stilbenes; Task Performance and Analysis; Young Adult

Dyslipidemia is an established feature of metabolic syndrome (MS) that is associated with an increased risk of atherosclerotic cardiovascular disease. Curcuminoids are natural products with anti-atherosclerotic and lipid-modifying effects but their efficacy in patients with MS has not yet been tested.. To investigate the effects of bioavailability-enhanced curcuminoids, as adjunctive to standard of care, on serum lipid concentrations in patients with MS.. Patients diagnosed with MS according to the NCEP-ATPIII criteria who were receiving standard of care were assigned to either curcuminoids (C3 complex(®); 1000 mg/day; n=50) or placebo (n=50; matched with drug capsules in shape and color) for 8 weeks. In order to improve the oral bioavailability, curcuminoids were co-administered with piperine (bioperine(®)) in a ratio of 100:1. Serum concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, small dense LDL (sdLDL), lipoprotein(a) [Lp(a)], and non-HDL-C were determined at baseline and at the end of 8-week treatment period.. Curcuminoids were more effective than placebo in reducing serum LDL-C, non-HDL-C, total cholesterol, triglycerides and Lp(a), and elevating HDL-C concentrations. However, changes in serum sdLDL levels were found to be comparable between the study groups. The effects of curcuminoids on triglycerides, non-HDL-C, total cholesterol and Lp(a) remained significant after adjustment for baseline values of lipids and body mass index.. Curcuminoids-piperine combination is an efficacious adjunctive therapy in patients with MS and can modify serum lipid concentrations beyond what is achieved with standard of care.

Topics: Adult; Alkaloids; Benzodioxoles; Curcumin; Female; Humans; Lipids; Male; Metabolic Syndrome; Middle Aged; Piperidines; Polyunsaturated Alkamides

A combination of bioactive food ingredients (capsaicinoids, epigallocatechin gallate, piperin, and l-carnitine, CBFI) may promote satiety and thermogenesis. The study was conducted in order to assess whether there is any effect on satiety, resting energy expenditure (REE), respiratory quotient, glucagon-like peptide-1 (GLP-1), free fatty acids (FFA) and glycerol release, following a standardized mixed meal with or without single consumption of a CBFI.. An 8-week randomized double-blind placebo-controlled trial.. Dietetic and Metabolic Unit, Azienda di Servizi alla Persona, University of Pavia and "Villa delle Querce" Clinical Rehabilitation Institute, Rome, Italy.. Thirty-seven overweight adults (body mass index [BMI]: 25-35).. Nineteen overweight subjects were included in the supplemented group (14 women, 5 men; age 46.4 ± 6.4; BMI: 30.5 ± 3.3) and 18 in the placebo group (13 women, 5 men; age 40.8 ± 11.5; BMI: 30.1 ± 2.6). Satiety was assessed using 100-mm visual analogue scales (VAS) and the area under the curve was calculated.. All measured parameters increased significantly in comparison with baseline in response to meal, both with CBFI and with placebo. However, throughout the study day, the supplemented group experienced a significantly greater increase than the placebo group in their sensation of satiety following acute administration of the supplement.. CBFI may therefore be of great value in the treatment of overweight patients by increasing satiety and stimulating thermogenesis.

Topics: Adult; Alkaloids; Area Under Curve; Basal Metabolism; Benzodioxoles; Capsaicin; Carnitine; Catechin; Dietary Supplements; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Glycerol; Humans; Male; Middle Aged; Obesity; Phytotherapy; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Satiation; Satiety Response

Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers.. A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing.. Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma C(max), AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05-0.08 μM and 0.6 μM, respectively).. The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes.

Topics: Acetaminophen; Alkaloids; Analgesics, Non-Narcotic; Area Under Curve; Benzodioxoles; Chromatography, High Pressure Liquid; Cross-Over Studies; Curcuma; Curcumin; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Double-Blind Method; Drug Interactions; Enzyme Inhibitors; Flurbiprofen; Half-Life; Humans; Hypnotics and Sedatives; Midazolam; Piperidines; Plant Extracts; Polyunsaturated Alkamides

This randomized, double blind, placebo-controlled, 8 week trial assessed the efficacy on metabolic changes produced by a consumption of a combination of bioactive food ingredients (epigallocatechin gallate, capsaicins, piperine and L-carnitine) versus a placebo, as part of a therapeutic 'lifestyle change' diet, in 86 overweight subjects. Forty-one patients (2/14 F/M; age 43.7 ± 8.5; BMI 30.3 ± 3.5 kg/m(2)) were randomized to the supplemented group and 45 (29/16; age 40.7 ± 10.2; BMI 30.0 ± 2.7) to the control group. We observed that consumption of the dietary supplement was associated with a significantly greater decrease in insulin resistance, assessed by homostasis model assessment (p < 0.001), leptin/adiponectin ratio (p < 0.04), respiratory quotient (p < 0.008). LDL-cholesterol levels (p < 0.01). Moreover, statistically significant differences were recorded between the two groups in relation to urinary norepinephrine levels (p < 0.001). Leptin, ghrelin, C-reactive protein decreased and resting energy expenditure increased significantly in the supplemented group (p < 0.05, 0.03, 0.02 and 0,02 respectively), but not in the placebo group; adiponectin decreased significantly in the placebo group (0.001) but not in the supplemented group, although no statistical significance between the groups was elicited. BMI, fat mass (assessed by DXA) and vascular endothelial growth factor significantly decreased, whilst the resting energy expenditure/free fat mass significantly increased in both groups. In general, a greater change was recorded in the supplemented group compared to the placebo, although no statistically significant difference between the two groups was recorded. These results suggest that the combination of bioactive food ingredients studied might be useful for the treatment of obesity-related inflammatory metabolic dysfunctions.

Topics: Adipokines; Adult; Alkaloids; Benzodioxoles; Capsaicin; Carnitine; Catechin; Diet, Reducing; Dietary Supplements; Double-Blind Method; Female; Humans; Inflammation Mediators; Insulin Resistance; Male; Middle Aged; Overweight; Piperidines; Polyunsaturated Alkamides; Time Factors; Weight Loss; Young Adult

Piperine, the active principle of piper species, is commonly used as a spice and adjuvant in various traditional systems of medicine. It has been known as a bioavailability-enhancer. The present study aimed at evaluating the effect of piperine on the steady-state pharmacokinetics of a single dose of carbamazepine in poorly controlled epilepsy patients on carbamazepine monotherapy. Patients (n = 10 each) receiving either 300 mg or 500 mg dose of carbamazepine twice daily were selected. After administration of carbamazepine, venous blood samples were collected at 0, 0.5, 1, 2, 4, 6, 9, 12 h. Subsequently, piperine (20 mg p.o.) was administered along with carbamazepine and samples were collected similarly. The pharmacokinetic parameters were compared by Students t-test. Piperine significantly increased the mean plasma concentrations of carbamazepine at most of the time points in both dose groups. There was a significant increase in AUC(0-12hr) (p < 0.001), average C(ss) (p < 0.001), t(1\\2el) (p < 0.05) and a decrease in K(el) (p < 0.05), in both the dose groups, whereas changes in K(a) and t(1\\2a) were not significant. Cmax (p < 0.01) and t(max) (p < 0.01) were increased significantly following piperine administration in the 500 mg dose group; however, these parameters were not significant in the lower dose group. Piperine could significantly enhance the oral bioavailability of carbamazepine, possibly by decreasing the elimination and/or by increasing its absorption.

Topics: Adult; Alkaloids; Area Under Curve; Benzodioxoles; Biological Availability; Carbamazepine; Dose-Response Relationship, Drug; Drug Interactions; Epilepsy; Female; Humans; Male; Middle Aged; Piper; Piperidines; Polyunsaturated Alkamides; Young Adult

Nevirapine is a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase and is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. Piperine (1-piperoylpiperidine) is an alkaloid and the main pungency principle in both black and long pepper. There are indications that piperine inhibits, rather than stimulates, drug metabolism in most cases, thus increasing the bioavailability and effect of some drugs.. This was a crossover, placebo-controlled pilot study conducted in a total of eight healthy adult males aged 20-40 years. Subjects were randomly assigned to receive piperine 20mg or placebo each morning for 6 days, and on day 7, nevirapine 200mg plus piperine 20mg or nevirapine plus placebo in a crossover fashion. Blood samples were collected from 1 to 144 hours post-dose for pharmacokinetic analysis.. Mean maximum plasma concentration (C(max)), area under the plasma concentration-time curve from 0 hours to the last measurable concentration (C(last)) [AUC(t)], AUC extrapolated to infinity (AUC(infinity)) and C(last) values of nevirapine were increased by approximately 120%, 167%, 170% and 146%, respectively, when co-administered with piperine. The treatments were well tolerated, indicating few or no clinical adverse effects.. This pilot study provided evidence for enhanced bioavailability of nevirapine when administered with piperine. Further in-depth studies in a large number of patients receiving different dosage regimens are required to confirm these results and further our understanding of a possible clinical advantage arising from the bioenhancement capabilities of piperine in the treatment of HIV infection.

Topics: Adult; Alkaloids; Anti-HIV Agents; Area Under Curve; Benzodioxoles; Chromatography, High Pressure Liquid; Cross-Over Studies; Drug Interactions; Fasting; Half-Life; Humans; Male; Mass Spectrometry; Nevirapine; Piperidines; Polyunsaturated Alkamides

The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilised because of poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h. Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects.

Topics: Adult; Alkaloids; Animals; Area Under Curve; Benzodioxoles; Chromatography, High Pressure Liquid; Curcumin; Drug Interactions; Female; Humans; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Spectrophotometry, Ultraviolet

Topical desensitization of the tongue was assessed during multiple bouts of exposure to capsaicin. In the first experiment subjects rated perceived irritation as 30 capsaicin stimuli (33 microM) were applied to the tongue tip in three blocks of 10, with 15 min breaks between blocks. Significant desensitization was measured at the beginning of the second and third blocks within each session. However, as stimulation continued within those blocks sensations of irritation grew toward undesensitized levels ('stimulus-induced recovery' (SIR)). Desensitization did not extend across days. The second experiment employed a 10-fold higher concentration of capsaicin (330 microM) to determine if SIR was limited to low levels of desensitization. SIR occurred as before within sessions, and the higher concentration produced desensitization across days that also exhibited recovery during the first block of stimuli on days 2 and 3. The third experiment included piperine, zingerone and citric acid as stimuli to determine if SIR was specific to capsaicin. Piperine produced SIR under conditions of both self- and cross-desensitization with capsaicin, whereas recovery failed to materialize with zingerone. Citric acid was not significantly cross-desensitized by capsaicin, so recovery could not be measured. Overall the results demonstrate that desensitization of the tongue produced by either capsaicin or piperine can be temporarily reversed if stimulation with either chemical is resumed for only a few minutes. The implications these findings may have for hypotheses about the mechanisms of capsaicin desensitization and sensitization as well as for clinical applications of capsaicin as a topical analgesic are discussed.

Topics: Administration, Oral; Adult; Alkaloids; Analysis of Variance; Benzodioxoles; Capsaicin; Citric Acid; Depression, Chemical; Dose-Response Relationship, Drug; Female; Guaiacol; Humans; Irritants; Logistic Models; Male; Piperidines; Polyunsaturated Alkamides; Reference Values; Stimulation, Chemical; Time Factors; Tongue

Curcumin (CUR) and piperine (PIP) are very well-known phytochemicals that claimed to have many health benefits and have been widely used in foods and traditional medicines. This study investigated the therapeutic efficacy of these compounds to treat Alzheimer's disease (AD). However, poor oral bioavailability and permeability of curcumin are a major challenge for formulation scientists. In this research study, the researcher tried to enhance the bioavailability and permeability of curcumin by a nanotechnological approach. In this research study, we developed a CUR-PIP-loaded SNEDDS in various oils. Optimised formulation NF3 was subjected to evaluate its therapeutic effectiveness on AD animal model in comparison with untreated AD model and treated group (by market formulation donepezil). On the basis of characterisation results, it is confirmed that NF3 formulation is the best formulation. The optimised formulation shows a significant dose-dependent manner therapeutic effect on AD-induced model. Novel formulation CUR-PIP solid-SNEDDS was successfully developed and optimised. It is expected that the developed S-SNEDDS can be a potential, safe and effective carrier for the oral delivery of curcumin to the brain. To date, this article is the only study of CUR-PIP-loaded S-SNEDDS for the treatment of AD.

Topics: Alzheimer Disease; Animals; Biological Availability; Curcumin; Drug Delivery Systems; Emulsions; Nanoparticles; Particle Size; Piperidines

Gastric cancer is one of the most frequent types of neoplasms worldwide, usually presenting as aggressive and difficult-to-manage tumors. The search for new structures with anticancer potential encompasses a vast research field in which natural products arise as promising alternatives. In this scenario, piperine, an alkaloid of the

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Humans; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Stomach Neoplasms

Pepper is a spice that has been used worldwide since the Age of Discovery. The substance that is responsible for the spiciness in pepper is piperine, a type of alkaloid. It has never been reported how piperine is degraded by microorganisms. In this study, we discovered a bacterium in the soil that is capable of catabolizing piperine as its sole nitrogen source. Furthermore, we discovered the enzyme involved in piperine metabolism. This enzyme decomposed the methylenedioxyphenyl group, which is the common structure in various plant-derived bioactive compounds such as sesamin, piperonal, safrole, and berberin. By utilizing this enzyme, piperine can be converted into a useful antioxidant compound. The findings about previously unknown metabolic pathways in nature can lead to the discovery of new enzymes and provide methods for the enzymatic synthesis of useful compounds.

Topics: Actinobacteria; Alkaloids; Piperidines; Polyunsaturated Alkamides

NF-κB contributes to the biosynthesis of various chemokines, cytokines, and enzymes. It plays many crucial roles in the upstream neuroinflammatory pathways. Briefly, the inhibitory IkB subunit is cleaved and phosphorylated by the IKK-α/β enzyme. It leads to the activation and translocation of the NF-κB (p50/p65) complex into the nucleus. Subsequently, the activated NF-κB interacts with the genomic DNA and contributes to expressing various proinflammatory cytokines. In the present study, we developed a novel NF-κB inhibitor encoded (D5) and investigated the efficacy of our druggable compound through several in silico, in vitro, and in situ analysis. The results demonstrated that D5 not only inhibited the mRNA expression of the IKK-α/β enzyme (around 86-96% suppression rate for both cell lines at 12 and 24 h time frames) but also by interacting to the active site of the mentioned kinase (dock score -6.14 and binding energy -23.60 kcal/mol) reduced the level of phosphorylated IkB-α in the cytosol around 96-99% and p65 subunit in the nucleus around 73-90% (among all groups in 12 and 24 h time points). Additionally, the results indicated that D5 suppressed the NF-κB target mRNA levels of TNF-α and IL-6 in a total average of around 92%. Overall, The results demonstrated that D5 in a considerably lower concentration than Dis (0.71 µM vs. 52.73 µM) showed significantly higher inhibitory efficacy on NF-κB translocation approx. 200-300%. The results suggested D5 as a potent NF-κB silencer, but further investigations are required to validate our outcomes.

Topics: Alkaloids; Benzodioxoles; Cell Line; Cytochrome P-450 Enzyme Inhibitors; Drug Development; Enzyme Inhibitors; Humans; I-kappa B Kinase; I-kappa B Proteins; Neuroinflammatory Diseases; NF-kappa B; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Protein Translocation Systems; Protein Transport; Signal Transduction; Transcription Factor RelA

Piperine is reported to ameliorate common metabolic diseases, however, its molecular mechanism is still unclear. In the present study, we examined whether piperine could stimulate glucagon-like peptide-1 (GLP-1) secretion in a human enteroendocrine cell line, Caco-2, and explored the potential mechanisms from the activation of human bitter taste receptors (TAS2Rs). It was found that TAS2R14 was highly expressed in Caco-2 cells, far more than TAS2R4 and TAS2R10. Piperine and flufenamic acid (FA, a known TAS2R14 agonist) markedly increased intracellular calcium mobilization and significantly enhanced the GLP-1 secretion, accompanied by elevated levels of proglucagon mRNA in Caco-2 cells compared with the control. Moreover, piperine and FA activated TAS2R14 signaling as evidenced by the increased mRNA and protein levels of TAS2R14, and the protein expression of its downstream key molecules including phospholipase C β2 (PLCβ2) and a transient receptor potential channel melastatin 5 (TRPM5). On the other hand, a G protein βγ subunit inhibitor Gallein or a PLC inhibitor U73122 alleviated piperine-stimulated GLP-1 secretion in Caco-2 cells. In the meantime, a flavanone hesperetin significantly attenuated piperine and FA induced the intracellular calcium mobilization and GLP-1 secretion. Furthermore, TAS2R14 knockdown reversed the piperine-triggered up-regulation of PLCβ2 and TRPM5 as well as increased the GLP-1 secretion in Caco-2 cells by TAS2R14 shRNA transfection. In summary, our findings demonstrated that piperine promoted the GLP-1 secretion from enteroendocrine cells through the activation of TAS2R14 signaling. Moreover, TAS2R14 was likely a target of piperine in the alleviation of metabolic diseases.

Topics: Alkaloids; Benzodioxoles; Caco-2 Cells; Enteroendocrine Cells; Glucagon-Like Peptide 1; Humans; Piperidines; Polyunsaturated Alkamides; Receptors, G-Protein-Coupled

In this work, the natural piperine moiety was utilised to develop two sets of piperine-based amides (

Topics: Alkaloids; Amides; Antineoplastic Agents; Apoptosis; Benzodioxoles; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Piperidines; Polyunsaturated Alkamides; Protein Kinase Inhibitors; Structure-Activity Relationship; Urea; Vascular Endothelial Growth Factor Receptor-2

Based on the free drug hypothesis, we hypothesized that food compounds that bind stronger to BSA than CUR inhibit the binding between BSA and CUR, and that this results in an increase of the cellular uptake and physiological activities of CUR. To verify this hypothesis, food compounds that bind stronger to BSA than CUR were identified. When THP-1 monocytes were co-treated with the identified compounds (

Topics: Alkaloids; Benzodioxoles; Cell Survival; Curcumin; Endocytosis; Humans; Piperidines; Polyunsaturated Alkamides; Serum Albumin; THP-1 Cells

Many natural extracts have been shown to minimize the toxicity of doxorubicin (Dox). Low piperine. To evaluate the effect of PFPE in attenuating the side effects of Dox.. Tumour-bearing Sprague Dawley rats were divided into five groups including normal, vehicle, 100 mg/kg BW of PFPE plus 2 mg/kg BW of Dox (P100 + Dox), 100 mg/kg BW of PFPE plus 2 mg/kg BW of Dox (P200 + Dox) and Dox. Rats were treated with Dox and/or PFPE three times/week for 4 weeks. Tumour burden, blood parameters, weight of internal organs and immunological data were investigated.. The addition of 200 mg/kg PFPE significantly restored the levels of AST from 174.60 ± 45.67 U/L in the Dox group near to normal levels at 109.80 ± 4.99 U/L. The combination of PFPE and Dox also decreased the levels of CXCL7, TIMP-1, sICAM-1 and l-selectin about 1.4-1.6-fold compared to Dox group. Feeding rats with 200 mg/kg BW of PFPE combination with Dox slightly increased Th1 from 161.67 ± 14.28 cells in Dox group to 200.75 ± 5.8 cells meanwhile suppressed Treg from 3088 ± 78 cells in Dox to 2561 ± 71 cells.. This study showed that PFPE ameliorated Dox toxicity in many aspects indicating the role of antioxidant and other substances in the extract on toxicity attenuation. This suggested the using of PFPE may be valuable for Dox treated patients.

Topics: Alkaloids; Animals; Antibiotics, Antineoplastic; Antioxidants; Benzodioxoles; Dose-Response Relationship, Drug; Doxorubicin; Female; Mammary Neoplasms, Experimental; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley

The study assessed the site dependent intestinal absorption of Daclatasvir and investigated the effects of piperine and omeprazole on such absorption utilizing in situ rabbit intestinal perfusion technique. The intestinal absorption of Daclatasvir was assessed in four segments: duodenum, jejunum, ileum, and colon. The effect of co-perfusion with omeprazole was monitored through the tested anatomical sites. The effect of piperine, a P-glycoprotein (P-gp) inhibitor on Daclatasvir absorption from jejunum and ileum was tested. The results showed that Daclatasvir was incompletely absorbed from the rabbit small and large intestine. The absorptive clearance per unit length (PeA/L) was site dependent and was ranked as colon > duodenum > jejunum > ileum. This rank is the opposite of the rank of P-gp intestinal content suggesting possible influence for P-gp. Co-perfusion with omeprazole increased PeA/L and this was evidenced also with reduced the L95% of Daclatasvir from both small and large intestinal segments. Significant enhancement in Daclatasvir absorption through jejunum and ileum was shown in presence of piperine. Daclatasvir showed site dependent intestinal absorption in a manner suggesting its affection by P-gp efflux. This effect was inhibited by piperine. Co-administration of Daclatasvir with omeprazole can enhance intestinal absorption a phenomenon which requires extension to human pharmacokinetic investigation.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Carbamates; Ileum; Imidazoles; Intestinal Absorption; Intestines; Jejunum; Omeprazole; Piperidines; Polyunsaturated Alkamides; Pyrrolidines; Rabbits; Valine

Anastrozole (ATZ) is a selective non-steroidal inhibitor widely used for the treatment of breast cancer in post-menopausal women. ATZ exerts its biological activity by inhibiting the enzyme aromatase, which is responsible for converting androgens to estrogens. Piperine (PIP), a natural alkaloid and the main component of black pepper, is used as a bioenhancer and for combating a variety of health issues ranging from upset stomach to dental problems.. ATZ has been reported to have poor water solubility and less bioavailability. The novel combination of ATZ and PIP was proposed to enhance the bioavailability of both the compounds. However, there are no reported studies on the simultaneous estimation of ATZ and PIP as well as stability studies to explore their potential interactions and degradation profiling.. A simple, accurate, precise, robust, sensitive, reliable, and economic analytical method for the simultaneous estimation of ATZ and PIP was developed using acetonitrile and water (60:40) as the mobile phase. Forced degradation studies and characterization of degradants were performed, and degradants were identified for molecular weight using LC-QTOF-ESI-MS; the structures of degradants were confirmed with mass accuracy measurements. The mechanism of each degradant has also been described in more detail in the manuscript.. A total of fourteen degradants were characterized and reported for their good human oral absorption. A precise, robust, accurate, cheap, and sensitive RP-HPLC-DAD simultaneous method for the estimation of ATZ and PIP has been developed. From the future point of view, there is huge scope to conduct pharmacological, pharmacodynamic, and drug-herb interaction studies based on this fruitful outcome. All the degradants may be screened against MDR-resistant breast cancer in the future to check their potential as a drug target.

Topics: Alkaloids; Anastrozole; Benzodioxoles; Breast Neoplasms; Drug Stability; Female; Humans; Piperidines; Polyunsaturated Alkamides; Water

Groundnut stem rot caused by Sclerotium rolfsii is a major constraint as it affects the productivity. Although managing this disease using synthetic fungicides is a more feasible method, environmental pollution and side effects caused by them demand some safe fungicides. Seven phytochemicals piperine, quercetin, reserpine, atropine sulfate, β-sitosterol, ethyl protocatechuate and salicylic acid were initially tested against S. rolfsii under in vitro methods. All the compounds exhibited significant effects on mycelial inhibition (except atropine sulfate), sclerotial development, ooze formation, maturity, sclerotial number and germination of S. rolfsii. The more active compounds, piperine, reserpine and β-sitosterol were then evaluated under glasshouse condition by adopting various application methods (seed treatment, foliar application and micro-injection at 2000 μg/mL) on groundnut plants challenged with and without S. rolfsii. All the treatments effectively reduced the plant mortality when tested every 15 days of infection with S. rolfsii. However, the magnitude of reduction varied among the treatments, with the mortality ranging between 9.37 % and 29.68 % compared to the control (40.68 %). The piperine-microinjected plants recorded minimum mortality (3.12 %). The defense enzymes (PAL and PPO) and key end products such as phenolics (total and individual) were determined in the leaf samples collected after 24, 48 and 72 h of infection with S. rolfsii to understand the systemic resistance induction effect. An increase in PAL and PPO activity was observed in all the samples. While microinjection of β-sitosterol caused a maximum PAL induction, piperine caused a maximum PPO activity. Further, samples of piperine treated group showed higher induction of phenolic acids (86.46 μg g

Topics: Alkaloids; Atropine; Basidiomycota; Benzodioxoles; Fungicides, Industrial; Piperidines; Plant Diseases; Polyunsaturated Alkamides; Reserpine; Sitosterols

Piperine is an alkaloid extracted from the seed of Piper spp., which has demonstrated a larvicidal effect against Ae. aegypti. The incorporation of piperine into nanostructured systems can increase the effectiveness of this natural product in the control of Ae. aegypti larvae. In this study, we evaluated the effectiveness of piperine loaded or not into two nanostructured systems (named NS-A and NS-B) prepared by the nanoprecipitation method. The Ae. aegypti larvae were exposed to different concentrations of piperine loaded or not (2 to 16 ppm) and the mortality was investigated after 24, 48, and 72 hours. The nanostructures prepared were spherical in shape with narrow size distribution and great encapsulation efficiency. The lethal concentration 50 (LC

Topics: Aedes; Alkaloids; Animals; Benzodioxoles; Insecticides; Larva; Mosquito Vectors; Nanostructures; Piperidines; Plant Extracts; Polymers; Polyunsaturated Alkamides

Isoniazid (INH) is a first-line chemotherapeutic drug employed in the management of tuberculosis. However, its extensive first-pass metabolism, short-life life, and low oral bioavailability confined its medical application. Therefore, the calcium ion-alginate-piperine microspheres (INH-CaSP Ms) was prepared to enhance encapsulation efficiency, controlled delivery, and oral bioavailability of INH. The INH-CaSP Ms was developed using a modified emulsification method and optimized via Box-Behnken design (BBD). Optimized INH-CaSP Ms were characterized for encapsulation efficiency, differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), bio-adhesion, in vitro dissolution, ex vivo permeation, and oral bioavailability studies. Characterization studies confirmed the formation of microspheres. The INH-CaSP Ms showed spherical microspheres with enhanced encapsulation efficiency (~ 93.03 ± 1.54% w/w). The optimized INH-CaSP Ms exhibited higher bio-adhesion around (~ 81.41 ± 1.31%). The INH-CaSP Ms enhanced the dissolution rate of INH (~ 57%) compared to pure INH (~ 57%) and INH-SA Ms (~ 81%) in simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.4). The same formulations improved the permeation rate of INH (~ 90%) compared to pure INH (~ 55%) and INH-SA Ms (~ 80%). The oral bioavailability results indicated that INH-CaSP Ms appreciably improved the oral bioavailability of INH via increasing the Cmax, Tmax, t

Topics: Alginates; Alkaloids; Benzodioxoles; Biological Availability; Calcium; Isoniazid; Microspheres; Piperidines; Polyunsaturated Alkamides; Spectroscopy, Fourier Transform Infrared

Piperine (PIP) is a herbal drug with well-known anticancer activity against different types of cancer including hepatocellular carcinoma. However, low aqueous solubility and extensive first-pass metabolism limit its clinical use. In this study, positively charged PIP-loaded nanostructured lipid carriers (PIP-NLCs) were prepared via melt-emulsification and ultra-sonication method followed by pectin coating to get novel pectin-coated NLCs (PIP-P-NLCs) targeting hepatocellular carcinoma. Complete in vitro characterization was performed. In addition, cytotoxicity and cellular uptake of nanosystems in HepG2 cells were evaluated. Finally, in vivo anticancer activity was tested in the diethylnitrosamine-induced hepatocellular carcinoma mice model. Successful pectin coating was confirmed by an increased particle size of PIP-NLCs from 150.28 ± 2.51 nm to 205.24 ± 5.13 nm and revered Zeta potential from 33.34 ± 3.52 mV to -27.63 ± 2.05 mV. Nanosystems had high entrapment efficiency, good stability, spherical shape, and sustained drug release over 24 h. Targeted P-NLCs enhanced the cytotoxicity and cellular uptake compared to untargeted NLCs. Furthermore, PIP-P-NLCs improved in vivo anticancer effect of PIP as proved by histological examination of liver tissues, suppression of liver enzymes and oxidative stress environment in the liver, and alteration of cell cycle regulators. To conclude, PIP-P-NLCs can act as a promising approach for targeted delivery of PIP to hepatocellular carcinoma.

Topics: Alkaloids; Animals; Benzodioxoles; Carcinoma, Hepatocellular; Drug Carriers; Lipids; Liver Neoplasms; Mice; Nanostructures; Particle Size; Pectins; Piperidines; Polyunsaturated Alkamides

Efficiency of drug delivery is product of drug properties and formulation design. Modulating drug's unfavorable properties such as poor solubility or permeation is the first step towards optimum delivery. By combining a drug with a selected bulky counter ion, it can be transformed into a low-melting point salt, i.e., an ionic liquid (IL), with favorable physicochemical properties. In this study, we prepared a novel IL of anti-inflammatory drug, ketoprofen (KP), to enable its transdermal administration. KP was paired with piperine (PI) forming equimolar KP-PI IL, via solvent evaporation. KP-PI IL showed extended stability. Thermal analysis and X-ray diffractometry proved that KP was transformed into a low-melting point amorphous form, while spectroscopic analysis and computational studies demonstrated that KP-PI interaction was mediated by hydrogen bonding. In the IL form, KP's solubility increased due to IL formation by 71 to 83%, while 218% more KP was permeated through rat skin in the IL form, than in a KP/PI mixture. Importantly, upon transdermal administration to rats with induced paw edema; KP-PI IL resulted in a 68% less paw swelling than KP/PI mixture. These findings demonstrate the utility of IL as an economic, simple and efficient strategy for improving the therapeutic application of drugs/drug combinations.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Ionic Liquids; Ketoprofen; Pharmaceutical Preparations; Piperidines; Polyunsaturated Alkamides; Rats

Cancer is a representative geriatric disease closely related to senescent cells and cell aging in tissues. Senescent cells that surround cancer tissues reduce the effects of various cancer treatments and induce cancer recurrence through senescence-associated secretory phenotype (SASP) secretion. Thus, for good therapeutic effect, candidate drugs should be selective for both cancer and senescent cells. In this study, we investigated the selective effect of piperine as a potential senostatic agent as well as an anticancer drug.. The effect of piperine on cytotoxicity and cell proliferation was tested by lactate dehydrogenase (LDH) or water-soluble tetrazolium salt (WST) assay. The levels of p16INK4a and p21, mitogen-activated protein kinases (MAPKs), and mammalian target of rapamycin (mTOR) were analyzed by Western blot analysis. The rejuvenation effects of piperine on the senescent cells were investigated by senescence-associated beta-galactosidase (SA-β-Gal) stain, mitochondria membrane potential (MMP) and reactive oxygen species (ROS) levels, and senescence-associated secretory phenotype (SASP) secretion after treatment with piperine in senescent cells.. While piperine induced high cytotoxicity in various cancer cell lines, it led to proliferating of premature senescent cells similar with nicotinamide (NA), which is known as a rejuvenating drug of senescent cells. Piperine differently affected cancer cells and premature senescent cells due to the different responses of intracellular signaling pathways and also reversed premature senescence phenotypes and modulated SASP secretion in premature senescent cells.. From these results, we propose piperine as an effective cancer treatment that can simultaneously induce senostatic effects and the removal of cancer cells, not as an adjuvant to the existing senostatics for cancer treatment.

Topics: Alkaloids; Benzodioxoles; Piperidines; Polyunsaturated Alkamides; Senotherapeutics

Piperine (PIP) was evaluated as a natural coformer in the preparation of multicomponent organic materials for enhancing solubility and dissolution rate of the poorly water-soluble drugs: curcumin (CUR), lovastatin (LOV), and irbesartan (IBS). A screening based on liquid assisted grinding technique was performed using 1:1 drug-PIP molar ratio mixtures, followed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) analyses. Three eutectic mixtures (EMs) composed of CUR-PIP, LOV-PIP, and IBS-PIP were obtained. Therefore, binary phase and Tamman's diagrams were constructed for each system to obtain the exact eutectic composition, which was 0.41:0.59, 0.29:0.71, and 0.31:0.69 for CUR-PIP, LOV-PIP, and IBS-PIP, respectively. Further, bulk materials of each system were prepared to characterize them through DSC, PXRD fully, Fourier transform infrared spectroscopy (FT-IR), and solution-state nuclear magnetic resonance (NMR) spectroscopy. In addition, the contact angle, solubility, and dissolution rate of each system were evaluated. The preserved characteristic in the PXRD patterns and FT-IR spectra of the bulk material of each system confirmed the formation of EM mixture without molecular interaction in solid-state. The formation of EM resulted in improved aqueous solubility and dissolution rate associated with the increased wettability observed by the decrease in contact angle. In addition, solution NMR analyses of CUR-PIP, LOV-PIP, and IBS-PIP suggested no significant intermolecular interactions in solution between the components of the EM. Hence, this study concludes that PIP could be an effective coformer to improve the solubility and dissolution rate of CUR, LOV, and IBS.

Topics: Alkaloids; Benzodioxoles; Cardiovascular Diseases; Curcumin; Irbesartan; Lovastatin; Piperidines; Polyunsaturated Alkamides; Powders; Spectroscopy, Fourier Transform Infrared

This study aimed to evaluate the piperine content, essential oil composition, and multi-elemental composition of black pepper samples according to different drying methods and harvest season. Differences in essential oil composition and B, Ca, K, Mg, and S were noted according to sampling campaign, indicating secondary metabolism plant alterations. Mechanical drying resulted in essential oil composition changes due to high temperature exposure during processing. Increases in Fe and Cr contents when employing mechanical dryers with direct heating were also observed, due to direct contact with metallic structures and particulate material from the burning process. The As and Pb contents of several samples were higher than the maximum permissible limits, reaching 0.46 and 0.56 mg kg

Topics: Alkaloids; Benzodioxoles; Humans; Oils, Volatile; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Seasons

The neuroprotective properties of piperine, the major alkaloid extracted from black pepper, have been under investigation, but its mechanism of action in excitotoxicity is still poorly understood. This study aimed to evaluate the protective effects of piperine with a focus on nerve growth factor (NGF) signalling in a kainic acid (KA) rat model of excitotoxicity. Rats were administered intraperitoneally (i.p.) piperine (10 or 50 mg/kg) before KA injection (15 mg/kg, i.p.). Our results show that KA exposure in rats caused seizure behaviour, intrinsic neuronal hyperactivity, glutamate elevation, hippocampal neuronal damage, and cognitive impairment. These KA-induced alterations could be restored to the normal state by piperine treatment. In addition, piperine decreased the expression of the NGF precursor proNGF and NGF-degrading protease matrix metalloproteinase 9, whereas it increased the expression of proNGF processing enzyme matrix metalloproteinase 7, NGF, and NGF-activated receptor TrkA in the hippocampus of KA-treated rats. Furthermore, KA decreased phosphorylation of the protein kinase B (Akt) and glycogen synthase kinase 3β (GSK3β) in the hippocampus, and piperine reversed these changes. Our data suggest that piperine protects hippocampal neurons against KA-induced excitotoxicity by upregulating the NGF/TrkA/Akt/GSK3β signalling pathways.

Topics: Alkaloids; Animals; Benzodioxoles; Excitatory Amino Acid Agonists; Glycogen Synthase Kinase 3 beta; Hippocampus; Kainic Acid; Nerve Growth Factor; Neuroprotection; Neuroprotective Agents; Neurotoxicity Syndromes; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; Rats

Topics: Alkaloids; Animals; Antimalarials; Benzodioxoles; COVID-19; Humans; Mammals; Molecular Docking Simulation; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Administration of Piper retrofractum extract (PRE) has been reported to alleviate edema, but the mechanism underlying this effect is unknown. Promotion of lymphangiogenesis is known to improve lymphedema, but the effect of PRE on lymphangiogenesis remains unclear. In the present study, we investigated whether PRE and specifically, piperine, the main component of PRE, can induce lymphangiogenesis. Treatments with PRE and piperine significantly promoted the proliferation, migration, and tube formation in human dermal lymphatic microvascular endothelial cells (HDLECs) but had no effect on the expression of lymphangiogenic factors. Furthermore, PRE and piperine significantly promoted the phosphorylation of the AKT and ERK proteins in HDLECs, and pretreatment with AKT and ERK inhibitors significantly attenuated the PRE- and piperine-induced lymphangiogenesis. These results indicate that PRE and piperine promote lymphangiogenesis via an AKT- and ERK-dependent mechanism. PRACTICAL APPLICATIONS: The lymphatic system plays various roles such as maintaining tissue fluid homeostasis, immune defense, and metabolism. Disruption of the lymphatic system results in insufficient fluid drainage, which causes edema. Currently, there are no effective treatments for lymphedema; therefore, the development of novel treatment strategies is desirable. In this study, we showed that PRE and its main component piperine promote lymphangiogenesis in lymphatic endothelial cells. Therefore, PRE has the potential to be used as a novel functional food for relieving lymphedema.

Topics: Alkaloids; Benzodioxoles; Endothelial Cells; Humans; Lymphangiogenesis; Lymphedema; Piper; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt

Piperine (PIP), a main active component isolated from Piper nigrum L., exerts neuroprotective effects in a rat model of ischemic stroke (IS). However, studies on the effects of PIP on neuroprotection and autophagy after IS are limited.. This study aimed to prove the protective effects of PIP against brain IS and elucidate its underlying mechanisms.. Specific pathogen-free male Sprague-Dawley rats were selected to establish a permanent middle cerebral artery occlusion model. The experiment was randomly divided into six groups: sham group, model group, PIP intervention group (10, 20, and 30 mg/kg group), and nimodipine group (Nimo group, 12 mg/kg). Neurological function score, postural reflex score, body swing score, balance beam test, and grip strength test were used to detect behavioral changes of rats. The area of cerebral infarction was detected by TTC staining, and the number and morphological changes of neurons were observed by Nissl and HE staining. In addition, the ultrastructure of hippocampal dentate gyrus neurons was observed using a transmission electron microscope. Western blot was used to detect the expression of PI3K/AKT/mTOR signaling pathway proteins and autophagy-related proteins, namely, Beclin1 and LC3, in the hippocampus and cortex. Cell experiments established an in vitro model of oxygen-glucose deprivation (OGD) with the HT22 cell line to verify the mechanism. The experiment was divided into five groups: control group, OGD group, OGD + PIP 20 μg/mL group, OGD + PIP 30 μg/mL group, and OGD + PIP 40 μg/mL group. CCK-8 was used to measure cell activity, and Western blot was used to measure the expression of PI3K/AKT/mTOR signaling pathway proteins and autophagy-related proteins (Beclin1 and LC3).. Compared with the model group, the neurological function scores, body swing scores, and postural reflex scores of rats in the 10, 20, and 30 mg/kg PIP intervention groups and Nimo groups decreased, whereas the balance beam score and grip test scores increased (all p < 0.05). After 10, 20, and 30 mg/kg PIP and Nimo intervention, the cerebral infarction area of pMCAO rats was reduced (p < 0.01), and Nissl and HE staining results showed that the number of neurons survived in the 30 mg/kg PIP and Nimo intervention groups increased. Cell morphology and structure were significantly improved (p < 0.05). Most of the hippocampal dentate gyrus neurons and their organelles gradually returned to normal in the 30 mg/kg PIP and Nimo intervention groups, with less neuronal damage. The expression levels of p-mTOR, p-AKT, and p-PI3K in the hippocampus and cortex of the 30 mg/kg PIP and Nimo intervention groups decreased, whereas the expression level of PI3K increased (all p < 0.05). In addition, the expression level of autophagy-related proteins, namely, Beclin1 and LC3-II, in the 30 mg/kg PIP and Nimo intervention groups decreased (all p < 0.05). Results of CCK-8 showed that after 1 h of OGD, the 30 and 40 μg/mL PIP intervention groups had higher cell viability than the OGD group (p < 0.01). Western blot results showed that compared with the OGD group, the expression level of p-mTOR, p-AKT, and p-PI3K in the 30 and 40 μg/mL PIP intervention groups decreased, and the expression level of PI3K increased (all p < 0.05). Moreover, the expression level of autophagy-related proteins, namely, Beclin1 and LC3-II, in the 30 and 40 μg/mL PIP intervention groups decreased (all p < 0.05).. This study shows that PIP is a potential compound with neuroprotective effects. PIP can inhibit the PI3K/AKT/mTOR pathway and autophagy. Its inhibition of autophagy is possibly related to modulating the PI3K/AKT/mTOR pathway. These findings provide new insights into the use of PIP for the treatment of IS and its underlying mechanism.

Topics: Alkaloids; Animals; Autophagy; Beclin-1; Benzodioxoles; Brain Injuries; Cerebral Infarction; Glucose; Ischemic Stroke; Male; Neuroprotective Agents; Oxygen; Phosphatidylinositol 3-Kinases; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Sincalide; Stroke; TOR Serine-Threonine Kinases

Piperine (1-piperoyl piperidine) is responsible for the pungent perception of dried black pepper (Piper nigrum) fruits and essentially contributes to the aromatic properties of this spice in combination with a blend of terpenoids. The final step in piperine biosynthesis involves piperine synthase (PS), which catalyzes the reaction of piperoyl CoA and piperidine to the biologically active and pungent amide. Nevertheless, experimental data on the cellular localization of piperine and the complete biosynthetic pathway are missing. Not only co-localization of enzymes and products, but also potential transport of piperamides to the sink organs is a possible alternative. This work, which includes purification of the native enzyme, immunolocalization, laser microdissection, fluorescence microscopy, and electron microscopy combined with liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS), provides experimental evidence that piperine and PS are co-localized in specialized cells of the black pepper fruit perisperm. PS accumulates during early stages of fruit development and its level declines before the fruits are fully mature. The product piperine is co-localized to PS and can be monitored at the cellular level by its strong bluish fluorescence. Rising piperine levels during fruit maturation are consistent with the increasing numbers of fluorescent cells within the perisperm. Signal intensities of individual laser-dissected cells when monitored by LC-ESI-MS/MS indicate molar concentrations of this alkaloid. Significant levels of piperine and additional piperamides were also detected in cells distributed in the cortex of black pepper roots. In summary, the data provide comprehensive experimental evidence of and insights into cell-specific biosynthesis and storage of piperidine alkaloids, specific and characteristic for the Piperaceae. By a combination of fluorescence microscopy and LC-MS/MS analysis we localized the major piperidine alkaloids to specific cells of the fruit perisperm and the root cortex. Immunolocalization of native piperine and piperamide synthases shows that enzymes are co-localized with high concentrations of products in these idioblasts.

Topics: Alkaloids; Benzodioxoles; Chromatography, Liquid; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Tandem Mass Spectrometry

Oral candidiasis, the most common mycotic infection of the human oral cavity is non-life-threatening yet, if untreated, may advance as systemic infections. The ability of Candida albicans to adapt sessile lifestyle imparts resistance to drugs and host immunity. Consequently, due to the limited effectiveness of conventional antifungal treatment, novel therapeutic strategies are required. In the present study, synergistic interaction of phytochemicals, piperine, and cinnamaldehyde against the biofilm and hyphal of C. albicans was evaluated. Minimum inhibitory concentration (MIC) and biofilm inhibitory concentration (BIC) of piperine and cinnamaldehyde against C. albicans were analyzed through microbroth dilution assay and crystal violet staining method, respectively. Combinatorial biofilm and hyphal inhibitory effect were investigated through checkerboard assay. In vitro results were validated through gene expression analysis. BIC of piperine and cinnamaldehyde was determined to be 32 μg/ml and 64 μg/ml, respectively. Interaction between these two phytocomponents was found to be synergistic and six different synergistic antibiofilm combinations were identified. Microscopic analysis of biofilm architecture also evidenced the biofilm and surface adherence inhibitory potential of piperine and cinnamaldehyde combinations. Phenotypic switching between yeast and hyphal morphological forms was influenced by synergistic combinations. qPCR analysis corroborated the results of in vitro activities. nrg1 and trp1, the negative transcriptional regulators of filamentous growth were upregulated whereas other genes that are involved in biofilm formation, filamentous growth, adhesion, etc. were found to be downregulated. These proficient phytochemical combinations provide a new therapeutic avenue for the treatment of biofilm-associated oral candidiasis and to combat the recurrent infections due to antibiotic resistance.

Topics: Acrolein; Alkaloids; Animals; Antifungal Agents; Benzodioxoles; Biofilms; Candida albicans; Candidiasis, Oral; Humans; Microbial Sensitivity Tests; Piperidines; Polyunsaturated Alkamides

Piperine (PIP) is the most active main component in pepper. The interaction of small molecules with biomolecules leads to structural and functional changes. In this study, the binding mechanism and antioxidant activity of PIP with hemoglobin (Hb) are presented using spectroscopic and computational methods. Results showed that the redox activity of PIP on Hb showed concentration dependence. Fluorescence and isothermal titration calorimetric experiments showed that the Hb-PIP system had a static quenching mechanism at a single binding site. The addition of PIP caused a slight perturbation to the secondary structure of Hb by structural analysis. The structural stability of the Hb-PIP binding system was demonstrated by molecular dynamics simulations, and molecular docking and thermodynamic constants confirmed that the electrostatic interaction force was dominant in the energy contribution of the system. Research results are conducive to the potential use of PIP in related meat products.

Topics: Alkaloids; Antioxidants; Benzodioxoles; Binding Sites; Hemoglobins; Molecular Docking Simulation; Piperidines; Polyunsaturated Alkamides; Protein Binding; Spectrometry, Fluorescence; Thermodynamics

Tumorectomy followed by radiotherapy, hormone, and chemotherapy, are the current mainstays for breast cancer treatment. However, these strategies have systemic toxicities and limited treatment outcomes. Hence, there is a crucial need for a novel controlled release delivery system for implantation following tumor resection to effectively prevent recurrence. Here, we fabricated polycaprolactone (PCL)-based electrospun nanofibers containing piperine (PIP), known for chemopreventive and anticancer activities, and also evaluated the impact of collagen (Coll) incorporation into the matrices. In addition to physicochemical characterization such as morphology, hydrophilicity, drug content, release properties, and mechanical behaviors, fabricated nanofibers were investigated in terms of cytotoxicity and involved mechanisms in MCF-7 and 4T1 breast tumor cell lines. In vivo antitumor study was performed in 4T1 tumor-bearing mice. PIP-PCL

Topics: Alkaloids; Animals; Benzodioxoles; Collagen; Mice; Nanofibers; Neoplasms; Piperidines; Polyesters; Polyunsaturated Alkamides

Topics: Alkaloids; Benzodioxoles; Emulsions; Humans; Piperidines; Polyunsaturated Alkamides; Vitiligo

Topics: Alkaloids; Anti-Inflammatory Agents; Antioxidants; Benzodioxoles; Cyclophosphamide; Cytokines; Humans; Inflammation; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Reactive Oxygen Species; Ubiquinone

Glioblastoma multiforme (GBM) cancer stem cells (GSCs) are one of the strongest contributing factors to treatment resistance in GBM. Identification of biomarkers capable of directly affecting these cells within the bulk tumor is a major challenge associated with the development of new targeting strategies. In this study, we focus on understanding the potential of the multifunctional extraordinaire survivin as a biomarker for GSCs. We analyzed the expression profiles of this gene using various publicly available datasets to understand its importance in stemness and other cancer processes. The findings from these studies were further validated using human GSCs isolated from a GBM cell line. In these GSCs, survivin was inhibited using the dietary phytochemical piperine (PIP) and the subsequent effects on stemness, cancer processes and Temozolomide were investigated. In silico analysis identified survivin to be one of the most significant differentially regulated gene in GSCs, in comparison to common stemness markers. Further validation studies on the isolated GSCs showed the importance of survivin in stemness, cancer progression and therapy resistance. Taken together, our study identifies survivin as a more consistent GSC marker and also suggests the possibility of using survivin inhibitors along with standard of care drugs for better therapeutic outcomes.

Topics: Alkaloids; Benzodioxoles; Brain Neoplasms; Cell Line, Tumor; Cytochrome P-450 Enzyme Inhibitors; Glioblastoma; Humans; Neoplastic Stem Cells; Piperidines; Polyunsaturated Alkamides; Survivin

Herein, we elucidate the biophysical aspects of the interaction of an important protein, Interleukin-6 (IL6), which is involved in cytokine storm syndrome, with a natural product with anti-inflammatory activity, piperine. Despite the role of piperine in the inhibition of the transcriptional protein NF-κB pathway responsible for activation of IL6 gene expression, there are no studies to the best of our knowledge regarding the characterisation of the molecular interaction of the IL6-piperine complex. In this context, the characterisation was performed with spectroscopic experiments aided by molecular modelling. Fluorescence spectroscopy alongside van't Hoff analyses showed that the complexation event is a spontaneous process driven by non-specific interactions. Circular dichroism aided by molecular dynamics revealed that piperine caused local α-helix reduction. Molecular docking and molecular dynamics disclosed the microenvironment of interaction as non-polar amino acid residues. Although piperine has three available hydrogen bond acceptors, only one hydrogen-bond was formed during our simulation experiments, reinforcing the major role of non-specific interactions that we observed experimentally. Root mean square deviation (RMSD) and hydrodynamic radii revealed that the IL6-piperine complex was stable during 800 ns of simulation. Taken together, these results can support ongoing IL6 drug discovery efforts.

Topics: Alkaloids; Benzodioxoles; Interleukin-6; Molecular Docking Simulation; Molecular Dynamics Simulation; Piperidines; Polyunsaturated Alkamides

In our study, our aim was to examine the cytotoxic and radio-sensitizing effect of the alkaloid piperine, a major pungent of black pepper, on two different human epithelial tumor cell lines in vitro. The growth of the human cell lines T98G (glioblastoma) and FaDu (hypopharyngeal carcinoma) was examined under the influence of piperine in different concentrations. In addition, after combined treatment with ionizing radiation, long-term survival was investigated with a colony formation assay. The proliferation was analyzed using the BrdU-assay, while the DNA repair capacity was examined via the γH2AX assay. Piperine reduced the growth of both cell lines in a concentration-dependent manner as well as a time-dependent one. After combined treatment with piperine and ionizing radiation, an inhibition of clonogenic survival could be proven. A reduced proliferation capacity and an additive effect on DNA damage 24 h after irradiation are possible causal mechanisms, which were also demonstrated for both cell lines. Based on the results presented in this study, piperine was shown to have cytotoxic antitumor activity and a radio-sensitizing effect in micromolar concentrations in the human tumor cells that were tested. Based on these results piperine represents a potential therapeutic option in radio-oncological treatment.

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; Glioblastoma; Humans; Hypopharynx; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Radiation Tolerance

Asian corn borer (

Topics: Alkaloids; Animals; Benzodioxoles; Chitinases; Moths; Piperidines; Polyunsaturated Alkamides

Acute pancreatitis was a common acute abdominal disease characterized by pancreatic acinar cell death and inflammation. Endoplasmic reticulum autophagy (ER-phagy) coud maintain cell homeostasis by degrading redundant and disordered endoplasmic reticulum and FAM134B and CCPG1 was main ER-phagy receptors. As a natural alkaloid, piperin is found in black pepper and has anti-inflammatory properties, whose effect on ER-phagy in pancreatitis has not been studied.. The objective of this study was to demonstrate the pivotal role of FAM134B and CCPG1 dependent ER-phagy for alleviating acute pancreatitis and explore the molecular mechanism of piperine in alleviating acute pancreatitis.. In this study we investigated the role of ER-phagy in acute pancreatitis and whether piperine could alleviate pancreatitis through ER-phagy regulation. We first detected endoplasmic reticulum stress (ER-stress) and ER-phagy in different degrees of acute pancreatitis. Then we used ER-stress and autophagy regulators to explore the relationship between ER-stress and ER-phagy in acute pancreatitis and their regulation of cell death. Through using FAM134B. In this study, we confirmed that with the progression of acute pancreatitis, the pancreatic endoplasmic reticulum stress increased continuously, but the ER-phagy increased first and then was inhibited. Meanwhile, in acute pancreatitis, ER-stress and ER-phagy interacted: endoplasmic reticulum stress can induce ER-phagy, but serious ER-stress would inhibit ER-phagy; and ER-phagy could alleviate ER-stress. Next, we found that piperine reduced ER-stress by enhancing FAM134B and CCPG1 dependent ER-phagy, thereby alleviating pancreatic injury.. Impaired ER-phagy was both a cause and a consequence of ER-stress in AP mice, which contributed to the transition from AP to SAP. Piperine targeting ER-phagy provided a new insight into the pharmacological mechanism of piperine in treating AP.

Topics: Acute Disease; Alkaloids; Animals; Autophagy; Benzodioxoles; Endoplasmic Reticulum Stress; Mice; Pancreatitis; Piperidines; Polyunsaturated Alkamides

γ-Glutamyl peptides, including glutathione (γ-Glu-Cys-Gly, GSH) and γ-glutamyl-valyl-glycine (γ-Glu-Val-Gly), have been shown to increase the intensity of basic tastes, such as salty, sweet, and umami, and flavor, including mouthfulness, but had no taste themselves at the concentrations tested. Although the mechanisms of action of γ-glutamyl peptides currently remain unclear, the involvement of the calcium sensing receptor (CaSR) has been suggested. Since GSH and γ-Glu-Val-Gly increase the pungency of some spices, the present study investigated their effects on the pungency of allyl isothiocyanate (AITC) using a sensory evaluation. GSH and γ-Glu-Val-Gly both significantly increased the pungency of AITC, while anserine, a peptide without CaSR activity, did not. GSH-induced increases in pungency were suppressed by NPS-2143, a CaSR inhibitor. Further, γ-Glu-Val-Gly significantly increased the pungency of piperine. The present results suggest that GSH and γ-Glu-Val-Gly increased the pungency by activating CaSR.

Topics: Alkaloids; Anserine; Benzodioxoles; Glutathione; Isothiocyanates; Oligopeptides; Peptides; Piperidines; Polyunsaturated Alkamides; Receptors, Calcium-Sensing

Fluid thickening is the main compensatory strategy for patients with oropharyngeal dysphagia (OD) associated with aging or neurological diseases, and there is still no pharmacological treatment. We aimed to compare the effects of increasing bolus viscosity with that of acute stimulation with TRPV1, TRPA1 or TRPM8 agonists on the biomechanics and neurophysiology of swallow response in patients with OD. We retrospectively analyzed seven studies from our laboratory on 329 patients with OD. The effect of increasing shear viscosity up to 3682 mPa·s was compared by videofluoroscopy and pharyngeal sensory evoked potentials (pSEP) with that of adding to the bolus: capsaicin (TRPV1, 150 μM/10 μM), piperine (TRPA1/V1, 1 mM/150 μM), menthol (TRPM8, 1 mM/10 mM), cinnamaldehyde-zinc (TRPA1, 100 ppm−70 mM), citral (TRPA1, 250 ppm) or citral-isopulegol (TRPA1-TRPM8, 250 ppm−200 ppm). Fluid thickening improved the safety of swallow by 80% (p < 0.0001) by delaying bolus velocity by 20.7 ± 7.0% and time to laryngeal vestibule closure (LVC) by 23.1 ± 3.7%. Capsaicin 150μM or piperine 1 mM significantly improved safety of swallow by 50% (p < 0.01) and 57.1% (p < 0.01) by speeding time to LVC by 27.6% (p < 0.001) and 19.5% (p < 0.01) and bolus velocity by 24.8% (p < 0.01) and 16.9% (p < 0.05), respectively. Cinnamaldehyde-zinc shortened the P2 latency of pSEPs by 11.0% (p < 0.01) and reduced N2-P2 amplitude by 35% (p < 0.01). In conclusion, TRPV1 and TRPV1/A1 agonists are optimal candidates to develop new pharmacological strategies to promote the recovery of brain and swallow function in patients with chronic OD.

Topics: Acrolein; Acyclic Monoterpenes; Alkaloids; Benzodioxoles; Biomechanical Phenomena; Capsaicin; Deglutition; Deglutition Disorders; Humans; Menthol; Piperidines; Polyunsaturated Alkamides; Retrospective Studies; Zinc

India is the largest producer in the world of black pepper and it is the center of origin for

Topics: Alkaloids; Antioxidants; Benzodioxoles; Catechin; Catechols; Chlorogenic Acid; Flavonoids; Gallic Acid; Phenols; Piper; Piper nigrum; Piperidines; Plant Extracts; Polyphenols; Polyunsaturated Alkamides; Solvents

Piperine (PIP) is a major phytoconstituent in black pepper which is responsible for various pharmacological actions such as anti-inflammatory, antioxidant, and antitumor activity. To investigate the effects and mechanisms of PIP on cigarette smoke (CS)-induced lung pathology using both in-vitro and in-vivo models. BEAS-2B and A549 cells were exposed to CS extract (CSE) for 48 h; BALB/c mice were exposed to CS (9 cigarettes/day, 4 days) to induce features of airway disease. PIP at doses of (0.25, 1.25, and 6.25 µM, in vitro; 1 and 10 mg/kg, in vivo, i.n) and DEX (1 µM, in vitro; 1 mg/kg, in vivo, i.n) were used to assess cytotoxicity, oxidative stress, epithelial−mesenchymal transition (EMT), Sirtuin1 (SIRT1), inflammation-related cellular signaling, and lung function. PIP treatment protects cells from CSE-induced lung epithelial cell death. PIP treatment restores the epithelial marker (p < 0.05) and decreases the mesenchymal, inflammatory markers (p < 0.05) in both in vitro and in vivo models. The PIP treatment improves the altered lung function (p < 0.05) in mice induced by CS exposure. Mechanistically, PIP treatment modulates SIRT1 thereby reducing the inflammatory markers such as IL-1β, IL-6 and TNF-α (p < 0.05) and enhancing the epigenetic marker HDAC2 (p < 0.05) and antioxidant marker Nrf2 (p < 0.05) expressions. Thus, PIP alleviates pulmonary inflammation by modulating the SIRT1-mediated inflammatory cascade, inhibits EMT, and activates Nrf2 signaling.

Topics: Animals; Antioxidants; Epithelial-Mesenchymal Transition; Lung; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; Nicotiana; Oxidative Stress; Piperidines; Pneumonia; Sirtuin 1; Smoke

The markedly low oral bioavailability of domperidone (anti-emetic drug) is associated with rapid first-pass metabolism in the intestine and liver. To counteract such affects, there is a need to devise a strategy to enhance absorption and subsequently bioavailability. Thus, the current study was aimed at synthesizing phytosomes consisting of phosphatidylcholine and piperine (a P-glycoprotein inhibitor). Phytosomes were prepared by salting-out method. The developed phytosomes were extensively characterized for size, zeta potential, polydispersity index, entrapment efficiency (EE %), infra-red spectroscopy, X-ray diffraction

Topics: Administration, Oral; Alkaloids; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Availability; Domperidone; Liposomes; Particle Size; Piperidines; Polyunsaturated Alkamides

Topics: Administration, Cutaneous; Alkaloids; Animals; Benzodioxoles; Dermatitis, Atopic; Lipids; Liposomes; Mice; Mice, Inbred BALB C; Piperidines; Polyunsaturated Alkamides; Skin; Skin Absorption

Topics: Alkaloids; alpha-Synuclein; Animals; Autophagy; Benzodioxoles; Ligand-Gated Ion Channels; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Parkinson Disease; Piperidines; Polyunsaturated Alkamides; Receptors, Purinergic P2X4

The major chemical marker of black pepper (Piper nigrum L) is piperine and its estimation is extremely important for quality assessment of black pepper. The methods for piperine quantification, to date, are laboratory based and use high end instruments like chromatographs, which require tedious sample processing and cause sample destruction.. In this article, we present a simple, rapid and green analytical method based on Raman spectroscopy for the quantitative assessment of piperine.. To assess the potential of the technique, we report the complete vibrational characterisation of the piperine with density functional theory (DFT) calculations.. The theoretical peaks were obtained at 1097 cm. The results demonstrate the efficacy of the Raman technique for the estimation of piperine in the dry fruit of Piper nigrum.

Topics: Alkaloids; Benzodioxoles; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Spectrum Analysis, Raman

Piperine (PIP), the main active ingredient in pepper, belongs to the cinnamamide alkaloid. PIP has been found to have functions, including anti-oxidation, immune regulation, anti-tumour and promotion of drug metabolism. The present study was mainly designed to reveal the anti-tumour effect of PIP against gastric cancer and the relevant mechanism. In brief, the undifferentiated human gastric cancer cell HGC-27 was used, which was treated with different concentrations of PIP. As a result, PIP could inhibit proliferation and induce apoptosis of HGC-27 cells in a dose-dependent manner. The mechanism of PIP was associated with ROS increase and mitochondrial damage, simultaneously, the expression of key proteins of apoptosis was affected, including Bcl-2, Bax, Cyt-c, Caspase-9 and Caspase-3. Pre-treatment of ROS scavenger NAC HGC-27 cells could significantly reduce PIP-induced apoptosis and inhibit the activation of apoptotic signals. Consistently, PIP could induce ROS to increase and activate apoptotic signals in the animal model. Therefore, the present study showed that PIP can induce the generation of ROS, thereby promoting the activation of mitochondrial apoptotic pathway and exerting anti-tumour effects.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Biomarkers; Caspase 3; Caspase 9; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Immunophenotyping; Membrane Potential, Mitochondrial; Mice; Mitochondria; Piperidines; Polyunsaturated Alkamides; Reactive Oxygen Species; Signal Transduction; Stomach Neoplasms; Xenograft Model Antitumor Assays

Glucocorticoids (GCs) are steroids that play an essential role in physiological processes and are valuable therapeutic agents against various diseases. The aim of our study was to evaluate the antioxidant effects of piperine (PIP) on steroid-induced oxidative stress in liver tissue.. We used 36 fertilized specific-pathogen-free (SPF) chicken eggs that were divided into the following 6 groups: group 1 (n=6), phosphate buffered saline (PBS) (pH 7.4 saline solution [0.9%] isotonic); group 2 (n=6), 0.50 µmol hydrocortisone succinate sodium (HC); group 3 (n=6), 0.50 µmol HC and 100 mg/kg piperine (PIP); group 4 (n=6), 0.50 µmol HC and 50 mg/kg PIP; group 5 (n=6), 0.50 µmol HC and 25 mg/kg PIP; and group 6 (n=6), 0.50 µmol HC and 10 mg/kg PIP. Chick embryos were removed from the eggs and the livers dissected from the embryos. The total antioxidant status (TAS), total oxidant status (TOS), reduced glutathione (GSH), and lipid peroxidation (malondialdehyde [MDA]) levels were measured.. The highest levels of GSH and TAS in the liver tissues were observed in group 3, with a significant difference from those in group 2 (p <0.001 and p =0.006, respectively). The lowest levels of MDA and TOS in the liver tissues were observed in group 3, with a significant difference from those in group 2 (p <0.001 and p =0.021, respectively).. The antioxidant and hepatoprotective properties of PIP were observed only at high doses.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Chemical and Drug Induced Liver Injury; Chick Embryo; Dose-Response Relationship, Drug; Glucocorticoids; Glutathione; Hydrocortisone; Lipid Peroxidation; Malondialdehyde; Oxidative Stress; Piperidines; Polyunsaturated Alkamides

Piperine and capsaicin are important molecules with biological and pharmacological activities. This study aimed to evaluate the cytogenotoxic and protective effect of piperine and capsaicin on Allium cepa cells. A. cepa roots were exposed to negative (2% Dimethylsulfoxide) and positive (Methylmethanesulfonate, MMS, 10 µg/mL) controls, and four concentrations (25-200 µM) of piperine or capsaicin (alone) or associated before, simultaneously or after with the MMS. Only the lowest concentration of piperine (25 µM) showed a protective effect because it was not genotoxic. Piperine and capsaicin were cytotoxic (50, 100 and 200 µM). Piperine (50 to 200 µM) caused a significant increase in the total average of chromosomal alterations of in A. cepa cells. For capsaicin, the genotoxic effect was dose-dependent with a significant increase for all concentrations, highlighting the significant presence of micronuclei and nuclear buds for the two isolates. In general, bioactive compounds reduced the total average of chromosomal alterations against damage caused by MMS, mainly micronuclei and/or nuclear buds. Therefore, the two molecules were cytotoxic and genotoxic at the highest concentrations, and did not have cytoprotective action, and the lowest concentration of piperine demonstrated important chemopreventive activity.

Topics: Alkaloids; Benzodioxoles; Capsaicin; DNA Damage; Onions; Piperidines; Plant Roots; Polyunsaturated Alkamides

The purpose of this study was to enhance the antitumor effect of piperine by constructing the nanoparticles modified with transferrin (Tf-PIP-NPs) and evaluating their efficacy in vitro and in vivo. The Tf-PIP-NPs were prepared by the solvent evaporation method, and their properties were characterized. The effects of Tf-PIP-NPs on cytotoxicity, cell uptake, apoptosis, and mitochondrial membrane potential were evaluated in HepG2 cells, MDA-MB-231 cells, and 4T1 cells. In a 4T1 tumor-bearing mouse model, the antitumor efficacy of Tf-PIP-NPs was assessed in terms of tumor volumes, changes in body weight, HE staining, and immunohistochemical analysis. With a mean particle size of 112.2 ± 1.27 nm, the zeta potential of (- 28.0 ± 1.6 mV) Tf-PIP-NPs were rapidly internalized by tumor cells after 1 h through the transferrin receptor (TfR)-mediated endocytosis pathway, significantly inducing cellular apoptosis and mitochondrial membrane potential loss. Although Tf-PIP-NPs had no significant difference with PIP-NPs in tumor volume inhibition due to the presence of tumor microenvironment, it could significantly upregulate the expression of related pro-apoptotic proteins and induce tumor necrosis. We used the self-assembly properties of glycyrrhizic acid (GL) and polymer-PLGA to encapsulate piperine and modified with the transferrin, which provided a promising approach to improve the antitumor efficacy for anticarcinogen.

Topics: Alkaloids; Animals; Benzodioxoles; Cell Line, Tumor; Drug Delivery Systems; Glycyrrhizic Acid; Mice; Nanoparticles; Particle Size; Piperidines; Polyunsaturated Alkamides; Transferrin

Currently, the weight loss effects of piperine have gained considerable attention; however, the underlying mechanism needs to be comprehensively elucidated. In the present study, we aimed to investigate the relationship between the weight loss effects of piperine and intestinal function. Based on the obtained results, piperine inhibited intestinal fatty acid absorption in both cellular and animal models. The underlying mechanism may be related to the downregulation of fatty acid absorption-related genes, fatty acid-binding protein 2 and cluster of differentiation 36, but not fatty acid transport protein 4. In addition, piperine repaired the tight junction damage induced by obesity by downregulating jejunal tumor necrosis factor-α and reducing lipopolysaccharide-induced damage on intestinal cell proliferation, thus enhancing intestinal barrier function, which is beneficial in reducing chronic inflammation associated with obesity. In conclusion, the anti-obesity effect of piperine is related to the enhancement of intestinal barrier function and inhibition of intestinal fatty acid absorption.

Topics: Alkaloids; Animals; Benzodioxoles; Fatty Acids; Intestinal Absorption; Intestinal Mucosa; Obesity; Piperidines; Polyunsaturated Alkamides

The diet of breastfeeding mothers could bring nurslings into contact with flavor compounds putatively contributing to early sensory programming of the infant. The study investigates whether tastants from a customary curry dish consumed by mothers are detectable in their milk afterwards and can be perceived by the infant.. Sensory evaluation identifies pungency as the dominating taste impression of the curry dish. Its ingredients of chili, pepper, and ginger suggest the flavor compounds capsaicin, piperine, and 6-gingerol as analytical targets. Breastfeeding mothers are recruited for an intervention trial involving the consumption of the curry dish and subsequent collection of milk samples for flavor compound analysis. Targeted and untargeted mass spectrometric (MS)- investigations identify exclusively piperine as an intervention-derived compound in human milk. However, concentrations are below the human taste threshold.. Piperine from pepper-containing foods transfers into the mother's milk within 1 h and is delivered to the nursling. Concentrations of 50 and 200 nM of piperine are 70-350 times below the human taste threshold, but TRPV1 (Transient Receptor Potential Vanilloid-1 ion channel) desensitization through frequent exposure to sub-taste-threshold concentrations could contribute to an increased tolerance at a later age.

Topics: Alkaloids; Benzodioxoles; Diet; Female; Humans; Infant; Milk, Human; Mothers; Piperidines; Polyunsaturated Alkamides

This study aimed to evaluate the role of spices/spice active principles on physical, biochemical, and molecular targets of bioaccessibility/bioavailability. Carotenoids-rich micellar fraction obtained through simulated digestion of green leafy vegetables (GLV) with individual or two/three combinations were correlated to their influence on bioaccessibility, cellular uptake, and basolateral secretion of carotenoids in Caco-2 cells. Results suggest that carotenoids' bioaccessibility depends on micelles physicochemical properties, which is affected due to the presence of co-treated dietary spices and their composition. Increased bioaccessibility of β-carotene (BC) and lutein (LUT) is found in GLV (spinach) digested with turmeric (TM) than red pepper (RP) and black pepper (BP). In contrast, enhanced cellular uptake and secretion of BC and LUT-rich triglyceride-rich lipoprotein is observed in the presence of RP and BP compared to the control group. In contrast, TM inhibited absorption, while retinol levels significantly reduced in the presence of TM and RP than BP. Control cells have indicated higher cleavage of β-carotene to retinol than the spice-treated group. Besides, spice active principles modulate facilitated transport of carotenoids by scavenger receptor class B type 1 (SR-B1) protein. The effect of spices on carotenoids' bioavailability is validated with active spice principles. Overall, carotenoids' bioavailability (cellular uptake and basolateral secretion) was found in the following order of treatments; piperine > capsaicin > piperine + capsaicin > curcumin + capsaicin + piperine > control > turmeric. These findings suggested that the interaction of specific dietary factors, including spice ingredients at the enterocyte level, could provide greater insight into carotenoid absorption. PRACTICAL APPLICATION: Spices/spice active principles play a role in the digestion process by stimulating digestive enzymes and bile acids secretion. Since carotenoids are lipid soluble and have low bioavailability, spice ingredients' influence on intestinal absorption of carotenoids is considered crucial. Hence, understanding the interaction of co-consumed spices on the absorption process of carotenoids may help to develop functional foods/formulation of nutraceuticals to improve their health benefits.

Topics: Alkaloids; Benzodioxoles; Biological Availability; Caco-2 Cells; Capsaicin; Capsicum; Carotenoids; Curcuma; Curcumin; Humans; Micelles; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Ursolic acid (UA) is a potent plant-based hepatoprotective agent having poor bioavailability, which hampers its therapeutic efficacy. The present study tries to overcome this limitation by combining it with piperine (PIP), a proven bioenhancer and hepatoprotective agent.. The type of interaction (synergism, addition, or antagonism) resulting between UA and PIP was analyzed and quantified by isobologram and combination index analysis. The hepatoprotective activity of UA and PIP was evaluated by measuring the level of hepatic marker enzymes. Pharmacokinetic analysis was carried out to ascertain the improvement of bioavailability.. The findings indicated that the combination of PIP and UA is an effective strategy in enhancing the bioavailability and hepatoprotective potential of UA.KEY MESSAGESUrsolic acid in a combination with piperine provides a synergistic hepatoprotective effect in carbon tetrachloride induced liver damage in rats.Piperine improves the pharmacokinetic properties of ursolic acid when given in combination.Piperine improves the relative oral bioavailability of ursolic acid by tenfold when combined together.

Topics: Alkaloids; Animals; Benzodioxoles; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Humans; Liver; Piperidines; Polyunsaturated Alkamides; Protective Agents; Rats; Triterpenes; Ursolic Acid

Black pepper (Piper nigrum L.), an important and long-cultivated spice crop, is native to South India and grown in the tropics. Piperine is the main pungent and bioactive alkaloid in the berries of black pepper, but the molecular mechanism for piperine biosynthesis has not been determined. MicroRNAs (miRNAs), which are classical endogenous noncoding small RNAs, play important roles in regulating secondary metabolism in many species, but less is known regarding black pepper or piperine biosynthesis.. To dissect the functions of miRNAs in secondary metabolism especially in piperine biosynthesis, 110 known miRNAs, 18 novel miRNAs and 1007 individual targets were identified from different tissues of black pepper by small RNA sequencing. qRT-PCR and 5'-RLM-RACE experiments were conducted to validate the reliability of the sequencing data and predicted targets. We found 3 miRNAs along with their targets including miR166-4CL, miR396-PER and miR397-CCR modules that are involved in piperine biosynthesis.. MiRNA regulation of secondary metabolism is a common phenomenon in plants. Our study revealed new miRNAs that regulate piperine biosynthesis, which are special alkaloids in the piper genus, and they might be useful for future piperine genetic improvement of black pepper.

Topics: Alkaloids; Benzodioxoles; Gene Expression Regulation, Plant; MicroRNAs; Piper nigrum; Piperidines; Plants, Genetically Modified; Polyunsaturated Alkamides; Reproducibility of Results; Sequence Analysis, RNA

G-quadruplex (G4) structures are considered a promising therapeutic target in cancer. Since Ayurveda, Piperine has been known for its medicinal properties. Piperine shows anticancer properties by stabilizing the G4 motif present upstream of the c-myc gene. This gene belongs to a group of proto-oncogenes, and its aberrant transcription drives tumorigenesis. The transcriptional regulation of the c-myc gene is an interesting approach for anticancer drug design. The present study employed a chemical similarity approach to identify Piperine similar compounds and analyzed their interaction with cancer-associated G-quadruplex motifs. Among all Piperine analogs, PIP-2 exhibited strong selectivity, specificity, and affinity towards c-myc G4 DNA as elaborated through biophysical studies such as fluorescence emission, isothermal calorimetry, and circular dichroism. Moreover, our biophysical observations are supported by molecular dynamics analysis and cellular-based studies. Our study showed that PIP-2 showed higher toxicity against the A549 lung cancer cell line but lower toxicity towards normal HEK 293 cells, indicating increased efficacy of the drug at the cellular level. Biological evaluation assays such as TFP reporter assay, quantitative real-time PCR (qRT- PCR), and western blotting suggest that the Piperine analog-2 (PIP-2) stabilizes the G-quadruplex motif located at the promoter site of c-myc oncogene and downregulates its expression. In conclusion, Piperine analog PIP-2 may be used as anticancer therapeutics as it affects the c-myc oncogene expression via G-quadruplex mediated mechanism.

Topics: A549 Cells; Alkaloids; Antineoplastic Agents; Apoptosis; Benzodioxoles; Down-Regulation; G-Quadruplexes; Gene Expression Regulation, Neoplastic; HEK293 Cells; HeLa Cells; Humans; Lung Neoplasms; MCF-7 Cells; Molecular Dynamics Simulation; Molecular Structure; Molecular Targeted Therapy; Piperidines; Polyunsaturated Alkamides; Promoter Regions, Genetic; Proto-Oncogene Proteins c-myc; Structure-Activity Relationship; Transcription, Genetic

Bisphenol A (BPA) is a chemical agent which can exert detrimental effects on the male reproductive system, especially the prostate gland. In this study we described the efficacy of the dietary agent curcumin, alone or combined with piperine, to suppress the impact of BPA on the prostate. Adult gerbils were divided into nine experimental groups (n = 7 each group), regarding control (water and oil), exposed to BPA (50 μg/kg/day in water) or curcumin (100 mg/kg) and/or piperine (20 mg/kg). To evaluate the effects of the phytotherapic agents, the other groups received oral doses every two days, BPA plus curcumin (BCm), piperine (BP), and curcumin + piperine (BCmP). BPA promoted prostatic inflammation and morphological lesions in ventral and dorsolateral prostate lobes, associated with an increase in androgen receptor-positive cells and nuclear atypia, mainly in the ventral lobe. Curcumin and piperine helped to minimize these effects. BPA plus piperine or curcumin showed a reduction in nuclear atypical phenotype, indicating a beneficial effect of phytochemicals. Thus, these phytochemicals minimize the deleterious action of BPA in prostatic lobes, especially when administered in association. The protective action of curcumin and piperine consumption is associated with weight loss, anti-inflammatory potential, and control of prostate epithelial cell homeostasis.

Topics: Alkaloids; Animals; Benzhydryl Compounds; Benzodioxoles; Carcinogenesis; Curcumin; Endocrine Disruptors; Gerbillinae; Male; Phenols; Phytochemicals; Piperidines; Polyunsaturated Alkamides; Prostate; Prostatic Neoplasms; Protective Agents

Adipocyte-derived leptin activates multiple oncogenic signaling, leading to breast cancer cell progression and metastasis. Hence, finding effective strategies to inhibit the oncogenic effects of leptin would provide a novel approach for disrupting obesity-associated breast cancer. In the current study, we explored the role of piperine, a major plant alkaloid from

Topics: Alkaloids; Animals; Benzodioxoles; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Diet; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; MicroRNAs; Obesity; Piperidines; Polyunsaturated Alkamides; PPAR alpha

Staphylococcus aureus causes numerous community-acquired and nosocomial infections in humans by exploiting biofilm. In this context, this study aims to impede the formation of Staphylococcus aureus biofilm by exposing the cells to a plant-based alkaloid, piperine. Our study revealed that piperine exhibited considerable antimicrobial activity against the test organism. However, we had tested the lower concentrations (up to 32 µg/mL) of piperine to observe whether they could show any antibiofilm activity against the same organism. Several experiments, like crystal violet (CV) assay, estimation of total biofilm protein, and fluorescence microscopic observations, established that lower concentrations (up to 16 µg/mL) of piperine showed efficient antibiofilm activity against Staphylococcus aureus. In this connection, we also noticed that the lower concentrations (8 and 16 µg/mL) of piperine showed a considerable reduction in microbial metabolic activity. Besides, it was also observed that the mentioned concentrations of piperine did not compromise the microbial growth of the target organism while exhibiting antibiofilm activity. To understand the underlying mechanism of microbial biofilm inhibition under the influence of piperine, we observed that the compound was found to accumulate reactive oxygen species in the bacterial cells that could play an important role in the inhibition of biofilm formation. Furthermore, the tested concentrations (8 and 16 µg/mL) of piperine were able to inhibit the motility of the test organism that might compromise the development of biofilm. Thus, piperine could be considered as a potential agent for the effective management of biofilm threat caused by Staphylococcus aureus.

Topics: Alkaloids; Anti-Bacterial Agents; Benzodioxoles; Biofilms; Humans; Microbial Sensitivity Tests; Piperidines; Polyunsaturated Alkamides; Reactive Oxygen Species; Staphylococcus aureus

Amphotericin B (AmB) exhibits potential antileishmanial activity, with only a little rate of recurrence. However, low bioavailability and severe nephrotoxicity are among the major shortcomings of AmB-based therapy. Various AmB nanoformulations have been developed, which to an extent, have reduced its toxicity and increased the drug efficacy. To further reduce the nonspecific tissue distribution and the cost of the treatment, the current AmB-based formulations require additional improvements. Combination of natural bioenhancers with AmB is expected to further increase its bioavailability. Therefore, we developed a nanoformulation of AmB and piperine (Pip), a plant alkaloid, known to enhance the bioavailability of various drugs, by entrapping them in guar gum, a macrophage targeting polymer. Owing to the ease of oral delivery, these nanoparticles (NPs) were coated with eudragit to make them suitable for oral administration. The formulated eudragit-coated AmB and Pip-loaded NPs (Eu-HDGG-AmB-Pip-NPs) exhibited controlled release of the loaded therapeutic agents and protected the drug from acidic pH. These NPs exhibited effective suppression of growth of both promastigotes and amastigotes of Leishmania donovani parasite under in vitro. In vivo evaluation of these NPs for therapeutic efficacy in golden hamster-L. donovani model demonstrated enhanced drug bioavailability, non-nephrotoxic nature, and potential antileishmanial activity with up to 96% inhibition of the parasite. Graphical abstract.

Topics: Alkaloids; Amphotericin B; Animals; Benzodioxoles; Cricetinae; Drug Carriers; Galactans; Leishmaniasis, Visceral; Mannans; Nanoparticles; Piperidines; Plant Gums; Polyunsaturated Alkamides

Piperine is the main active component of Piper longum L., which is also the main component of anti-sciatica Mongolian medicine Naru Sanwei pill. It has many pharmacological activities such as anti-inflammatory and immune regulation. This paper aims to preliminarily explore the potential mechanism of piperine in the treatment of sciatica through network pharmacology and molecular docking. TCMSP, ETCM database and literature mining were used to collect the active compounds of Piper longum L. Swiss TargetPrediction and SuperPred server were used to find the targets of compounds. At the same time, CTD database was used to collect the targets of sciatica. Then the above targets were compared and analyzed to select the targets of anti-sciatica in Piper longum L. The Go (gene ontology) annotation and KEGG pathway of the targets were enriched and analyzed by Metascape database platform. The molecular docking between the effective components and the targets was verified by Autodock. After that, the sciatica model of rats was established and treated with piperine. The expression level of inflammatory factors and proteins in the serum and tissues of rat sciatic nerve were detected by ELISA and Western blot. HE staining and immunohistochemistry were carried out on the sciatica tissues of rats. The results showed that Piper longum L. can regulate the development of sciatica and affect the expressions of PPARG and NF-kB1 through its active ingredient piperine, and there is endogenous interaction between PPARG and NF-kB1.

Topics: Alkaloids; Animals; Benzodioxoles; Drugs, Chinese Herbal; Male; Molecular Docking Simulation; Piper; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Sciatica; Technology

Macrophages are the main players involved in inflammation. Intercellular adhesion molecule-1 (ICAM-1) facilitates macrophage polarization prior to extravasation into inflamed tissue. Piperine, a natural product derived from black pepper, possesses useful biological and pharmacological activities. In the current study, the possible anti-inflammatory effect of piperine on the expression of ICAM-1 on J774.1 murine macrophage cell line was investigated.. Lipopolysaccharide (LPS)-stimulated J774.1 cells were cultured in the presence of different concentrations of piperine to examine the changes in ICAM-1 expression by real-time PCR and flow cytometry.. We found that piperine decreased ICAM-1 gene expression level from 2.4 ± 0.25 RFC (relative fold change) in LPS-only treated cells to 0.85 ± 0.525 RFC at 1µg/ml (p<0.05), 0.43 ± 0.27 RFC at 10µg/ml (p<0.01), and 0.26 ± 0.25 RFC at 20µg/ml (p<0.01). In flow cytometry, piperine at all concentrations significantly decreased ICAM-1 surface expressions (P<0.05). The geometric mean fluorescence intensity (g-MFI) in LPS-only treated cells (792 ± 57.3) decreased to 482±70 g-MFI at 20 μg/ml piperine.. According to the results of this study, by decreasing the expression of ICAM-1, piperine has been suggested to reduce inflammation and have the potential to provide therapeutic benefits for immune-mediated diseases.

Topics: Alkaloids; Animals; Benzodioxoles; Cell Line; Cell Survival; Intercellular Adhesion Molecule-1; Lipopolysaccharides; Macrophages; Mice; Piper nigrum; Piperidines; Polyunsaturated Alkamides

P-glycoprotein (P-gp)/MDR-1 plays a major role in the development of multidrug resistance (MDR) by pumping the chemotherapeutic drugs out of the cancer cells and reducing their efficacy. A number of P-gp inhibitors were reported to reverse the MDR when co-administered with chemotherapeutic drugs. Unfortunately, none has approved for clinical use due to toxicity issues. Some of the P-gp inhibitors tested in the clinics are reported to have cross-reactivity with CYP450 drug-metabolizing enzymes, resulting in unpredictable pharmacokinetics and toxicity of co-administered chemotherapeutic drugs. In this study, two piperine analogs (3 and 4) having lower cross-reactivity with CYP3A4 drug-metabolizing enzyme are identified as P-glycoprotein (P-gp) inhibitors through computational design, followed by synthesis and testing in MDR cancer cell lines over-expressing P-gp (KB Ch

Topics: Alkaloids; Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Benzodioxoles; Binding Sites; Cell Line, Tumor; Cell Survival; Cytochrome P-450 CYP3A; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Molecular Docking Simulation; Multidrug Resistance-Associated Proteins; Neoplasms; NF-kappa B; Piperidines; Polyunsaturated Alkamides; Vincristine

Candida albicans is a member of pathogens with potential drug resistance threat that needs novel chemotherapeutic strategies. Considering the multifarious biological activities including bioenhancer activity, anti-Candida potential of piperine was evaluated against planktonic/biofilm and hyphal growth of C. albicans alone or in combination as a synergistic agent with fluconazole. Piperine inhibits planktonic growth at or less than 15 μg/ml, hyphae induction at 5 μg/ml concentration, and exhibits stage-dependent activity against biofilm growth of a fluconazole-resistant strain of C. albicans (ATCC10231). Though piperine couldn't kill inoculum completely at minimum inhibitory concentration (MIC), it is fungicidal at higher concentrations, as shown in apoptosis assay. FIC index values indicate that piperine exhibits excellent synergistic activity with fluconazole against planktonic (0.123) and biofilm (0.215) growth of an FLC resistant strain. Mode of anti-Candida activity was studied by identifying piperine responsive proteins wherein the abundance of 25 proteins involved in stress response, signal transduction and cell cycle were modulated (22 up and 3 down-regulated) significantly in response to piperine (MIC50). Modulation of the proteins involved suggests that piperine affects membrane integrity leading to oxidative stress followed by cell cycle arrest and apoptosis in C. albicans. Flow cytometry-based mitochondrial membrane potential (MMP), cell cycle and apoptosis assay, as well as real-time quantitative polymerase chain reaction analysis of selected genes, confirms piperine induced oxidative stress (TRR1), cell cycle arrest and apoptosis (CaMCA1). Based on our results, we conclude that piperine inhibits planktonic and difficult-to treat-biofilm growth of C. albicans by affecting membrane integrity thereby inducing oxidative stress and apoptosis.. Piperine inhibit Candida albicans growth (planktonic and biofilm) significantly in our study. Piperine exhibits excellent synergistic potential with fluconazole The proteome analysis suggests that piperine induced membrane damage leads to oxidative stress followed by cell cycle arrest and apoptosis.

Topics: Alkaloids; Antifungal Agents; Apoptosis; Benzodioxoles; Biofilms; Candida albicans; Candidiasis; Drug Resistance, Fungal; Drug Synergism; Fluconazole; Hyphae; Microbial Sensitivity Tests; Oxidative Stress; Piperidines; Plant Extracts; Polyunsaturated Alkamides

Piperine (PIP) is an alkaloid which is potent as a therapeutic agent. However, its applications are restricted by its poor water solubility. Nanosponges (NS) derived from polymers are versatile carriers for poor water-soluble substances. The aim of this work was to synthesize β-cyclodextrin NS, by microwave-assisted fusion, for the encapsulation of PIP. Different formulations of NS were synthesized by varying the molar ratio of β-cyclodextrin:diphenyl carbonate (β-CD:DPC; 1:2, 1:6 and 1:10). NS specimens derived from 1:2, 1:6 and 1:10 β-CD:DPC molar ratios exhibited degree of substitution values of 0.345, 0.629 and 0.878, respectively. The crystallinity of NS was enhanced by increasing diphenyl carbonate concentration. A high degree of crosslinking in the NS increased the loading efficiency due to increased surface area available for bioactive inclusion. This study demonstrated the feasibility of synthesizing NS derived from β-cyclodextrin of high crystallinity for the encapsulation of PIP at high loading capacity.

Topics: Alkaloids; Benzodioxoles; beta-Cyclodextrins; Drug Compounding; Microwaves; Nanostructures; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Solubility

In this study, we have exploring the binding mechanisms of the two anticancer alkaloid noscapine (NOS) and piperine (PIP) with tRNA using different spectroscopy and computational method. Absorbance and emission spectra revealed that both the drugs show strong binding with tRNA, where NOS intercalate between the base pairs of tRNA and PIP binds in the groove of tRNA. Competitive binding study and steady state anisotropy further confirms the intercalative mode of binding between NOS and tRNA and groove binding in PIP-tRNA complex. The observed thermodynamic parameters suggested that NOS-tRNA complex formation is endothermic and entropy driven, however it was exothermic, and enthalpy driven in case of PIP-tRNA complex. CD and time resolved fluorescence studies show the structural perturbations and conformational change in tRNA structure with NOS as well as PIP. Molecular docking studies are comparable with experimental results and further confirmed that the hydrophobic interactions involved in the NOS-tRNA binding, whereas hydrogen binding and van der Waals interactions play important role in the PIP-tRNA complex formation. This study can be useful to understand the potential binding and resultant tRNA damage by alkaloids and deigned new target specific anticancer drug.

Topics: Alkaloids; Benzodioxoles; Binding Sites; Circular Dichroism; Molecular Docking Simulation; Noscapine; Piperidines; Polyunsaturated Alkamides; RNA, Transfer; Thermodynamics

Piperine, as the most abundant alkaloid in pepper, gained a lot of attention for possible antioxidant and therapeutic properties. Electrochemical techniques were applied to widely evaluate the redox behavior of piperine by comparison to that of well-known antioxidants: ascorbic acid, protocatechuic acid, syringic acid, tyrosine and capsaicin used as controls. Also, electrochemistry was involved in an innovative way to investigate the potential antioxidant properties of piperine combined with different in vitro peroxidation and reducing assays: (i) 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH) scavenging; (ii) 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) scavenging; (iii) ferric ions (Fe

Topics: Alkaloids; Antioxidants; Ascorbic Acid; Benzodioxoles; Biphenyl Compounds; Cyclic N-Oxides; Electrochemical Techniques; Free Radical Scavengers; Free Radicals; Hydrogen Peroxide; Iron; Oxidation-Reduction; Picrates; Piperidines; Polyunsaturated Alkamides

miRNA-mediated pyroptosis play crucial effects in the development of myocardial ischaemia/reperfusion (I/R) injury (MIRI). Piperine (PIP) possesses multiple pharmacological effects especially in I/R condition. This study focuses on whether PIP protects MIRI from pyroptosis via miR-383-dependent pathway. Rat MIRI model was established by 30 minutes of LAD ligation and 4 hours of reperfusion. Myocardial enzymes, histomorphology, structure and function were detected to evaluate MIRI. Recombinant adenoviral vectors for miR-383 overexpression or miR-383 silencing or RP105 knockdown were constructed, respectively. Luciferase reporter analysis was used to confirm RP105 as a target of miR-383. Pyroptosis-related markers were measured by Western blotting assay. The results showed that I/R provoked myocardial injury, as shown by the increases of LDH/CK releases, infarcted areas and apoptosis as well as worsened function and structure. Pyroptosis-related mediators including NLRP3, cleaved caspase-1, cleaved IL-1β and IL-18 were also reinforced after MIRI. However, PIP treatment greatly ameliorated MIRI in parallel with pyroptotic repression. In mechanistic studies, MIRI-caused elevation of miR-383 and decrease of RP105/PI3K/AKT pathway were reverted by PIP treatment. Luciferase reporter assay confirmed RP105 as a miR-383 target. miR-383 knockdown ameliorated but miR-383 overexpression facilitated pyroptosis and MIRI. Moreover, the anti-pyroptotic effect from miR-383 silencing was verified to be relied on the RP105/PI3K/AKT signalling pathway. Additionally, our present study further indicated the miR-383/RP105/AKT-dependent approach resulting from PIP administration against pyroptosis in MIRI. Therefore, PIP treatment attenuates MIRI and pyroptosis by regulating miR-383/RP105/AKT pathway, and it may provide a therapeutic manner for the treatment of MIRI.

Topics: Alkaloids; Animals; Antigens, CD; Benzodioxoles; Cardiotonic Agents; Male; MicroRNAs; Myocardial Reperfusion Injury; Phosphatidylinositol 3-Kinases; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; Pyroptosis; Rats, Sprague-Dawley; Signal Transduction

The persistent activation of intestinal mechanistic target of rapamycin complex 1 (mTORC1) triggered by mucosal stress has been linked to deregulation of the gut immune response resulting in intestinal inflammation and cell death. The present study investigated the regulatory properties of food-derived mTORC1 modulators, curcumin, and piperine, toward the polarization of stimulated macrophages and the differentiation of monocytes at two mTORC1 activity levels (baseline and elevated). To that end, we created stable human THP-1 monocytes exhibiting normal or constitutively active mTORC1. Curcumin or its combination with piperine, but not piperine alone, suppressed mTORC1 kinase activity, curtailed lipopolysaccharide-mediated inflammatory response of THP-1 macrophages, and repressed macrophage activation by inhibiting signaling pathways involved in M1 (mTORC1) and M2 (mTORC2 and cAMP response element binding protein) polarization. The effects of piperine in the curcumin/piperine combination were modest overall, indicating it was curcumin that modulated differentiating monocytes into acquiring a M0 macrophage phenotype characterized by low inflammatory cytokine output.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Cell Differentiation; Cell Survival; Curcuma; Curcumin; Cytokines; Humans; Immunity; Lipopolysaccharides; Macrophage Activation; Macrophages; Mechanistic Target of Rapamycin Complex 1; Monocytes; Phenotype; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Signal Transduction; THP-1 Cells

The modulatory effects of piperine on drug metabolizing enzymes play an important role in the control of pharmacokinetic and the bioavailability properties of the administered drugs. The present study investigated the effect of piperine and piperine-donepezil co-administration on cognitive functions and synaptic plasticity at hippocampal perforant pathway (PP) to dentate gyrus (DG) synapses in an experimental model of Alzheimer's disease (AD).. Intracerebroventricularly (ICV) streptozotocin (STZ) injected rats were treated once daily with piperine, donepezil and piperine combined with donepezil for 4 weeks. Cognitive performance was evaluated using passive avoidance and Morris water maze performance tasks. Analysis of evoked field potentials was done to explore possible effects on input/output response, paired-pulse facilitation and long-term synaptic plasticity (LTP) at PP to DG synapses of hippocampus.. Rats subjected to ICV injection of STZ exhibited cognitive deficit associated with a hippocampal oxidative stress, effects that were reversed by chronic treatment with piperine or donepezil and or piperine combined with donepezil. Chronic treatment with piperine or donepezil restored the disruptive effects of STZ on LTP without altering basal synaptic transmission.. We found that optimal hippocampal function is dependent on tissue redox homeostasis. Piperine might reduce the synaptotoxic effects of STZ on hippocampal synaptic neurotransmission and correspondently is a good potential for neuroprotection against oxidative damage from ICV injection of STZ. These results suggest that piperine or donepezil significantly ameliorate cognitive deficit and LTP induction by attenuating oxidative status.

Topics: Alkaloids; Alzheimer Disease; Animals; Avoidance Learning; Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Disease Models, Animal; Donepezil; Drug Therapy, Combination; Hippocampus; Male; Neuronal Plasticity; Nootropic Agents; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Streptozocin; Treatment Outcome

Curcumin, a molecule of immense pharmacological significance is also known to exhibit poor aqueous solubility and low bioavailability. Different strategies have been adopted to enhance the aqueous solubility of curcumin, but report on the effect of traditional excipients on curcumin solubility still stand in need of. Here, we presented the significance of different traditional excipients used in anti-inflammatory formulations on curcumin solubility. The endeavor has been undertaken with the hypothesis that "traditional formulation used since ages have a scientific basis". To meet the quest we encapsulated 28 different formulations containing varying concentrations of milk, sugar, cow milk fat, and black pepper in alginate hydrogels. After the characterization of formulations through FT-IR, solubility studies were conducted. Milk was found to be an essential component for improved curcumin availability. Individually, cow milk fat and piperine exhibited lesser effect but their synergistic effect was observed in the presence of milk. Dual behavior of sugar has been observed. Traditionally used excipients greatly enhanced the solubility of curcumin. The results have also been validated through anti-oxidant activities of different formulations. Intermolecular interactions have been explained using Molecular modeling studies.

Topics: Alginates; Alkaloids; Animals; Antioxidants; Benzodioxoles; Curcuma; Curcumin; Drug Liberation; Excipients; Hydrogels; Milk; Models, Molecular; Piperidines; Polyunsaturated Alkamides; Solubility; Sucrose

In present study, we have developed W/O/W microemulsion (ME) containing piperine (PiP) as a permeation enhancer and albumin (Alb) serving as a stabilizer for oral delivery of insulin (INS). The resultant formulation, ME(INS)-PiP-Alb exhibited droplet size of 3.35 ± 0.25 μm along with polydispersity index (PDI) of 0.30 ± 0.10. The formulation process employed for developing ME(INS)-PiP-Alb showed no effect on INS's chemical and conformational stability. Further, ME(INS)-PiP-Alb was able to maintain desired attributes (size & PDI) along with INS stability in simulated gastrointestinal fluids. Also, ME(INS)-PiP-Alb rendered higher protection to INS in presence of pepsin and trypsin than ME(INS)-PiP. In qualitative Caco-2 cell uptake, INS loaded ME's showed higher uptake in comparison to free INS. Whereas, in permeability studies ME(INS)-PiP-Alb showed ~4 and ~1.5-fold enhanced permeation than free INS and ME(INS) without PiP groups respectively. Also, in ex vivo intestinal permeation studies similar fold increment in permeation were observed. Interestingly, the pharmacodynamic studies revealed ~3.2-fold higher hypoglycemic effect in animals treated with ME(INS)-PiP-Alb in comparison to ME(INS)-PiP. Similarly, the pharmacokinetic studies also revealed ~1.6 fold higher AUC for ME(INS)-PiP-Alb than ME(INS)-PiP. Thus, in vivo results suggested that Alb as a stabilizer can assist in improving the hypoglycemic effect of the developed ME with PiP. Hence, this strategy can also be extrapolated for delivering other bio-macromolecules orally.

Topics: Administration, Oral; Albumins; Alkaloids; Animals; Benzodioxoles; Blood Glucose; Caco-2 Cells; Drug Stability; Emulsions; Goats; Humans; Hypoglycemic Agents; Insulin; Male; Particle Size; Piperidines; Polyunsaturated Alkamides; Rats

Widely accessible food phytochemicals such as curcumin have been reported to have anti-inflammatory and anticarcinogenic properties. However, curcumin has poor absorption in the gut, and piperine has been of interest as a dietary compound that can enhance curcumin bioavailability. The aim of this study was to develop and optimize a technique using reversed-phase chromatography with multi-wavelength detection for the simultaneous measurement of curcumin and piperine in various biological matrices. Emodin was used as an internal standard. Protein precipitation and liquid-liquid extraction based on acetonitrile provided good recovery of these analytes. A 150 mm × 4.6 mm I.D. Luna C18 column was used under isocratic conditions to separate curcumin, piperine, and emodin with baseline resolution, and with good separation from other sample components, in as little as 4 min. The detection limits for curcumin and piperine were 3 and 7 ng/mL, respectively. This method has been used to quantitate these compounds in samples such as human intestinal epithelial cell lysates and mouse plasma or GI tissues in research aimed at examining the bioavailability of curcumin in the presence of piperine.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Curcumin; Emodin; Humans; Limit of Detection; Linear Models; Male; Mice; Piperidines; Polyunsaturated Alkamides; Reproducibility of Results

Rhipicephalus microplus is responsible for high economic losses in livestock and its control has become difficult due to the establishment of tick populations resistant to commercial acaricides. This study aimed to evaluate the in vitro larvicidal effect of the alkaloids berberine and piperine, and also to investigate their inhibitory mechanisms against the acetylcholinesterase enzyme. The effects of the alkaloids on larvae were observed through the immersion test at the following concentrations: 1.5; 3; 6; 12; 16 and 24 mM. Berberine and piperine presented larvicidal activity greater than 95 %, not differing from 100 % for the positive fipronil control (p > 0.05). Of the two alkaloids, piperine had a lower effective concentration (EC), with an EC

Topics: Acaricides; Alkaloids; Animals; Benzodioxoles; Berberine Alkaloids; Cholinesterase Inhibitors; Computer Simulation; Larva; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Rhipicephalus; Tick Control

Amyloidosis is the process of fibril formation responsible for causing several diseases in the human being that involve protein aggregation such as Alzheimer's, Parkinson's, Huntington's disease, and type II diabetes. Natural phytocompounds such as curcumin shown promising anti-amyloidogenic activity. In the present study, selective phytocompounds such as piperine, cinnamaldehyde, eugenol, and cuminaldehyde present in Piper nigrum L, Cinnamomum zeylanicum Blume, Eugenia caryophyllus Thumb, and Cuminum cyminum L, respectively were analyzed for anti-amyloidogenic activity using hen egg white-lysozyme (HEWL) as a model system. Out of the selected phytocompounds, piperine showed the most significant anti-amyloidogenic activity, as evident from in vitro assays that were validated by in silico molecular docking study. Piperine showed 64.7 ± 3.74% inhibition of amyloid formation at 50 μM concentration, as observed by Thioflavin T assay. Subsequently, the anti-amyloidogenic activity of piperine was further validated by congo red, intrinsic fluorescence assay, and transmission electron microscopy analysis. The in silico molecular binding interaction showed piperine with the highest docking score and glide energy. Piperine was found to be interacting with amyloidogenic region residues and Trp62, the most important residue involved in the amyloidogenesis process. In conclusion, piperine can be used as a positive lead for a potential therapeutic role in targeting diseases involved amyloidogenesis.

Topics: Acrolein; Alkaloids; Amyloidogenic Proteins; Animals; Benzaldehydes; Benzodioxoles; Benzothiazoles; Binding Sites; Chickens; Cymenes; Eugenol; Fluorescent Dyes; Humans; Molecular Docking Simulation; Muramidase; Phytochemicals; Piperidines; Polyunsaturated Alkamides; Protective Agents; Protein Aggregates; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Spectrometry, Fluorescence

Nasopharyngeal cancer is a malignancy developing from the nasopharynx epithelium due to smoking and nitrosamine-containing foods. Nasopharyngeal cancer is highly endemic to Southeast Asia. Eugenol and piperine have shown many anticancer activities on numerous cancer types, like colon, lung, liver, and breast cancer. In this study, we amalgamated eugenol and piperine loaded with a polyhydroxy butyrate/polyethylene glycol nanocomposite (Eu-Pi/PHB-PEG-NC) for better anticancer results against nasopharyngeal cancer (C666-1) cells. In the current study, nasopharyngeal cancer cell lines C666-1 were utilized to appraise the cytotoxic potential of Eug-Pip-PEG-NC on cell propagation, programmed cell death, and relocation. Eu-Pi/PHB-PEG-NC inhibits cellular proliferation on C666-1 cells in a dose-dependent manner, and when compared with 20 µg/ml, 15 µg/ml of loaded mixture evidently restrained the passage aptitude of C666-1 cells, this was attended with a downregulated expression of mitochondrial membrane potential. Treatment with 15 µg/ml Eu-Pi/PHB-PEG-NC suggestively amplified cell apoptosis in the C666-1 cells. Furthermore, its cleaved caspase-3, 8, and 9 and Bax gene expression was augmented and Bcl-2 gene expression was diminished after Eu-Pi/PHB-PEG-NC treatment. Additionally, our data established that the collective effect of Eu-Pi/PHB-PEG-NC loaded micelles inhibited the expansion of C666-1 cells augmented apoptosis connected with the intrusion of PI3K/Akt/mTOR signaling pathway.

Topics: Alkaloids; Apoptosis; Benzodioxoles; Cell Line, Tumor; Drug Carriers; Elafin; Eugenol; Humans; Nanocomposites; Nasopharyngeal Neoplasms; Piperidines; Polyethylene Glycols; Polyhydroxyalkanoates; Polyunsaturated Alkamides; Prohibitins; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Herbals that are widely consumed as therapeutic alternatives to conventional drugs for cardiovascular diseases, may lead to herb-drug interactions (HDIs). Atorvastatin (ATR) is drug of choice for hyperlipidemia and is extensively metabolized through CYP3A4 enzyme. Thus, we postulate that concomitant administration of ATR with piperine (PIP, potent inhibitor of CYP3A4 enzyme)/ridayarishta (RID, cardiotonic herbal formulations containing PIP) may lead to potential HDI. A simple, accurate, sensitive high-performance liquid chromatography-photodiode array detection method using Kromasil-100 C18 column, mobile phase acetonitrile: 30 mM phosphate buffer (55:45 v/v) pH 4.5 with flow rate gradient programming was developed to study the potential HDI in rats. Method was found to be linear (2-100 ng/mL) with Lower Limit of Detection (LLOD) 2 ng/mL. The precision (%CV < 15%), accuracy (-1.0 to -10% R.E) with recoveries above 90% from rat plasma of ATR and IS were obtained. The pharmacokinetic (PK) interactions studies on co-administration of ATR (8.4 mg/kg, p.o.) with PIP (35 mg/kg, p.o.), demonstrated a threefold increase in Cmax of ATR (P < 0.01) with significant increase in AUC0-t/AUC0-∞ compared to ATR alone indicating potential PK-HDI. However co-administration of RID (4.2 mL/kg, p.o.) showed less significant changes (P > 0.05) indicating low HDI. The pharmacodynamic effects/interactions study (TritonX-100 induced hyperlipidemic model in rats) suggested no significant alterations in the lipid profile on co-administration of PIP/RID with ATR, indicating that there may be no significant pharmacodynamic interactions.

Topics: Alkaloids; Animals; Atorvastatin; Benzodioxoles; Chromatography, High Pressure Liquid; Herb-Drug Interactions; Limit of Detection; Linear Models; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Rats; Rats, Wistar; Reproducibility of Results

Natural piperine from black pepper is known to function as hypocholesterolemic agent, but how it lowers the blood cholesterol remains unclear. In this study, we found that intragastric administrations of piperine (25 mg/kg/day) for 8 weeks significantly reduced the plasma triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in high-fat diet (HFD)-fed mice. H&E staining indicated that piperine significantly decreased hepatic lipid accumulation compared with the control group. The Oil Red O staining further showed that piperine attenuated lipid deposition in liver HepG2 cells in a concentration-dependent manner. Mechanistically, piperine treatment caused a significant upregulation of hepatic scavenger receptor B1 (SR-B1) in the liver and transporter protein of ATP binding cassette SGM8 (ABCG8) in the small intestine. Taken together, our findings demonstrate the role of natural piperine in improving lipid metabolic profile that is involved in the reverse cholesterol transport (RCT)-mediated mechanism through upregulation of SR-B1 in the liver and ABCG8 in the small intestine.

Topics: Alkaloids; Animals; Anticholesteremic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 8; Benzodioxoles; Biological Transport; Diet, High-Fat; Hep G2 Cells; Humans; Intestine, Small; Lipids; Lipoproteins; Liver; Male; Metabolome; Mice; Mice, Inbred ICR; Piperidines; Polyunsaturated Alkamides; Scavenger Receptors, Class B; Up-Regulation

This study examined effect of berberine and piperine on neuroprotective potential of neostigmine in the management of neurological disorders.. Berberine and neostigmine were weighed (30 g), dissolved in distilled water (30 mL) separately, while, 30 mg piperine was dissolved in ethanol (0.45 mL), made up to 30 mL with distilled water. Antioxidant activities in 2, 2-diphenyl-1-picrylhydrazyl radical (DPPH), 2, 2-azinobis (3-ethylbenzothiazoline-6-sulfonate) radical (ABTS), Fe-chelation, ferric reducing properties (FRAP), nitric oxide (NO) and hydroxyl (OH) radical scavenging abilities and Fe. The result revealed that tested compounds inhibited enzymes activities dose-dependently. However, berberine (IC. Both alkaloids demonstrated antiradical scavenging ability comparable to neostigmine action against Alzheimer's disease (AD). The modulatory and antioxidant berberine and piperine properties on these enzymes (AChE, BChE and MAO) could be possible underlying mechanisms in employing these compounds as a complementary therapy in neurodegenerative diseases (NDDs) management.

Topics: Acetylcholinesterase; Alkaloids; Antioxidants; Benzodioxoles; Berberine; Butyrylcholinesterase; Cholinesterase Inhibitors; Neostigmine; Piperidines; Plant Extracts; Polyunsaturated Alkamides

α-Amylase and α-glucosidase are important therapeutic targets for the management of type 2 diabetes mellitus. The inhibition of these enzymes decreases postprandial hyperglycemia. In the present study, compounds found in commercially available herbs and spices were tested for their ability to inhibit α-amylase and α-glucosidase. These compounds were acetyleugenol, apigenin, cinnamic acid, eriodictyol, myrcene, piperine, and rosmarinic acid.. The enzyme inhibitory nature of the compounds was evaluated using in silico docking analysis with Maestro software and was further confirmed by in vitro α-amylase and α-glucosidase biochemical assays.. The relationships between the in silico and in vitro results were well correlated; a more negative docking score was associated with a higher in vitro inhibitory activity. There was no significant (P > .05) difference between the inhibition constant (K. Several of the herbal compounds studied could regulate postprandial hyperglycemia. Using herbal plants has several advantages including low cost, natural origin, and easy cultivation. These compounds can easily be consumed as teas or as herbs and spices to flavor food.. 背景: α-淀粉酶和α-葡萄糖苷酶是2型糖尿病治疗的重要靶点。抑制这些酶可以降低餐后高血糖。在本研究中, 测试了在市售草药和香料中发现的化合物对α-淀粉酶和α-葡萄糖苷酶的抑制能力。这些化合物是乙酰亮酚、芹菜素、肉桂酸、芥子醇、月桂烯、胡椒碱和迷迭香酸。 方法: 用Maestro软件进行电子对接分析, 并通过体外α-淀粉酶和α-葡萄糖苷酶生化测定进一步证实化合物的抑酶活性。 结果: 体内和体外结果之间有很好的相关性；对接得分越低, 体外抑制活性越高。广泛应用的α-葡萄糖苷酶和α-淀粉酶抑制剂阿卡波糖与芹菜素、芥子醇和胡椒碱的抑制常数(Ki)值无显著性差异(P>0.05)。对于α-淀粉酶, 阿卡波糖的Ki值与芹菜素、肉桂酸、迷迭香酸无显著差异(P>0.05)。另外采用了硫代罗丹明B(SRB)比色法检测中药复方对C2C12和HepG2细胞活力的影响。乙酰亮酚、肉桂酸、月桂烯、胡椒碱和迷迭香酸的IC50值与阿卡波糖相似(P>0.05)。 结论: 所研究的几种中草药化合物具有调节餐后高血糖的作用。使用中草药植物具有成本低、来源天然、易于栽培等优点。这些化合物可以很容易地作为茶或草药和香料食用并为食物调味。.

Topics: Acarbose; Alkaloids; alpha-Amylases; alpha-Glucosidases; Apigenin; Benzodioxoles; Chemical Phenomena; Computer Simulation; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Flavanones; Glycoside Hydrolase Inhibitors; Hep G2 Cells; Humans; Hypoglycemic Agents; Molecular Docking Simulation; Piperidines; Plants, Medicinal; Polyunsaturated Alkamides; Spices

Piperine (1-piperoyl piperidine), a major alkaloid constituent of. Healthy human erythrocytes and erythrocytes membrane was stressed with free radical inducer chemical;. The results demonstrate that treatment of erythrocytes with piperine (10. The study concludes that piperine possesses potent anti-oxidant potential which may explain many of its observed biological effects.

Topics: Alkaloids; Benzodioxoles; Erythrocytes; Humans; Oxidative Stress; Piperidines; Polyunsaturated Alkamides

Multidrug resistance (MDR) is the main challenge in the treatment of chronic myeloid leukemia (CML), and P-glycoprotein (P-gp) overexpression is an important mechanism involved in this resistance process. However, some compounds can selectively affect MDR cells, inducing collateral sensitivity (CS), which may be dependent on P-gp. The aim of this study was to investigate the effect of piperine, a phytochemical from black pepper, on CS induction in CML MDR cells, and the mechanisms involved. The results indicate that piperine induced CS, being more cytotoxic to K562-derived MDR cells (Lucena-1 and FEPS) than to K562, the parental CML cell. CS was confirmed by analysis of cell metabolic activity and viability, cell morphology and apoptosis. P-gp was partially required for CS induction. To investigate a P-gp independent mechanism, we analyzed the possibility that poly (ADP-ribose) polymerase-1 (PARP-1) could be involved in piperine cytotoxic effects. It was previously shown that only MDR FEPS cells present a high level of 24 kDa fragment of PARP-1, which could protect these cells against cell death. In the present study, piperine was able to decrease the 24 kDa fragment of PARP-1 in MDR FEPS cells. We conclude that piperine targets selectively MDR cells, inducing CS, through a mechanism that might be dependent or not on P-gp.

Topics: Alkaloids; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; Benzodioxoles; Cell Survival; Cytochrome P-450 Enzyme Inhibitors; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Piperidines; Polyunsaturated Alkamides

Piperine, the major pharmacological ingredient of pepper, can delay the procession of "obesity to diabetes". However, the underlying mechanism remains unclear. This study aims to investigate whether piperine protects against β-cell dysfunction by inhibiting macrophage accumulation and M. Pre-diabetic model was induced by feeding 60% high-fat diet (HFD) in C57BL/6C mice, piperine (15 or 30 mg/kg/day) and rosiglitazone (4 mg/kg/day) were given orally for 8 weeks. Oral glucose tolerance test (OGTT), insulin tolerance test (ITT), fasting blood glucose (FBG), total cholesterol (TC) and triglyceride (TG) were used to assay the disorder of glycolipid metabolism. Serum levels of cytokines and insulin were measured by Elisa. Hyperglycemic clamp assay was carried out to evaluate β-cell function. RT-PCR, immunofluorescence and western blot were used to detect the expression of biomarkers associated with macrophage polarization and β-cell dedifferentiation.. Piperine markedly ameliorates the dedifferentiation and dysfunction of β-cell by inhibiting the accumulation and M

Topics: Adipose Tissue; Alkaloids; Animals; Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Inflammation; Insulin-Secreting Cells; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Piperidines; Polyunsaturated Alkamides

Celecoxib (CXB), a selective COX-2 inhibitor NSAID, has exhibited prominent anti-proliferative potential against numerous cancers. However, its low bioavailability and long term exposure related cardiovascular side effects, limit its clinical application. In order to overcome these limitations, natural bioactive compounds with lower toxicity profile are used in combination with therapeutic drugs. Therfore, in this study Piperine (PIP), a natural chemo-preventive agent possessing drug bioavailability enhancing properties, was considered to be used in combination with low doses of CXB.. We hypothesized that the combination of PIP with CXB will have a synergistic anti-proliferative effect on colon cancer cells.. The potency of PIP and CXB alone and in combination was evaluated in HT-29 human colon adenocarcinoma cells and mechanism of growth inhibition was investigated by analyzing the players in apoptotic and Wnt/β-catenin signaling pathways.. The effect of PIP on the oral bioavailability of CXB in mice was investigated using HPLC analysis. The study investigated the synergistic anti-proliferative effect of CXB and PIP on HT-29 cells and IEC-6 non-tumorigenic rat intestinal epithelial cells by SRB cell viability assay. Further, the cellular and molecular mechanism(s) involved in the anti-proliferative combinatorial effect was extensively explored in HT-29 cells by flow cytometry and western blotting. The in vivo efficacy of this combination was studied in CT26.WT tumor syngeneic Balb/c mice model.. PIP as a bioenhancer increased the oral bioavailability of CXB (129%). The IC50 of CXB and PIP were evaluated to select doses for combination treatment of HT-29 cells. The drug combinations having combination index (CI) less than 1 were screened using CompuSyn software. These combinations were significantly cytotoxic to HT-29 cells but IEC-6 were least effected. Further, the mechanism behind CXB and PIP mediated cell death was explored. The co-treatment led to reactive oxygen species generation, mitochondrial dysfunction, caspase activation and enhanced apoptosis in HT-29 cells. Additionally, the combination treatment synergistically modulated Wnt/β-catenin pathway, downregulated the stemness markers and boosted therapeutic response in CT26 syngeneic Balb/c mice.. The outcomes of the study suggests that combining CXB and PIP offers a novel approach for the treatment of colon cancer.

Topics: Alkaloids; Animals; Antineoplastic Agents; Apoptosis; Benzodioxoles; beta Catenin; Celecoxib; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colonic Neoplasms; Cyclooxygenase 2 Inhibitors; Drug Synergism; Humans; Mice; Piperidines; Polyunsaturated Alkamides; Rats; Wnt Signaling Pathway

Human Cytochrome P450 2J2 (CYP2J2) as an important metabolic enzyme, plays a crucial role in metabolism of polyunsaturated fatty acids (PUFAs). Elevated levels of CYP2J2 have been associated with various types of cancer, and therefore it serves as a potential drug target. Herein, using a high-throughput screening approach based on enzymic activity of CYP2J2, we rapidly and effectively identified a novel natural inhibitor (Piperine,

Topics: Alkaloids; Benzodioxoles; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Development; High-Throughput Screening Assays; Humans; Models, Molecular; Molecular Structure; Piperidines; Polyunsaturated Alkamides; Recombinant Proteins; Structure-Activity Relationship

A set of 12 analogues of piperine was designed, replacing the amide functional group of the molecule with different aliphatic and aromatic ester functional groups. Molecular docking studies of these molecules with FDA-approved target proteins for anti-bacterial drugs were done. The binding energy of the proteins and the ligands were low and the analogues were found to be drug-like based on the ADME results; hence, the molecules were synthesized. The synthesized compounds were tested for their anti-bacterial property against six bacterial species via Agar well-diffusion method. Acinetobacter baumannii, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus epidermidis were the strains tested. The overall susceptibility is higher in gram-positive. The analogues showed better activity than piperine. The analogues, propyl piperic ester (P3) and 2-fluorophenyl piperic ester (P9) and 4-fluorophenyl piperic ester (P10) showed comparatively bigger inhibition zones for all the strains.

Topics: Alkaloids; Anti-Bacterial Agents; Benzodioxoles; Fatty Acids, Unsaturated; Humans; Microbial Sensitivity Tests; Microbial Viability; Molecular Docking Simulation; Molecular Structure; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship

Black pepper (Piper nigrum L.) is the world's most popular spice and is also used as an ingredient in traditional medicine. Its pungent perception is due to the interaction of its major compound, piperine (1-piperoyl-piperidine) with the human TRPV-1 or vanilloid receptor. We now identify the hitherto concealed enzymatic formation of piperine from piperoyl coenzyme A and piperidine based on a differential RNA-Seq approach from developing black pepper fruits. This enzyme is described as piperine synthase (piperoyl-CoA:piperidine piperoyl transferase) and is a member of the BAHD-type of acyltransferases encoded by a gene that is preferentially expressed in immature fruits. A second BAHD-type enzyme, also highly expressed in immature black pepper fruits, has a rather promiscuous substrate specificity, combining diverse CoA-esters with aliphatic and aromatic amines with similar efficiencies, and was termed piperamide synthase. Recombinant piperine and piperamide synthases are members of a small gene family in black pepper. They can be used to facilitate the microbial production of a broad range of medicinally relevant aliphatic and aromatic piperamides based on a wide array of CoA-donors and amine-derived acceptors, offering widespread applications.

Topics: Acyltransferases; Alkaloids; Benzodioxoles; Piper nigrum; Piperidines; Plant Proteins; Polyunsaturated Alkamides

A pair of stereoisomers of new 4,5-dihydroxypiperine was isolated from P. retrofractum and showed profound activity on AlCl

Topics: Alkaloids; Aluminum Chloride; Animals; Behavior Therapy; Benzodioxoles; Dementia; Dose-Response Relationship, Drug; Molecular Structure; Piperaceae; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship; Zebrafish

A series of novel piperine derivatives were synthesized with high yield and were evaluated for its antifilarial potential against the bovine filarial parasite Setaria cervi. Among 21 (3a-3u) compounds screened, three of them (3k, 3l, 3s) showed significant potential against all the developmental stages (oocytes, microfilariae and adult) of the filarial worm in time and dose dependent manner. 3l showed the highest efficacy among the selected three compounds. These three compounds were further evaluated for both in vitro and in vivo toxicity analyses which further fortified the benign nature of the selected compounds. The antifilarial activities they exhibited were clearly fuelled through disparity of the internal redox homeostasis as evidenced from the alterations in the enzymatic and non-enzymatic antioxidants level which ultimately shifted towards activation of pro-apoptotic signaling cascade eventually leading to the death of the parasites. The ability of the compound 3l to bind thioredoxin reductase and CED-3 protein are the key findings of this study. The present study supported with several biological experiments is therefore a maiden report on the antifilarial effectiveness of these novel piperine derivatives.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Cattle; Homeostasis; Oxidation-Reduction; Piperidines; Polyunsaturated Alkamides; Setaria Nematode

Piperine is an alkaloid that has extensive pharmacological activity and impacts other active substances bioavailability due to inhibition of CYP450 enzymes, stimulation of amino acid transporters and

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Alkaloids; Animals; Benzodioxoles; Blood-Brain Barrier; Calorimetry, Differential Scanning; Humans; Piperidines; Polyunsaturated Alkamides; Solubility; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction

Our goal was to examine the anticancer effects of piperine against the resistant human ovarian cancer cells and to explore the molecular mechanisms responsible for its anticancer effects. Our study used drug-sensitive ovarian cancer cell line W1 and its sublines resistant to paclitaxel (PAC) and topotecan (TOP). We analyzed the cytotoxic effect of piperine and cytostatic drugs using an MTT assay. The impact of piperine on protein expression was determined by immunofluorescence and Western blot. We also examined its effect on cell proliferation and migration. We noticed a different level of piperine resistance between cell lines. Piperine increases the cytotoxic effect of PAC and TOP in drug-resistant cells. We observed an increase in PTPRK expression correlated with decreased pTYR level after piperine treatment and downregulation of P-gp and BCRP expression. We also noted a decrease in COL3A1 and TGFBI expression in investigated cell lines and increased COL3A1 expression in media from W1PR2 cells. The expression of Ki67 protein and cell proliferation rate decreased after piperine treatment. Piperine markedly inhibited W1TR cell migration. Piperine can be considered a potential anticancer agent that can increase chemotherapy effectiveness in cancer patients.

Topics: Aldehyde Dehydrogenase 1 Family; Alkaloids; Antineoplastic Agents; Benzodioxoles; Cell Line, Tumor; Cell Survival; Collagen Type III; Drug Resistance, Neoplasm; Extracellular Matrix Proteins; Female; Humans; Ovarian Neoplasms; Paclitaxel; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Retinal Dehydrogenase; Transforming Growth Factor beta

The valuable aroma compound piperonal with its vanilla-like olfactory properties is of high interest for the fragrance and flavor industry. A lipoxygenase (LOX

Topics: Aldehydes; Alkaloids; Benzaldehydes; Benzodioxoles; Lipoxygenase; Molecular Structure; Oxidation-Reduction; Piperidines; Pleurotus; Polyunsaturated Alkamides

The present research work is designed to prepare and evaluate piperine liposomes and piperine-chitosan-coated liposomes for oral delivery. Piperine (PPN) is a water-insoluble bioactive compound used for different diseases. The prepared formulations were evaluated for physicochemical study, mucoadhesive study, permeation study and in vitro cytotoxic study using the MCF7 breast cancer cell line. Piperine-loaded liposomes (PLF) were prepared by the thin-film evaporation method. The selected liposomes were coated with chitosan (PLFC) by electrostatic deposition to enhance the mucoadhesive property and in vitro therapeutic efficacy. Based on the findings of the study, the prepared PPN liposomes (PLF3) and chitosan coated PPN liposomes (PLF3C1) showed a nanometric size range of 165.7 ± 7.4 to 243.4 ± 7.5, a narrow polydispersity index (>0.3) and zeta potential (-7.1 to 29.8 mV). The average encapsulation efficiency was found to be between 60 and 80% for all prepared formulations. The drug release and permeation study profile showed biphasic release behavior and enhanced PPN permeation. The in vitro antioxidant study results showed a comparable antioxidant activity with pure PPN. The anticancer study depicted that the cell viability assay of tested PLF3C2 has significantly (

Topics: Alkaloids; Antineoplastic Agents; Antioxidants; Benzodioxoles; Cell Adhesion; Cell Survival; Chitosan; Drug Carriers; Drug Delivery Systems; Drug Liberation; Humans; In Vitro Techniques; Inhibitory Concentration 50; Liposomes; MCF-7 Cells; Microscopy, Electron, Transmission; Particle Size; Permeability; Piperidines; Polyunsaturated Alkamides; Spectroscopy, Fourier Transform Infrared

Although the etiology of sciatica remains uncertain, there is increasing evidence that the disease process of sciatica is associated with the levels of inflammatory factors. Piperine, an alkaloid isolated from Piper nigrum, has previously been demonstrated to inhibit inflammation and analgesic effects. The purpose of this study is to verify the regulatory relationship between miR-520a and p65 and to explore how miR-520a/P65 affects the level of cytokines under the action of piperine, so as to play a therapeutic role in sciatica. Through ELISA experiment, we confirmed that four inflammatory factors (IL-1β, TNF-α, IL-10, TGF-β1) can be used as evaluation indexes of sciatica. The differentially expressed miRNA was screened as miR-520a, by microarray technology, and the downstream target of miR-520a was P65 by bioinformatics. Real-time fluorescence quantitative PCR confirmed that the expression of miR-520a was negatively correlated with pro-inflammatory cytokines, positively correlated with anti-inflammatory cytokines and negatively correlated with p65 expression at mRNA level. The expression of p65 was positively correlated with pro-inflammatory cytokines and negatively correlated with anti-inflammatory cytokines at the protein level verified by ELISA and Western blot. HE staining analysis showed that the nerve fibers were repaired by piprine, the vacuoles were significantly reduced, and the degree of nerve fiber damage was also improved. Immunohistochemical analysis showed that the expression of p65 decreased after administration of piperine. Dual-luciferase reporter gene assay confirmed that the luciferase signal decreased significantly after cotransfection of miR-520a mimics and p65 3'UTR recombinant plasmid. To sum up, in the rat model of non-compressed lumbar disc herniation, piperine plays a significant role in analgesia. MiR-520a can specifically and directly target P65, and piperine can promote the expression of miR-520a, then inhibit the expression of p65, down-regulate the pro-inflammatory factors IL-1β and TNF-α, and up-regulate the effects of anti-inflammatory factors IL-10 and TGF-β1, so as to treat sciatica.

Topics: Alkaloids; Animals; Benzodioxoles; Inflammation; MicroRNAs; Piperidines; Polyunsaturated Alkamides; Rats; Sciatica

Divya-Swasari-Vati is a calcium containing polyherbal ayurvedic medicine prescribed for the lung-related ailments observed in the current pandemic of Severe Acute Respiratory Syndrome Coronavirus 2 infections. The formulation is a unique quintessential blend of nine herbs cited in Ayurvedic texts for chronic cough and lung infection. Analytical standardization of herbal medicines is the pressing need of the hour to ascertain the quality compliance. This persuaded us to develop a simple, rapid, and selective high-performance thin-layer chromatographic method for Divya-Swasari-Vati quality standardization. The developed method was validated for the quantification of marker components, gallic acid, cinnamic acid, piperine, eugenol and glycyrrhizin, against reference standards in five different batches of Divya-Swasari-Vati. The analytes were identified by visualization at 254 nm, and by matching their retention factor with authentic standards. The developed method was validated as per the guidelines recommended by the International Council for Harmonization for parameters like, linearity, limit of detection, limit of quantification, accuracy, and precision. Therefore, the developed novel high-performance thin-layer chromatographic process could be employed for rapid standardization of Divya-Swasari-Vati and other related herbal formulation, which would aid in quality manufacturing and product development.

Topics: Alkaloids; Benzodioxoles; Chromatography, Thin Layer; Cinnamates; Eugenol; Gallic Acid; Glycyrrhizic Acid; Humans; Lung Diseases; Medicine, Ayurvedic; Molecular Structure; Piperidines; Plant Extracts; Plants, Medicinal; Polyunsaturated Alkamides

The objective of this paper is to confine piperine, a poor oral bioavailable herbal drug into bile salt based nano vesicles for improving its aqueous solubility, hence, its therapeutic activity. Piperine-loaded bilosomes were fabricated adopting thin film hydration technique according to 3

Topics: Administration, Oral; Alkaloids; Animals; Antiviral Agents; Benzodioxoles; Bile Acids and Salts; Biological Availability; Cytochrome P-450 Enzyme Inhibitors; Drug Delivery Systems; Drug Liberation; Liposomes; Mice; Middle East Respiratory Syndrome Coronavirus; Molecular Docking Simulation; Nanostructures; Piperidines; Plants, Medicinal; Polyunsaturated Alkamides; Surface-Active Agents

The insect chitinase

Topics: Alkaloids; Animals; Benzodioxoles; Chitinases; Moths; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Plant-derived natural medicines have been extensively studied for anti-inflammatory or antioxidant properties, but challenges to their clinical use include low bioavailability, poor solubility in water, and difficult-to-control release kinetics. Nanomedicine may offer innovative solutions that can enhance the therapeutic activity and control release kinetics of these agents, opening the way to translating them into the clinic. Two agents of particular interest are rutin (Ru), a flavonoid, and piperine (Pip), an alkaloid, which exhibit a range of pharmacological activities that include antioxidant and anti-inflammatory effects. In this work, nanoformulations were developed consisting of two metal-organic frameworks (MOFs) with surface modifications, Ti-MOF and Zr-MOF, each of them loaded with Ru and/or Pip. Both MOFs and nanoformulations were characterized and evaluated

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Antioxidants; Benzodioxoles; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Carriers; Drug Combinations; Drug Liberation; Hydrogen-Ion Concentration; Male; Metal-Organic Frameworks; Nanoparticles; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Rutin

COVID-19 is now pandemic throughout the world, and scientists are searching for effective therapies to prevent or treat the disease. The combination of curcumin and piperine is a potential option for the management of COVID-19 based on several mechanisms including antiviral, anti-inflammatory, immunomodulatory, antifibrotic, and antioxidant effects. Here, we describe the probable mechanism of curcumin-piperine against COVID-19. Administration of curcumin-piperine combination appears as a potential strategy to counterbalance the pathophysiological features of COVID-19 including inflammation. The optimal dose and duration of curcumin-piperine supplementation should be determined in the future.

Topics: Alkaloids; Benzodioxoles; COVID-19; Curcumin; Humans; Piperidines; Polyunsaturated Alkamides; SARS-CoV-2

Ischemic stroke (IS) is a rapidly increasing global burden and is associated with severe neurological decline and mortality. There is urgent requirement of the efforts, aimed to identify therapeutic strategies that are effective in clinic to promote significant recovery from IS. Studies have shown that mitochondria mediated neuroprotection can be a competent target against ischemic damage. Therefore, we examined whether mitochondrial impairment is regulated by Piperine (PIP), an alkaloid of Piper Longum, which has neuroprotective activity against ischemic brain injury. In this study, transient middle cerebral artery occlusion (tMCAO) surgery was performed on male Wistar rats for 90 min followed by 22.5 h of reperfusion for mimicking the IS condition. This study consisted of three groups: sham, tMCAO and tMCAO + PIP (10 mg/kg b.wt., p.o/day for 15 days), and studied for behavioral tests, infarct volume, brain pathological changes, mitochondrial dysfunction, inflammation alongwith cell survival status. PIP pre-treatment showed reduction in neurological alterations and infarct volume. In addition, PIP pre-treatment suppressed the mitochondrial dysfunction and might have anti-apoptotic potential by preventing Cytochrome c (Cyt c) release from mitochondria to cytoplasm and caspase 3 activation. It also regulates pro-apoptotic, Bax and anti-apoptotic, Bcl-2 proteins accompanied by glial fibrillary acidic protein (GFAP) positive cells in cortex region. Quantitative Reverse transcription-polymerase chain reaction (qRT-PCR) results also showed that PIP reduced the expression of pro-inflammatory protein, interleukin-1 β (IL-1β) and enhanced cell survival by restoring the activity of brain derived neurotrophic factor (BDNF) and its transcription protein, cAMP response element binding protein (CREB). Taken together, PIP reduced the mitochondrial dysfunction, neurological impairment, and enhanced neuronal survival. In conclusion, our findings reinforce PIP as an effective neuroprotective agent and provide important evidence about its role as a potential target to serve as a promising therapy for treatment of IS.

Topics: Alkaloids; Animals; Benzodioxoles; Brain Ischemia; Cell Survival; Cytochrome P-450 Enzyme Inhibitors; Ischemic Stroke; Male; Mitochondria; Neuroprotection; Neuroprotective Agents; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Oral squamous cellular carcinoma (OSCC) is considered a life-threatening disease with detection in late stages, which forces us to opt for dangerous treatment with a combination of chemotherapy and radiotherapy. Herbal components such as piperine and quercetin are derived from edible sources, proving their anticancer potential against oral cancer cells in vitro. Encapsulation into lipid matrix-mediated nanostructured lipid carriers (NLCs) can make both drugs bio-accessible. NLCs were synthesised using the high shear homogenisation method and characterised for their physicochemical properties, followed by in vitro cellular evaluation in FaDu oral cancer cells. NLCs showed negatively charged particles smaller than 180 nm with a polydispersity index (PDI) of <0.3. Both drugs were found to encapsulate sufficiently, with >85% entrapment efficiency and an improved drug release profile compared to their pristine counterparts. Differential scanning calorimetry (DSC) thermograms showed conversion into an amorphous matrix in lyophilized NLCs, which was supported by X-ray diffraction (XRD) analysis. The cytotoxicity assay showed the IC

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Drug Liberation; Drug Screening Assays, Antitumor; Fatty Acids; Humans; Membrane Potential, Mitochondrial; Mouth Neoplasms; Nanoparticle Drug Delivery System; Nanostructures; Particle Size; Piperidines; Polyunsaturated Alkamides; Quercetin; Rats; Squamous Cell Carcinoma of Head and Neck; Tissue Distribution

Inflammation, demyelination, glial activation, and oxidative damage are the most pathological hallmarks of multiple sclerosis (MS). Piperine, a main bioactive alkaloid of black pepper, possesses antioxidant, anti-inflammatory, and neuroprotective properties whose therapeutic potential has been less studied in the experimental autoimmune encephalomyelitis (EAE) models. In this study, the efficiency of piperine on progression of EAE model and myelin repair mechanisms was investigated. EAE was induced in female Lewis rats and piperine and its vehicle were daily administrated intraperitoneally from day 8 to 29 post immunization. We found that piperine alleviated neurological deficits and EAE disease progression. Luxol fast blue and H&E staining and immunostaining of lumbar spinal cord cross sections confirmed that piperine significantly reduced the extent of demyelination, inflammation, immune cell infiltration, microglia, and astrocyte activation. Gene expression analysis in lumbar spinal cord showed that piperine treatment decreased the level of pro-inflammatory cytokines (TNF-α, IL-1β) and iNOS and enhanced IL-10, Nrf2, HO-1, and MBP expressions. Piperine supplementation also enhanced the total antioxidant capacity (FRAP) and reduced the level of oxidative stress marker (MDA) in the CNS of EAE rats. Finally, we found that piperine has anti-apoptotic and neuroprotective effect in EAE through reducing caspase-3 (apoptosis marker) and enhancing BDNF and NeuN expressing cells. This study strongly indicates that piperine has a beneficial effect on the EAE progression and could be considered as a potential therapeutic target for MS treatment. Upcoming clinical trials will provide a deeper understanding of piperine's role for the treatment of the MS.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Astrocytes; Benzodioxoles; Caspase 3; Cytokines; Disease Progression; Drug Evaluation, Preclinical; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Expression Regulation; Microglia; Nerve Tissue Proteins; Neuroprotective Agents; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Random Allocation; Rats; Rats, Inbred Lew

Parkinson's disease (PD) is a neurodegenerative disorder caused by selective dopaminergic neuronal loss. Rotenone is a neurotoxin that selectively destroys dopaminergic neurons, leading to PD-like symptoms. Quercetin possesses antioxidant, anti-inflammatory, and neuroprotective properties but a major drawback is its low bioavailability. Therefore, the present study was designed to evaluate the neuroprotective effect of quercetin in combination with piperine against rotenone- and iron supplement-induced model of PD. Rotenone was administered at a dose of 1.5 mg/kg through an intraperitoneal route with iron supplement at a dose of 120 μg/g in diet from day 1 to day 28. Pre-treatment with quercetin (25 and 50 mg/kg, p.o.), piperine (2.5 mg/kg, p.o.) alone, quercetin (25 mg/kg, p.o.) in combination with piperine (2.5 mg/kg), and ropinirole (0.5 mg/kg, i.p.) was administered for 28 days 1 h prior to rotenone and iron supplement administration. All behavioral parameters were assessed on weekly basis. On the 29th day, all animals were sacrificed and striatum was isolated for biochemical (LPO, nitrite, GSH, mitochondrial complexes I and IV), neuroinflammatory (TNF-α, IL-1β, and IL-6), and neurotransmitter (dopamine, norepinephrine, serotonin, GABA, glutamate) estimation. Quercetin treatment attenuated rotenone- and iron supplement-induced motor deficits and biochemical and neurotransmitter alterations in experimental rats. However, combination of quercetin (25 mg/kg) with piperine (2.5 mg/kg) significantly enhanced its neuroprotective effect as compared with treatment with quercetin alone. The study concluded that combination of quercetin with piperine contributed to superior antioxidant, anti-inflammatory, and neuroprotective effect against rotenone- and iron supplement-induced PD in experimental rats.

Topics: Alkaloids; Benzodioxoles; Corpus Striatum; Dietary Supplements; Drug Synergism; Electron Transport Complex I; Electron Transport Complex IV; Glutathione; Indoles; Interleukin-1beta; Interleukin-6; Iron; Lipid Peroxidation; Neuroprotective Agents; Neurotransmitter Agents; Nitrites; Parkinson Disease, Secondary; Piperidines; Polyunsaturated Alkamides; Quercetin; Rotenone; Tumor Necrosis Factor-alpha

A simple, rapid method of the detection of piperine in black pepper is reported using a voltammetric sensor based on a glassy carbon (GC) electrode with analysis following a short one-step extraction using ethanol. The method is based on a novel potential sweep designed to maximise signal sizes and shown with context of the present analytical challenge to be essential for gathering data allowing the construction of a linear calibration curve for the analysis in the relevant range namely 0.25-5.0 mM.

Topics: Alkaloids; Benzodioxoles; Calibration; Carbon; Electrochemical Techniques; Electrodes; Food Analysis; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Aging-related cholinergic dysfunction, extensive neuroinflammation and oxidative stress in brain are predominant pathogenic factors for dementia. In the present study, we aimed to evaluate the protective effects of piperine, an alkaloid nutrient component of Piper nigrum, against cognitive impairment in a senescent mouse model induced by D-galactose (D-Gal) and to explore the underlying mechanisms. Senescent mouse model was established by repeated subcutaneous injection of D-Gal (150 mg/kg, once daily for 42 days). Fourteen days after the first D-Gal exposure, piperine (2.5, 5, 10 mg/kg) or vehicle was intraperitoneally administered once daily for 28 days. The cognitive function of mice was evaluated by Morris water maze test (MWM). Twenty-four hours after behavioral test, the cholinergic function and oxidative stress level in mouse hippocampus were measured by spectrophotometric assays. In addition, the hippocampal levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1β and interleukin-6, were quantified using enzyme-linked immunosorbent assay. Expressions of glycogen synthase kinase-3β (GSK-3β) and its upstream or downstream molecules including phosphatidylinositol 3-kinase (PI3K)，protein kinase B (AKT), protein kinase C (PKC), NF-E2-related factor 2, nuclear factor-κB and microtubule-associated protein tau in hippocampus were determined by western blotting, immunohistochemical or immunofluorescent staining. Our data revealed that chronic D-Gal exposure in mice led to cognitive impairment in MWM, along with cholinergic malfunction, extensive oxidative stress and neuroinflammation, as well as hyperphosphorylation of tau protein in hippocampus. All these neurochemical, neuroinflammatory and cognitive alterations could be ameliorated by 4-week repeated piperine administration. Moreover, piperine also reversed D-Gal-induced GSK-3β activation through modulating PKC and PI3K/AKT pathways in senescent mouse hippocampus, suggesting GSK-3β-related signaling might be involved in the benefits of piperine against D-Gal-induced cognitive decline in mice.

Topics: Aging; Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Cellular Senescence; Cognition; Cognition Disorders; Cytokines; Galactose; Glutathione; Glycogen Synthase Kinase 3 beta; Hippocampus; Inflammation; Lipid Peroxidation; Male; Maze Learning; Mice; Models, Animal; Neurons; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Protein Kinase C; Reactive Oxygen Species; Signal Transduction

Piperine has been associated with neuroprotective effects and monoamine oxidase (MAO) inhibition, thus being an attractive scaffold to develop new antiparkinsonian agents. Accordingly, we prepared a small library of piperine derivatives and screened the inhibitory activities towards human MAO isoforms (hMAO-A and hMAO-B). Structure-activity relationship (SAR) studies pointed out that the combination of α-cyano and benzyl ester groups increased both potency and selectivity towards hMAO-B. Kinetic experiments with compounds 7, 10 and 15 indicated a competitive hMAO-B inhibition mechanism. Compounds 15 and 16, at 10 μM, caused a small but significant decrease in P-gp efflux activity in Caco-2 cells. Compound 15 stands out as the most potent piperine-based hMAO-B inhibitor (IC

Topics: Alkaloids; Benzodioxoles; Caco-2 Cells; Cell Differentiation; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Humans; Ligands; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship; Tumor Cells, Cultured

Microdialysis has been the only direct method of continuously measuring the unbound drug concentrations in extracellular fluid at a specific brain region with respect to time in the same animal. However, not every compound is suitable for microdialysis system as demonstrated by their inconsistent "by gain" and "by loss" in-vitro microdialysis probe recoveries leading to over- or under- estimated in-vivo concentrations. Therefore, our current study was proposed aiming to develop simple exclusion criteria for drug candidates that are not suitable for microdialysis system investigation. Through literature research, the properties ((LogP, pKa, water solubility and unbound fraction in plasma and brain) of drugs that have been reported for microdialysis studies were summarized. The exclusion criteria were developed by evaluating the impact of such properties on the consistency of in-vitro "by gain" and "by loss" recoveries of microdialysis probe. As a result, forty-five compounds were identified from literatures, among which doxorubicin, docetaxel, omeprazole, donepezil and phenytoin were found to have inconsistent in-vitro "by gain" and "by loss" microdialysis probe recoveries and subsequently selected for the exclusion criteria analysis. It was found that compounds with limited water solubility (less than 1 g/L) and unbound fraction in plasma (f

Topics: Alkaloids; Animals; Benzamidines; Benzodioxoles; Brain; Carbamazepine; Central Nervous System Agents; Extracellular Fluid; Male; Microdialysis; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley

Systemic lupus erythematosus (SLE) is a chronic multi-system inflammatory disease associated with autoantibody formation. Clinical management of lupus is associated with multiple adverse events. Resveratrol is a phytoalexin with several pharmacological properties. This study aimed to evaluate the combinatorial effect of resveratrol (25 mg/kg and 50 mg/kg) and its bio-enhancer piperine (1/10th dose of resveratrol) on pristane-induced SLE murine model. Mice were injected with 0.5 ml of pristane and after 2 months they were orally dosed with resveratrol combinations for 4 months. Determined by indirect immunofluorescence, resveratrol was unable to abrogate autoantibody formation. The increased IFN-α, IL-6 and TNF-α was mitigated by low dose of resveratrol and piperine (RP-1). None of the doses regulated the increase in nitric oxide. Lipogranulomas associated with injected pristane were not observed after RP-1 and high dose of resveratrol (Res-2) treatment. Lupus mice witnessed IgG and IgM immune complexes by direct immunofluorescence assay and associated histopathological observations in kidneys, liver, lung, spleen and skin. None of the treatment regimens were able to regulate the manifestations observed in spleen and skin. RP-1 and Res-2 proved beneficial in kidney, liver and lungs and were able to ameliorate lupus associated manifestations. Renal manifestations (proteinuria and decreased creatinine in urine) were successfully mitigated by RP-1 and Res-2 and high dose combination of resveratrol and piperine. Oxidative stress (reactive oxygen species by flowcytometry and catalase, superoxide dismutase, glutathione peroxidase, reduced glutathione and lipid peroxidation by biochemical analysis) was evident by pristane injection. These were regulated by different doses of resveratrol alone and in combination with piperine. Hence, resveratrol when used in combination with piperine successfully reduces some measures of morbidity with little or no effect on mortality associated with lupus.

Topics: Alkaloids; Animals; Autoantibodies; Benzodioxoles; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Lupus Erythematosus, Systemic; Mice; Mice, Inbred BALB C; Piperidines; Polyunsaturated Alkamides; Resveratrol; Terpenes; Treatment Outcome

Alzheimer's disease (AD) is a complex neurological disorder with contributions from genetic and environmental factors. High-resolution metabolomics (HRM) has the potential to identify novel endogenous and environmental factors involved in AD. Previous metabolomics studies have identified circulating metabolites linked to AD, but lack of replication and inconsistent diagnostic algorithms have hindered the generalizability of these findings. Here we applied HRM to identify plasma metabolic and environmental factors associated with AD in two study samples, with cerebrospinal fluid (CSF) biomarkers of AD incorporated to achieve high diagnostic accuracy.. Liquid chromatography-mass spectrometry (LC-MS)-based HRM was used to identify plasma and CSF metabolites associated with AD diagnosis and CSF AD biomarkers in two studies of prevalent AD (Study 1: 43 AD cases, 45 mild cognitive impairment [MCI] cases, 41 controls; Study 2: 50 AD cases, 18 controls). AD-associated metabolites were identified using a metabolome-wide association study (MWAS) framework.. An MWAS meta-analysis identified three non-medication AD-associated metabolites in plasma, including elevated levels of glutamine and an unknown halogenated compound and lower levels of piperine, a dietary alkaloid. The non-medication metabolites were correlated with CSF AD biomarkers, and glutamine and the unknown halogenated compound were also detected in CSF. Furthermore, in Study 1, the unknown compound and piperine were altered in MCI patients in the same direction as AD dementia.. In plasma, AD was reproducibly associated with elevated levels of glutamine and a halogen-containing compound and reduced levels of piperine. These findings provide further evidence that exposures and behavior may modify AD risks.

Topics: Aged; Aged, 80 and over; Alkaloids; Alzheimer Disease; Benzodioxoles; Biomarkers; Chromatography, Liquid; Cognitive Dysfunction; Female; Glutamine; Humans; Male; Mass Spectrometry; Metabolome; Metabolomics; Middle Aged; Piperidines; Polyunsaturated Alkamides

Topics: Alkaloids; Animals; Benzodioxoles; Biological Products; Culex; Dose-Response Relationship, Drug; Hydrazines; Insecticides; Molecular Structure; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship

Black pepper (Piper nigrum L.) is known for its high content of piperine, a cinnamoyl amide derivative regarded as largely responsible for the pungent taste of this widely used spice. Despite its long history and worldwide use, the biosynthesis of piperine and related amides has been enigmatic up to now. In this report we describe a specific piperic acid CoA ligase from immature green fruits of P. nigrum. The corresponding enzyme was cloned and functionally expressed in E. coli. The recombinant enzyme displays a high specificity for piperic acid and does not accept the structurally related feruperic acid characterized by a similar C-2 extension of the general C6-C3 phenylpropanoid structure. The enzyme is also inactive with the standard set of hydroxycinnamic acids tested including caffeic acid, 4-coumaric acid, ferulic acid, and sinapic acid. Substrate specificity is corroborated by in silico modelling that suggests a perfect fit for the substrate piperic acid to the active site of the piperic acid CoA ligase. The CoA ligase gene shows its highest expression levels in immature green fruits, is also expressed in leaves and flowers, but not in roots. Virus-induced gene silencing provided some preliminary indications that the production of piperoyl-CoA is required for the biosynthesis of piperine in black pepper fruits.

Topics: Alkaloids; Benzodioxoles; Coenzyme A Ligases; Fruit; Gene Silencing; Piper nigrum; Piperidines; Plant Proteins; Polyunsaturated Alkamides

Breast cancer has become a worldwide threat, and chemotherapy remains a routine treatment. Patients are forced to receive continuous chemotherapy and suffer from severe side effects and poor prognosis. Natural alkaloids, such as piperine (PP) and piperlongumine (PL), are expected to become a new strategy against breast cancer due to their reliable anticancer potential. In the present study, cell viability, flow cytometry, and Western blot assays were performed to evaluate the suppression effect of PP and PL, alone or in combination. Data showed that PP and PL synergistically inhibited breast cancer cells proliferation at lower doses, while only weak killing effect was observed in normal breast cells, indicating a good selectivity. Furthermore, apoptosis and STAT3 signaling pathway-associated protein levels were analyzed. We demonstrated that PP and PL in combination inhibit STAT3 phosphorylation and regulate downstream molecules to induce apoptosis in breast cancer cells. Taken together, these results revealed that inactivation of STAT3 was a novel mechanism with treatment of PP and PL, suggesting that combination application of natural alkaloids may be a potential strategy for prevention and therapy of breast cancer.

Topics: Alkaloids; Apoptosis; Benzodioxoles; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dioxolanes; Female; Humans; MCF-7 Cells; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Signal Transduction; STAT3 Transcription Factor

Mast cells play an important role in inflammatory and allergic diseases. MAS-related G protein-coupled receptor X2 (MRGPRX2) is a novel G protein-coupled receptor in mast cells that mediates drug-induced anaphylactoid reactions. Piperine has been reported to have anti-inflammatory and anti-allergic pharmacological activities. However, whether the pharmacological effects are regulated by MRGPRX2 has not yet been reported. The purpose of this study was to assess the anti-anaphylactoid effect of Piperine and to explore its potential mechanism. The anti-anaphylactoid effect of Piperine was assessed by an in vivo mouse hindpaw extravasation model. Mast cell intracellular calcium mobilization was measured by a calcium imaging assay. An enzyme immunoassay was used to evaluate the release of pro-inflammatory factors from stimulated mast cells. Activated mast cell related signals were assessed by western blot. A cell membrane chromatography assay was used to determine the binding characteristics of Piperine and MRGPRX2. The results showed that Piperine suppressed mast cell intracellular Ca

Topics: Alkaloids; Anaphylaxis; Animals; Benzodioxoles; Disease Models, Animal; Humans; Male; Mast Cells; Mice; Piperidines; Polyunsaturated Alkamides; Receptors, G-Protein-Coupled

Obesity is one of the major risk factor for cardiovascular and metabolic diseases. A disproportional accumulation of fat at visceral (VAT) compared to subcutaneous sites (SAT) has been suspected as a key detrimental event. We used non-targeted metabolomics profiling to reveal metabolic pathways associated with higher VAT or SAT amount among subjects free of metabolic diseases to identify possible contributing metabolic pathways. The study population comprised 491 subjects [mean (standard deviation): age 44.6 yrs (13.0), body mass index 25.4 kg/m² (3.6), 60.1% females] without diabetes, hypertension, dyslipidemia, the metabolic syndrome or impaired renal function. We associated MRI-derived fat amounts with mass spectrometry-derived metabolites in plasma and urine using linear regression models adjusting for major confounders. We tested for sex-specific effects using interactions terms and performed sensitivity analyses for the influence of insulin resistance on the results. VAT and SAT were significantly associated with 155 (101 urine) and 49 (29 urine) metabolites, respectively, of which 45 (27 urine) were common to both. Major metabolic pathways were branched-chain amino acid metabolism (partially independent of insulin resistance), surrogate markers of oxidative stress and gut microbial diversity, and cortisol metabolism. We observed a novel positive association between VAT and plasma levels of the potential pharmacological agent piperine. Sex-specific effects were only a few, e.g. the female-specific association between VAT and O-methylascorbate. In brief, higher VAT was associated with an unfavorable metabolite profile in a sample of healthy, mostly non-obese individuals from the general population and only few sex-specific associations became apparent.

Topics: Adipose Tissue; Adult; Alkaloids; Ascorbic Acid; Benzodioxoles; Biomarkers; Cross-Sectional Studies; Female; Humans; Hydrocortisone; Insulin Resistance; Intra-Abdominal Fat; Magnetic Resonance Imaging; Male; Metabolic Networks and Pathways; Metabolome; Middle Aged; Organ Size; Piperidines; Polyunsaturated Alkamides; Sex Factors; Subcutaneous Fat

Piperine (Pip) has been widely studied for its multiple activities such as antidepressant, anti-epileptic, and so forth. However, the poor water solubility coupled with low bioavailability may inevitably hinder the application of Pip in the clinical setting. In this study, a formulation strategy was proposed to spontaneously resolve the low bioavailability and dose dividing issue of Pip. The matrix pellets (Pip-SR-pellets) consisting of Pip solid dispersion (Pip-SD) and hydroxypropylmethyl cellulose-K100 were developed to achieve an increased and sustained release profile

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biological Availability; Delayed-Action Preparations; Dogs; Drug Compounding; Drug Liberation; Drug Stability; Excipients; Male; Piperidines; Polyunsaturated Alkamides; Solubility; Surface Properties; Tablets

Piperine, a major alkaloid of the fruit of black pepper plants, selectively inhibits the growth of triple-negative breast cancer cells but its lipophilicity restricts possible clinical application. This study therefore determined the feasibility of encapsulating piperine in nanoparticles (NPs) to increase its solubility in an aqueous environment.. Piperine-loaded biodegradable methoxy poly(ethylene glycol)-poly(lactic-co-glycolic) acid copolymer-based NPs were produced by single emulsion solvent extraction and thin-film hydration. Growth and viability of triple-negative breast cancer (TNBC) cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Annexin-V-FLUOS/propidium iodide staining, respectively.. Thin-film hydration was superior to single emulsion solvent extraction, yielding piperine-loaded NPs with an average size of 50 nm. Piperine-loaded NPs inhibited TNBC cell growth and induced apoptosis while sparing normal fibroblasts.. It is feasible to deliver a cytotoxic concentration of piperine to TNBC cells via NPs with the potential for improved bioavailability and solubility in biological fluids.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Apoptosis; Benzodioxoles; Cell Line, Tumor; Emulsions; Female; Humans; Nanoparticles; Piperidines; Polyesters; Polyethylene Glycols; Polyunsaturated Alkamides; Triple Negative Breast Neoplasms

Day to day consumption of black pepper raise concern about the detailed information about their medicinal, pharmaceutical values and knowledge about the biocompatibility with respect to ecosystem. This study investigates the in vivo selective molecular biocompatibility of its seed cover (SC) and seed core (SP) powder extract using embryonic zebrafish model. Gas chromatography mass spectrometry (GCMS) analysis of the extract prepared by grinding showed presence of different components with "piperine" as principle component. Biocompatibility analysis showed dose and time dependent selective effect of SC and SP with LC50 of 30.4 μg/ml and 35.6 μg/ml, respectively on survivability, hatching and heartbeat rate in embryonic zebrafish. Mechanistic investigation elucidated it as effect of accumulation and internalization of black pepper leading to their influence on structure and function of cellular proteins hatching enzyme (he1a), superoxide dismutase (sod1) and tumor protein (tp53) responsible for delayed hatching, oxidative stress induction and apoptosis. The study provided insight to selective biocompatibility of black pepper expedient to produce higher quality spices with respect to pharmaceutical, clinical and environmental aspects.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Oxidative Stress; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Seeds; Superoxide Dismutase; Tumor Suppressor Protein p53; Zebrafish; Zebrafish Proteins

In recent days, reported researches demonstrated that encapsulation of natural hydrophobic drug molecules (Piperine) into the biodegradable polymer system with nanoformulations opens a novel prospect in bio-nanomedicine field. Generally, the nanostructured materials embedded with the drug molecules could render enhanced efficiency in therapies. Piperine is a chief alkaloid compound of natural black pepper exhibits excellent anti-convulsant efficiency in the anti-epileptic treatment. Nonetheless, the poor water solubility of the piperine molecules has some difficulties in drug delivery and clinical applications. Herein we report the synthesis of Copper oxide quantum dots coated Hyaluronic acid (HA)/ Poly(lactic-co-glycolic acid) (PLGA) with for the effective delivery of piperine in the targeted drug delivery for epilepsy treatment. The physicochemical characterization was performed using the as prepared material. The crystal structure, surface morphology and the elemental composition were investigated from XRD, SEM, TEM and EDX analyses respectively. The surface morphology clearly stated the loading of CuO QDs loaded HA/PLGA microspheres. The capping of the polymer matrix was also studied using FTIR analysis. A Photoluminescence spectrum is also recorded. This study was illustrating that Piperine loaded CuQDs@HA/PLGA nanostructures exhibit improved neuroprotection and encourage the activation of astrocytes in chemical kindling model of epilepsy. This proposed material could be a novel and effective therapeutic platform for the targeted drug delivery systems.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Cell Line; Cell Survival; Copper; Drug Delivery Systems; Drug Design; Drug Liberation; Epilepsy; Humans; Luminescence; Male; Pentylenetetrazole; Piperidines; Polylactic Acid-Polyglycolic Acid Copolymer; Polyunsaturated Alkamides; Quantum Dots; Rats, Wistar

Kelch-like ECH-associated protein (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) protein-protein interaction has become an important drug target for the treatment of Alzheimer's disease. In this study, we found a novel piperine derivative (HJ22) synthesized by our group with great ability to bind to Keap-1 and activate Keap1-Nrf2-ARE signaling pathway in vitro, driving us to investigate the beneficial effects of HJ22 on ibotenic acid (IBO)-induced neurological disorders in rats and underlying mechanisms. Interestingly, HJ22 significantly ameliorated IBO-induced cognitive impairment in Morris water maze, Y-maze and passive avoidance tests. Moreover, HJ22 significantly attenuated cholinergic dysfunction and neuronal morphological changes via inhibiting apoptotic cell death induced by IBO. Notably, HJ22 inhibited the interaction between Keap1 and Nrf2, and subsequently up-regulated nuclear Nrf2 expression, thereby inhibiting oxidative stress and Thioredoxin-interacting protein (TXNIP)-mediated Nod-like receptor protein 3 (NLRP3) inflammasome activation. These findings demonstrated that HJ22 exhibited potent therapeutic effects against IBO-induced cognitive impairment by alleviating cholinergic damage, oxidative stress, apoptosis and neuroinflammation, which might be partly attributed to its inhibitory activity on Keap1-Nrf2 protein-protein interaction.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Cells, Cultured; Cognitive Dysfunction; Disease Models, Animal; Humans; Ibotenic Acid; Inflammasomes; Inflammation; Kelch-Like ECH-Associated Protein 1; Neurons; NF-E2-Related Factor 2; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Protein Binding; Protein Interaction Domains and Motifs; Rats; Rats, Sprague-Dawley

Piperine is an alkaloid naturally found in black pepper with a myriad of pharmacological attributes. Piperine's most far reaching indication is drug absorption enhancment, with supportive data regarding its ability to inhibit first pass effect mechanisms. However, alongside these findings, the role of piperine as an absorption enhancer is undermined with publications stating an apparent effect of a metabolic inducer. The aim of this work is to investigate the effect of repeated administration of piperine in a lipid-based formulation ,on oral absorption of cannabidiol (CBD), compared to acute piperine dosing. The effect of piperine on CBD absorption was determined pre-clinically in the freely moving rat model. Results of this work demonstrated that there was no significant difference in piperine's effect, when given chronically or in a single dose regimen. Both groups resulted in approximate 2.5-fold increase in oral bioavailability of CBD compared to control group without piperine.

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biological Availability; Cannabidiol; Male; Oral Mucosal Absorption; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Curcumin (CUR) is a natural polyphenol present in the rhizomes of Curcuma longa and possesses diverse pharmacological effects, especially anti-carcinogenic effects against several types of cancers. Unfortunately, this novel compound has poor aqueous solubility and bioavailability that limit its pharmaceutical effects. The use of polymeric nanocapsules has been applied in order to overcome such problems. Thus, our present study aimed at developing two novel polymeric nanoparticles (NPs) systems that encapsulate either curcumin alone (CURN) or with piperine (CURPN), which acts as a glucuronidation inhibitor and increases the bioavailability of CUR. The NPs were successfully designed by self-assembled nanoprecipitation method and their characteristics were identified by Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM), Dynamic Light Scattering (DLS), and Zeta potential analysis. The drug release profiles of NPs were monitored under different pH, and their cytotoxic effects were assessed in vitro against Caco-2 cells and in vivo against dimethylhydrazine-induced colon cancer in mice. The FTIR and XRD analyses and SEM images showed amorphous and spherical shaped CURN and CURPN of 80-100 nm sized diameter. In vitro drug release study showed that pH triggered the maximum release of CUR in basic medium compared to acidic and neutral media, and following Higuchi model. CUR nanoencapsulation enhanced its physiochemical properties and drug loading and release. In vitro and in vivo studies showed that CUR NPs exerted selective and potential cytotoxic effects against colon cancer cells. The addition of piperine facilitated the encapsulation and drug loading of CUR. Thus, CUR nanoencapsulation enhanced the solubility and bioavailability of curcumin rendering it more effective against colon cancer.

Topics: Alkaloids; Animals; Antineoplastic Agents; Benzodioxoles; Caco-2 Cells; Colonic Neoplasms; Curcumin; Female; Humans; Mice; Mice, Inbred BALB C; Nanocapsules; Piperidines; Polyamines; Polyunsaturated Alkamides

This research evaluated a feed additive (benzoic acid, eugenol, thymol, and piperine), associated or not with colistin, in weaned piglets feeding. The parameters evaluated were growth performance, apparent total tract digestibility (ATTD) of nutrients, diarrhea incidence, intestinal morphology, relative weights of digestive organs, microbial diversity, and the percentages of operational taxonomic units of microorganisms in the cecum content of pigs. One-hundred and eight crossbred piglets (5.3 ± 0.5 kg) were used in a three-phase feeding program (21 to 35, 36 to 50, 51 to 65 d of age) and fed a control diet with no inclusion of growth promoter feed additive, a diet with 40 ppm of colistin, a diet with 0.3% of alternative additive, and a diet with 0.3% of alternative additive and 40 ppm of colistin. The diets were based on corn, soybean meal, dairy products, and spray-dried blood plasma and formulated to provide 3.40, 3.38, and 3.20 Mcal of ME/kg and 14.5, 13.3, and 10.9 g/kg of digestible lysine, in phases 1, 2, and 3, respectively. The piglets were housed three per pen, with nine replicates per diet, in a complete randomized block design based on initial BW. The data were submitted to ANOVA and means were separated by Tukey test (5%), using SAS. Pigs fed diets with the alternative feed additive had greater (P < 0.05) ADG (114.3 vs. 91.8 g) and ADFI (190.1 vs. 163.3 g) in phase 1 than pigs fed diets without the product. The alternative additive improved (P < 0.05) ATTD of crude protein (CP) in phase 1 (71.0% vs. 68.6%), gross energy in phases 1 (77.4% vs. 75.2%) and 3 (79.0% vs. 77.1%), and dry matter in phase 3 (79.1% vs. 77.1%). The antibiotic inclusion in the diets increased (P < 0.05) ATTD of CP in phase 1 (71.5% vs. 68.2%). The alternative feed additive tended (P = 0.06) to increase (46%) normal feces frequency, decreased (P < 0.05) goblet cells count (104.3 vs. 118.1) in the jejunum, and decreased (P < 0.05) small intestine (4.60% vs. 4.93%) and colon (1.41% vs. 1.65%) relative weights, compared with pigs not fed with the alternative additive. There was a tendency (P = 0.09) for a lower concentration of Escherichia-Shigella (1.46% vs. 3.5%) and lower (P < 0.05) percentage of Campylobacter (0.52% vs. 10.21%) in the cecum content of piglets fed diets containing essential oils and benzoic acid compared with pigs fed diets without the alternative feed additive. The alternative feed additive was effective in improving growth performance, diets digestibil

Topics: Alkaloids; Animal Feed; Animals; Benzodioxoles; Benzoic Acid; Diet; Digestion; Energy Metabolism; Eugenol; Food Additives; Gastrointestinal Microbiome; Gastrointestinal Tract; Glycine max; Male; Nutrients; Oils, Volatile; Piperidines; Polyunsaturated Alkamides; Swine; Thymol; Weaning; Zea mays

The practical difficulty of parenteral application of fish vaccines against devastating fish diseases diverted the interest toward oral vaccination. Search for effective methods to enhance the oral uptake of viral and bacterial vaccines is continuing. The current research focus on a new role of mucosal fish vaccine adjuvants inducing the antigen uptake by enhancing vascularity or increasing intestinal permeability. Some inflammatory substances cause reversible pathology to the intestinal epithelium, which could be employed for the transepithelial passage of vaccine particles. The natural inflammatory substances used were capsaicin, piperine, and okadaic acid as 1 mg, 2 mg, and 1 μg/fish, respectively. Two inactivated vaccines were used as antigens to test the effect of these inflammatory substances in two different fish hosts. Tested vaccines were inactivated redspotted grouper nervous necrosis virus vaccine in sevenband grouper (Epinephelus septemfasciatus) and inactivated Edwardsiella tarda vaccine in red sea bream (Pagrus major) fish models. The inflammatory substances and each vaccine were anally intubated to fish. Capsaicin proved to be effectively aiding the transepithelial passage of vaccine particles more than piperine, while okadaic acid had no detectable effect.

Topics: Adjuvants, Immunologic; Administration, Oral; Alkaloids; Animals; Bacterial Vaccines; Benzodioxoles; Biological Transport; Capsaicin; Fish Diseases; Okadaic Acid; Piperidines; Polyunsaturated Alkamides; Sea Bream; Viral Vaccines

The plant extract piperine is used as a traditional Chinese medicine due to its anti‑inflammatory effects and efficacy against numerous types of cancer. The aim of the present study was to investigate the antitumor mechanism of piperine in human osteosarcoma U2OS and 143B cell lines. The effects of piperine on cell apoptosis and invasion of human osteosarcoma cells were assessed using flow cytometry and Transwell assays. Moreover, western blotting was used to measure the effects of piperine on the protein expression levels of the metastasis markers matrix metalloproteinase‑2 (MMP‑2) and vascular endothelial growth factor (VEGF). In addition, the involvement of the Wnt/β‑catenin signaling pathway in modulating the effects of piperine was examined via western blot analysis. The results of MTT and Transwell invasion assays indicated that piperine treatment dose‑dependently reduced U2OS and 143B cell viability and invasion. Furthermore, a significant reduction was identified in MMP‑2, VEGF, glycogen synthase kinase‑3β and β‑catenin protein expression levels, as well as the expression levels of their target proteins cyclooxygenase‑2, cyclin D1 and c‑myc, in U2OS cells after piperine treatment. In addition, similar results were observed in 143B cells. Therefore, the present study demonstrated the efficacy of piperine in osteosarcoma, and identified that the Wnt/β‑catenin signaling pathway may modulate the antitumor effects of piperine on human U2OS and 143B cells.

Topics: Alkaloids; Antineoplastic Agents; Apoptosis; Benzodioxoles; beta Catenin; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin D1; Cyclooxygenase 2; Flow Cytometry; Glycogen Synthase Kinases; Humans; Matrix Metalloproteinase 2; Neoplasm Invasiveness; Osteosarcoma; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-myc; Vascular Endothelial Growth Factor A; Wnt Signaling Pathway

We still do not have effective treatment for hippocampal demyelination and memory deficit, the two common comorbidities in multiple sclerosis (MS). This study aimed to assess the therapeutic effect of Piperine (the main alkaloid of black pepper) in an experimental model of demyelination.. Demyelination was induced in male Wistar rats by bilateral injection of lysolecithin (LPC) into the CA1 region of the hippocampus. Piperine (5, 10, 20 mg/kg) was daily injected intraperitoneally three days post LPC injection for ten days. The spatial memory was examined by the Morris water maze task. Demyelination and astrocyte activation were assessed by an immunohistological study. The gene expression analysis of TNF-α, IL1-β, NF-κB, IL-10, Foxp3, iNOS, Nrf2, HO1, MBP, and BDNF was done using qPCR. The total antioxidant capacity of hippocampal tissue was measured using FRAP assay.. Our results showed that piperine improved the memory performance and myelin repair in the hippocampal demyelination model. Piperine inhibited iNOS expression concomitant with enhanced expression levels of Nrf2, HO1 and the total antioxidant capacity in the hippocampal tissue. Piperine treatment significantly reduced the gene expression level of TNF-α, IL1-β, NF-κB, and glial activation in the injured area; however, the mRNA level of IL-10, Foxp3, BDNF and MBP were significantly increased.. We found piperine to be an effective treatment for spatial memory impairment and myelin repair in the hippocampal demyelination model. However, further experimental evidence is needed to investigate the precise mechanisms underlying piperine as a promising therapeutic target in MS patients.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Cytokines; Demyelinating Diseases; Gene Expression Regulation; Hippocampus; Lysophosphatidylcholines; Male; Maze Learning; Memory Disorders; Models, Animal; Myelin Sheath; Neuroprotective Agents; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Spatial Memory

Multiple sclerosis (MS) is the most popular chronic and debilitating inflammatory disease of the central nervous system (CNS) that remains incurable. Dihydroorotate dehydrogenase (DHODH) is critical to the activity of T lymphocytes and represents a potential therapeutic target for MS. Here we identify piperine, a bioactive constituent of black pepper, as a potent inhibitor of DHODH with an IC

Topics: Alkaloids; Animals; Benzodioxoles; Biological Products; Blood-Brain Barrier; Crystallography, X-Ray; Dihydroorotate Dehydrogenase; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Female; Humans; Jurkat Cells; Mice, Inbred C57BL; Models, Molecular; Molecular Targeted Therapy; Myelin Sheath; Myelin-Oligodendrocyte Glycoprotein; Oxidoreductases Acting on CH-CH Group Donors; Peptide Fragments; Piperidines; Polyunsaturated Alkamides; Spleen

In recent years, piperine has attracted much attention due to its various biological effects as a neuroprotective agent. Therefore, clarification of the possible side effects of piperine is important to identify its potential pharmacological action. Thus, the effects of piperine on the long-term plasticity of perforant pathway to dentate gyrus synapses were studied in hippocampus of an animal model of Alzheimer's disease (AD). Adult male rats were injected with intracerebroventricular (ICV) streptozotocin (STZ) bilaterally, on days 1 and 3 (3 mg/kg). The STZ-injected rats were treated with different doses of piperine for 4 weeks before being used in behavioral, electrophysiological and histopathological experiments. The passive-avoidance test was conducted on all animals in order to determine the cognitive performance. Rats were placed in a stereotaxic frame to implant a recording electrode in the hippocampal dentate gyrus and a stimulating electrode in the perforant path. Additionally, we assessed the density of survived neurons stained by cresyl violet. In this study, chronic administration of piperine low dose improved the ICV-STZ induced learning and long-term potentiation (LTP) impairments with no significant effect on baseline synaptic activity. In contrast, remarkable learning and long-term plasticity impairments were observed in rats treated by high dose of piperine in comparison to the other groups. Interestingly, this impaired hippocampal LTP was accompanied by an obvious alteration in baseline activity and significantly decreased neuronal numbers within the hippocampus. Therefore, our data provides a new understanding of the piperine supplementation effects on hippocampal electrophysiological profile although the consequences may be either beneficial or detrimental.

Topics: Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Disease Models, Animal; Hippocampus; Long-Term Potentiation; Male; Memory; Memory Disorders; Neuronal Plasticity; Neuroprotective Agents; Neurotoxicity Syndromes; Piperidines; Polyunsaturated Alkamides; Rats, Wistar; Streptozocin; Time Factors

Quercetin and piperine are often used as an add-on therapy for various diseases, however both drug exhibits poor aqueous solubility and photosensitivity issue. Therefore, the aim of the present study is to improve the pharmaceutical challenges by incorporating both the drugs in nanostructured lipid carriers (NLCs) and to develop a sensitive, selective, accurate and precise reverse-phase high performance liquid chromatography (RP-HPLC) method for the simultaneous analysis of both drugs in NLCs. Effective chromatographic separation of quercetin and piperine was achieved on Hypersil gold C-18 column and mobile phase consisting of a mixture of acetonitrile and HPLC grade water (pH 2.6, adjusted with 2%v/v glacial acetic acid) in an isocratic elution mode. The flow rate of the mobile phase was 1 mL/min, column temperature at 35 ± 0.2 °C and the injection volume was 20 μL. The retention time for quercetin and piperine were found to be at 2.80 min and 10.36 min, respectively and detected at an isobestic wavelength of 346 nm using a photodiode array (PDA) detector. The method was found to be specific for the simultaneous analysis of quercetin and piperine in presence of NLCs matrix, accurate (>90%) and precise (%RSD < 2%). The validated RP-HPLC method effectively utilised to determine the percentage drug entrapment efficiency cum percentage drug loading of quercetin and piperine in NLCs enriched formulations along with the secondary estimation of in vitro cumulative percentage drug release study. The results were found to be reliable, hence the validated RP-HPLC method could be further used for the simultaneous detection and quantification of both these drugs in other lipid-based nano-formulations such as solid-lipid nanoparticles, polymer-lipid hybrid nanoparticles, lipid drug conjugates, etc. in in vitro and in vivo.

Topics: Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Drug Carriers; Drug Liberation; Lipids; Nanostructures; Piperidines; Polyunsaturated Alkamides; Quercetin

Topics: Alkaloids; Animals; Apoptosis; Behavior, Animal; Benzodioxoles; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Kelch-Like ECH-Associated Protein 1; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; NF-E2-Related Factor 2; Parkinson Disease; PC12 Cells; Piperidines; Polyunsaturated Alkamides; Rats; Structure-Activity Relationship

Systemic lupus erythematosus is a multisystem autoimmune disease. Apart from usual treatments, approximately 50% of lupus patients use complementary medicine. Resveratrol is a phytoalexin with various pharmacological properties. We hypothesised that prophylactic treatment with resveratrol may abrogate manifestations in pristane-induced murine model of lupus-like disease and piperine; a bio-enhancer of resveratrol may enhance these properties. The prophylactic effect of resveratrol (25 mg/kg body weight: P-Res) alone and in combination with piperine (2.5 mg/kg body weight: P-RP) were assessed. P-Res and P-RP were equally efficient in mitigating oxidative stress (enzyme activity of catalase, superoxide dismutase, glutathione peroxidase and level of reduced glutathione, lipid peroxidation, and reactive oxygen species). Inflammation is associated with an increase in inflammatory cytokines. IL-6 was decreased by 71.60% with P-Res, and TNF-α was reduced by 59.70% with P-Res and 62.66% with P-RP (p < 0.05). Prevention of renal pathologies was evident by reduction in creatinine level by P-RP (p < 0.05) and abrogation of proteinuria (P-Res and P-RP). P-RP was efficient in restoring histopathology of liver and lungs and decreased immune complexes in lungs. P-Res proved more beneficial by extenuating lipogranulomas, histopathological manifestations in kidney, liver, and lungs, and eliminating immune complexes in liver and lungs. None of the treatments could regulate auto-antibody formation. Resveratrol decreases the susceptibility of developing pathogenesis in murine model of lupus-like disease. The results also conclude that addressing the bioavailability of resveratrol using it in combination with piperine does not prove more efficacious in preventing lupus-associated pathologies than resveratrol alone.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Cytokines; Disease Models, Animal; Female; Inflammation; Kidney; Lipid Peroxidation; Liver; Lung; Lupus Erythematosus, Systemic; Mice; Mice, Inbred BALB C; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Resveratrol; Terpenes

Switchable-hydrophilicity solvent liquid-liquid microextraction and dispersive liquid-liquid microextraction were compared for the extraction of piperine from Piper nigrum L. prior to its analysis by using high-performance liquid chromatography with UV detection. Under optimum conditions, limits of detection and quantitation were found as 0.2-0.6 and 0.7-2.0 μg/mg with the two methods, respectively. Calibration graphs showed good linearity with coefficients of determination (R

Topics: Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Cyclohexylamines; Ethylamines; Food Contamination; Hydrophobic and Hydrophilic Interactions; Liquid Phase Microextraction; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Solvents; Spectrophotometry, Ultraviolet; Ultraviolet Rays

Triple-negative breast (TNBC) cancer that is upregulated with epidermal growth factor receptor (EGFR), and devoid of both the hormonal receptors and epidermal growth factor receptor 2 (HER 2), has led to a concept of treating TNBC with EGFR-targeted therapeutics. The combination of paclitaxel (PTX) and piperine (PIP) may improve the bioavailability of paclitaxel for cancer therapy. TPGS (vit E-PEG 1000-succinate)-coated liposomes were prepared with PTX alone or in combination with PIP, and either with (targeted) or without (non-targeted) cetuximab (CTX) conjugation. The Bradford assay indicated that 75% of CTX has been conjugated on the liposomes. The size and percent encapsulation of PTX&PIP co-loaded liposomes were found to be in the range of 204 to 218 nm and 31-73%, respectively. The drug release rate was found to be higher at pH 5.5 in comparison with release at pH 6.4 and pH 7.4. Cellular uptake and toxicity studies on MDA-MB-231 cells showed that PTX&PIP co-loaded targeted liposomes have demonstrated superior uptake and cytotoxicity than their non-targeted counterparts. The IC

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Benzodioxoles; Cell Line, Tumor; Drug Compounding; Drug Stability; Drug Synergism; ErbB Receptors; Female; Freeze Drying; Humans; Liposomes; Paclitaxel; Piperidines; Polyunsaturated Alkamides; Receptor, ErbB-2; Triple Negative Breast Neoplasms

Cancer metastasis is the primary cause of death in patients diagnosed with colorectal cancer. Piperine, an active nontoxic ingredient in pepper, has potent anti-inflammatory and anti-cancer properties. However, little is known about the anti-migratory and anti-invasive effects of piperine on colorectal cancer. We demonstrated piperine inhibited the migration and invasion of colorectal cancer cells. Then, we found piperine reversed the biomarker expression of epithelial-to-mesenchymal transition (EMT), and suppressed the EMT regulator Snail. Furthermore, signal transducers and activators of transcription 3 (STAT3) was downregulated by piperine. Finally, STAT3 inhibitors were applied to observe the role of STAT3 in colorectal cancer migration, invasion and EMT. Collectively, piperine inhibits colorectal cancer migratory and invasive capacities through STAT3/Snail mediated EMT. Therefore, piperine could be applied as a possible therapeutic regimen for the prevention of colorectal cancer metastasis.

Topics: Alkaloids; Benzodioxoles; Cell Line, Tumor; Cell Movement; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Humans; Piperidines; Polyunsaturated Alkamides; Snail Family Transcription Factors; STAT3 Transcription Factor

The current study explored the efficacy of piperine in attenuating arsenic induced high fat diet aggravated oxidative stress mediated injury in hepatic and cardiac tissues of male Wistar rats. Oral administration of piperine significantly (p < 0.05) reduced the levels of organ specific and oxidative stress biomarkers in arsenic and high fat diet treated rat hepatic and cardiac tissues in a dose dependant manner with the dose of 60 mg/kg b.w. exhibiting maximum protection. Arsenic induced high fat diet aggravated oxidative stress mediated damages in liver and heart tissues led to decreased activities of antioxidant enzymes, ROS generation, diminished activities of Krebs' cycle and respiratory chain enzymes, collapsed mitochondrial membrane potential, mitochondrial DNA damage along with altered lipid metabolism and inflammatory cytokine levels. Histochemical and histopathological studies supported the above findings. Piperine efficiently counteracted the arsenic induced high fat diet aggravated oxidative stress mediated damages by modulating antioxidant defense mechanism along with free radical quenching ability. These findings indicate that piperine protected the arsenic induced high fat diet aggravated hepatic and cardiac injuries which underline the importance of piperine in providing a possible therapeutic regime for the amelioration of arsenic-induced high fat diet aggravated oxidative stress mediated organ damages.

Topics: Alkaloids; Animals; Antioxidants; Arsenic; Benzodioxoles; Diet, High-Fat; Heart Injuries; Liver; Male; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Reactive Oxygen Species

The solubility values and thermodynamic parameters of a natural phytomedicine/nutrient piperine (PPN) in Transcutol-HP (THP) + water combinations were determined. The mole fraction solubilities (

Topics: Alkaloids; Benzodioxoles; Ethylene Glycols; Piperidines; Polyunsaturated Alkamides; Solubility; Thermodynamics; Water

Peroxisome proliferator-activated receptor. In the research, we synthesized a series of piperine derivatives and then used a fluorescence polarization-based. A total of 30 piperine derivatives were synthesized and evaluated. Compound

Topics: Alkaloids; Benzodioxoles; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Ligands; Molecular Docking Simulation; Molecular Structure; Piperidines; Polyunsaturated Alkamides; PPAR gamma; Structure-Activity Relationship

Inspired by the remarkable bioactivities exhibited by the natural products, piperine and piperlongumine, we synthesised eight natural product-inspired analogues to further investigate their structures. For the first time, we confirmed the structure of the key cyclised dihydropyrazolecarbothioamide piperine analogues including the use of two-dimensional (2D)

Topics: Alkaloids; Benzodioxoles; Dioxolanes; Humans; Interleukin-1beta; Molecular Docking Simulation; Nuclear Magnetic Resonance, Biomolecular; Piperidines; Polyunsaturated Alkamides; Transcription Factor RelA

Aflatoxins produced by

Topics: Aflatoxins; Alkaloids; Antifungal Agents; Aspergillus; Benzodioxoles; Biosynthetic Pathways; Capsaicin; Capsicum; DNA-Binding Proteins; Fruit; Fungal Proteins; Gene Expression Regulation, Fungal; Genes, Fungal; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Transcription Factors

More than 94% of colorectal cancer cases have mutations in one or more Wnt/β-catenin signaling pathway components. Inactivating mutations in APC or activating mutations in β-catenin (CTNNB1) lead to signaling overactivation and subsequent intestinal hyperplasia. Numerous classes of medicines derived from synthetic or natural small molecules, including alkaloids, have benefited the treatment of different diseases, including cancer, Piperine is a true alkaloid, derived from lysine, responsible for the spicy taste of black pepper (Piper nigrum) and long pepper (Piper longum). Studies have shown that piperine has a wide range of pharmacological properties; however, piperine molecular mechanisms of action are still not fully understood. By using Wnt/β-catenin pathway epistasis experiment we show that piperine inhibits the canonical Wnt pathway induced by overexpression of β-catenin, β-catenin S33A or dnTCF4 VP16, while also suppressing β-catenin nuclear localization in HCT116 cell line. Additionally, piperine impairs cell proliferation and migration in HCT116, SW480 and DLD-1 colorectal tumor cell lines, while not affecting the non-tumoral cell line IEC-6. In summary, piperine inhibits the canonical Wnt signaling pathway and displays anti-cancer effects on colorectal cancer cell lines.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Benzodioxoles; beta Catenin; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; HCT116 Cells; HEK293 Cells; Humans; Piper nigrum; Piperidines; Polyunsaturated Alkamides; TCF Transcription Factors; Wnt Signaling Pathway; Wnt3A Protein

Temozolomide (TMZ) is an alkylating chemotherapy agent used in the clinical treatment of glioblastoma multiforme (GBM) patients. Piperine (PIP) is a naturally occurring pungent nitrogenous substance present in the fruits of peppers. We investigated the anti-cancer efficacies of PIP alone and in combination with TMZ in GBM cellsusingparameters such as cell proliferation, cellular apoptosis,caspase-8/-9/-3 activities, cell cycle kinetics, wound-healing ability, and loss of mitochondrial membrane potential (MMP). Treatment with PIP and alow concentration of PIP-TMZ, inhibited cell growth, similar to TMZ.PIP-TMZ promoted apoptosis by activation of caspase-8/-9/-3, MMP loss, and inhibition of

Topics: Alkaloids; Apoptosis; Benzodioxoles; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Glioma; Humans; Membrane Potential, Mitochondrial; Piperidines; Polyunsaturated Alkamides; Temozolomide

Mastitis, inflammation in the breast, affects breastfeedingwomenin the postpartumperiod. In the present study, we investigated the protective effects of piperine against mastitis using a mouse mastitis model. LPS-induced mastitis was established by injecting LPS into the canals of the mammary gland. Piperine was given intraperitoneally 1 h before and 12 h after LPS treatment. The results showed that the LPS-induced mammary histopathological changes and MPO activity were attenuated by piperine. LPS-induced inflammatory cytokines TNF-α andIL-1β were also inhibited by piperine. Furthermore, LPS-induced NF-κB activation was suppressed by the treatment with piperine. In addition, we found piperine dose-dependently increased the expression of PPARγ. All of these results suggested that piperine had protective effects against LPS-induced mastitis and that the mechanism may be mediated through the activation of PPARγ.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Benzodioxoles; Disease Models, Animal; Female; Humans; Immunohistochemistry; Interleukin-1beta; Lipopolysaccharides; Mammary Glands, Human; Mastitis; Mice; Mice, Inbred BALB C; NF-kappa B; Peroxidase; Piperidines; Polyunsaturated Alkamides; PPAR gamma; Tumor Necrosis Factor-alpha; Up-Regulation

Breast cancer is the leading cause of cancer mortality in women worldwide. Conventional cancer treatment is costly and results in many side effects. Dietary bioactive compounds may be a potential source for breast cancer prevention and treatment. In this scenario, the aim of this study was to investigate the effects of the bioactive compounds resveratrol, curcumin and piperine (R-C-P) on MCF-7 breast cancer cells and to associate them to Glyoxalase 1 (GLO1) activity. The findings indicate that R-C-P exhibits cytotoxicity towards MCF-7 cells. R-C-P decreased mitochondrial membrane potential (ΔΨm) by 1.93-, 2.04- and 1.17-fold, respectively. Glutathione and N-acetylcysteine were able to reverse the cytotoxicity of the assessed bioactive compounds in MCF-7 cells. R-C-P reduced GLO1 activity by 1.36-, 1.92- and 1.31-fold, respectively. R-C-P in the presence of antimycin A led to 1.98-, 1.65- and 2.16-fold decreases in D-lactate levels after 2 h of treatment, respectively. Glyoxal and methylglyoxal presented cytotoxic effects on MCF-7 cells, with IC

Topics: Alkaloids; Benzodioxoles; Breast Neoplasms; Curcumin; Female; Humans; Lactoylglutathione Lyase; MCF-7 Cells; Membrane Potential, Mitochondrial; Piperidines; Polyunsaturated Alkamides; Resveratrol

Myocardial infarction (MI) eventually exacerbates inflammatory response due to the release of inflammatory and pro-inflammatory factors. The aim of this study is to explore the protective efficacy of piperine supplementation against the inflammatory response in isoproterenol (ISO)-induced MI. Masson Trichome staining was executed to determine myocardial tissue architecture. Immunohistochemistry was performed for IL-6, TNF-α. RT-PCR studies were performed to ascertain the gene expression of IL-6, TNF-α, iNOS, eNOS, MMP-2, MMP-9, and collagen-III. Western blotting was performed to determine expression of HIF-1α, VEGF, Nrf-2, NF-ƙB, Cox-2, p-38, phospho-p38, ERK-1/2, phospho-ERK-1/2, and collagen-I. HIF-1α, VEGF, and iNOS expression were significantly upregulated with concomitant decline in eNOS expression in the heart myocardial tissue of rats received ISO alone whereas piperine pretreatment prevented these changes in ISO administered rats. Current results revealed ROS-mediated activation of MAPKs, namely, p-p38, p-ERK1/2 in the heart tissue of ISO administered group. Piperine pretreatment significantly prevented these changes in ISO treated group. NF-κB is involved in the modulation of gene expressions responsible for tissue repair. ISO-induced NF-κB-p65 expression was significantly reduced in the group pretreated with piperine and mitigated extent of myocardial inflammation. A significant increase in cardiac fibrosis upon ISO treatment was reported due to the increased hydroxyproline content, MMP-2 & 9 and upregulation of collagen-I protein compared to control group. All these cardiac hypertrophy markers were decreased in 'piperine pretreated ISO administered group' compared to group received ISO injection. Current findings concluded that piperine as a nutritional intervention could prevent inflammation of myocardium in ISO-induced MI.

Topics: Adrenergic beta-Agonists; Alkaloids; Animals; Benzodioxoles; Cardiomegaly; Cytokines; Endothelium; Fibrosis; Inflammation; Isoproterenol; Male; Myocardial Infarction; Myocardium; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Signal Transduction; Transcription Factor RelA

The combinational therapy is often considered as a desire in chemotherapy despite some limitations. This study aimed to encapsulate two natural-based drugs, curcumin (CUR), and piperine (PIP) into highly biocompatible albumin nanoparticles for anticancer applications.. A simultaneous exertion of CUR and PIP in a biocompatible drug delivery system with the minimum side effects and no limitations was achievable in this work for cancer treatment.. Curcumin and piperine co-loaded human serum albumin nanoparticles (CUR-PIP-HSA-NPs) were synthesized by the self-assembly method. The effectiveness of the codelivery system was evaluated physically, chemically, and pharmaceutically. Moreover, the anticancer activity of CUR-PIP-HSA-NPs was studied on MCF-7 cells by MTT assay.. CUR-PIP-HSA-NPs showed appropriate stability with an average particle size of 154.7 ± 5.2 nm. Loading of drugs was demonstrated by Fourier transform infrared (FT-IR) and differential scanning calorimetry (DSC) analyses. The drug encapsulation efficiencies (DEEs) of CUR and PIP in NPs were 85.3% ± 1.46% and 81.7%, ± 1.67%, respectively. Furthermore, the drug loading efficiency (DLE) of CUR-PIP-HSA-NPs was 8.71% ± 0.24%. The circular dichroism (CD) examination of the NPs confirmed that the conformational structure of albumin remained unchanged during the synthesis. In addition, the cytotoxicity experiments demonstrated the high potential of CUR-PIP-HSA-NPs against breast cancer (MCF-7) cells in the presence of PIP as both bioenhancer and anticancer drug with the capability of suppressing the effect of multidrug resistance (MDR).. The results suggest that CUR-PIP-HSA-NPs can be employed as a practical drug delivery system in cancer treatment with synergistic effects of both CUR and PIP.

Topics: Alkaloids; Benzodioxoles; Curcumin; Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Particle Size; Piperidines; Polyunsaturated Alkamides; Serum Albumin, Human; Spectroscopy, Fourier Transform Infrared

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biological Availability; Caco-2 Cells; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Combinations; Drug Compounding; Drug Liberation; Humans; Microsomes, Liver; Permeability; Piperidines; Polyunsaturated Alkamides; Rats; Solubility; Triterpenes; Ursolic Acid

Piperine, an alkaloid isolated from Piper nigrum L., has been demonstrated to have many pharmacological effects and several health benefits. The aim of this work was to study the metabolic profiles of piperine in mouse, rat, dog and human hepatocytes.. The biotransformation was carried out by incubating piperine with hepatocytes at 37°C. After incubation for 2 h, the samples were pretreated and analyzed using liquid chromatography combined with diode-array detection and high-resolution mass spectrometry (LC/DAD-HRMS). The structures of the metabolites were assigned through a comparison of their accurate masses and product ions with those of the parent compound.. A total of 20 metabolites were detected, and the structures were proposed. Piperine was metabolized through the following pathways: (a) oxidation to form a catechol derivative, which further underwent methylation, glucuronidation, glutathione (GSH) conjugation, and hydroxylation followed by opening of the piperidine ring; (b) hydroxylation to form a carbinolamine intermediate followed by opening of the piperidine ring and the formation of alcohol and acid derivatives; and (c) hydroxylation to form stable hydroxylated metabolites. In mouse, the formation of the catechol derivative (M12) and hydroxylation (M11) were the major metabolic pathways; in rat, the formation of the catechol derivative (M12) and glucuronidation (M9) were the main pathways; and in dog and human, the formation of the catechol derivative (M12) was the predominant pathway. No human-specific metabolite was observed.. This study provided some new information on the metabolic profiles of piperine, which should be of great importance in the study of the pharmacology and toxicity of this compound.

Topics: Alkaloids; Animals; Benzodioxoles; Cells, Cultured; Chromatography, Liquid; Dogs; Hepatocytes; Humans; Mass Spectrometry; Mice; Piperidines; Polyunsaturated Alkamides; Rats

Topics: Algorithms; Alkaloids; Benzodioxoles; Binding Sites; Biophysical Phenomena; Circular Dichroism; Interleukin-1beta; Kinetics; Models, Chemical; Molecular Docking Simulation; Molecular Dynamics Simulation; Piperidines; Polyunsaturated Alkamides; Protein Binding; Protein Conformation; Spectrometry, Fluorescence; Thermodynamics

The nutraceutical system of curcumin-piperine in 2-hydroxypropyl-β-cyclodextrin was prepared by using the kneading technique. Interactions between the components of the system were defined by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR). Application of hydroxypropyl-β-cyclodextrin as a carrier-solubiliser improved solubility of the curcumin-piperine system, its permeability through biological membranes (gastrointestinal tract, blood-brain barrier) as well as the antioxidant, antimicrobial and enzyme inhibitory activities against acetylcholinesterase and butyrylcholinesterase.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Acetylcholinesterase; Alkaloids; Anti-Infective Agents; Antioxidants; Benzodioxoles; Biological Transport; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Curcumin; Dietary Supplements; Drug Carriers; Drug Compounding; Gastrointestinal Tract; Humans; Piperidines; Polyunsaturated Alkamides; Solubility

Metabolic inflammation is an essential event in obesity-induced diabetes and insulin resistance. In obesity, an increasing number of macrophages recruited into visceral adipose tissues undergo significant M. Newborn mice were subcutaneously (s.c.) injected with monosodium glutamate (MSG) to establish a diabetes model. After 24 weeks, the MSG obese mice were divided into three groups and treated with piperine (40 mg/kg/day), metformin (150 mg/kg/day) and vehicle for 10 successive weeks, respectively.. The obesity model was successfully established, as the body weight, insulin resistance, fasting blood glucose (FBG) and dyslipidemia were significantly increased. The 10-week administration of piperine to the obese mice not only significantly decreased the elevated FBG (Model: 6.45 ± 0.41 mM; Piperine: 4.72 ± 0.44 mM, p < 0.01), serum TC (Model: 5.66 ± 0.66 mM; Piperine: 3.55 ± 0.30 mM, p < 0.01) and TG (Model: 1.41 ± 0.08 mM; Piperine: 0.94 ± 0.05 mM, p < 0.001), but also enhanced the glucose infusion rate in the hyperglycemic clamp experiment. Meanwhile, piperine improved glucose intolerance and insulin resistance in MSG obese mice. Piperine markedly decreased the total and differential white blood cell (WBC) count, the serum levels of lipopolysaccharide (LPS) and pro-inflammatory cytokines such as galectin-3 (Gal-3) and interleukin-1β (IL-1β). Furthermore, piperine clearly down-regulated the mRNA levels of pro-inflammatory cytokines and the protein levels of M. Piperine served as an immunomodulator for the treatment of obesity-related diabetes through its anti-inflammatory effects, which might be achieved by inhibiting macrophages M

Topics: Adipose Tissue; Alkaloids; Animals; Benzodioxoles; Body Weight; Cytochrome P-450 Enzyme Inhibitors; Cytokines; Female; Flavoring Agents; Glucose Intolerance; Inflammation; Insulin Resistance; Macrophages; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Piperidines; Polyunsaturated Alkamides; Sodium Glutamate

Nanoencapsulation is the promising approach to enhance the therapeutic potential of a drug. In the present investigation, piperine-loaded nanocapsules (NCs) was prepared and evaluated for antitrypanosomal activity against the parasite Trypanosoma evansi, a causative agent of trypanosomiasis. Piperine, a bioactive compound was selected as an alternative for drugs that have been used for the treatment of the disease from decades to overcome the toxic effects or drug resistance effect. Moreover, piperine has reported to possess therapeutic potential against other Trypanosoma spp. and has also been reported to cause reactive oxygen species (ROS) mediated effect in cancer cells that was the other reason for the selection. To date, piperine and its nanoformulations have not been evaluated for their growth inhibitory effect against T. evansi. Piperine-loaded NCs exhibited more significant antitrypanosomal effect at approximately three-times less IC

Topics: Alkaloids; Analysis of Variance; Animals; Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Horses; Inhibitory Concentration 50; Leukocytes, Mononuclear; Nanocapsules; Piperidines; Polyunsaturated Alkamides; Reactive Oxygen Species; Trypanosoma

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Alkaloids; Anti-Bacterial Agents; Antioxidants; Benzodioxoles; Drug Compounding; Hydrophobic and Hydrophilic Interactions; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Molecular Docking Simulation; Piperidines; Polyunsaturated Alkamides; Solubility; Spectroscopy, Fourier Transform Infrared; Vitamin E; X-Ray Diffraction

Metabolic Syndrome (MetS) is increasing worldwide regardless of culture, genetic, gender, and geographic differences. While multiple individual risk factors, such as obesity, hypertension, diabetes, and hyperlipidemia, can cause cardiovascular disease (CVD), it is the intercurrence of these risk factors that defines MetS as a cluster that creates an environment for atherosclerosis and other manifestations of CVD. Despite the advances in the knowledge and management of each of the components of MetS, there are two molecular biology processes, chronic inflammation and oxidative stress, which are still underdiagnosed and undertreated. In order to assess the effect of a dietary supplement on chronic inflammation in MetS, we conducted a clinical trial with volunteers receiving a formula composed of resveratrol, piperine and alpha tocopherol (FRAMINTROL

Topics: Aged; Alkaloids; alpha-Tocopherol; Benzodioxoles; Biomarkers; C-Reactive Protein; Chronic Disease; Dietary Supplements; Female; Ferritins; Humans; Inflammation; Luminescent Measurements; Male; Metabolic Syndrome; Middle Aged; Neutrophils; Oxidative Stress; Oxygen Consumption; Piperidines; Polyunsaturated Alkamides; Resveratrol; Time Factors

Piperine, a bioactive alkaloid, is known to have anticancer activities. Hence, in this study, the effectiveness of piperine pretreatment as a strategy for radio-sensitizing colorectal adenocarcinoma cell line (HT-29) was analyzed. For this, HT-29 cells were pretreated with piperine (12.5 and 25 µg/mL) and exposed to γ-radiation (1.25 Gy) and analyzed for various effector pathways to elucidate the possible mode of action in comparison to individual treatments. The proliferation efficiency of the cells was analyzed by trypan blue dye exclusion assay and MTT assay. The synergistic effects of the combination treatment were analyzed with compuSyn software. Downstream signaling pathways leading to apoptosis were studied using flowcytometry, immunofluorescence, and immunoblot assays. It was observed that combination treatment arrested HT-29 cells at G2/M phase nearly 2.8 folds higher than radiation treatment alone, inducing the radio-resistant cells to undergo apoptosis through mitochondria-dependent pathway. In addition, activation of caspase-3 and cleavage of poly(ADP-ribose) polymerases-1, the key molecular events in apoptotic signaling, were significantly enhanced. Activation of estrogen receptor beta (ERβ), a nuclear hormone transcription factor promoting tumor suppression represents a novel clinical advance towards management and prevention of cancers. Interestingly, the expression of ERβ was increased in the cells treated with piperine. In conclusion, piperine pretreatment enhances radio-sensitization in HT-29 cells by inducing the cells to undergo apoptosis hence, can be used as a classic candidate for colon cancer sensitization towards radiotherapy. PRACTICAL APPLICATION: Piperine induces enhanced radiosensitization of colon cancer cell line (HT-29) by interfering with the cancer cell line proliferation, DNA damage, and apoptosis.

Topics: Alkaloids; Apoptosis; Benzodioxoles; Caspase 3; Cell Line, Tumor; Cell Proliferation; HT29 Cells; Humans; Mitochondria; Neoplasms; Piperidines; Poly (ADP-Ribose) Polymerase-1; Polyunsaturated Alkamides; Radiation; Signal Transduction

To investigate the possible protective mechanisms of piperine against acetaminophen (APAP)-induced hepatotoxicity in mice.. Mice were given APAP (650 mg/kg i.p. once) with or without pretreatment with piperine (50 mg/kg/day orally for 3 days).. APAP caused liver toxicity as indicated by increased serum alanine aminotransferase and liver microscopic pathology, decreased hepatic superoxide dismutase and glutathione reductase activities, without affecting nuclear factor erythroid 2-related factor 2 (Nrf2) expression. APAP administration induced inflammation and apoptosis manifested as increased NF-κB p65 and dysregulation of caspase 3/Bcl2 expression, respectively. In addition, APAP increased the expression of transforming growth factor-β receptor-associated binding protein 1 (TGFBRAP1). On the other hand, pretreatment with piperine improved liver function and structure, reserved hepatic antioxidative defense, and attenuated inflammatory and apoptotic markers. Interestingly, piperine administration enhanced hepatic TGFBRAP1 expression compared to APAP alone.. The hepatoprotective effects of piperine against APAP are mediated via its antioxidant, anti-inflammatory, and anti-apoptotic effects, in addition to regulation of TGFBRAP1.

Topics: Acetaminophen; Alkaloids; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Benzodioxoles; Caspase 3; Chemical and Drug Induced Liver Injury; HSP90 Heat-Shock Proteins; Liver; Male; Mice; NF-E2-Related Factor 2; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Transcription Factor RelA

The increase in intracellular reactive oxygen and nitrogen species plays a key role in ultraviolet B (UV-B)-induced inflammatory responses in the human skin. Piperine exhibits many pharmacological benefits. In the present study, the photoprotective effects and the possible underlying mechanisms of the anti-inflammatory effects of piperine on UV-B-irradiated keratinocytes were investigated. Piperine exerted strong, direct scavenging effects on DPPH radicals and exhibited free radical scavenging capabilities as demonstrated by the DCFH-DA and Griess assays. Consistent with these results, 10, 20, and 40 μM piperine pretreatments attenuated UV-B irradiation-induced keratinocyte cytotoxicity as reported by the resazurin assay. The highest concentration of piperine inhibited UV-B irradiation-induced cell apoptosis, as revealed by Hoechst 33342 staining. Moreover, we demonstrated the anti-inflammatory effects of piperine using western blot analysis, real-time PCR, and ELISA. Pretreatment with piperine suppressed the activation of phosphorylated p38, JNK, and AP-1 as well as the levels of COX-2/PGE

Topics: Alkaloids; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Benzodioxoles; Celecoxib; Cell Line; Dose-Response Relationship, Drug; Humans; Inflammation; Keratinocytes; Piperidines; Polyunsaturated Alkamides; Skin; Ultraviolet Rays

Parkinson's disease (PD) is the most common progressive neurodegenerative disease known to impart bradykinesia leading to diverse metabolic complications. Currently, scarcity of effective drug candidates against this long-term devastating disorder poses a big therapeutic challenge. Here, we have synthesized biocompatible, polycrystalline, and uniform piperine-coated gold nanoparticles (AuNPs

Topics: Alkaloids; Animals; Benzodioxoles; Drosophila melanogaster; Gold; Metal Nanoparticles; Neurodegenerative Diseases; Oxidative Stress; Paraquat; Piperidines; Polyunsaturated Alkamides

This article is to investigate the effect of piperine on the small intestine of mice with Parkinson's disease with dementia(PDD). Ninety-six C57 BL/6 mice of SPF grade were randomly divided into 8 groups(male, 12 in each group): normal group, model group, autophagy inhibitor group(6-amino-3-methylpurine, 3 MA, 30 mg·kg~(-1)), autophagy activator group(rapamycin, 1 mg·kg~(-1)), low, medium, and high dose piperine groups(10, 20, 40 mg·kg~(-1)), and medopar group(112.5 mg·kg~(-1)). Except for the normal group, mice in each group were injected subcutaneously with reserpine(0.1 mg·kg~(-1)) once every 48 hours for 40 days. In addition, on the 20 th day of administration, except for the normal group, the mice in the other groups were subjected to bilateral common carotid artery occlusion to finally prepare PDD models. At the same time, each group was given the corresponding drug treatment once a day for 40 days. After the last administration, the behavioral changes of mice were observed by autonomic activity experiment and hot plate experiment. The expression levels of α-synuclein(α-syn) and tyrosine hydroxylase(TH) in the small intestine were detected by immunohistochemistry. The expression levels of beclin-1, microtubule-associated protein 1 light chain 3 B(LC3 B) and p62 in the small intestine were detected by immunofluorescence assay. Hematoxylin-eosin staining was used to observe the pathological morphology of small intestine tissues in each group. Enzyme-linked immunosorbent assay was adopted for detection of β-amyloid precursor protein(APP), p-tau, acetylcholine transferase(ChAT), interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) in small intestine. Real-time fluorescent quantitative polymerase chain reaction was used to detect the expression of α-syn, TH, beclin-1, microtubule-associated protein 1 light chain 3(LC3), and p62 mRNA and mmu-miR-99 a-5 p in the small intestine. The results of this study showed that, as compared with the model group, the number of activities, the expression levels of ChAT, TH, and p62 were significantly increased in the 3 MA group, the various piperine dose groups, and the medopar group(P<0.05), and their first foot licking time was shortened; APP, p-tau, IL-6, TNF-α, α-syn, beclin-1, LC3 B and mmu-miR-99 a-5 p expression levels were significantly reduced(P<0.05). However, as compared with the model group, the number of activities, ChAT, TH, and p62 expression levels in the rapamycin group were significantly reduce

Topics: Alkaloids; Animals; Autophagy; Benzodioxoles; Dementia; Intestine, Small; Male; Mice; Parkinson Disease; Piperidines; Polyunsaturated Alkamides

BACKGROUND Piperine has been reported to inhibit proliferation and induce apoptosis in various cancer cells. This study aimed to explore the efficacy and underlying mechanism of piperine in human gastric cancer. MATERIAL AND METHODS MTT assay was performed to examine the effect of piperine (concentrations of 0-300 μM) on the proliferation of human gastric cancer SNU-16 cells and normal human gastric epithelial GES-1 cells. Flow cytometry and Western blot were used to determine cell apoptosis and the expression level of protein (Cyto C, cleaved PARP, cleaved caspase-3, Bax, Bcl-2, Bad, Bcl-xl, PI3K, pPI3K, Akt, and pAkt), respectively. To further investigate the anti-tumor mechanism of piperine in SNU-16 cells, we used a small-molecule Akt activator SC79 in this study. The in vivo mechanism of piperine against gastric cancer was evaluated using a xenograft tumor model. RESULTS The results showed that piperine inhibited proliferation and induced apoptosis of SNU-16 cells. Piperine upregulated the protein expression of Bax, Bad, Cyto C, cleaved PARP, and cleaved caspase-3, but downregulated the protein expression of Bcl-2, Bcl-xl, pPI3k, and pAkt. However, SC79 reversed the function of piperine on the apoptosis-related proteins. An in vivo study revealed that, compared with the control group, the tumor volume of mice treated with piperine was significantly reduced. Piperine enhanced cleaved caspase-3 expression but decreased Ki-67 expression in a dose-dependent manner. Moreover, the nontoxicity effect of piperine was confirmed by H&E staining analysis in kidney and heart tissues of mice. CONCLUSIONS Our findings suggest that piperine inhibits proliferation and induces apoptosis of human gastric cancer cells through inhibition of the PI3K/Akt signaling pathway.

Topics: Alkaloids; Animals; Antineoplastic Agents; Apoptosis; bcl-Associated Death Protein; bcl-X Protein; Benzodioxoles; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cytochromes c; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphatidylinositol 3-Kinases; Piperidines; Poly(ADP-ribose) Polymerases; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Stomach Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays

Pandemic H1N1 influenza virus respiratory illness has become an inevitable global health concern. With antigenic drift, it becomes necessary to have drugs over tailor-made HIN1 vaccine every year. In the current study, we screened many Piperine derivative in which, N-5-(3,4-dimethoxyphenyl)-2E,4E-pentadienylpiperidine (AB05) and was further studied for anti-H1N1influenza virus activity and compared with other stains in-vitro on MDCK cell line. Initial cytotoxic doses of AB05 for the MDCK cell line were > 25µM. The results showed a dose-dependent reduction of the viral plaque's in the adsorption assay with EC

Topics: Alkaloids; Animals; Antiviral Agents; Benzodioxoles; Dogs; Influenza A Virus, H1N1 Subtype; Madin Darby Canine Kidney Cells; Molecular Docking Simulation; Molecular Structure; Neuraminidase; Piper; Piperidines; Polyunsaturated Alkamides; Protein Structure, Tertiary; Viral Proteins

Cadmium (Cd) has a remarkable property of generating oxidative stress. It upregulates the level of reactive oxygen species, which generates damage to lipids, proteins, and DNA The level of oxidative stress by Cd is observed by inhibitory effects of antioxidant enzymes such as catalase, superoxide dismutase, glutathione reductase, and glutathione peroxidase. Piperine is one of the plant-derived alkaloids isolated from

Topics: Alkaloids; Antioxidants; Benzodioxoles; Cadmium; Humans; Leukocytes, Mononuclear; Lipid Peroxidation; Oxidative Stress; Piper; Piperidines; Plant Extracts; Polyunsaturated Alkamides

A facile, multicomponent (MCR) atom-economic synthesis of novel spiro-oxindolo pyrrolizidine adducts of piperine has been achieved via an intermolecular 1,3-dipolar azomethine ylide cycloaddition reaction. Either of the two conjugated double bonds in piperine takes part in the reaction to produce two regioisomeric adducts in racemic form. Acenaphthoquinone, ninhydrin and different isatin derivatives were reacted with proline and piperine to afford a never before reported library of 22 compounds. The structures of the products were determined by 1D/2D NMR, mass spectral analysis and confirmed by X-ray crystallography of selected products. Chiral HPLC separation was performed to measure the specific rotation and CD spectra of the enantiomers for two racemic compounds.

Topics: Alkaloids; Azo Compounds; Benzodioxoles; Cycloaddition Reaction; Models, Molecular; Molecular Conformation; Oxindoles; Piperidines; Polyunsaturated Alkamides; Pyrroles; Spiro Compounds; Stereoisomerism; Thiosemicarbazones

Communicated by Ramaswamy H. Sarma.

Topics: Alkaloids; Benzodioxoles; Computer Simulation; Density Functional Theory; Piper nigrum; Piperidines; Polyunsaturated Alkamides

An efficient ultra-performance liquid chromatography with diode-array detector method was established for simultaneous determination of six active components in Roukou Wuwei pills, namely gallic acid, piperine, costundide, dehydrocostus lactone, isoalantolactone and alantolactone. Chromatographic separation of six components was successfully achieved on an Waters BEH C

Topics: Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Gallic Acid; Lactones; Limit of Detection; Linear Models; Piperidines; Polyunsaturated Alkamides; Reproducibility of Results; Sesquiterpenes

Ginkgo biloba extract (GBE) is widely used as herbal medicine. Preventive effect of GBE against dementia, including Alzheimer's disease, has been reported. The bioactive compounds in GBE that impart these beneficial effects, flavonoids and terpene lactones, have poor bioavailability. Our previous study found distribution of bioactive compounds of sesame extract in mice brain after mixing it with turmeric oil. Here, we evaluate the distribution of bioactive compounds of GBE by combining it with the mixture of sesame extract and turmeric oil (MST). The content of terpene lactones in mice serum was significantly increased in a dose-dependent manner after administration of GBE. However, the contents of terpene lactones in mice brain were not significantly changed. Concentration of ginkgolide A in mice brain increased significantly when GBE was co-administrated with MST than when GBE was administered alone. These results suggest that MST may be effective in enhancing the bioavailability of ginkgolide A in GBE.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Brain; Curcuma; Ginkgo biloba; Ginkgolides; Lactones; Male; Mice; Phytochemicals; Piper; Piperidines; Plant Extracts; Plant Oils; Polyunsaturated Alkamides; Sesamum

Topics: Acetylcholinesterase; Algorithms; Alkaloids; Benzodioxoles; Catalytic Domain; Crystallography; Humans; Hydrogen Bonding; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Piperidines; Polyunsaturated Alkamides; Protein Binding

Background In the present study, we investigated the antibacterial, anthelmintic, and analgesic activities of methanol extract of P. sylvaticum leaves (MEPSL) in experimental models. Then, computational analysis (in silico molecular docking and PASS prediction) was performed to determine the potent phytoconstituents of total six isolated compounds of this plant for antibacterial and anthelmintic activities. Methods Qualitative and quantitative phytochemical studies were carried out by established methods. In vitro antibacterial activity was determined by disc diffusion technique and anthelmintic activity was tested against Tubifex tubifex worm whereas analgesic activity was determined by the acetic acid-induced writhing test in mice. Molecular docking study was performed using Schrödinger Maestro 10.1 and an online tool used for PASS prediction. Results Our phytochemical study revealed the presence of alkaloids, flavonoids, saponins, and also indicated a substantial amount of phenols (65.83 mg), flavonoids (102.56 mg), and condensed tannins (89.32 mg). MEPSL showed good antibacterial activity against both gram-positive and gram-negative bacteria. Our result exhibited that MEPSL has strong anthelmintic action compared to standard levamisole. In addition, the extract also showed a dose-dependent and statistically significant analgesic activity at the doses of 200 and 400 mg/kg, body weight. Docking studies showed that piperine and piperlonguminine have the best scores for the tested enzymes. PASS predicted the antibacterial and anthelmintic activity of both phytoconstituents. Conclusions This study suggests that MEPSL possess significant antibacterial, anthelmintic, and analgesic activities which could be related to the presence of several phytochemicals. The phytoconstituents, i.e. piperine and piperlonguminine were found to be most effective in computational studies.

Topics: Alkaloids; Analgesics; Animals; Anthelmintics; Anti-Bacterial Agents; Benzodioxoles; Dioxolanes; Mice; Microbial Sensitivity Tests; Molecular Docking Simulation; Oligochaeta; Piper; Piperidines; Plant Extracts; Plant Leaves; Polyunsaturated Alkamides

Oxyresveratrol is a major bioactive component derived from the heartwood of Artocarpus lacucha. This compound exerts several biological activities, including neuroprotective effects in vitro and in vivo. However, there is limited pharmacokinetic information on this compound, especially its distribution in neuronal tissue and its route of excretion. The aim of this study was to investigate the pharmacokinetic profiles of oxyresveratrol alone and in combination with piperine as a bioenhancer in rats.. Male Wistar rats were administered with oxyresveratrol 10 mg/kg, oxyresveratrol 10 mg/kg plus piperine 1 mg/kg via intravenous or oxyresveratrol 100 mg/kg, oxyresveratrol 100 mg/kg plus piperine 10 mg/kg via oral gavage. Plasma, internal organs, urine, and feces were collected. Determination of the oxyresveratrol concentration in biological samples was performed by liquid chromatography tandem mass spectrometry.. The combination with piperine had shown a significantly higher maximum concentration in plasma approximately 1500 μg/L within 1-2 h after oral dosing, and could increase oral bioavailability of oxyresveratrol approximately 2-fold. Oxyresveratrol could widely distributed most of the internal organs with a tissue to plasma ratio of 10-100 fold within 5 min after dosing. Urinary excretion of oxyresveratrol glucuronide was the major route of excretion after administration of oxyresveratrol alone and in combination with piperine.. The addition of piperine could enhance some of the pharmacokinetic properties of oxyresveratrol via both intravenous and oral administration. This pharmacokinetic information will be useful for appropriate strategies to develop oxyresveratrol as a phytopharmaceutical product.

Topics: Administration, Intravenous; Administration, Oral; Alkaloids; Animals; Artocarpus; Benzodioxoles; Drug Interactions; Male; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Rats; Rats, Wistar; Stilbenes

The activity of rifampin (RIF) and piperine was evaluated at the relative transcript levels of 12 efflux pumps (EPs), and an additional mechanism was proposed to be behind the synergic interactions of piperine plus RIF in

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Binding Sites; DNA-Directed RNA Polymerases; Drug Synergism; Drug Therapy, Combination; Molecular Docking Simulation; Mycobacterium tuberculosis; Piperidines; Polyunsaturated Alkamides; Reverse Transcriptase Polymerase Chain Reaction; Rifampin

Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation and fibrosis. Currently, there are no drugs for the treatment of pancreatic fibrosis associated with CP. Piperine, a natural alkaloid found in black pepper, has been reported to show anti‑inflammatory, anti‑oxidative, and antitumor activities. Although piperine exhibits numerous properties in regards to the regulation of diverse diseases, the effects of piperine on CP have not been established. To investigate the effects of piperine on CP in vivo, we induced CP in mice through the repetitive administration of cerulein (50 µg/kg) six times at 1‑h intervals, 5 times per week, for a total of 3 weeks. In the pre‑treatment groups, piperine (1, 5, or 10 mg/kg) or corn oil were administrated orally at 1 h before the first cerulein injection, once a day, 5 times a week, for a total of 3 weeks. In the post‑treatment groups, piperine (10 mg/kg) or corn oil was administered orally at 1 or 2 week after the first cerulein injection. Pancreases were collected for histological analysis. In addition, pancreatic stellate cells (PSCs) were isolated to examine the anti‑fibrogenic effects and regulatory mechanisms of piperine. Piperine treatment significantly inhibited histological damage in the pancreas, increased the pancreatic acinar cell survival, reduced collagen deposition and reduced pro‑inflammatory cytokines and chemokines. In addition, piperine treatment reduced the expression of fibrotic mediators, such as α‑smooth muscle actin (α‑SMA), collagen, and fibronectin 1 in the pancreas and PSCs. Moreover, piperine treatment reduced the production of transforming growth factor (TGF)‑β in the pancreas and PSCs. Furthermore, piperine treatment inhibited TGF‑β‑induced pSMAD2/3 activation but not pSMAD1/5 in the PSCs. These findings suggest that piperine treatment ameliorates pancreatic fibrosis by inhibiting TGF‑β/SMAD2/3 signaling during CP.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Benzodioxoles; Disease Models, Animal; Female; Fibrosis; Mice; Mice, Inbred C57BL; Pancreas; Pancreatitis, Chronic; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

After oral route of administration, drug absorption is unpredictable and is governed by various factors such as multi drug resistance-1 (MDR1) an efflux transporter and drug metabolizing enzymes (like CYP3A4, CYP3A37, CYP2D6) at intestine and liver. Naturally available phyto chemicals like piperine and quercetin as well as some floroquinolones are known to inhibit MDR1 and CYP3A37 activity and increases bioavailability of co-administered drugs. This study was carried out to investigate the effect of piperine and quercetin alone or in combination with marbofloxacin on CYP3A37 and MDR1 mRNA expression levels in liver and intestine of broiler chicken. After oral administration of piperine and quercetin for 3 consecutive days followed by with or without oral administration of marbofloxacin for 5 days, CYP3A37 and MDR1 mRNA expression levels were determined using quantitative real-time PCR. Total of 36 broiler chickens in seven individual groups were treated with different regimen and the mRNA expression levels at duodenum and liver were analyzed with apt statistical tools. After piperine and quercetin combined treatment with marbofloxacin, CYP3A37 mRNA expression levels were significantly down regulated by 20.57 (p = .034) and 25.95 (p = .003) folds; and MDR1 mRNA expression levels were also significantly down regulated by 11.33 (p = .012) and 33.59 (p = .006) folds in liver and duodenum, respectively. Down regulation of CYP3A37 and MDR1 mRNA in liver and duodenum indicate the combined pretreatment of piperine and quercetin may be useful for improving the pharmacokinetics of orally administered drugs which are substrates for CYP3A37 and MDR1.

Topics: Alkaloids; Animals; Anti-Bacterial Agents; Antioxidants; Aryl Hydrocarbon Hydroxylases; ATP Binding Cassette Transporter, Subfamily B, Member 1; Avian Proteins; Benzodioxoles; Chickens; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P450 Family 3; Duodenum; Fluoroquinolones; Gene Expression Regulation; Liver; Piperidines; Polyunsaturated Alkamides; Quercetin; Random Allocation; RNA, Messenger

Black pepper (Piper nigrum), dubbed the 'King of Spices' and 'Black Gold', is one of the most widely used spices. Here, we present its reference genome assembly by integrating PacBio, 10x Chromium, BioNano DLS optical mapping, and Hi-C mapping technologies. The 761.2 Mb sequences (45 scaffolds with an N50 of 29.8 Mb) are assembled into 26 pseudochromosomes. A phylogenomic analysis of representative plant genomes places magnoliids as sister to the monocots-eudicots clade and indicates that black pepper has diverged from the shared Laurales-Magnoliales lineage approximately 180 million years ago. Comparative genomic analyses reveal specific gene expansions in the glycosyltransferase, cytochrome P450, shikimate hydroxycinnamoyl transferase, lysine decarboxylase, and acyltransferase gene families. Comparative transcriptomic analyses disclose berry-specific upregulated expression in representative genes in each of these gene families. These data provide an evolutionary perspective and shed light on the metabolic processes relevant to the molecular basis of species-specific piperine biosynthesis.

Topics: Acyltransferases; Alkaloids; Benzodioxoles; Carboxy-Lyases; Chromosome Mapping; Chromosomes; Cytochrome P-450 Enzyme System; Gene Expression Profiling; Genome, Plant; Genomics; Glycosyltransferases; Phylogeny; Piper nigrum; Piperidines; Polyunsaturated Alkamides

The present work aimed to accomplish a comparative and principled study on desolvation and self-assembly methods for synthesis of piperine-loaded human serum albumin nanoparticles (PIP-HSA-NPs). Among drugs, PIP was selected as the hydrophobic model drug. The response surface methodology (RSM)-central composite design (CCD) was employed to precisely study the processes and the interactions between the factors affecting the methods. Optimization was performed to obtain the best formulations for both procedures. Both optimized PIP-HSA-NPs prepared by the two methods were stable and semi-spherical with the size less than 200 nm. The self-assembled PIP-HSA-NPs which were prepared under the optimized conditions with drug encapsulation efficiency (DEE) of 76.8% ± 0.44%, and drug loading efficiency (DLE) of 8.92% ± 0.3% had significantly higher DEE and DLE than the optimized particles obtained from the desolvation method with DEE of 34.1% ± 0.32% and DLE of 1.68 ± 0.11%. The secondary structure of HSA did not change much in self-assembled PIP-HSA-NPs compared to desolvated PIP-HSA-NPs. The self-assembled PIP-HSA-NPs showed more cumulative drug release than desolvated NPs, causing them to have more cytotoxicity on MCF-7 cells at high concentrations. These findings introduce the self-assembly technique as the better chemical method to produce a practical cost-effective carrier for many hydrophobic drugs.

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Drug Carriers; Drug Liberation; Drug Screening Assays, Antitumor; Humans; Hydrophobic and Hydrophilic Interactions; MCF-7 Cells; Nanoparticles; Particle Size; Piperidines; Polyunsaturated Alkamides; Serum Albumin, Human; Solubility; Structure-Activity Relationship; Surface Properties

The aim of the present study was to enhance the pharmaceutical potential and oral bioavailability of piperine, which is the bioactive constituent of

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biological Availability; Drug Delivery Systems; Male; Microscopy, Electron, Scanning; Nanoparticles; Particle Size; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

The aim of this research was to assess regional difference in the intestinal absorption of ranitidine HCl as an indicator for the potential effect of P-glycoprotein (P-gp) efflux transporters.. In situ rabbit intestinal perfusion was used to investigate absorption of ranitidine HCl, a substrate for P-gp efflux from duodenum, jejunum, ileum and colon. This was conducted both in the presence and absence of piperine as P-gp inhibitor.. Ranitidine HCl was incompletely absorbed from rabbit intestine. The length normalized absorptive clearance (PeA/L) of ranitidine HCl was ranked as colon > duodenum > jejunum > ileum. This is the reverse order of the magnitude of P-gp expression. Coperfusion of piperine with ranitidine HCl significantly increased the PeA/L of ranitidine HCl from jejunum and ileum with no significant change on the absorption from duodenum and colon. This was confirmed by significant reduction in the length required for complete ranitidine HCl absorption from jejunum and ileum in presence piperine.. The results indicate that P-gp transporters play a major role in determining regional difference in intestinal absorption of ranitidine HCl. Thus, the regional absorption of drugs may be taken as an indirect indication for the role of P-gp in intestinal absorption.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Intestinal Absorption; Intestinal Mucosa; Intestines; Membrane Transport Proteins; Piperidines; Polyunsaturated Alkamides; Rabbits

Studies have documented the anti-inflammatory effects of spices, which may be related to treatment of chronic diseases. The purpose of this study was to evaluate the influence of curcumin and piperine and their association on experimental periodontal repair in rats.. Periodontitis was induced via the installation of a ligature around the first molar. After 15 days, the ligatures were removed, and the rats were separated into groups (12 animals per group): (i) curcumin, (ii) piperine, (iii) curcumin+piperine, (iv) corn oil vehicle, and (v) control group (animals had ligature-induced periodontitis but were not treated). The compounds were administered daily, for 15 days by oral gavage. Animals were euthanized at 5 and 15 days, and hemimaxillae and gingival tissues were harvested. Bone repair was assessed by μCT (microcomputer tomography). Histological sections were stained with hematoxylin/eosin (H/E) for the assessment of cellular infiltrate or picrosirius red for quantification of collagen content, and subjected to immunohistochemistry for detecting NF-ĸB. Gingival tissues were used to evaluate levels of TGF-β and IL-10 (ELISA).. Curcumin and piperine increased the TGF-β level, significantly improved the collagen repair, and decreased the cellularity and activation of NF-ĸB in the periodontal tissues, but only curcumin caused a significant increase in early bone repair.. Curcumin and piperine promoted a substantive effect on tissue repair; however, there was not synergistic effect of compounds administered in combination.. Curcumin and piperine stimulates the tissue repair and may be potential candidates for the treatment of periodontal disease.

Topics: Alkaloids; Animals; Benzodioxoles; Cats; Curcumin; Male; Periodontitis; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Piperine is the key bioactive factor in black pepper, and has been reported to alleviate cerebral ischemic injury. However, the mechanisms underlying its neuroprotective effects following cerebral ischemia remain unclear. In this study, rats were administered vehicle (dimethyl sulfoxide) or piperine, 20 mg/kg, daily for 14 days before focal cerebral artery occlusion. After occlusion for 2 h followed by reperfusion for 24 h. Histological examinations were used to assess whether piperine has a neuroprotective effect in the rat model of cerebral ischemia/reperfusion injury. The levels of proteins in the ischemic penumbra were evaluated by isobaric tags for relative and absolute quantitation-based proteomics. A total of 3687 proteins were identified, including 23 proteins that were highly significantly differentially expressed between the control and piperine groups. The proteomic findings were verified by immunofluorescence and western blot analysis. Interestingly, piperine administration downregulated a number of critical factors in the complement and coagulation cascades, including complement component 3, fibrinogen gamma chain, alpha-2-macroglobulin, and serpin family A member 1. Collectively, our findings suggest that the neuroprotective effects of piperine following cerebral ischemia/reperfusion injury are related to the regulation of the complement and coagulation cascades.

Topics: Alkaloids; Animals; Benzodioxoles; Brain; Brain Ischemia; Male; Neuroprotective Agents; Piperidines; Polyunsaturated Alkamides; Protein Interaction Domains and Motifs; Proteomics; Rats; Rats, Sprague-Dawley; Reperfusion Injury

The first-line anti-epileptic agent carbamazepine has narrow therapeutic index and can potentially interact with piperine, the major component from black pepper. The present study aimed to delineate the mechanism of such interaction for safe usage of carbamazepine during epilepsy control.. The effect of piperine on carbamazepine hepatic metabolism was examined using rat or human liver microsomes. Mechanistic static model was applied to predict the extent of interaction. In addition, liver microsomal activities, mRNAs and protein expressions of genes regulating carbamazepine metabolism were evaluated after two weeks oral administrations of 3.5 and 35 mg/kg piperine in rats. Moreover, the effect of piperine on the xenobiotic receptor constitutive androstane receptor (CAR) was further accessed.. We have demonstrated the time-dependent inhibition by piperine on carbamazepine metabolism as the interaction mechanism. Prolonged use of piperine at high dose could increase carbamazepine concentrations through inhibiting metabolic enzyme activities and their related genes expressions.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Carbamazepine; Cytochrome P-450 Enzyme Inhibitors; Humans; Male; Microsomes, Liver; Piperidines; Polyunsaturated Alkamides; Rats, Sprague-Dawley; Time Factors

Piperine has been widely used as a bioenhancer. Simvastatin belongs to a group of medicines known as statins. It acts by inhibiting HMG CoA reductase and acts primarily as a hypolipidemic agent. In this study some derivatives of Piperine were synthesized. They were studied for their bioenhencing effect (10 mg kg

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biological Availability; Drug Compounding; Drug Synergism; Dyslipidemias; Feasibility Studies; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Simvastatin

Although silybin serves as a well-known hepatoprotective agent with prominent anti-inflammatory, anti-oxidant and anti-fibrotic activities, its low bioavailability limits its application in the treatment of chronic liver diseases. However, novel formulation products with increased solubility were not sufficient to achieve pharmacologically meaningful concentrations of silybin in the clinical studies even used at high dosage.. We hypothesized that inhibiting efflux transporter(s) and/or glucuronidation by piperine might enhance the bioavailability and efficacy of silybin.. Pharmacokinetics of silybin given alone or in-combination with piperine was determined by a validated LC-MS method. A CCl. In the present study, we demonstrated for the first time that piperine as a bioenhancer increased the bioavailability of silybin (146%- 181%), contributing to a boosted therapeutic effect in CCl. Efflux transporters play an important role in the pharmacokinetic behavior of flavolignans, and modulating these transporters by bioenhancer such as piperine could enhance the in vivo absorption of silybin, leading to more effective treatments.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Benzodioxoles; Biological Availability; Caco-2 Cells; Chemical and Drug Induced Liver Injury; Hepatocytes; Humans; Male; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Piperidines; Polyunsaturated Alkamides; Protective Agents; Rats, Sprague-Dawley; Silybin

The etiopathogenesis of steroid-induced cataracts is unknown. One hypothesis is that the higher reactive oxygen species (ROS) levels play an important role in the pathogenesis of several disorders, including the evolution of cataracts. This study investigated the antioxidant effects of piperine in our steroid-induced chick embryo lens model.. The study included 36 specific pathogen-free (SPF) fertilized eggs divided into six groups: phosphate buffer saline (PBS, pH 7.4 Saline Solution (0.9%) isotonic) group (G1), hydrocortisone succinate sodium (HC)-treated group (G2), 100 mg/kg piperine and HC treated group (G3), 50 mg/kg piperine and HC treated group (G4), 25 mg/kg piperine and HC treated group (G5), and 10 mg/kg piperine and HC treated group (G6). On the 15th day of incubation, the SPF eggs in the six groups were removed from the incubator; all were injected using insulin injectors into the chorioallantoic membrane. On day 17, all of the chick embryos were removed from the eggs and all lenses were dissected from the embryos. Cataract formation was evaluated in all lenses, and total antioxidant status (TAS), total oxidant status (TOS), reduced glutathione (GSH), and lipid peroxidation (MDA, malondialdehyde) levels were measured in all lens.. The lenses in the G1 group had higher levels of GSH and TAS (p < 0.01), and lower levels of MDA and TOS than the G2 group (p < 0.05 and p < 0.01, respectively). Group 3 had higher levels of GSH and TAS (p < 0.001 and p < 0.001 respectively), and lower levels of MDA and TOS than the G2 group (p < 0.01 and p < 0.001, respectively).. Steroid therapy causes a decrease in GSH and TAS levels and an increase in TOS and MDA levels in lens tissues, indicating increased oxidative stress. Piperine exerts its effects as an antioxidant substance, in increasing doses.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Cataract; Chick Embryo; Glutathione; Hydrocortisone; Lens, Crystalline; Malondialdehyde; Piperidines; Polyunsaturated Alkamides

Curcumin (CUR) has gained increasing interest worldwide due to multiple biological activities. However, the therapeutic application remains limited because of its low aqueous solubility, intestinal metabolism and poor membrane permeability. In present study, an excipient-free CUR solid dispersion co-formed with piperine (PIP), the absorption enhancer involving metabolism-permeability, was successfully prepared by melting and quench cooling (co-amorphous CUR-PIP). The co-amorphous CUR-PIP exhibited superior performance in non-sink dissolution compared with crystalline and amorphous CUR, and showed physically stable at least 3 months, attributing to the strong molecular interactions between CUR and PIP as evaluated by FTIR spectra. Furthermore, the combination of PIP with CUR in the co-amorphous formulation could inhibit the glucuronidation of CUR, as exhibited in the in vitro assay of rat intestinal microsomes. The co-amorphous CUR-PIP would also exhibit higher gastrointestinal membrane permeability of CUR, as confirmed by P

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Cells, Cultured; Curcumin; Drug Delivery Systems; Drug Stability; Humans; Intestinal Absorption; Intestinal Mucosa; Piperidines; Polyunsaturated Alkamides; Rats; Solubility

Previous studies have demonstrated that different curcumin extracts are able to influence cell metabolic activity vitality in human papillary thyroid carcinoma TPC-1 cells. We continued the study using the most effective extract and adding other nutraceuticals such as piperine and vitamin E, in order to define the possible role of these in modulating the genetic expression of cell markers and to understand the effectiveness in modulating the regression of cancer phenotype. Cells were treated with one extract of curcumin (Naturex

Topics: Alkaloids; Apoptosis Regulatory Proteins; Benzodioxoles; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Drug Synergism; Humans; Piperidines; Polyunsaturated Alkamides; Thyroid Cancer, Papillary; Vitamin E

Piperine is a major pungent alkaloid present in black pepper (Piper nigrum L). This study investigated the potential anticancer effects of piperine on human melanoma cells and explored the potential pharmacological mechanisms in vitro and in vivo.. Studies were performed using the MTT assay, 4',6-diamidino-2-phenylindole (DAPI) staining, western blotting, a xenograft model, the terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and immunohistochemistry.. Piperine inhibited the growth of melanoma cells. Several apoptotic events were observed following treatment, as revealed by DAPI staining. Piperine increased the expression of BCL2-associated X, apoptosis regulator (BAX), cleaved poly(ADP-ribose)polymerase, cleaved caspase-9, phospho-c-Jun N-terminal kinase and phospho-p38, and reduced that of B-cell lymphoma 2 (BCL2), X-chromosome-linked inhibitor of apoptosis, and phospho-extracellular signal-regulated protein kinase (ERK1/2) in a concentration-dependent manner. Treatment of mice for 4 weeks with piperine inhibited tumor growth without apparent toxicity. Piperine increased the expression of apoptotic cells and cleaved-caspase-3 protein and reduced the expression of phospho-ERK1/2 protein in melanoma tumors.. Piperine suppressed the growth of human melanoma cells by the induction of apoptosis via the inhibition of tumor growth of human melanoma cells and tumor xenograft models.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Benzodioxoles; Cell Line, Tumor; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinases; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Skin Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays

Piperine is the crucial alkaloid component of black pepper (Piper nigrum Linn.) and has neuroprotective effects. Because inhibition of glutamatergic excitatory neurotransmission is a possible mechanism involved in neuroprotection, we investigated the effect of piperine on the 4-aminopyridine (4-AP)-evoked release of glutamate from rat hippocampal synaptosomes. Piperine inhibited 4-AP-evoked glutamate release, and the inhibition was prevented by the chelation of extracellular Ca2+ ions and a vesicular transporter inhibitor. Piperine reduced the 4-AP-evoked elevation of intrasynaptosomal Ca2+ levels but did not affect the synaptosomal membrane potential. In the presence of ω-conotoxin MVIIC, an N- and P/Q-type channel blocker, the piperine-mediated inhibition of 4-AP-evoked glutamate release was markedly reduced; however, dantrolene and CGP37157, which are intracellular Ca2+-release inhibitors, did not alter the piperine effect. In addition, immunocytochemical analysis confirmed the presence of presynaptic 5-hydroxytryptamine 1A (5-HT1A) receptor proteins. The glutamate release-inhibiting effect of piperine was discovered to be prevented by the 5-HT1A receptor antagonist WAY100635 and the G protein βγ subunit inhibitor gallein; however, it was unaffected by the adenylate cyclase inhibitor SQ22536 or the protein kinase A inhibitor PKI622. These results suggest that piperine inhibits glutamate release from rat hippocampal nerve terminals by reducing Ca2+ influx through N- and P/Q-type Ca2+ channels and that the activation of presynaptic 5-HT1A receptors and the G protein βγ subunit is involved in this effect.

Topics: 4-Aminopyridine; Alkaloids; Animals; Benzodioxoles; Calcium; Calcium Channels; Glutamic Acid; GTP-Binding Protein beta Subunits; GTP-Binding Protein gamma Subunits; Hippocampus; Male; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Synaptosomes

Tuberculosis, caused by Mycobacterium tuberculosis has been one of the primal afflictions to human, and owing to the current scenario of drug resistance, newer drugs, and alternate targets are required to mitigate the disease. FtsZ is a GTP hydrolyzing protein, conserved in prokaryotes that plays a central role in Z-ring formation during cell division cytokinesis stage. This study employs the use of pharmacophore models derived from two different datasets based on Mtb-FtsZ GTPase inhibition and whole cell antibacterial activity, to virtually screen and shortlist novel compounds from In-house small molecule library as Mtb-FtsZ inhibitors and evaluate their in-vitro and ex-vivo activity. The results revealed Piperine (IC

Topics: Alkaloids; Anti-Bacterial Agents; Bacterial Proteins; Benzodioxoles; Cell Division; Coumarins; Cytokinesis; Cytoskeletal Proteins; Databases, Chemical; Drug Evaluation, Preclinical; GTP Phosphohydrolases; Humans; Molecular Docking Simulation; Mycobacterium smegmatis; Mycobacterium tuberculosis; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship

Piperine is an attractive therapeutic alkaloid from black pepper that exhibits a broad spectrum of pharmacological properties over various pathological disorders including cancer. Voltage gated K

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Apoptosis; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; G1 Phase Cell Cycle Checkpoints; Humans; Male; Membrane Potentials; Patch-Clamp Techniques; PC-3 Cells; Phytotherapy; Piperidines; Polyunsaturated Alkamides; Potassium Channels, Voltage-Gated; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

To explore effective extraction method and to find active constituents, we investigated the biological activity of three extracts and isolated active compounds from the fruits of Piper longum L.. Three extracts from the fruits were obtained by reflux, ultrasonic and supercritical fluid extraction, respectively. Active compounds were isolated by the bioassay-guided method. The anti-inflammatory activity, antiproliferation activity and cytotoxicity were evaluated. The apoptosis was detected by Hoechst 33258 staining assay. The relevant proteins were investigated by Western blot assay.. The anti-inflammatory activity and cytotoxicity of supercritical fluid extract (SE) were stronger than those of the other two extracts. Among all isolated compounds, the anti-inflammatory activity of eight compounds was stronger than that of indomethacin, and compounds 8, 9, 11, 14 and 15 were found to possess anti-inflammatory effect for the first time. Compounds 1, 2, 3 and 14 exhibited significant cytotoxicity against cancer cells. SE and piperine were found to reduce colony formation, inhibit cell migration and promote apoptosis through increasing cleaved PARP and the ratio of Bax/Bcl-2.. The anti-inflammatory and antitumour effects of SE were better than those of the other two extracts. The compounds responsible for the activity were elucidated. SE and piperine inhibit cell growth through apoptosis.

Topics: Alkaloids; Anti-Inflammatory Agents; Antineoplastic Agents; Apoptosis; Benzodioxoles; Cell Line; Cell Line, Tumor; Cell Movement; Fruit; Humans; Macrophages; Piper; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-bcl-2

A fluorometric imaging plate reader (FLIPR) assay utilizing Chinese hamster ovary (CHO) cells stably transfected with GABA

Topics: Alkaloids; Animals; Benzodioxoles; Biological Assay; Biphenyl Compounds; CHO Cells; Chromatography, High Pressure Liquid; Cricetulus; Fluorometry; Indenes; Lignans; Magnolia; Oocytes; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Receptors, GABA-A; Sesquiterpenes; Valerian; Xenopus laevis

Resveratrol and piperine are proven for their therapeutic benefits to treat various diseases. Due to their synergistic actions and combined drug delivery application, a rapid and specific RP-HPLC method was developed and validated as per ICH guidelines, by using an isosbestic point. The chromatographic separation was performed with Luna 5 μ 100 Å C-18(2) HPLC column by using acetonitrile (ACN): phosphate buffer (0.01% orthophosphoric acid) (55:45) as mobile phase, at 1 mL/min of flow rate and 330 nm. The developed method was found to be linear over the concentration range of 0.25-8 μg/mL with correlation coefficient value >0.999. The developed method was accurate (percent recovery 98.06-101.74%), precise (percent relative standard deviation <2.0%), and robust. The limit of detection and limit of quantification for resveratrol were found to be 0.02 and 0.08 μg/mL, respectively and 0.04 and 0.11 μg/mL, for piperine, respectively. The developed method was also validated in human plasma as per ICH guidelines. Moreover, stress degradation studies of both phytoconstituents were studied and the relevancy of the developed method was analyzed on cubosome nanoformulation. A good separation of drug peaks was observed in the presence of the degradation products. This method could thus be used for regular in vitro and in vivo estimation of piperine and resveratrol.

Topics: Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Drug Stability; Humans; Limit of Detection; Linear Models; Piperidines; Polyunsaturated Alkamides; Reproducibility of Results; Resveratrol

In this study, poly-(lactic-co-glycolic) acid (PLGA) was conjugated with aspartic acid and was characterized by nuclear magnetic resonance and Fourier transform infrared spectroscopy. Docetaxel-loaded polymeric micelles were prepared, and piperine was tagged. The neuroblastoma cytotoxicity studies revealed a substantially higher cytotoxic potential of the developed system to that of plain docetaxel, which was further corroborated by cellular uptake employing confocal laser scanning microscopy. The hemocompatible system was able to enhance the pharmacokinetic profile in terms of 6.5-fold increment in bioavailability followed by a 3.5 times increase in the retention time in comparison with the plain drug. The single-point brain bioavailability of docetaxel was amplified by 3.3-folds, signifying a better uptake and distribution to brain employing these carriers. The findings are unique as the physically adsorbed piperine was released before the DTX, increasing the propensity of curbing the CYP3A4 enzyme, which plays a vital role in the degradation of docetaxel. Meanwhile, piperine might have compromised the P-gp efflux mechanism, which can be ascribed to the enhanced retention of the drug at the target site. The elevated target site concentrations and extended residence by a biocompatible nanocarrier supplemented with co-delivery of piperine inherit immense promises to deliver this BCS class IV drug more safely and effectively.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Benzodioxoles; Biological Availability; Brain; Cell Line, Tumor; Docetaxel; Humans; Micelles; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Spectroscopy, Fourier Transform Infrared

Piperine, the major alkaloid constituent of black pepper, has been reported to possess a wide range of pharmacological effects on the central nervous system, including antidepressant, anticonvulsant and anti-ischemic activities. In the present study, we aimed to investigate the therapeutic potential and neuroprotective mechanisms of piperine in an experimental mouse model of sporadic Alzheimer's disease (sAD) induced by intracerebroventricular (ICV) infusion of streptozotocin (STZ). STZ was infused bilaterally at a dose of 1.5 mg/kg/day on day 1 and day 3. From day 8, piperine (2.5-10 mg/kg body weight) was administered intraperitoneally once daily for 15 consecutive days. The locomotor activity and cognitive performance of mice were evaluated using open field test and Morris water maze test, respectively. On day 23, all animals were sacrificed, and the hippocampus was used for biochemical, neurochemical and neuroinflammatory determinations. Our data revealed that the ICV-STZ-infused sAD mouse showed an increased oxidative-nitrosative stress, an altered neurotransmission and an elevated neuroinflammation in hippocampus, as well as significant cognitive deficits. All these alterations can be ameliorated by piperine in a dose-dependent manner. In summary, our findings predict a therapeutic potential of piperine against cognitive deficits in sAD mouse. This effect might be due to its abilities to ameliorate oxidative-nitrosative stress, restore neurotransmission and reduce neuroinflammation.

Topics: Alkaloids; Alzheimer Disease; Animals; Benzodioxoles; Cognition Disorders; Disease Models, Animal; Hippocampus; Inflammation; Infusions, Intraventricular; Male; Maze Learning; Memory Disorders; Mice; Neuroprotective Agents; Nitrogen; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Streptozocin

Topics: Algorithms; Alkaloids; Animals; Benzodioxoles; Binding Sites; Circular Dichroism; Hydrogen Bonding; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Piperidines; Polyunsaturated Alkamides; Protein Binding; Rats; Serum Albumin; Spectrometry, Fluorescence; Thermodynamics

Piperine, the principle pungent compound in black peppers, is known to activate the capsaicin receptor TRPV1 ion channel. How piperine interacts with the channel protein, however, remains unclear. Here we show that piperine binds to the same ligand-binding pocket as capsaicin but in different poses. There was no detectable detrimental effect when T551 and E571, two major sites known to form hydrogen bond with capsaicin, were mutated to a hydrophobic amino acid. Computational structural modeling suggested that piperine makes interactions with multiple amino acids within the ligand binding pocket, including T671 on the pore-forming S6 segment. Mutations of this residue could substantially reduce or even eliminate piperine-induced activation, confirming that T671 is an important site. Our results suggest that the bound piperine may directly interact with the pore-forming S6 segment to induce channel opening. These findings help to explain why piperine is a weak agonist, and may guide future efforts to develop novel pharmaceutical reagents targeting TRPV1.

Topics: Alkaloids; Animals; Benzodioxoles; Capsaicin; Hydrogen Bonding; Ion Channel Gating; Mice; Mutation; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship; TRPV Cation Channels

Supercritical fluid technologies offer an innovative method for food industry and drug discovery from natural sources. The aim of the study is to investigate the anti-tumor activity of piperine rich extract by supercritical fluid (SFE) from black pepper (Piper nigrum). In silico docking simulations predicted anti-tumor molecular mechanism and protein-piperine hydrophobic interactions, showing hydrogen bonds between piperine and residue Ser5 inside the ATP binding site in CDK2. Moreover, piperine interacts with peptide substrate residue Lys8 inside its binding site in Cyclin A molecule. Other predicted interaction showed piperine inside the hydrophobic groove of Bcl-xL. Confirming the docking simulation, in vitro assays with SFE (40 °C/30 MPa) showed cytotoxicity to MCF-7 cells (IC50 = 27.8 ± 6.8 μg/ml) correlated to increased apoptosis. Balb/c mice-bearing Ehrlich Ascites Carcinoma (EAC) group that received the SFE (100 mg/kg/day) showed tumor growth inhibition (60%) and increased mice survival (50%), probably related to cell cycle arrest (G2/M) and increased apoptosis. In vivo treatments with SFE increased the expression of pro-apoptotic proteins (p53 and Bax), inhibited cell cycle proteins (CDK2, Cyclin A) and anti-apoptotic protein (Bcl-xL). Thus, confirming in silico predicted inhibitory interactions. These results clearly showed promising performance of the piperine-rich fraction recovered from black pepper, drawing attention to its use as complementary therapy for cancer.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-X Protein; Benzodioxoles; Carbon Dioxide; Cyclin-Dependent Kinase 2; G2 Phase Cell Cycle Checkpoints; Humans; Male; MCF-7 Cells; Mice, Inbred BALB C; Molecular Docking Simulation; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Solid Phase Extraction

An ultra-high performance supercritical fluid chromatography-photodiode array detection-mass spectrometry (UHPSFC-MS) method for quality control of Piper longum L. has been developed and optimized. Hexane/isopropanol (70/30, v/v) was determined as the final injection solvent and methanol as the organic modifier. A design-of-experimental (DoE) approach was used to optimize column temperature, back-pressure and the gradient slope simultaneously using Trefoil CEL1 column. The back-pressure, temperature, flow rate were set at 130 bar, 32.5 °C and 1.0 mL/min, respectively. Positive electrospray ionization was used in the single ion monitoring mode. The 12 analytes were analyzed within 8 min using the optimized conditions. The linearities of the standard calibrations were satisfactory with coefficients of determination (R

Topics: Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Chromatography, Supercritical Fluid; Fruit; Limit of Detection; Mass Spectrometry; Methanol; Piper; Piperidines; Polyunsaturated Alkamides; Principal Component Analysis; Quality Control; Solvents; Temperature

Piperine, an alkaloid from black pepper, has demonstrated beneficial effects in central nervous system, especially in epilepsy control. However, its therapeutic application remains limited due to the low aqueous solubility of piperine. Thus, the present study aimed to formulate piperine into a more solubilized form to enhance its oral bioavailability and facilitate its development as a potential anti-epileptic treatment. The nanoprecipitation method was applied to prepare piperine nanoparticles, which were then examined under transmission electron microscopy. A spherical nanosized particle was obtained with small particle size (average particle size 130.20 ± 1.57 nm), narrow size distribution (polydispersity index 0.195 ± 0.002) and efficient entrapment (entrapment efficiency 92.2 ± 2.5%). Compared with the unformulated piperine, nanosized piperine had a much faster dissolution rate with 3 times higher accumulated drug release after 24 h. After oral administration at 3.5 mg/kg in rats, the nanosized piperine formulations could improve its oral bioavailability by 2.7-fold with 16 times higher concentrations in brain at 10 h postdosing. Moreover, the piperine nanoparticles exhibited effective protection against pentylenetetrazol-induced seizures in both zebrafish and mice. In summary, the present study provided a simple formulation strategy for oral administration of piperine to overcome its limitation in water solubility. The developed formulations could effectively enhance oral bioavailability of piperine with promising anti-epileptic effect, which could be applied as a potential therapy in epilepsy control.

Topics: Administration, Oral; Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Biological Availability; Drug Liberation; Embryo, Nonmammalian; Epilepsy; Male; Mice; Nanoparticles; Piperidines; Polyunsaturated Alkamides; Rats, Sprague-Dawley; Tissue Distribution; Zebrafish

Carbamazepine (CBZ) with piperine, the active ingredient in black pepper, which is omnipresent in food and may be potentially used for epilepsy control owing to its anticonvulsant effects, can be coadministered to epileptic patients. Since piperine has previously demonstrated its inhibition of the CYP3A-mediated metabolism of CBZ to carbamazepine-10,11-epoxide (CBZE), the present study aimed to investigate the impact of piperine on CBZ pharmacokinetics (PKs) in rats and pharmacodynamics in zebrafish and mouse acute seizure models. Plasma and brain PKs were studied in rats after a single-dose or 2-week combined oral administration of piperine (3.5/35 mg/kg, q.d.) and CBZ (40 mg/kg, t.i.d.) by blood sampling and brain microdialysis. Although no PK change was noticed after a single coadministration, significantly decreased plasma and brain concentrations of CBZ and CBZE with inhibited rat liver Cyp3a2 were demonstrated after long-term combined administration. Our developed compartmental model for the PK characterization of CBZ and CBZE in the blood and brain further estimated that coadministration with high-dose piperine could lead to decreases of 26%, 35%, and 38% in bioavailability, metabolism, and brain uptake of CBZ, respectively. Regardless of the PK changes, a limited impact on the antiepileptic effect of CBZ was found after the coadministration of CBZ and piperine in the tested seizure models. In conclusion, single-dose cotreatment of CBZ and piperine did not result in any significant PK or pharmacodynamic interactions, whereas their long-term cotreatment could lead to inhibited liver metabolism and the markedly reduced systemic and brain exposure of CBZ and CBZE.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Brain; Carbamazepine; Cytochrome P-450 Enzyme Inhibitors; Disease Models, Animal; Drug Interactions; Epilepsy; Liver; Male; Mice; Mice, Inbred C57BL; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Tissue Distribution; Zebrafish

The fruit from various pepper plants has been employed for the seasoning of food, as perfuming agents, and also as traditional medicines. Phytochemicals isolated from different pepper species have been found to modulate the pharmacokinetics of orally administered drugs. This study investigated the possibility to apply capsaicin and piperine (extracted alkaloids) as modulators for drug delivery across the nasal epithelium. Both a nasal epithelial cell line (RPMI 2650) and excised sheep nasal tissue were used as models to investigate the effects of the selected pepper compounds on drug permeation. FITC-dextran 4400 (MW 4400 Da) was used as a large molecular weight marker compound for paracellular transport, while rhodamine 123 was used as a marker compound that is a substrate for P-glycoprotein-mediated efflux. From the permeation results, it was clear that capsaicin inhibited P-glycoprotein efflux to a larger extent, while piperine showed drug permeation enhancement via other mechanisms. The cell cytotoxicity studies indicated that capsaicin was noncytotoxic up to a concentration of 200 µM and piperine up to a concentration of 500 µM as indicated by cell viability above 80%. The histological analysis of the excised nasal tissue and cultured RPMI 2650 cell layers indicated that some damage occurred after treatment with 200 µM capsaicin, but no changes were observed for piperine up to a concentration of 50 µM.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Capsaicin; Drug Delivery Systems; Nasal Mucosa; Pharmaceutical Vehicles; Piperidines; Polyunsaturated Alkamides; Sheep

Previously, we reported that piperine, one of the major pungent components in black pepper, attenuates adipogenesis by repressing PPARγ activity in 3T3-L1 preadipocytes. However, the epigenetic mechanisms underlying this activity remain unexplored. Here, gene set enrichment analysis using microarray data indicated that there was significant downregulation of adipogenesis-associated and PPARγ target genes and upregulation of genes bound with H3K27me3 in response to piperine. As shown by Gene Ontology analysis, the upregulated genes are related to lipid oxidation and polycomb repressive complex 2 (PRC2). Chromatin immunoprecipitation assays revealed that PPARγ (and its coactivators), H3K4me3, and H3K9ac were less enriched at the PPAR response element of three adipogenic genes, whereas increased accumulation of H3K9me2, H3K27me3, and Ezh2 was found, which likely led to the reduced gene expression. Further analysis using three lipolytic genes revealed the opposite enrichment pattern of H3K4me3 and H3K27me3 at the Ezh2 binding site. Treatment with GSK343, an Ezh2 inhibitor, elevated lipolytic gene expression by decreasing the enrichment of H3K27me3 during adipogenesis, which confirms that Ezh2 plays a repressive role in lipolysis. Overall, these results suggest that piperine regulates the expression of adipogenic and lipolytic genes by dynamic regulation of histone modifications, leading to the repression of adipocyte differentiation.

Topics: Adipocytes; Adipogenesis; Alkaloids; Benzodioxoles; Cell Differentiation; Histone Code; Humans; Piperidines; Polyunsaturated Alkamides

Topics: Acetylcysteine; Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Glutathione; Humans; Isomerism; Microsomes, Liver; Piperidines; Polyunsaturated Alkamides; Tandem Mass Spectrometry

High performance liquid chromatography is an integral analytical tool in assessing drug product stability. HPLC methods should be able to separate, detect, and quantify the various drug-related degradants that can form on storage or manufacturing, plus detect any drug-related impurities that may be introduced during synthesis.. A simple, economic, selective, precise, and stability-indicating HPLC method has been developed and validated for analysis of Rifampicin (RIFA) and Piperine (PIPE) in bulk drug and in the formulation.. Reversed-phase chromatography was performed on a C18 column with Buffer (Potassium Dihydrogen Orthophosphate) pH 6.5 and Acetonitrile, 30:70), (%, v/v), as mobile phase at a flow rate of 1 mL min-1.. The detection was performed at 341 nm and sharp peaks were obtained for RIFA and PIPE at retention time of 3.3 ± 0.01 min and 5.9 ± 0.01 min, respectively. The detection limits were found to be 2.385 ng/ml and 0.107 ng/ml and quantification limits were found to be 7.228ng/ml and 0.325ng/ml for RIFA and PIPE, respectively. The method was validated for accuracy, precision, reproducibility, specificity, robustness, and detection and quantification limits, in accordance with ICH guidelines.. Stress study was performed on RIFA and PIPE and it was found that these degraded sufficiently in all applied chemical and physical conditions. Thus, the developed RP-HPLC method was found to be suitable for the determination of both the drugs in bulk as well as stability samples of capsule containing various excipients.

Topics: Alkaloids; Benzodioxoles; Capsules; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Drug Stability; Hydrolysis; Limit of Detection; Piperidines; Polyunsaturated Alkamides; Rifampin

Deltamethrin (DLM) is a well-known pyrethroid insecticide which is widely used in the agriculture and home pest control due to restriction on the sale of organophosphate. DLM induced apoptosis is well known but its mechanism is still unclear. This study has been designed to find out its mechanism of apoptosis with the help of computational methods along with in vivo methods. The QikProp and ProTox results have shown that DLM has good oral absorption. The docking results reveal that DLM has a strong binding affinity toward the CD4, CD8, CD28 and CD45 receptors. Further, to understand the toxicity of DLM on lymphoid cells, a single dose of DLM (5 mg/kg, oral for seven days) has been administered to male Balb/c mice and cytotoxicity (MTT assay), oxidative stress indicators (glutathione, reactive oxygen species) and apoptotic markers (caspase-3 activity, DNA fragmentation) have been assessed in thymic and splenic single cell suspensions. Lowering of body weight, cellularity and loss in cell viability have been observed in DLM treated mice. The significant increase in ROS and GSH depletion in spleen and thymus, indicate the possible involvement of oxidative stress. The spleen cells appear more susceptible to the adverse effects of DLM than thymus cells. Further, for the amelioration of its effect, two structurally different bioactive herbal extracts, piperine and curcumin have been evaluated and have shown the cytoprotective effect by inhibiting the apoptogenic signaling pathways induced by DLM.

Topics: Alkaloids; Animals; Antioxidants; Apoptosis; Benzodioxoles; Caspase 3; Cell Survival; Curcumin; Cytoprotection; Glutathione; Insecticides; Male; Mice, Inbred BALB C; Molecular Docking Simulation; Nitriles; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Protein Binding; Protein Conformation; Pyrethrins; Reactive Oxygen Species; Receptors, Immunologic; Spleen; Structure-Activity Relationship; Thymus Gland; Time Factors

Serious side effects such as gastric intestinal ulcer, bleeding etc. are associated with most of the antiinflammatory and analgesic drugs. So, there is a need to search novel, potent, and safer antiinflammatory and analgesic drug.. Based on "biology-oriented synthesis approach", piperine alkaloid was isolated from Piper nigrum L. and some derivatives of piperine having azomethine, sulfamoyl, propanoyl, acetamoyl and heterocyclic oxadiazole were synthesized. The structures of synthetic derivatives were confirmed by using different spectroscopic techniques such as 1H-, 13C-NMR, EI-MS, and IR. Melting points were also determined for all compounds. Piperine and its all the synthetic derivatives were subjected to comparative in vivo evaluation of analgesic and antiinflammatory activities at the oral dose of 6 mg/kg/day. Analgesic activity was evaluated by tail immersion, hot plate and acetic acid writhing methods. While, antiinflammatory activity was evaluated by carrageenan-induced paw inflammation. In silico studies of all synthetic compounds was also conducted on COX-2 and adenosine kinase enzymes.. A number of derivatives showed enhanced antiinflammatory and analgesic activities as compared to piperine and standard drug diclofenac.. The newly identified molecules may serve as lead for the future research in connection of potent and safer antiinflammatory and analgesic drug candidate.

Topics: Adenosine Kinase; Alkaloids; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Cyclooxygenase 2 Inhibitors; Female; Humans; Male; Mice; Molecular Docking Simulation; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Cinnamates; Cytochrome P-450 Enzyme Inhibitors; Depsides; Drug Interactions; Piperidines; Plasma; Polyunsaturated Alkamides; Rats; Rosmarinic Acid

Staphylococcus aureus is often found in orthopaedic infections and may be protected from commonly prescribed antibiotics by forming biofilms or growing intracellularly within osteoblasts. To investigate the effect of non-antibiotic compounds in conjunction with antibiotics to clear intracellular and biofilm forming S. aureus causing osteomyelitis. SAOS-2 osteoblast-like cell lines were infected with S. aureus BB1279. Antibiotics (vancomycin, VAN; and dicloxacillin, DICLOX), bacterial efflux pump inhibitors (piperine, PIP; carbonyl cyanide m-chlorophenyl hydrazone, CCCP), and bone morphogenetic protein (BMP-2) were evaluated individually and in combination to kill intracellular bacteria. We present direct evidence that after gentamicin killed extracellular planktonic bacteria and antibiotics had been stopped, seeding from the infected osteoblasts grew as biofilms. VAN was ineffective in treating the intracellular bacteria even at 10× MIC; however in presence of PIP or CCCP the intracellular S. aureus was significantly reduced. Bacterial efflux pump inhibitors (PIP and CCCP) were effective in enhancing permeability of antibiotics within the osteoblasts and facilitated killing of intracellular S. aureus. Confocal laser scanning microscopy (CLSM) showed increased uptake of propidium iodide within osteoblasts in presence of PIP and CCCP. BMP-2 had no effect on growth of S. aureus either alone or in combination with antibiotics. Combined application of antibiotics and natural agents could help in the treatment of osteoblast infected intracellular bacteria and biofilms associated with osteomyelitis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1086-1092, 2018.

Topics: Alkaloids; Anti-Bacterial Agents; Benzodioxoles; Bone Morphogenetic Protein 2; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Cell Line, Tumor; Dicloxacillin; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Host-Pathogen Interactions; Humans; Microbial Sensitivity Tests; Osteoblasts; Osteomyelitis; Piperidines; Polyunsaturated Alkamides; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Piperine has been shown to have antioxidant activity and a cognitive-enhancing effect following long-term oral administration. In a comparative study of memantine, the current investigation threw light on the cognitive benefits of piperine. Lipid peroxidation and the ferric reducing antioxidant power (FRAP) of cerebrospinal fluid (CSF) and hippocampus in streptozotocin (STZ)-induced experimental dementia of the Alzheimer's type was measured. After reaching a criterion in a memory test, STZ-induced rats received piperine [2.5, 5, and 10mg/kg, intraperitoneally (i.p.)], vehicle, and memantine (10mg/kg, i.p.) for two weeks after the first STZ administration, or two weeks before and one week after, as a preventive approach. After the behavioral studies, samples were taken for biochemical and histological assays. An appropriate concentration of piperine (2.5mg/kg), on a daily basis, effectively increased the number of correct (non-repeated) arm entries and repressed reentry to a previously visited arm, in terms of reference errors as well as memantine (10mg/kg, i.p.), irrespective of the dose administered. The cognitive-enhancing effect induced by piperine at a relevant dose was simultaneous with CSF and hippocampal malonaldehyde decrement, and the redox balance was established to some extent by maintaining the FRAP levels of CSF near to those of the control. Similarly, the neuroprotective properties of piperine are in accordance with histopathological outcomes, which have shown an increased number of live cresyl violet (CV)-positive neurons in a dentate gyrus (DG) subregion. Therefore, the effects of piperine on the redox balance of CSF and hippocampal neurons may certainly contribute to the cognitive-enhancing activity of the drug.

Topics: Alkaloids; Analysis of Variance; Animals; Antibiotics, Antineoplastic; Avoidance Learning; Benzodioxoles; Cognition Disorders; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Hippocampus; Lipid Peroxidation; Male; Malondialdehyde; Maze Learning; Memantine; Memory, Short-Term; Neurons; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Streptozocin

Recent evidence suggests that encapsulation of hydrophobic drugs in biodegradable polymers opens a new horizon in nanomedicine filed. Piperine, a main alkaloid form of black pepper possesses potent anticonvulsant activity. However, the low water solubility of piperine has limited its clinical application. In this study, piperine was loaded on chitosan-sodium tripolyphosphate nanoparticles (CS-STPP NPs) and the effect of piperine NPs on seizures behavior and astrocytes activation was assessed in pentylentetrazol (PTZ)-induced kindling model. Animals have received the daily injection of free piperine or piperine NPs at doses of 5 or 10mg/kg, 10days before PTZ injections and their intraperitoneally (i.p) administration continued until the last PTZ injection. The neuroprotective effects of piperine NPs were evaluated using nissl staining and immunostaining against NeuN. Astrocytes activation was examined by GFAP immunostaining. Behavioral data showed that piperine NPs have inhibited the development of seizure parameters compared to the free piperine groups. In addition, the levels of cell loss and astrocytes activation were reduced in piperine NPs groups. In conclusion, these data suggest that piperine NPs enhance the neuroprotection and ameliorate the astrocytes activation in chemical kindling model of epilepsy. This may provide an effective therapeutic strategy for the treatment of epilepsy disorder.

Topics: Alkaloids; Animals; Astrocytes; Benzodioxoles; Chitosan; Disease Models, Animal; Epilepsy; Humans; Hydrophobic and Hydrophilic Interactions; Kindling, Neurologic; Mice; Nanoparticles; Neurons; Organophosphorus Compounds; Pentylenetetrazole; Piperidines; Polyunsaturated Alkamides; Stearic Acids

Parkinson's disease (PD) is a multifactorial neurological disorder caused by selective dopaminergic neuronal loss. Quercetin (QC) in combination with piperine (bioenhancer) acts as potential antioxidant, anti-inflammatory and neuroprotective against 6-OHDA rat model of PD. Rats were injected 6-OHDA (8μg/2μl, saline) unilaterally, intranigrally once into right SNpc. Pre-treatment with QC (25 and 50mg/kg, p.o.) alone and combination of QC (25mg/kg, p.o.) with piperine (2.5mg/kg, p.o.) were given for 14days starting from 8th day of 6-OHDA infusion. Post lesions were confirmed by rotational behavior with amphetamine (2.5mg/kg, i.p.) and motor coordination was assessed by narrow beam walk, open field and rotarod apparatus on the weekly basis. On 22nd day, animals were sacrificed and striatum homogenates were used for biochemical (LPO, GSH, Nitrite), neuroinflammatory (TNF-α, IL-1 β and IL-6) and neurotransmitter (dopamine, norepinephrine, serotonin, GABA, glutamate) analysis. Rats pre-treated with QC alone and in combination with piperine have significantly attenuated the 6-OHDA induced rotational behavior and motor deficits. Further, these drugs have significantly improved antioxidant potential, decreased striatal proinflammatory cytokines level as well as restored neurotransmitters level. The neuroprotective enhancement of QC along with piperine is attributed through antioxidant, anti-inflammatory and preventing neurotransmitter alteration mechanisms.

Topics: Alkaloids; Animals; Benzodioxoles; Brain Chemistry; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glutathione; Hand Strength; Locomotion; Male; Neurodegenerative Diseases; Neuroprotective Agents; Neurotransmitter Agents; Nitrites; Oxidopamine; Piperidines; Polyunsaturated Alkamides; Psychomotor Performance; Quercetin; Rats; Rats, Wistar; Sympatholytics; Thiobarbituric Acid Reactive Substances; Time Factors

Black pepper (Piper nigrum) contains a variety of alkamides. Among them, piperine has been reported to have antidepressant-like effects in chronically stressed mice, but little is known about the biological activity of other alkamides. In this study, we investigated the effects of alkamides from white pepper (P. nigrum) on neuronal cells. Twelve alkamides were isolated from white pepper MeOH extracts, and their chemical structures were identified by NMR and MS analyses. The compounds were subjected to assays using the luciferase-reporter gene under the control of the BDNF promoter or cAMP response element in mouse neuroblastoma Neuro-2a cells. In both assays, marked reporter-inducing activity was observed for piperine (1), piperettine (2) and piperylin (7), all of which have in common an (E)-5-(buta-1,3-dien-1-yl)benzo[d] [1, 3] dioxole moiety. Piperettine (2) and piperylin (7) tended to increase endogenous BDNF protein levels. Furthermore, piperylin (7) promoted retinoic acid-induced neurite outgrowth. These results suggest that piperylin (7), or analogues thereof, may have a beneficial effect on disorders associated with dysregulation of BDNF expression, such as depression.

Topics: Alkaloids; Animals; Benzodioxoles; Brain-Derived Neurotrophic Factor; Mice; Neuronal Outgrowth; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Transfection

Piperine amide analogs are synthesized by replacement of the piperidine moiety with different types of cyclic amines, including adamantyl and monoterpene-derived fragments. The compounds are screened for activity against Mycobacterium tuberculosis H37Rv. The most potent compounds are the 1-adamantyl and the monoterpene-derived hybrids, which combine nanomolar antimycobacterial activity with low cytotoxicity against human cells. The presence of quaternary carbon atom as main structural requirement for anti-TB activity is pointed out by a QSAR study. The most promising compound is the (+)-isopinocampheylamine-derived amide which is characterized with selectivity index of 1387.8.

Topics: Alkaloids; Antitubercular Agents; Benzodioxoles; Mycobacterium tuberculosis; Piperidines; Polyunsaturated Alkamides

To investigate compound-protein binding mode and molecular dynamic simulation of P-glycoprotein (P-gp), in silico studies were performed to compare 12 naturally occurring compounds using two softwares. The net results showed that piperine (PIP) had the best binding affinity. In vitro studies on doxorubicin (DOX)-resistant NCI/ADR-RES cells, known to express P-gp, showed that, dose-dependently, PIP significantly increased intracellular accumulation of rhodamine-123 and had cytotoxic effects accessed by MTT assay. In addition, PIP at 25 and 50μM significantly potentiated DOX-induced cytotoxicity on the same cell line. P-gp ATPase assay showed that both DOX and PIP had dose-dependent inhibition of orthovandate-sensitive ATPase activity, indicating they are both P-gp inhibitors, with IC

Topics: Adenosine Triphosphatases; Alkaloids; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B; Benzodioxoles; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Resistance, Neoplasm; Humans; Molecular Docking Simulation; Piperidines; Polyunsaturated Alkamides

NO donor drugs showed a significant therapeutic effect in the treatment of many diseases, such as arteriopathies, various acute and chronic inflammatory conditions, and several degenerative diseases. NO-releasing anti-inflammatory drugs are the prototypes of a novel class of compounds, combining the pharmacological activities of anti-inflammatory and anti-nociceptive of drugs with those of NO, thus possessing potential therapeutic applications in a great variety of diseases. In this study, we designed and predicted biological activity by targeting cyclooxygenase type 2 (COX-2) and NF-κB subunits and pharmacological profiling along with toxicity predictions of various N-aryl piperamides linked via an ester bond to a spacer that is bound to a NO-releasing moiety (-ONO2). The result of absorption, distribution, metabolism and excretion and Docking studies indicated that among 51 designed molecules PA-3'K showed the best binding potential in both the substrate and inhibitory binding pocket of the COX-2 enzyme with affinity values of -9.33 and -5.12 for PDB ID 1CVU and 3LN1, respectively, thereby having the potential to be developed as a therapeutic agent. The results of cell viabilities indicated that PA-3'k possesses the best cell viability property with respect to its dose (17.33 ng/ml), with 67.76% and 67.93% viable cells for CHME3 and SVG cell lines, respectively.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Cell Line; Computer Simulation; Cyclooxygenase 2 Inhibitors; Drug Design; Humans; Models, Molecular; Molecular Docking Simulation; Neuritis; NF-kappa B; Nitric Oxide Donors; Piperidines; Polyunsaturated Alkamides; Protein Transport; Structure-Activity Relationship; Tissue Distribution

Piperine is an alkaloid responsible for the pungency of black pepper and long pepper. It is reported to have various biological actions such as anti-oxidative and anti-inflammatory, and aids cancer prevention. Antioxidants have been shown to promote osteoblast differentiation. However, osteoblast differentiation by piperine has not yet been elucidated. Piperine-induced expression of the osteogenic genes such as distal-less homeobox 5 (Dlx5), inhibitor of DNA binding-1 (Id1), and runt-related transcription factor 2 (Runx2) was investigated using RT-PCR. In addition, alkaline phosphatase (ALP) activity and mineralization was found to be increased by piperine treatment. Finally, we confirmed that piperine induced phosphorylation of AMPK in MC3T3-E1 cells. Taken together, these results demonstrate that piperine enhance osteoblast differentiation through AMPK phosphorylation in MC3T3-E1 cells.

Topics: 3T3 Cells; Alkaloids; AMP-Activated Protein Kinase Kinases; Animals; Antioxidants; Benzodioxoles; Cell Differentiation; Core Binding Factor Alpha 1 Subunit; Dose-Response Relationship, Drug; Gene Expression Regulation, Developmental; Mice; Osteoblasts; Osteogenesis; Piperidines; Polyunsaturated Alkamides; Protein Kinases

In a screening of natural products for allosteric modulators of GABA

Topics: Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Humans; Microsomes, Liver; Piperidines; Polyunsaturated Alkamides; Receptors, GABA-A; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Darunavir ethanolate (DRV) is an efficient protease inhibitor (PI) used in the treatment of human immunodeficiency virus (HIV) type-1 patients. An isocratic reversed-phase HPLC method was developed to monitor concentration of darunavir in in vitro intestinal fluid samples in everted sac absorption model in the presence of bioenhancers, viz., piperine, quercetin, naringenin. The method was validated and successfully applied to everted sac and pharmacokinetic studies in rats. The absorption profiles of DRV and apparent permeability coefficients were determined. The proposed method was found to be simple, rapid, robust and selective and was applied for continuous ex vivo monitoring of DRV in everted sac absorption studies. Of the three bioenhancers screened at different concentrations, piperine caused highest and significant 1.5-fold increase in apparent permeability of DRV across everted sac tissue. Further, co-administration of piperine significantly increased the maximum plasma concentration of DRV by 1.18-fold confirming the enhancement in its absorption.

Topics: Alkaloids; Animals; Benzodioxoles; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Darunavir; Flavanones; Intestinal Absorption; Limit of Detection; Linear Models; Male; Piperidines; Polyunsaturated Alkamides; Quercetin; Rats; Rats, Wistar; Reproducibility of Results

Spinocerebellar ataxia 17 (SCA17) belongs to the family of neurodegenerative diseases caused by polyglutamine (polyQ) expansion. In SCA17, polyQ expansion occurs in the TATA box binding protein (TBP) and leads to the misfolding of TBP and the preferential degeneration in the cerebellar Purkinje neurons. Currently there is no effective treatment for SCA17. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a recently identified neurotrophic factor, and increasing MANF expression ameliorated SCA17 neuropathology in TBP-105Q knock-in (KI) mouse model, indicating that MANF could be a therapeutic target for treating SCA17.. In this study, we screened a collection of 2000 FDA-approved chemicals using a stable cell line expressing luciferase reporter, which is driven by MANF promoter. We identified several potential candidates that can induce the expression of MANF. Of these inducers, piperine is an agent that potently induces the luciferase expression or MANF expression.. Addition of piperine in both cellular and mouse models of SCA17 alleviated toxicity caused by mutant TBP. Although mutant TBP is primarily localized in the nuclei, the polyQ expansion in TBP is able to induce ER stress, suggesting that nuclear misfolded proteins can also elicit ER stress as cytoplasmic misfolded proteins do. Moreover, piperine plays its protective role by reducing toxicity caused by the ER stress.. Our study established piperine as a MANF-based therapeutic agent for ER stress-related neuropathology in SCA17.

Topics: Alkaloids; Animals; Benzodioxoles; Brain; Endoplasmic Reticulum Stress; Mice; Mice, Transgenic; Nerve Degeneration; Nerve Growth Factors; Neuroprotective Agents; Piperidines; Polyunsaturated Alkamides; TATA-Box Binding Protein

Pungent spice constituents such as piperine, capsaicin and [6]-gingerol consumed via daily diet or traditional Chinese medicine, have been reported to possess various pharmacological activities. These dietary phytochemicals have also been reported to inhibit P-glycoprotein (P-gp) in vitro and act as an alternative to synthetic P-gp modulators. However, the in vivo effects on P-gp inhibition are currently unknown. This study aimed to test the hypothesis that phytochemical P-gp inhibitors, i.e., piperine, capsaicin and [6]-gingerol, modulate the in vivo tissue distribution of doxorubicin, a representative P-gp substrate. Mice were divided into four groups and each group was pretreated with intraperitoneal injections of control vehicle, piperine, capsaicin, or [6]-gingerol and doxorubicin (1 mg/kg) was administered via the penile vein. The concentrations of the phytochemicals and doxorubicin in the plasma and tissues were determined by LC-MS/MS. The overall plasma concentration-time profiles of doxorubicin were not significantly affected by piperine, capsaicin, or [6]-gingerol. In contrast, doxorubicin accumulation was observed in tissues pretreated with piperine or capsaicin. The tissue to plasma partition coefficients, K

Topics: Alkaloids; Animals; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Transport; Capsaicin; Catechols; Doxorubicin; Fatty Alcohols; Mice; Phytochemicals; Piperidines; Polyunsaturated Alkamides; Tissue Distribution

Ginsenoside Rh2 (Rh2) is one of the major bioactive ginsenosides in Panax ginseng. However, the oral bioavailability of Rh2 is low, with P-glycoprotein (P-gp) and CYP3A4 being reported to be the main factors. The purpose of the present study was to determine the enhancing effect of piperine on the oral bioavailability as well as bioactivity of Rh2. The inhibitory effect of piperine on P-gp and CYP3A4 was determined using a Caco-2 monolayer model and a recombinant CYP3A4 metabolic system, respectively. The pharmacokinetics of oral Rh2 (10 mg·kg

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biological Availability; Caco-2 Cells; Cytochrome P-450 CYP3A; Drugs, Chinese Herbal; Ginsenosides; Humans; Interleukin-2; Panax; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley

Piperine, an alkaloid derived from natural products, has been demonstrated to exert antitumor activities in vivo and in vitro. However, its anti‑tumor effect has not yet been illustrated in the prostate cancer (PCa) metastatic process. Thus, the present study explored the influence of piperine on PCa and the underlying molecular mechanism. Cell migration was detected via the Transwell chamber model. Total protein was identified by western blot analysis. The data revealed that piperine markedly repressed cell proliferation and migration, and induced apoptosis in PCa DU145. In addition, LY294002, an protein kinase B (Akt) inhibitor, greatly suppressed the expression level of phospho (p)‑Akt, matrix metalloproteinase (MMP)‑9 and p‑mammalian target of rapamycin (mTOR), suggesting that the activation of the Akt/mTOR/MMP‑9 signaling pathway may participate in regulating cell migration in PCa. Furthermore, piperine reduced the expression of p‑Akt, MMP‑9 and p‑mTOR. Together, these data indicated that piperine may serve as a promising novel therapeutic agent to better overcome PCa metastasis.

Topics: Alkaloids; Apoptosis; Benzodioxoles; Cell Line, Tumor; Cell Movement; Chromones; Humans; Male; Matrix Metalloproteinase 9; Morpholines; Neoplasm Metastasis; Piperidines; Polyunsaturated Alkamides; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

The MTT assay was first used to determine the cytotoxicity of doxorubicin, the alkaloids, and digitonin alone, and then their combinations. Furthermore, rhodamine (Rho) 123 and calcein-AM were used to detect the effects of alkaloids on the activity of P-gp.. Capsaicin and piperine synergistically enhanced the cytotoxicity of doxorubicin in Caco-2 and CEM/ADR 5000 cells. Furthermore, capsaicin and piperine increased the intracellular accumulation of the fluorescent P-glycoprotein (P-gp) substrates rhodamine and calcein and inhibited their efflux from the MDR cell lines.. Our study has demonstrated that capsaicin and piperine are P-gp substrates and have potential chemosensitizing activity, which might be interesting for the development of novel modulators of multidrug resistance.

Topics: Alkaloids; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Transport; Caco-2 Cells; Capsaicin; Capsicum; Cell Line, Tumor; Doxorubicin; Drug Combinations; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Fluoresceins; Gene Expression; HCT116 Cells; Humans; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rhodamine 123

Phase II biotransformation reactions have been gaining more attention due to their acknowledged significance in drug bioavailability, drug development, and drug-drug interactions. However, the predominant role of phase I metabolism has always overshadowed phase II metabolism, resulting in insufficient data regarding its mechanisms. In this paper, we investigate the effect of an advanced lipid based formulation on the phase II metabolism process of glucuronidation, occuring in the enterocytes monolayer. The investigated formulation is a self-emulsifying drug delivery system, termed pro-nano lipospheres, which contains the natural absorption enhancer piperine. To evaluate the effect of this formulation on direct glucuronidation we chose the model molecule raloxifene. First, glucuronidation is the main clearance pathway of this compound without involvement of preceding mechanisms. Second, raloxifene's extensive glucuronidation site is primarily at the intestine. Raloxifene's oral bioavailability was determined in a series of pharmacokinetic experiments using the freely moving rat model. In order to test the effect of the formulation on the relevant UGT enzymes reported in the clinic, we used the in vitro method of UGT-Glo Assay. Coadministration of raloxifene and piperine pro-nano lipospheres to rats resulted in a 2-fold increase in the relative oral bioavailability of raloxifene. However, coadministration of raloxifene with blank pro-nano lipospheres had no effect on its oral bioavailability. In contrast to the difference found in vivo between the two vehicles, both formulations extended an inhibitory effect on UGT enzymes in vitro. Ultimately, these findings prove the ability of the formulation to diminish intestinal direct phase II metabolism which serves as an absorption obstacle for many of today's marketed drugs. Pro-nano lipospheres is a formulation that serves as a platform for the simultaneous delivery of the absorption enhancer and a required drug. The discrepancy found between the in vivo and in vitro models demonstrates that the in vitro method may not be sensitive enough to distinguish the difference between the formulations.

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biological Availability; Chemistry, Pharmaceutical; Drug Delivery Systems; Emulsions; Excipients; Intestines; Lipids; Male; Metabolic Detoxication, Phase II; Nanoparticles; Piperidines; Polyunsaturated Alkamides; Raloxifene Hydrochloride; Rats; Rats, Wistar

Brain tumor has a low prognosis with only 15% survival rate (5 years after diagnosis). Many of the current therapeutics have limited activity due to their inability to cross the blood brain barrier which retards drug accumulation in tumor site and causes drug resistance. Piperine, a phytochemical drug with poor solubility, could be an alternative to current therapeutics after evading its solubility and permeability limitations. Piperine micellization was optimized to improve drug solubility. Positively charged trimethyl-chitosan was synthesized then electrostatically adsorbed onto piperine nanomicelles forming core-shell nanoparticles. Physicochemical and morphological characterizations, and in-vitro release were performed. Cytotoxicity on human brain cancer cell line (Hs683) was evaluated using IC50 determination, cell cycle arrest analysis, apoptosis and enzyme-linked immunosorbent assay. Optimum piperine-loaded core-shell nanoparticles were successfully fabricated with double-phase release model. Significant improvement in cytotoxicity than free drug was noted with increasing in G2/M-phase and pre-GI-phase population, apoptotic/necrotic rates and inhibition of CDK2a.

Topics: Alkaloids; Antineoplastic Agents; Apoptosis; Benzodioxoles; Brain Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Chitosan; Drug Carriers; Drug Liberation; Humans; Inhibitory Concentration 50; Micelles; Nanoparticles; Piperidines; Polyunsaturated Alkamides; Solubility

Topics: Alkaloids; Antiprotozoal Agents; Benzodioxoles; Capsaicin; Chromatography, High Pressure Liquid; Drug Synergism; Inhibitory Concentration 50; Leishmania infantum; Leishmaniasis, Visceral; Magnetic Resonance Spectroscopy; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Piperidines; Polyunsaturated Alkamides; Spectrophotometry, Ultraviolet

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).\ \ This article has been retracted at the request of the Editor-in-Chief.\ \ Given the comments of Dr Elisabeth Bik regarding this article “… the Western blot bands in all 400+ papers are all very regularly spaced and have a smooth appearance in the shape of a dumbbell or tadpole, without any of the usual smudges or stains. All bands are placed on similar looking backgrounds, suggesting they were copy/pasted from other sources, or computer generated”, the journal requested the authors to provide the raw data. However, the authors were not able to fulfil this request and therefore the Editor-in-Chief decided to retract the article.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Apoptosis; Benzodioxoles; Cell Line; Cell Survival; Chondrocytes; Cytokines; Dose-Response Relationship, Drug; Down-Regulation; Inflammation; Lipopolysaccharides; Mice; MicroRNAs; Myeloid Differentiation Factor 88; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Up-Regulation

Topics: Alkaloids; Anthracenes; Apoptosis; Benzodioxoles; Caspase 3; Caspase 9; Caspase Inhibitors; Cell Proliferation; Cell Survival; Female; Humans; Imidazoles; MAP Kinase Kinase 4; Oligopeptides; Ovarian Neoplasms; p38 Mitogen-Activated Protein Kinases; Piperidines; Polyunsaturated Alkamides; Pyridines; Tumor Suppressor Proteins

Malaria continues to be a major health concern and affects more than 200 million people a year. Drugs currently used for treatment of malaria are increasingly rendered ineffectual by the ongoing emergence of parasite resistance. For any new drugs, however, knowledge of their membrane permeability is an essential pre-requisite for eventual use. Treatment failure and emergence of resistance can occur as a result of reduced availability of the drug at the desired site of action. Cellbased permeability assays such as Caco-2 cell monolayers serve as a model for predicting drug absorption and efflux, and provide an estimate of drug bioavailability.. Here we have studied the bi-directional transport of new anti-malarial compounds, artemisone and artemiside, as well as reference compounds, namely the known anti-malarial drug artemether, and caffeine and atenolol.. The Caco-2 cell monolayer model was used to assess the membrane permeation properties of these compounds, and to identify if they are subject to P-gp associated efflux, in the presence and absence of verapamil. The effect of piperine on the transport of the compounds that were identified to be P-gp substrates was also assessed. Samples withdrawn from the acceptor chambers at pre-determined time intervals were analysed by means of high-performance liquid chromatography (HPLC).. Transport results in terms of the absorptive direction revealed that artemisone and artemether had low absorption rates relative to the reference compounds. It was further demonstrated that artemisone is slightly effluxed, and although both artemether and artemiside were susceptible to P-gp mediated efflux, it appears that other efflux proteins may also be involved.. The low permeability of anti-malarial drugs must be borne in mind during development of effective dosage regimens of new drugs.

Topics: Alkaloids; Antimalarials; Artemisinins; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Transport; Caco-2 Cells; Humans; Permeability; Piperidines; Polyunsaturated Alkamides; Verapamil

Persistent activation of the mechanistic target of rapamycin complex 1 (mTORC1) is linked to sustained inflammation and progression of colorectal cancer. Widely available dietary phenolics, curcumin and piperine are purported to have antiinflammatory and anticarcinogenic activities through yet-to-be-delineated multitarget mechanisms. Piperine is also known to increase the bioavailability of dietary components, including curcumin. The objective of the study was to determine whether curcumin and piperine have individual and combined effects in the setting of gut inflammation by regulating mTORC1 in human intestinal epithelial cells. Results show that curcumin repressed (a) mTORC1 activity (measured as changes in the phosphorylation state of p70 ribosomal protein S6 kinase B1 and 40S ribosomal protein S6) in a dose-dependent manner (2.5-20 μM, P<.007) and (b) synthesis of nascent proteins. Piperine inhibited mTORC1 activity albeit at comparatively higher concentrations than curcumin. The combination of curcumin + piperine further repressed mTORC1 signaling (P<.02). Mechanistically, curcumin may repress mTORC1 by preventing TSC2 degradation, the conserved inhibitor of mTORC1. Results also show that a functional mTORC1 was required for the transcription of TNFα as Raptor knockdown abrogated TNFα gene expression. Curcumin, piperine and their combination inhibited TNFα gene expression at baseline but failed to do so under conditions of mTORC1 hyperactivation. TNF∝-induced cyclooxygenase-2 expression was repressed by curcumin or curcumin + piperine at baseline and high mTORC1 levels. We conclude that curcumin and piperine, either alone or in combination, have the potential to down-regulate mTORC1 signaling in the intestinal epithelium with implications for tumorigenesis and inflammation.

Topics: Alkaloids; Benzodioxoles; Caco-2 Cells; Cell Differentiation; Curcumin; Cyclooxygenase 2; Drug Synergism; HT29 Cells; Humans; Mechanistic Target of Rapamycin Complex 1; Piperidines; Polyunsaturated Alkamides; Protein Synthesis Inhibitors; Signal Transduction; Tuberous Sclerosis Complex 2 Protein; Tumor Necrosis Factor-alpha

Piperine (E,E-) is a naturally occurring pungent and spicy constituent of black pepperand is also used as an added flavoring ingredient to foods and beverages. Piperine has been determined safe under conditions of intended use as a flavoring substance by regulatory and scientific expert bodies. While concurring with the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and Flavor and Extract Manufacturers Association (FEMA) Expert Panel on the safety of piperine, the European Food Safety Authority (EFSA) requested additional toxicological data. The results of a 90-day GLPcompliant dietary study, conducted in Sprague-Dawley rats at target doses of 0, 5, 15, or 50 mg/kg bw/day, to respond to this request are presented herein. No adverse effects were found attributable to ingestion of piperine. Statistically significant changes in food consumption, body weight gain, and plasma cholesterol levels were not considered adverse as discussed in this paper. Therefore, the oral no-observed-adverse-effect level (NOAEL) was determined to be the highest dose tested of 50 mg/kg bw/day. EFSA derived a lower NOAEL of 5 mg/kg bw/day based on increased plasma cholesterol levels which still affords an adequate margin of safety of over 48,000 and concluded that piperine is not of safety concern.

Topics: Alkaloids; Animals; Benzodioxoles; Cholesterol; Dietary Exposure; Dose-Response Relationship, Drug; Feeding Behavior; Female; Male; No-Observed-Adverse-Effect Level; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Weight Gain

Allergic asthma is an inflammatory condition accompanied by inflammation as well as oxidative stress. Supplementation of an anti-inflammatory agent having antioxidant properties may have therapeutic effects against this disease. Over the recent decades, the interest in combination therapy as new alternative medication has increased and it offers numerous benefits along with noticeable lack of toxicity as well as side effects. In this study, protective effects of curcumin alone and in combination with piperine were evaluated in mouse model of allergic asthma. Balb/c mice were sensitized on days 0, 7, and 14 and challenged from days 16-30 on alternate days with ovalbumin (OVA). Mice were pretreated with curcumin (Cur; 10 and 20 mg/kg) and piperine (Pip; 5 mg/kg) alone and in combination via the intraperitoneal route on days 16-30 and compared with intranasal curcumin (5 mg/kg) treatment. Blood, bronchoalveolar lavage fluid (BALF), and lungs were collected after mice were sacrificed on day 31st. Mice immunized with OVA have shown significant increase in airway inflammation and oxidative stress as determined by oxidative stress markers. A significant suppression was observed with all the treatments, but intranasal curcumin treatment group has shown maximum suppression. So, among all the treatment strategies utilized, intranasal curcumin administration was most appropriate in reducing inflammation and oxidative stress and possesses therapeutic potential against allergic asthma. Present study may prove the possibility of development of curcumin nasal drops towards treatment of allergic asthma.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Asthma; Benzodioxoles; Bronchoalveolar Lavage Fluid; Curcumin; Drug Administration Routes; Drug Therapy, Combination; Inflammation; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Oxidative Stress; Piperidines; Polyunsaturated Alkamides

Topics: Alkaloids; Antineoplastic Agents; Apoptosis; Bee Venoms; Benzodioxoles; Biomarkers, Tumor; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Resistance, Multiple; Drug Synergism; Estrogen Receptor alpha; Female; Hesperidin; Humans; MCF-7 Cells; Piperidines; Polyunsaturated Alkamides; RNA, Messenger; Tamoxifen; Up-Regulation

Tuberculosis (TB) is an important public health problem worldwide and the emergence of multidrug-resistant (MDR) TB and extensively drug-resistant (XDR) TB worsened the global context. The resistance in Mycobacterium tuberculosis, the causative agent of TB, can partially derive from efflux pumps (EPs) activity in plasma membrane. Due to the recent discovery of piperine (PIP), an organic alkaloid compound, increasing the bioavailability of various drugs, the current assay evaluated the combined activity of PIP and anti-TB drugs in susceptible and resistant M. tuberculosis clinical isolates. The minimum inhibitory concentrations for isoniazid, rifampicin, ethambutol, streptomycin and PIP were determined by resazurin microtiter assay and the combined effects of anti-TB drugs with PIP determined by resazurin drug combination microtiter assay and time-kill curve. The efflux pump inhibitor activity of PIP was determined by bromide accumulation assay and cytotoxicity carried out in VERO cells and J774. A1 macrophages. PIP showed to have EPI activity and RIF + PIP and SM + PIP combinations showed synergistic effect, but low effect in enhancing the killing in M. tuberculosis H

Topics: Alkaloids; Animals; Antitubercular Agents; Bacterial Proteins; Benzodioxoles; Chlorocebus aethiops; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Membrane Transport Proteins; Microbial Sensitivity Tests; Microbial Viability; Mycobacterium tuberculosis; Piperidines; Polyunsaturated Alkamides; Vero Cells

Interactions of cancer cells with their microenvironment play a significant role in defining the severity of the disease. In search of novel compounds with anti-inflammatory and anticancerous capabilities, the effects of purified compound piperine were investigated in Neuro-2a cell line. The neuronal lineage of Neuro-2a cell line was confirmed by using antibody against β-III tubulin protein. The cells were treated with different concentrations of piperine (μM: 10, 50 and 100) for 48 hrs at 37ºC. A dose of 100 µM was selected that induces a 50% inhibition in the cell growth calculated by MTT and morphometery assays. The result shows that in the presence of piperine neurite outgrowth was decreased in a dose dependent manner. The gene expression of TN-C, TNfnD and TnfnC were significantly reduced whereas the expression intensities of TnfnA1, TnfnA2, CSPGs and Laminin were significantly elevated when compared to their respective untreated controls. Similarly proinflammatory marker COX-2 expression was significantly inhibited in the presence of piperine when compared to untreated controls. This is the first time we have illustrated that irrespective of increased expressions of CSPGs, a significant reduction in Tenascin-C and its TNfnD and TNfnC domains are necessary to inhibit the tumor progression. Taken together, the capabilities of piperine to induce an apoptosis by decreasing the neurite outgrowth, proliferation rate and expression of TN-C and COX-2 in Neuro-2a cell line confirmed for its anticancerous and anti-inflammatory potential.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Benzodioxoles; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Neurons; Piperidines; Polyunsaturated Alkamides

Alzheimer's disease (AD) is a neurodegenerative disorder that has no cure till now. Piperine (PIP) is an alkaloid characterized by memory-enhancing properties but challenging oral delivery obstacles. The objectives of this study are as follows: preparation of microemulsion (ME) as a proposed oral PIP nanocarrier for treatment of Alzheimer's disease and testing its safety on the brain and other internal organs. This study employs bioactive surfactants in the common safe doses to improve PIP targeting to the brain. Selected ME systems encompassed Caproyl 90 (oil)/Tween 80/Cremophor RH 40 (surfactant) and Transcutol HP (co-surfactant). The particle size of the prepared formulations was less than 150 nm with negative zeta potential. The in vivo results showed a superior effect of ME over free PIP. Colchicine-induced brain toxicity results showed the safety of ME on brain cells. Nevertheless, toxicological results showed a potential ME nephrotoxicity. Oral microemulsion increased PIP efficacy and enhanced its delivery to the brain resulting in better therapeutic outcome compared to the free drug. However, the toxicity of this nanosystem should be carefully taken into consideration on chronic use.

Topics: Administration, Oral; Alkaloids; Alzheimer Disease; Animals; Benzodioxoles; Brain; Drug Delivery Systems; Emulsions; Humans; Piperidines; Polyunsaturated Alkamides; Rats, Wistar

In continuation of our program to discover new potential pesticidal agents, thirty-one piperine analogs containing isoxazoline/pyrazoline scaffold were prepared, and confirmed by infrared spectra, proton/carbon-13 nuclear magnetic resonance spectra, and high-resolution mass spectra. The structures of compounds VIIb and VIIIc were further determined by

Topics: Alkaloids; Animals; Benzodioxoles; Cell Line; Isoxazoles; Lepidoptera; Molecular Structure; Pesticides; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Tetranychidae; Toxicity Tests

Several chemical compounds can restore pigmentation in vitiligo through mechanisms that vary according to disease etiology. In the present study, we investigated the melanogenic activity of six structurally distinct compounds, namely, scopoletin, kaempferol, chrysin, vitamin D

Topics: Alkaloids; Animals; Benzodioxoles; Benzyl Compounds; Cholecalciferol; Flavonoids; Humans; Kaempferols; Melanins; Monophenol Monooxygenase; Pigmentation; Piperidines; Polyunsaturated Alkamides; Purines; Scopoletin; Vitiligo; Zebrafish

Lupus nephritis (LN) is a leading cause of mortality. The activation of NLRP3 inflammasome contributed to LN development and thus became a therapeutic target. Here we assessed the therapeutic potential of piperine, a bioactive compound known to target NLRP3 inflammasome, on LN development both in vivo and in vitro.. LN was induced in BALB/c mice via intraperitoneal injection of pristane. Upon treatment with increasing doses of piperine, we assessed renal lesions, measured serum levels of pro-inflammatory cytokines, and examined expressions of key components of NLRP3 inflammasome in kidney. To explore the molecular mechanisms, we treated the proximal tubular epithelial HK-2 cells with lipopolysaccharide (LPS) and ATP, and examined the effects of piperine on pyroptosis and the activation of NLRP3 inflammasome. Furthermore, we assessed the significance of AMPK signaling in piperine functions in HK-2 cells.. In pristane-injected mice, piperine significantly ameliorated LN development in a dose-dependent manner, which was associated with the inhibition of NLRP3 inflammasome and the reduction of serum IL-1β, but not of IL-18 level. In HK-2 cells, piperine potently inhibited pyroptosis and the activation of NLRP3 inflammasome in response to LPS + ATP. The effects of piperine were mediated by blocking AMPK activation, and the AMPK agonist metformin bypassed the activities of piperine, and resumed pyroptosis as well as the activation on NLRP3 inflammasome.. By targeting AMPK, piperine significantly suppressed the activation of NLRP3 inflammasome, inhibited the release of pro-inflammatory cytokines, blocked the pyroptosis of tubular epithelial cells, and thus suppressed the development of LN.

Topics: Alkaloids; AMP-Activated Protein Kinase Kinases; Animals; Anti-Inflammatory Agents; Benzodioxoles; Cells, Cultured; Epithelial Cells; Humans; Inflammasomes; Kidney; Lupus Nephritis; Male; Metformin; Mice; Mice, Inbred BALB C; NLR Family, Pyrin Domain-Containing 3 Protein; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Protein Kinases; Pyroptosis; Signal Transduction

Glutathione-S-transferase also referred as GST is one of the major detoxification enzymes in parasitic helminths. The crucial role played by GST in various chronic infections has been well reported. The dependence of nematodes on detoxification enzymes to maintain their survival within the host established the crucial role of GST in filariasis and other related diseases. Hence, this well-established role of GST in filariasis along with its greater nonhomology with its human counterpart makes it an important therapeutic drug target. Here in this study, we have tried to explore the inhibitory potential of some of the well-reported natural ant-filarial compounds against the GST from Wuchereria bancrofti (W.bancrofti) and Brugia malayi (B.malayi). In silico virtual screening, approach was used to screen the selected natural compounds against GST from W.bancrofti and B.malayi. On the basis of our results, here we are reporting some of the natural compounds which were found to be very effective against GSTs. Along with we have also revealed the characteristic of the active site of BmGST and WbGST and the role of important active site residues involve in the binding of natural compounds within the active site of GSTs. This information will oped doors for using natural compounds as anti-filarial therapy and will also be helpful for future drug discovery.

Topics: Alkaloids; Animals; Anthelmintics; Benzodioxoles; Biological Products; Brugia malayi; Capsaicin; Catalytic Domain; Curcumin; Drug Evaluation, Preclinical; Glutathione Transferase; Molecular Docking Simulation; Piperidines; Polyunsaturated Alkamides; Strychnine; Wuchereria bancrofti

The aim of this study was to evaluate gamma-aminobutyric acid (GABA)- and piperine-induced erythropoietin (EPO) and EPO-receptor expression.. The effect of GABA and piperine on cell viability was examined using kidney epithelial cells. Expression levels of EPO and EPO-R mRNA and protein were evaluated in response to GABA and piperine treatments. GABA- and piperine-mediated activation of the mitogen-activated protein kinase (MAPK) signaling pathway was investigated. Additionally, EPO function was evaluated using conditioned media containing EPO. The GABA receptor type involved in this process was identified.. Messenger RNA and protein expression levels of EPO and EPO-R significantly increased in response to treatment with GABA, piperine, or the combination of both, compared with control. GABA plus piperine synergistically enhanced EPO and EPO-R expression through p38 and c-Jun N-terminal kinase (JNK) MAPK signaling pathways, but not through the extracellular signal-regulated kinase (ERK) MAPK pathway. SB203580 and SP600125 (p38 and JNK pathway inhibitors, respectively) attenuated GABA plus piperine-induced EPO and EPO-R expression. Treatment of macrophages with EPO-containing conditioned media induced mRNA expression of interleukin (IL)-10 and nuclear factor (NF)-κB due to the interaction between EPO and EPO-R. Interestingly, GABA-induced EPO and EPO-R expression was mediated through GABA. These findings demonstrate that GABA plus piperine-mediated p38 and JNK MAPK activation increases EPO and EPO-R expression, resulting in up-regulation of IL-10 and NF-κB.

Topics: Alkaloids; Animals; Benzodioxoles; Cell Line; Cell Survival; Drug Synergism; Epithelial Cells; Erythropoietin; gamma-Aminobutyric Acid; Gene Expression Regulation; Interleukin-10; Kidney; LLC-PK1 Cells; MAP Kinase Signaling System; NF-kappa B; Piperidines; Polyunsaturated Alkamides; Receptors, Erythropoietin; RNA, Messenger; Swine; Up-Regulation

Mycobacterial efflux pumps play a major role in the emergence of antimycobacterial drug resistance. Of particular interest is the proteinaceous multi-drug efflux pump protein Rv1258c that encodes a tetracycline/aminoglycoside resistance (TAP-2)-like efflux pump which is active in susceptible and drug resistant Mycobacterium tuberculosis. Rv1258c is implicated in drug resistance to numerous antimycobacterials including first line drugs rifampicin and isoniazid as well as fluoroquinolone and aminoglycoside antibiotic classes. To date, compounds like verapamil and piperine have been shown to inhibit Rv1258c but no direct evidence for binding or mode of action exist. Therefore in the present study we generated an accurate 3D model of Rv1258c using MODELLER and validated its structure using molecular dynamic simulation studies with GROMACS software. The 3D-structures of Rv1258c and the homologous template 1pw4 were simulated within a POPE/POPG lipid bilayer and found to behave similar. Another important finding was the identification of one local energy minima state of the apo protein, which speaks to the flexibility of the protein and will be investigated further. Extraction of one of the open channel conformations of Rv1258c and blind docking of various structurally diverse putative inhibitors and substrates, allowed for the identification of a probable binding site. Spectinamide was found to bind to a different location on the outside surface of the protein suggesting its ability to avoid the efflux channel. We further identified 246 putative compounds that showed higher binding affinity values to Rv1258c compared to piperine and verapamil. Interaction analysis of the top 20 purchasable compounds identified crucial hydrogen bond interactions with Ser26, Ser45 and Glu243 as well as a pi-pi stacking interaction with Trp32 that accounted for the strong affinity of these compounds for Rv1258c. Future studies will entail purchasing a number of compounds for in vitro activity testing against Mycobacterium tuberculosis.

Topics: Alkaloids; Amino Acid Sequence; Antitubercular Agents; ATP-Binding Cassette Transporters; Bacterial Proteins; Benzodioxoles; Binding Sites; Drug Resistance, Multiple, Bacterial; Hydrogen Bonding; Molecular Docking Simulation; Molecular Dynamics Simulation; Mycobacterium tuberculosis; Piperidines; Polyunsaturated Alkamides; Principal Component Analysis; Protein Structure, Tertiary; Sequence Alignment; Thermodynamics; Verapamil

Piperine is an attractive therapeutic alkaloid from black pepper that exhibits a broad spectrum of pharmacological properties over various pathological disorders including cancer. Voltage-gated K+ channels (KV) play an important role in regulating cancer cell proliferation and are considered as potential targets for the treatment of cancer. However, there is a paucity of information with regard to the implication of piperine in KV associated anticancer activities on human prostate cancer cells LNCaP and PC-3 cells. Therefore, the primary objective of the present study was to elucidate the anticancer action of piperine that might be mediated via voltage-gated K+ current (IK) blockade.. Whole-cell patch clamp was used to record the modulatory effects of piperine on IK expressed in LNCaP and PC-3 cells. Moreover, the anticancer activity of piperine was evaluated by MTT assay, flow cytometry and live/dead assay.. Piperine significantly inhibited IK in a dose-dependent manner with an effective IC50 dose 39.91 µM in LNCaP and 49.45 µM in PC-3 cells. Also, piperine induced a positive shift in the relative activation curve in both cells. Blockade of IK by piperine exerted G0/G1 phase cell cycle arrest that led to inhibition of cell proliferation and induced apoptosis in a dose-dependent manner.. We showed that the anticancer effects of piperine are directly correlated with the blockade of IK in LNCaP and PC-3 cells. The study also confirmed that IK inhibition by piperine might be responsible for its anticancer activities in prostate cancer cells.

Topics: Alkaloids; Antineoplastic Agents; Apoptosis; Benzodioxoles; Cell Cycle Checkpoints; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Male; Membrane Potentials; PC-3 Cells; Piperidines; Polyunsaturated Alkamides; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Prostatic Neoplasms; Signal Transduction

Secreted venom Phospholipase A

Topics: Alkaloids; Animals; Benzodioxoles; Binding Sites; Kinetics; Molecular Dynamics Simulation; Molecular Structure; Phospholipases A2, Secretory; Piperidines; Polyunsaturated Alkamides; Protein Binding; Protein Conformation; Snake Venoms; Surface Plasmon Resonance

Tendinopathy is a common clinical pathology found in athletes and workers with mixed treatment results. Piperine, a major alkaloid found in the black and long pepper, has been demonstrated to have variety of pharmacological properties such as analgesic and anti-inflammatory effects. The present study was designed to investigate the effects of piperine on collagenase-induced Achilles tendon injury. Rats were intratendineously injected with collagenase in the right Achilles tendon, followed by intragastrical administration of piperine (100 mg/kg). Morphological structure and biochemical analysis of glycosaminoglycans, hydroxyproline, collagen III, and the activity of matrix metallopeptidases in the tendon tissues were performed. Our results showed that collagenase injection resulted in clear degenerative changes in the tendon. Administration of piperine improved the morphological structure of tendon, increased glycosaminoglycans and hydroxyproline levels, and inhibited the expression and activities of MMP-2 and MMP-9. Furthermore, piperine inhibited the activation of ERK and p38 signaling pathways in injured tendon. These results indicate a beneficial role of piperine against collagenase-induced tendon injury.

Topics: Achilles Tendon; Alkaloids; Animals; Benzodioxoles; Collagenases; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Mitogen-activated protein kinases (MAPKs) and AMP-activated protein kinase α (AMPKα) play critical roles in the process of cardiac hypertrophy. Previous studies have demonstrated that piperine activates AMPKα and reduces the phosphorylation of extracellular signal-regulated kinase (ERK). However, the effect of piperine on cardiac hypertrophy remains completely unknown. Here, we show that piperine-treated mice had similar hypertrophic responses as mice treated with vehicle but exhibited significantly attenuated cardiac fibrosis after pressure overload or isoprenaline (ISO) injection. Piperine inhibited the transformation of cardiac fibroblasts to myofibroblasts induced by transforming growth factor-β (TGF-β) or angiotensin II (Ang II) in vitro. This anti-fibrotic effect was independent of the AMPKα and MAPK pathway. Piperine blocked activation of protein kinase B (AKT) and, downstream, glycogen synthase kinase 3β (GSK3β). The overexpression of constitutively active AKT or the knockdown of GSK3β completely abolished the piperine-mediated protection of cardiac fibroblasts. The cardioprotective effects of piperine were blocked in mice with constitutively active AKT. Pretreatment with GW9662, a specific inhibitor of peroxisome proliferator activated receptor-γ (PPAR-γ), reversed the effect elicited by piperine in vitro. In conclusion, piperine attenuated cardiac fibrosis via the activation of PPAR-γ and the resultant inhibition of AKT/GSK3β.

Topics: Alkaloids; Angiotensin II; Anilides; Animals; Benzodioxoles; Cell Differentiation; Cells, Cultured; Cytochrome P-450 Enzyme Inhibitors; Fibroblasts; Fibrosis; Glycogen Synthase Kinase 3 beta; Heart; Isoproterenol; Male; Mice; Mice, Inbred C57BL; Myocardium; Myofibroblasts; Piperidines; Polyunsaturated Alkamides; PPAR gamma; Proto-Oncogene Proteins c-akt; RNA Interference; RNA, Small Interfering; Signal Transduction; Transforming Growth Factor beta

Redox mediated cancer therapeutics are of immense interest in the recent decade due to their anticancer activity. Piperine is the principal alkaloid of black and long pepper. Although its anticancer activity has been reported in number of cancers , the precise molecular mechanism of action remains to be unravelled. Hence, in this study, for the first time, we delineated the mechanistic insight into the effect of piperine against hepatocellular carcinoma (HCC).MTT analysis determined the dose and time dependent cytotoxicity of piperine against Hep G2 cells. Further molecular studies evidenced the prooxidant property of piperine by inducing H

Topics: Alkaloids; Animals; Antineoplastic Agents; Apoptosis; Benzodioxoles; Carcinoma, Hepatocellular; Catalase; Cell Line, Tumor; Cell Proliferation; Hepatocytes; Humans; Liver Neoplasms; Male; Mitochondria; Molecular Docking Simulation; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-met; Rats; Rats, Wistar; Reactive Oxygen Species; Receptor, Fibroblast Growth Factor, Type 1; Receptor, IGF Type 1; Transforming Growth Factor beta1

Piperine is a major constituent of Piper nigrum L. and is a naturally bioactive alkaloid. Structural changes in piperine have been shown to result in different biological effects. The present study aims to investigate piperine metabolites in rat plasma, bile, urine, and feces after oral administration.. The metabolic pathway of piperine in vivo was investigated using ultra-high-performance liquid chromatography (UHLPC) combined with electrospray ionization quadruple time-of-flight tandem mass spectrometry (QTOF-MS). Piperine metabolites were found and identified by fragmentation patterns and accurate mass measurements.. The 12 metabolites detected and identified were divided into three groups: methylenedioxycyclic ring-opening metabolites (M01-M08), methylenedioxycyclic ring-oxidizing metabolites (M09-M11), and piperidine ring-cleavage metabolites (M12). Seven piperine metabolites, including M02, M03, M04, M05, M09, M10 and M11, were reported for the first time in the literature.. Results showed that the principal metabolism pathways of piperine in rat were reduction and demethylation after ring-opening, and that UHPLC/QTOF-MS can serve as an important analytical platform to gather the piperine metabolism profile. Copyright © 2017 John Wiley & Sons, Ltd.

Topics: Alkaloids; Animals; Benzodioxoles; Bile; Chromatography, High Pressure Liquid; Feces; Male; Metabolic Networks and Pathways; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

Endoplasmic reticulum (ER) is the key organelle involved in protein folding and maturation. Emerging studies implicate the role of ER stress in the development of chronic kidney disease. Thus, there is an urgent need for compounds that could ameliorate ER stress and prevent CKD. Piperine and its analogs have been reported to exhibit multiple pharmacological activities; however, their efficacy against ER stress in kidney cells has not been studied yet. Hence, the goal of this study was to synthesize amide-substituted piperine analogs and screen them for pharmacological activity to relieve ER stress using an in vitro model of tunicamycin-induced ER stress using normal rat kidney (NRK-52E) cells. Five amide-substituted piperine analogs were synthesized and their chemical structures were elucidated by pertinent spectroscopic techniques. An in vitro model of ER stress was developed using tunicamycin, and the compounds of interest were screened for their effect on cell viability, and the expression of ER chaperone GRP78, the pro-apoptotic ER stress marker CHOP, and apoptotic caspases 3 and 12 (via western blotting). Our findings indicate that exposure to tunicamycin (0.5 μg/mL) for 2 h induces the expression of GRP78 and CHOP, and apoptotic markers (caspase-3 and caspase-12) and causes a significant reduction in renal cell viability. Pre-treatment of cells with piperine and its cyclohexylamino analog decreased the tunicamycin-induced upregulation of GRP78 and CHOP and cell death. Taken together, our findings demonstrate that piperine and its analogs differentially regulate ER stress, and thus represent potential therapeutic agents to treat ER stress-related renal disorders. Graphical Abstract Piperine (PIP) reduces the expression of ER stress markers (GRP78 and CHOP) induced by pathologic stimuli and consequently decreases the activation of apoptotic caspase-12 and caspase-3; all of which contributes to its chemical chaperone and cytoprotective properties to protect renal cells against ER stress and ER stress-induced cell death, and would ultimately prevent the development of chronic kidney disease.

Topics: Alkaloids; Amides; Animals; Apoptosis; Benzodioxoles; Caspase 12; Caspase 3; Cell Line; Cell Survival; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Fatty Acids, Unsaturated; Heat-Shock Proteins; Piperidines; Polyunsaturated Alkamides; Rats; Structure-Activity Relationship; Transcription Factor CHOP; Tunicamycin; Up-Regulation

Piperine alkaloid, an important constituent of black pepper, exhibits numerous therapeutic properties, whereas its usage as a drug is limited due to its poor solubility in aqueous medium, which leads to poor bioavailability.. Herein, a new method has been developed to improve the solubility of this drug based on the development of solid dispersions with improved dissolution rate using hydrophilic carriers such as sorbitol (Sor), polyethylene glycol (PEG) and polyvinyl pyrrolidone K30 (PVP) by solvent method. Physical mixtures of piperine and carriers were also prepared for comparison.. The physicochemical properties of the prepared solid dispersions were examined using SEM, TEM, DSC, XRD and FT-IR. In vitro dissolution profile of the solid dispersions was recorded and compared with that of the pure piperine and physical mixtures. The effect of these carriers on the aqueous solubility of piperine has been investigated.. The solid dispersions of piperine with Sor, PEG and PVP exhibited superior performance for the dissolution of piperine with a drug release of 70%, 76% and 89%, respectively after 2 h compared to physical mixtures and pure piperine, which could be due to its transformation from crystalline to amorphous form as well as the attachment of hydrophilic carriers to the surface of poorly water-soluble piperine.. Results suggest that the piperine solid dispersions prepared with improved in vitro release exhibit potential advantage in delivering poorly water-soluble piperine as an oral supplement.

Topics: Alkaloids; Benzodioxoles; Biological Availability; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Drug Carriers; Drug Compounding; Hydrophobic and Hydrophilic Interactions; Piperidines; Polyethylene Glycols; Polyunsaturated Alkamides; Povidone; Solubility; Spectroscopy, Fourier Transform Infrared

Piperine is a nitrogenous pungent substance exhibiting multifunctional pharmacological properties. However, the mechanism underlying its anticancer potential is not well elucidated in human oral squamous carcinoma (KB) cell line. The anticancer potential of piperine was evaluated through potent biomarkers viz. reactive oxygen species (ROS), cellular apoptosis, and loss of mitochondrial membrane potential (MMP). In addition, cell cycle kinetics and caspases-3 activity were also carried out to confirm anticancer activity of piperine. Results showed that various concentrations (25-300 μM) of piperine exposure reduced the cell viability of KB cells significantly (P < 0.01). Piperine induced significant (P < 0.01) dose-related increment in ROS production and nuclear condensation. Moreover, piperine stimulated cell death by inducing loss of MMP, and caspase-3 activation. Cell cycle study revealed that piperine arrested the cells in G2/M phase and decreased the DNA content. Findings of this study suggest the efficacy of piperine in inducing cell death via the decrease in MMP and ROS liberation followed by caspase-3 activation and cell cycle arrest. Further assessment of the anticancer potency of piperine is needed for anticancer drug development.

Topics: Alkaloids; Antineoplastic Agents; Apoptosis; Benzodioxoles; Carcinoma, Squamous Cell; Caspase 3; Cell Cycle Checkpoints; Cell Proliferation; Humans; KB Cells; Membrane Potential, Mitochondrial; Mitochondria; Mouth Neoplasms; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Reactive Oxygen Species

Domperidone is a commonly used antiemetic drug. The oral bioavailability of domperidone is very low due to its rapid first pass metabolism in the intestine and liver. Piperine, the main alkaloid present in black pepper has been reported to show inhibitory effects on Cytochrome P-450 (CYP-450) enzymes and P-glycoprotein (P-gp). In the present study we investigated the effect of piperine pretreatment on the intestinal transport and oral bioavailability of domperidone in male Wistar rats.. The intestinal transport of domperidone was evaluated by an in-vitro non-everted sac method and in-situ single pass intestinal perfusion (SPIP) study. The oral pharmacokinetics of domperidone was evaluated by conducting oral bioavailability study in rats.. A statistically significant improvement in apparent permeability (Papp) was observed in rats pretreated with piperine compared to the respective control group. The effective permeability (Peff) of domperidone was increased in the ileum of the piperine treated group. Following pretreatment with piperine, the peak plasma concentration (Cmax) and area under the concentration- time curve (AUC) were significantly increased. A significant decrease in time to reach maximum plasma concentration (Tmax), clearance and elimination rate constant (Kel) was observed in rats pretreated with piperine.. Piperine enhanced the oral bioavailability of domperidone by inhibiting CYP3A1 and P-gp in rats. This observation suggests the possibility that the combination of piperine with other CYP3A4 and P-gp dual substrates may also improve bioavailability. Further clinical studies are recommended to verify this drug interaction in human volunteers and patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Topics: Administration, Oral; Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Availability; Cytochrome P-450 CYP3A; Domperidone; Enzyme Inhibitors; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Chronic ultraviolet radiation (UV-R) exposure causes skin disorders like erythema, edema, hyperpigmentation, photoaging and photocarcinogenesis. Recent research trends of researchers have focused more attention on the identification and use of photo stable natural agents with photoprotective properties. Piperine (PIP), as a plant alkaloid, is an important constituent present in black pepper (Piper nigrum), used widely in ayurvedic and other traditional medicines and has broad pharmacological properties. The study was planned to photoprotective efficacy of PIP in human keratinocyte (HaCaT) cell line. We have assessed the UV-R induced activation of transcription factor NF-κB in coordination with cell death modulators (Bax/Bcl-2 and p21). The LC-MS/MS analysis revealed that PIP was photostable under UV-A/UV-B exposure. PIP (10μg/ml) attenuates the UV-R (A and B) induced phototoxicity of keratinocyte cell line through the restoration of cell viability, inhibition of ROS, and malondialdehyde generation. Further, PIP inhibited UV-R mediated DNA damage, prevented micronuclei formation, and reduced sub-G1 phase in cell cycle, which supported against photogenotoxicity. This study revealed that PIP pretreatment strongly suppressed UV-R induced photodamages. Molecular docking studies suggest that PIP binds at the active site of NF-κB, and thus, preventing its translocation to nucleus. In addition, transcriptional and translational analysis advocate the increased expression of NF-κB and concomitant decrease in IkB-α expression under UV-R exposed cells, favouring the apoptosis via Bax/Bcl-2 and p21 pathways. However, PIP induced expression of IkB-α suppress the NF-κB activity which resulted in suppression of apoptotic marker genes and proteins that involved in photoprotection. Therefore, we suggest the applicability of photostable PIP as photoprotective agent for human use.

Topics: Alkaloids; bcl-2-Associated X Protein; Benzodioxoles; Binding Sites; Catalytic Domain; Cell Cycle Checkpoints; Cell Line; Cell Survival; Comet Assay; DNA Damage; Humans; Keratinocytes; Lipid Peroxidation; Microscopy, Fluorescence; Molecular Docking Simulation; NF-kappa B; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-bcl-2; Radiation-Protective Agents; Reactive Oxygen Species; Signal Transduction; Ultraviolet Rays

Poly(3,4-ethylenedioxythiophene) (PEDOT) nanoparticles are loaded with curcumin and piperine by in situ emulsion polymerization using dodecyl benzene sulfonic acid both as a stabilizer and a doping agent. The loaded drugs affect the morphology, size, and colloidal stability of the nanoparticles. Furthermore, kinetics studies of nonstimulated drug release have evidenced that polymer···drug interactions are stronger for curcumin than for piperine. This observation suggests that drug delivery systems based on combination of the former drug with PEDOT are much appropriated to show an externally tailored release profile. This is demonstrated by comparing the release profiles obtained in presence and absence of electrical stimulus. Results indicate that controlled and time-programmed release of curcumin is achieved in a physiological medium by applying a negative voltage of -1.25 V to loaded PEDOT nanoparticles.

Topics: Alkaloids; Benzodioxoles; Bridged Bicyclo Compounds, Heterocyclic; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Nanoparticles; Particle Size; Piperidines; Polymers; Polyunsaturated Alkamides; Thiophenes

The lipophilic phytocannabinoids cannabidiol (CBD) and Δ

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biological Availability; Cannabidiol; Curcumin; Dronabinol; Drug Delivery Systems; Emulsions; Excipients; Gastrointestinal Absorption; Lipids; Male; Nanoparticles; Piperidines; Polyunsaturated Alkamides; Rats, Wistar; Resveratrol; Stilbenes

P-glycoprotein (P-gp) is a drug transporter that effluxes chemotherapeutic drugs and is implicated in the development of resistance of cancer cells to chemotherapeutic drugs. To date, no drug has been approved to inhibit P-gp and restore chemotherapy efficacy. Moreover, majority of the reported inhibitors have high molecular weight and complex structures, making it difficult to understand the basic structural requirement for P-gp inhibition. In this study, two structurally simple, low molecular weight piperine analogs Pip1 and Pip2 were designed and found to better interact with P-gp than piperine in silico. A one step, acid-amine coupling reaction between piperic acid and 6,7-dimethoxytetrahydroisoquinoline or 2-(3,4-dimethoxyphenyl)ethylamine afforded Pip1 and Pip2, respectively. In vitro testing in drug resistant P-gp overexpressing KB (cervical) and SW480 (colon) cancer cells showed that both analogs, when co-administered with vincristine, colchicine or paclitaxel were able to reverse the resistance. Moreover, accumulation of P-gp substrate (rhodamine 123) in the resistant cells, a result of alteration of the P-gp efflux, was also observed. These investigations suggest that the natural product analog - Pip1 ((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H)-yl)penta-2,4-dien-1-one) - is superior to piperine and could inhibit P-gp function. Further studies are required to explore the full potential of Pip1 in treating drug resistant cancer.

Topics: Alkaloids; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Binding Sites; Drug Resistance, Neoplasm; Humans; Molecular Docking Simulation; Piperidines; Polyunsaturated Alkamides; Protein Binding

Aspergillus flavus, a soil-borne pathogen, represents a danger for humans and animals since it produces the carcinogenic mycotoxin Aflatoxin B1 (AFB1). Approaches aiming the reduction of this fungal contaminant mainly involve chemicals that may also be toxic. Therefore, identification and characterization of natural anti-aflatoxigenic products represents a sustainable alternative strategy. Piperine, a major component of black and long peppers, has been previously demonstrated asan AFB1-inhibitor; nevertheless its mechanism of action was yet to be elucidated. The aim of the present study was to evaluate piperine's molecular mechanism of action in A. flavus with a special focus on oxidative stress response. For that, the entire AFB1 gene cluster as well asa targeted gene-network coding for fungal stress response factors and cellular receptors were analyzed. In addition to this, fungal enzymatic activities were also characterized. We demonstrated that piperine inhibits aflatoxin production and fungal growth in a dose-dependent manner. Analysis of the gene cluster demonstrated that almost all genes participating in aflatoxin's biosynthetic pathway were down regulated. Exposure to piperine also resulted in decreased transcript levels of the global regulator veA together with an over-expression of genes coding for several basic leucine zipper (bZIP) transcription factors such as atfA, atfB and ap-1 and genes belonging to superoxide dismutase and catalase's families. Furthermore, this gene response was accompanied by a significant enhancement of catalase enzymatic activity. In conclusion, these data demonstrated that piperine inhibits AFB1 production while positively modulating fungal antioxidant status in A. flavus.

Topics: Aflatoxin B1; Alkaloids; Aspergillus flavus; Benzodioxoles; Fungal Proteins; Gene Expression; Gene Expression Regulation, Fungal; Multigene Family; Oxidative Stress; Piperidines; Polyunsaturated Alkamides

Piperine, one of the major bioactive constituents isolated from natural flavorings and medicinal-culinary herbs, possesses various biological activities. In the present study, an integrated strategy based on ultra high-performance liquid chromatography/high resolution mass spectrometry was established to reveal piperine metabolism in rats. First of all, post-acquisition data-mining methods, including high resolution extracted ion chromatograms (HREICs) and multiple mass defect filtering (MMDF), were used to screen piperine metabolite candidates in a full-scan HRMS

Topics: Alkaloids; Animals; Benzodioxoles; Chromatography, High Pressure Liquid; Data Mining; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

We previously reported that piperine, an active alkaloidal principal of black and long peppers, enhances drug bioavailability by inhibiting drug metabolism. Another mechanism influencing drug availability/uptake is its free fraction. Since piperine is highly lipophilic, we hypothesize that it could also interact with drugs through binding displacement and influence their bioavailability. Accordingly, using equilibrium dialysis, we investigated whether piperine alters the binding of model drug ligands, that is flunitrazepam, diazepam, warfarin, salicylic acid, propranolol, lidocaine, and disopyramide to human plasma (n = 4). Since alterations in binding influence drug disposition, we also studied the effects of piperine on the uptake of plasma bound

Topics: Adult; Alkaloids; Benzodioxoles; Biological Transport; Brain; Endothelial Cells; Humans; Male; Piperidines; Plasma; Polyunsaturated Alkamides; Protein Binding

To investigate the effect of piperine on the disorder of glucose metabolism in the cell model with insulin resistance (IR) and explore the molecules mechanism on intervening the upstream target of AMPK signaling pathway. The insulin resistance models in HepG2 cells were established by fat emulsion stimulation. Then glucose consumption in culture supernatant was detected by GOD-POD method. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of leptin(LEP) and adiponectin(APN) in culture supernatant; Real-time quantitative PCR was used to assess the mRNA expression of APN and LEP; and the protein expression levels of LepR, AdipoR1, AdipoR2 and the activation of AMPK signaling pathway were detected by Western blot analysis. The results showed that piperine, rosiglitazone and AMPK agonist AICAR could significantly elevate the glucose consumption in insulin resistance cell models, enhance the level of APN, promote APN mRNA transcripts and increase the protein expression of Adipo receptor. Meanwhile,AMPKα mRNA and р-AMPKα protein expressions were also increased in piperine treated cells, but both LEP mRNA expression and LepR protein expressions were decreased in piperine treated group. The results indicated that piperine could significantly ameliorate the glucose metabolism disorder in insulin resistance cell models through regulating upstream molecules (APN and LEP) of AMPK signaling pathway, and thus activate the AMPK signaling pathway.

Topics: Alkaloids; AMP-Activated Protein Kinase Kinases; Benzodioxoles; Glucose; Hep G2 Cells; Humans; Insulin Resistance; Piperidines; Polyunsaturated Alkamides; Protein Kinases; Signal Transduction

To establish a determination method for the contents of paeonol, eugenol and piperine in receptor liquid and to research the transdermal permeability of Huoxue Zhitong patch. The contents of paeonol, eugenol and piperine in receptor liquid were determined by high pressure liquid chromatography(HPLC); and the receptor liquid was optimized by taking accumulative amount penetrated within 24 hours, percutaneous permeation rate and skin irritation as indexes. In vitro Franz diffusion experiment was applied to assess the percutaneous penetration characteristics and regularity of Huoxue Zhitong patch. The results showed that the accumulative penetration amount and penetration rate by using PEG 400-ethanol-normal saline 3∶3∶4 as receptor liquid were higher than those by using propylene glycol∶ethanol∶normal saline 3∶3∶4 and ethanol-normal saline 3∶7, the and skin irritation of PEG 400-ethanol-normal saline 3∶3∶4 was smaller than propylene glycol:ethanol: normal saline 3∶3∶4. Results of percutaneous permeability experiments displayed that the accumulative amount penetrated of paeonol, eugenol and piperine within 24 hours was 2.84, 19.9, and 0.753 μg•cm⁻² respectively in Huoxue Zhitong patch and the penetration rate was 0.18, 1.22, and 0.02 μg•cm⁻²•h⁻¹ respectively. Thus, the permeation of paeonol, eugenol and piperine through the skin was a diffusion process, which was irrelevant to their content in patch.

Topics: Acetophenones; Administration, Cutaneous; Alkaloids; Animals; Benzodioxoles; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Eugenol; Permeability; Piperidines; Polyunsaturated Alkamides; Skin; Skin Absorption; Transdermal Patch

Piperine (PP), an alkaloid from black and long peppers (Piper nigrum Linn &Piper longum Linn), exhibits antitumor activities in vitro and in vivo. We investigated the ability of piperine (PP) to reverse the drug resistance of human cervical cancer cells. In our study, the cervica cancer cells resistant to mitomycin-C (MMC) treatment were used. We found the growth inhibitory effects of piperine on human cervical cancer cell, which were resistant to MMC. Piperine and MMC co-treatment resulted in a dose-dependent suppression of the cell proliferation. Decreasing of phosphorylated-signal transducer and activator of transcription (p-STAT3) was linked to the suppression of p65 by PP and MMC combinational treatment. Additionally, the presence of PP potentiated the effects of MMC on apoptosis induction in cervical cancer cells with drug resistance, which was dependent on Bcl-2 inhibition. The pro-apoptotic proteins of Bax and Bid were up-regulated, accompanied with Caspase cleavage. Moreover, in mice xenograft models, the combined therapy inhibited tumor growth compared to the PP or MMC mono-therapy group. Our data indicated a novel therapeutic strategy of PP to potentiate MMC-induced anti-tumor effect on cervical cancer cells with drug resistance through blocking p-STAT3/p65 and Bcl-2 activation.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Female; Humans; Male; Mice; Mice, Nude; Mitomycin; NF-kappa B; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; STAT3 Transcription Factor; Uterine Cervical Neoplasms

Stress occurs in everyday life and persistence of it causes memory loss. Bioflavonoids like quercetin are reported to have poor bioavailability and limited therapeutic potential against stress induced neurological disorders. Therefore, the present study is an attempt to elucidate the therapeutic potency of combination of quercetin with piperine; a bioavailability enhancer against chronic unpredictable stress (CUS)-induced behavioral and biochemical alterations. Laca mice were subjected to a series of stressful events for a period of 28 days. Quercetin (20, 40 and 80 mg/kg, p.o.), piperine (20 mg/kg, p.o.) and their combinations were administered daily 30 min before CUS procedure. Piracetam (100 mg/kg, i.p.) served as a standard control. CUS caused impaired spatial navigation in Morris water maze test and poor retention in elevated plus maze task. Further, there was significant increase in brain oxidative stress markers and neuro-inflammation (TNF-α). This was coupled with marked rise in acetylcholinesterase and serum corticosterone levels. Co-administration of piperine with quercetin significantly elevated their potential to restore these behavioral, biochemical and molecular changes associated with mouse model of CUS. These results suggest that piperine enhances the neuroprotective effects of quercetin against CUS-induced oxidative stress, neuro-inflammation and memory deficits.

Topics: Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Biological Availability; Chronic Disease; Cognitive Dysfunction; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Male; Mice, Inbred Strains; Neurogenic Inflammation; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Quercetin; Stress, Psychological

Topics: Alanine; Alkaloids; Benzodioxoles; Humans; Inhibitor of Apoptosis Proteins; Molecular Docking Simulation; Molecular Dynamics Simulation; Neoplasms; Piperidines; Polyunsaturated Alkamides; Protein Binding; Survivin; User-Computer Interface

Studies were made to increase the yield of piperine extraction using Naviglio Extractor® solid-liquid dynamic extractor (SLDE) from fruits of Piper longum. The effects of ratio w/v were investigated and optimised for the best method. The maximum yield of piperine (317.7 mg/g) from P. longum fruits was obtained in SLDE 1:50 ethanol extract. Extraction yields of piperine obtained from Soxhlet extraction, decotion (International Organization for Standardization) and conventional maceration extraction methods were found to be 233.7, 231.8 and 143.6 mg/g, respectively. The results of the present study indicated that Naviglio Extractor® is an effective technique for the extraction of piperine from long pepper.

Topics: Alkaloids; Benzodioxoles; Fruit; Piper; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Solid Phase Extraction

Inhibition of cytochrome P450 (P450) enzymes (CYP) has been shown to lower the metabolism of drugs that are P450 substrates and to consequently alter their pharmacokinetic profiles. Curcumin (CUR), piperine (PIP), and capsaicin (CAP) are spice components (SC) that inhibit the activities of a range of P450 enzymes, but the selection of which SC to be prioritized for further development as an adjuvant will depend on the ranking order of the inhibitory potential of the SCs on specific P450 isozymes. We used common human recombinant enzyme platforms to provide a comparative evaluation of the inhibitory activities of CUR, PIP, and CAP on the principal drug-metabolizing P450 enzymes. SC-mediated inhibition of CYP3A4 was found to rank in the order of CAP (IC

Topics: Alkaloids; Benzodioxoles; Capsaicin; Curcumin; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Humans; Molecular Structure; Piperidines; Polyunsaturated Alkamides; Recombinant Proteins; Spices

6-hydroxy dopamine (6-OHDA) is a neurotoxin which on intranigral administration produces severe nigrostriatal damage with motor and cognitive deficit in animals. Curcumin (CMN) in combination with bioenhancer piperine (PP) in 6-hydroxydopamine-induced Parkinsonian rats was used to investigate the antioxidant, neuromodulatory and neuroprotective mechanisms.. Hemi-Parkinson's rat model was developed with intranigral infusion of 6-OHDA (8 μg/2 μl, once, unilaterally), treatment with CMN (25 and 50 mg/kg) and combination of PP (2.5 mg/kg) with CMN (25 mg/kg) was given daily for 21 days starting from the 7th day after 6-OHDA infusion. The behavioral (locomotor, grip strength, and narrow beam walk) parameters were studied on weekly basis. On 22nd day, isolated brain preparations were subjected to biochemical (lipid peroxidation, glutathione, and nitrite), neuroinflammatory (IL-1β, IL-6, and TNF- α), and neurochemical (DA, NE, 5- HT, GABA, Glutamate, DOPAC, HVA, and 5-HIAA) analysis.. Oral administration of CMN had significantly prevented behavioral, neuroinflammatory, and neurochemical changes and preserved the antioxidant potential of the nigrostriatum in rats treated with 6-OHDA.. In the present study, PP and CMN had afforded a better neuroprotective effect compared to alone treatment on behavior, biochemical, neuroinflammatory, and neurochemical parameters in rats.

Topics: Alkaloids; Animals; Benzodioxoles; Corpus Striatum; Curcumin; Drug Therapy, Combination; Hand Strength; Locomotion; Male; Motor Skills Disorders; Neuroprotective Agents; Oxidopamine; Piperidines; Polyunsaturated Alkamides; Random Allocation; Rats; Rats, Wistar

Increased macrophage cholesterol efflux (ChE) is considered to have anti-atherosclerotic effect counteracting cardiovascular disease. The principle pungent ingredient of the fruits of Piper nigrum, piperine, is identified in this study as a ChE inducer in THP-1-derived macrophages, and mechanisms underlying this effect are explored.. Without affecting cell viability, piperine concentration-dependently enhances ChE in THP-1-derived macrophages from 25 to 100 μM. The expression level of the key cholesterol transporter protein ATP-binding cassette transporter A1 (ABCA1) is significantly upregulated by piperine, as revealed by western blot analyses. However, two other ChE-mediating transporter proteins, ATP-binding cassette transporter G1 (ABCG1) and scavenger receptor class B member 1 (SR-B1), remain unaffected. Piperine exerts no influence on ABCA1 mRNA levels, but significantly inhibits the degradation of ABCA1, as evident by an increased half-life of the protein in the presence of cycloheximide. Furthermore, it is found that piperine likely interferes with the calpain-mediated ABCA1 degradation pathway and exhibits significant inhibition of calpain activity.. Our findings suggest that piperine promotes ChE in THP-1-derived macrophages by upregulation of ABCA1, which might be mediated by inhibition of calpain activity. This novel bioactivity makes the dietary constituent piperine a good candidate to be further explored for therapeutic or preventive applications in the context of atherosclerosis.

Topics: Algorithms; Alkaloids; Atherosclerosis; ATP-Binding Cassette Transporters; Benzodioxoles; Biological Transport; Cell Survival; Cholesterol; Half-Life; Humans; Macrophages; Piper nigrum; Piperidines; Polyunsaturated Alkamides; RNA, Messenger; Scavenger Receptors, Class B; Up-Regulation

Piperine, the chief alkaloid isolated from Piper nigrum, has been known to have anti-inflammatory effect. However, the effects of piperine on neuroinflammation have not been reported. In the present study, we evaluated the effects of piperine on neuroinflammation in BV2 microglia and investigated the molecular mechanism. The results showed that piperine significantly inhibited LPS-induced TNF-α, IL-6, IL-1β, and PGE

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Benzodioxoles; Cell Line; Cytokines; Dinoprostone; Heme Oxygenase-1; Inflammation Mediators; Lipopolysaccharides; Membrane Proteins; Mice; Microglia; NF-E2-Related Factor 2; NF-kappa B; Piper nigrum; Piperidines; Polyunsaturated Alkamides; RNA, Small Interfering

Curcumin (CUR) is known to exert numerous health-promoting effects in pharmacological studies, but its low bioavailability hinders the development of curcumin as a feasible therapeutic agent. Piperine (PIP) has been reported to enhance the bioavailability of curcumin, but the underlying mechanism remains poorly understood. In an attempt to find the mechanism by which piperine enhances the bioavailability of curcumin, the dosage ratio (CUR: PIP) and pre-treatment with piperine were hypothesized as key factors for improving the bioavailability in this combination. Therefore, combining curcumin with piperine at various dose ratios (1:1 to 100:1) and pre-dosing with piperine (0.5-8 h prior to curcumin) were designed to investigate their contributions to the pharmacokinetic parameters of curcumin in rats and their effects on the expression of UGT and SULT isoforms. It was shown that the C

Topics: Alkaloids; Animals; Arylsulfotransferase; Benzodioxoles; Biological Availability; Caco-2 Cells; Colon; Curcumin; Drug Interactions; Glucuronosyltransferase; Hep G2 Cells; Humans; Liver; Male; Piperidines; Polyunsaturated Alkamides; Rats, Sprague-Dawley

Piperine (PIP) has been found to inhibit P-glycoprotein (P-gp) function in rats, suggesting that it may have the potential to modulate P-gp-mediated drug efflux in humans. The aim of this study was to evaluate the effect of PIP on the pharmacokinetics of fexofenadine (FEX), a P-gp substrate, in healthy volunteers.. An open-label, two-period, sequential study involving 12 healthy volunteers was conducted. A single oral dose of FEX 120 mg was given to volunteers during the control phase and after the treatment phase. A once-daily oral dose of PIP 20 mg was given to volunteers during the treatment phase (10 days). Blood samples were collected at predefined time intervals, and plasma samples containing FEX were analyzed by liquid chromatography-tandem mass spectrometry.. Treatment with PIP significantly increased maximum plasma concentration of FEX [406.9 (control) vs. 767 ng/mL (treatment)] and area under the plasma concentration-time curve [3403.7 (control) vs. 5724.7 ng.h/mL (treatment)] when compared to the control phase. In contrast, PIP treatment significantly decreased apparent oral clearance of FEX [35.4 (control) vs. 20.7 L/h (treatment)] as compared to the control. There was no significant change observed in the half life and renal clearance of FEX between the treatment phase and control phase.. The results suggest that altered pharmacokinetics and enhanced bioavailability of FEX might be attributed to PIP-mediated inhibition of P-gp drug efflux. Therefore, intake of PIP or dietary supplements containing PIP may potentially enhance the absorption or bioavailability of P-gp substrate drugs in addition to FEX.

Topics: Adult; Alkaloids; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Availability; Half-Life; Healthy Volunteers; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Piperidines; Polyunsaturated Alkamides; Terfenadine

The phytochemical profile of Macropiper excelsum (G.Forst.) Miq. subsp. excelsum (Piperaceae), a shrub which is widespread in New Zealand, was investigated by LC-MS-guided isolation and characterization via HR-ESI-TOF-MS and NMR spectroscopy. The isolated compounds were sensorily evaluated to identify their contribution to the overall taste of the crude extract with sweet, bitter, herbal and trigeminal impressions. Besides the known non-volatile Macropiper compounds, the lignans (+)-diayangambin and (+)-excelsin, four further excelsin isomers, (+)-diasesartemin, (+)-sesartemin, (+)-episesartemin A and B were newly characterized. Moreover, piperine and a number of piperine analogues as well as trans-pellitorine and two homologues, kalecide and (2E,4E)-tetradecadienoic acid N-isobutyl amide were identified in M. excelsum, some of them for the first time. Methyl(2E,4E)-7-(1,3-benzodioxol-5-yl)hepta-2,4-dienoate was identified and characterized for the first time in nature. Sensory analysis of the pure amides indicated that they contributed to the known chemesthetic effects of Macropiper leaves and fruits. Since the pungent piperine has been shown to affect glucose and fatty acid metabolism in vivo in previous studies, piperine itself and four of the isolated compounds, piperdardine, chingchengenamide A, dihydropiperlonguminine, and methyl(2E,4E)-7-(1,3-benzodioxol-5-yl)hepta-2,4-dienoate, were investigated regarding their effects on glucose and fatty acid uptake by enterocyte-like Caco-2 cells, in concentrations ranging from 0.1 to 100 μM. Piperdardine showed the most pronounced effect, with glucose uptake increased by 83 ± 18% at 100 μM compared to non-treated control cells. An amide group seems to be advantageous for glucose uptake stimulation, but not necessarily for fatty acid uptake-stimulating effects of piperine-related compounds.

Topics: Alkaloids; Benzodioxoles; Caco-2 Cells; Fatty Acids, Unsaturated; Fruit; Humans; Intestines; Lignans; New Zealand; Piperidines; Polyunsaturated Alkamides

Pain is the main symptom of most musculoskeletal disorders and can be caused by inflammation in association with oxidative stress. Thai herbal Sahatsatara formula (STF), a polyherbal formula, has been traditionally used for relieving muscle pain and limb numbness. This study aimed to investigate biologically active compounds of STF and its pharmacological effects related to antioxidant and anti-inflammatory activities.. The identification of possibly active compounds of STF was performed by high performance liquid chromatography (HPLC). Moreover, this study also assessed the free radical scavenging activities of STF and its components using DPPH radical scavenging assay and their inhibitory effects on IL-1β-induced intracellular reactive oxygen species (ROS) formation in primary human dermal fibroblasts (NHDFs) using DCFDA-flow cytometry analysis. Modulation of human gene expression by STF and its active compounds was investigated by microarray analyzed through Gene Ontology (GO) classification and pathway enrichment analysis.. HPLC analysis has revealed the presence of gallic acid (GA) and piperine (PP) as the major compounds in STF extracts. Our finding discovered that STF and its active compounds (GA and PP) yielded free radical scavenging activities and abilities to inhibit IL-1β-induced cellular ROS formation in NHDFs. Furthermore, microarray analysis demonstrated that a total of 84 genes (54 upregulated and 30 downregulated) were significantly affected by IL-1β involved in inflammatory cytokines, chemokines, transcription factors, cell adhesion molecules and other immunomodulators participating in NF-κB signaling. The significantly upregulated genes in IL-1β-treated in NHDFs participate in interleukin and cholecystokinin (CCRK) signaling pathways. The GO analysis of the target genes showed that all test compounds including indomethacin, STF and its active compounds, can downregulate the genes involved in NF-кB signaling pathway in IL-1β-treated NHDFs compared to the cells treated with IL-1β alone.. STF and its active compounds possessing antioxidant actions can modulate the effects of IL-1β-mediated alteration of gene expression profiles associated with inflammatory signaling in NHDFs.

Topics: Alkaloids; Anti-Inflammatory Agents; Antioxidants; Benzodioxoles; Fibroblasts; Gallic Acid; Humans; Interleukin-1beta; Oxidative Stress; Piperidines; Plant Extracts; Plants, Medicinal; Polyunsaturated Alkamides; Skin; Thailand; Transcriptome

Myocardial infarction due to ischemia accounts for majority of deaths among cardiovascular disorders. Isoproterenol (ISO) induced myocardial infarction and the protection offered by piperine was investigated in the present report. Lipid profile analysis by determining the levels of cholesterol, phospholipids, triglycerides and lipoproteins in serum and heart tissues showed anti-dyslipidemic action of piperine against ISO induced myocardial injury by modulating the ISO induced altered lipid profiles, maintaining to near control values. ISO treatment increased TBARS levels, PCC, serum markers of heart, depleted antioxidant status (GSH, SOD, CAT, GPx and GST) in tissues and, total, protein- and non-protein-sulfhydryl levels in serum and heart tissues. Piperine pre-treatment decreased the levels of serum markers, lipid peroxidation and PCC with increased antioxidant status in the heart tissues of ISO administered rats. Increased levels of the glycoprotein components in serum and decreased levels in heart tissues upon ISO administration were restored to near normal levels by piperine pre-treatment. Our present reports also showed the modulatory effect of piperine on membrane bound ATPase's showing protection against ISO induced changes in membrane fluidity. The present study proved piperine as a potent therapeutic agent with its antioxidant and anti-dyslipidemic action against ISO induced myocardial infarction.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Biomarkers; Heart; Isoproterenol; Lipid Peroxidation; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Piperine has several well-documented anti-inflammatory properties; however, little is known regarding its effect on humoral immunity. In this study, we describe the immunosuppressive effect of piperine on B lymphocytes, which are integral to the humoral immune response. Mouse B cells were cultured in the absence or presence of non-cytotoxic concentrations (25, 50, and 100 μM) of piperine during T-dependent or T-independent stimulation. Piperine inhibited B cell proliferation by causing G0/G1 phase cell cycle arrest in association with reduced expression of cyclin D2 and D3. The inhibitory effect of piperine was not mediated through transient receptor potential vanilloid-1 ion channel (TRPV1) because piperine also inhibited the proliferation of B cells from TRPV1-deficient mice. Expression of class II major histocompatibility complex molecules and costimulatory CD40 and CD86 on B lymphocytes was reduced in the presence of piperine, as was B cell-mediated antigen presentation to syngeneic T cells. In addition, piperine inhibited B cell synthesis of interleukin (IL)-6 and IL-10 cytokines, as well as IgM, IgG2b, and IgG3 immunoglobulins. The inhibitory effect of piperine on B lymphocyte activation and effector function warrants further investigation for possible application in the treatment of pathologies related to inappropriate humoral immune responses. Copyright © 2017 John Wiley & Sons, Ltd.

Topics: Alkaloids; Animals; B-Lymphocyte Subsets; B-Lymphocytes; Benzodioxoles; Cell Proliferation; Cells, Cultured; G1 Phase Cell Cycle Checkpoints; Interleukin-10; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Piper nigrum; Piperidines; Polyunsaturated Alkamides; T-Lymphocytes

Allogeneic hematopoetic stem cell transplantation (allo-HSCT) is a standard treatment for leukemia and other hematologic malignancies. The major complication of allo-HSCT is graft-versus-host-disease (GVHD), a progressive inflammatory illness characterized by donor immune cells attacking the organs of the recipient. Current GVHD prevention and treatment strategies use immune suppressive drugs and/or anti-T cell reagents these can lead to increased risk of infections and tumor relapse. Recent research demonstrated that epigallocatechin gallate (EGCG), a component found in green tea leaves at a level of 25-35% at dry weight, may be useful in the inhibition of GVHD due to its immune modulatory, anti-oxidative and anti-angiogenic capacities. In murine allo-HSCT recipients treated with EGCG, we found significantly reduced GVHD scores, reduced target organ GVHD and improved survival. EGCG treated allo-HSCT recipients had significantly higher numbers of regulatory T cells in GVHD target organs and in the blood. Furthermore, EGCG treatment resulted in diminished oxidative stress indicated by significant changes of glutathione blood levels as well as glutathione peroxidase in the colon. In summary, our study provides novel evidence demonstrating that EGCG ameliorates lethal GVHD and reduces GVHD-related target organ damage. Possible mechanisms are increased regulatory T cell numbers and reduced oxidative stress.

Topics: Alkaloids; Allografts; Animals; Antioxidants; Benzodioxoles; Catechin; Disease Models, Animal; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neovascularization, Pathologic; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Quercetin; T-Lymphocytes, Regulatory; Tea

This study characterizes the human metabolic response to piperine, a curcumin extract, and the details of its underlying molecular mechanism. Using

Topics: 3T3-L1 Cells; Alkaloids; AMP-Activated Protein Kinases; Animals; Benzodioxoles; Cell Line; Cytochrome P-450 Enzyme Inhibitors; Gene Expression Regulation; Glucose; Lactic Acid; Metabolomics; Mice; Muscle Fibers, Skeletal; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Protein Processing, Post-Translational; Proton Magnetic Resonance Spectroscopy; Rats; Signal Transduction; Uncoupling Protein 1

The herbal formula (Sahatsatara, STF), the Thai traditional poly-herbal recipe, has been used for treatment of muscle pain, anti-flatulence and numbness on hands and feet, with the caution when used in hypertensive patients. However, there is no scientific evidence to prove its effects on cardiovascular system. Piperine is the proposed major active compound in STF. It is shown to have antihypertensive effect in the L-NAME-induced endothelial dysfunction rats.. This study investigated the pharmacokinetics, mechanism of action, as well as the hemodynamic and vasoactive effect and toxicity of STF and piperine using spontaneously hypertensive rats (SHR) and normal Wistar rats (NWR).. The amount of piperine in STF was measured by ultra performance liquid chromatography (UPLC). SHR and NWR were gavaged with piperine (50mg/kg/day) or STF (100, 300, or 1000mg/kg/day) alone or together with L-NAME (in drinking water) for 28 days. Hemodynamic effects were monitored by noninvasive tail cuff every 7 days. Vasorelaxation effect on the thoracic aorta in organ chamber was observed through force transducer at the end of the experiment. Biochemical parameters for kidney and liver toxicity were measured. In addition, pharmacokinetic study was performed using non-compartment analysis.. The amount of piperine in STF was 1.29%w/w. Both STF and piperine did not affect blood pressure and heart rate in both SHR and NWR. Interestingly, STF and piperine increased acetylcholine-induced vasorelaxation of isolated thoracic aorta and have vascoluprotective effect in nitric oxide (NO) impaired rats. No liver or kidney toxicity was found in this study. Non-compartment pharmacokinetic analysis showed that the time to reach maximum concentration (T. STF had no effect on blood pressure in both SHR and NWR. However, it was able to relax isolated thoracic aorta and had the potential for vasculoprotective effect in hypertensive and NO impaired condition. The effects of STF were comparable to those of piperine.

Topics: Alkaloids; Animals; Antihypertensive Agents; Benzodioxoles; Blood Pressure; Hypertension; Male; Phytotherapy; Piperidines; Plant Extracts; Plants, Medicinal; Polyunsaturated Alkamides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Thailand; Vasodilation

The purpose of this work was to formulate piperine solid lipid nanoparticle (SLN) dispersion to exploit its efficacy orally and topically. Piperine SLN were prepared by melt emulsification method and formula was optimized by the application of 3

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Benzodioxoles; Drug Compounding; Excipients; Freund's Adjuvant; In Vitro Techniques; Lipids; Male; Nanoparticles; Particle Size; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Surface-Active Agents

Endophytic fungi have been reported to have the acquired ability to synthesize host plant specific medicinal natural products. Many fungi with such properties have been characterized and optimized for the conditions which favor maximal production of desired products. However, the inherent plant colonization property of promising endophytic fungi is least studied. Exploiting the transgenome functioning of these fungi have immense applications to add beneficial features to nonhost plants. In the present study, the endophytic fungus Phomopsis sp. isolated from Piper nigrum was confirmed for piperine production by HPLC and LCMS/MS. Further, the fungal isolate was studied for its colonization ability in Oryza sativa. Interestingly, the fungi treated plants were found to have significant plant growth enhancement when compared to the control. Further screening of extract from treated plants by HPLC and LCMS/MS resulted in the confirmation of presence of piperine. The observed result is extremely significant as it opens up novel applications of endophytic fungal colonization in taxonomically diverse plants.

Topics: Alkaloids; Ascomycota; Benzodioxoles; Chromatography, High Pressure Liquid; Chromatography, Liquid; Endophytes; Oryza; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Tandem Mass Spectrometry

The project was intended to the phytochemical characterisation from the rudimentary methanolic extract of Chenopodium ambrosioides Linn., which escorts to the isolation of stigmasterol (1), β-sitosterol (2), octadecanoic acid (3), scopoletin (4) and 1-piperoylpiperidine (5). Literature validates the medicinal authentication of these compounds extorted from other sources, while our previous findings regarding microbial activities of different solvent systems fractions are favouring the presence of medicinally important compounds in this species. Herein, however, we report these natural products for the first time from this species.

Topics: Alkaloids; Benzodioxoles; Chenopodium ambrosioides; Methanol; Phytochemicals; Piperidines; Plant Extracts; Plants, Medicinal; Polyunsaturated Alkamides; Sitosterols; Solvents; Stigmasterol

To establish a method for detecting micro-dialysis recovery of paeonol, eugenol and piperine in Huoxue Zhitong patch, in order to provide the basis for further percutaneous pharmacokinetics studies. The concentrations of paeonol, eugenol and piperine in dialysates were determined by HPLC, and probe deliveries were calculated respectively. The effects of concentration and calibration approaches on the micro-dialysis probe deliveries of the three components were investigated, and their probe absorbability, in vitro and in vivo probe stability and repeatability were also studied.The results indicated that little paeonol, eugenol and piperine were observed in probes with 30% alcohol as the perfusate, and could be cleaned from probe in a short time. And the in vivo and in vitro probe deliveries of three components were stable within 8 h, drug-containing solution and blank perfusate were alternatively used for three times, and the in vivo and in vitro probe deliveries of three components were basically unchanged. The in vitro recoveries of paeonol, eugenol and piperine with a range of concentration were respectively (45.7±4.66)%, (27.82±2.95)%, (41.3±3.96)%, which indicated no concentration independent. Under the same conditions, the similar delivery was observed by dialysis, retrodialysis and no-net flux. Therefore, the concentrations of analyses of the collected fraction could be calibrated by in vitro or in vivo recoveries. Meanwhile, this also proved that the micro-dialysis method built by this study is applicable to the study on percutaneous pharmacokinetics of Huoxue Zhitong patch.

Topics: Acetophenones; Alkaloids; Benzodioxoles; Drug Delivery Systems; Eugenol; Microdialysis; Piperidines; Polyunsaturated Alkamides; Transdermal Patch

Using pepper fruit of Hainan as raw material and 95% ethanol as solvent, the alkaloid in pepper is extracted with reflux method in this paper. The piperonylic acid is removed by adjusting the pH; the fat-soluble substance being removed by adding ethyl ether; the piperine alkaloid being purified with acetone by recrystallization anddetected with HPLC, as well as characterized with IR. The characterizations of piperine are discussed. Meanwhile, B3LYP/6-31G (d,p) method of DFT is applied to optimize the structure, calculate frequency and energy of pepper alkaloid, then obtain four kinds of configurations (configuration Ⅰ as Piperine, configuration Ⅱ as Iso Piperine, configuration Ⅲ as Iso Chavicine, configuration Ⅳ as Chavicine) with 64 kinds of stability conformational structure. The distribution of the thermodynamic equilibrium of stable conformations of four kinds of configurations of the molecular is calculated with Gibbs free energy at room temperature (298.15 K). And IR spectra of the experimental were compared with the IR spectra of the theoretical. The results show that the alkaloid extracted from pepper is mainly conformer 1 in configuration Ⅰ, that is, Piperine; after purifying, the content of piperine is 7% with the purity of 99%. With analysis, the methods of extraction, separation and purification of piperine in this paper achieve good results. Established models are in good agreement with the experimental results. This research is of great significance in guiding extracting process, building structural model and the characterization and application of piperine.

Topics: Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Molecular Conformation; Piper nigrum; Piperidines; Polyunsaturated Alkamides

P-glycoprotein (P-gp) efflux is the major cause of multidrug resistance (MDR) in tumors when using anticancer drugs, moreover, poor bioavailability of few drugs is also due to P-gp efflux in the gut. Rapamycin (RPM) is in the clinical trials for breast cancer treatment, but its P-gp substrate property leads to poor oral bioavailability and efficacy. The objective of this study is to formulate and evaluate nanoparticles of RPM, along with a chemosensitizer (piperine, PIP) for improved oral bioavailability and efficacy. Poly(d,l-lactide-co-glycolide) (PLGA) was selected as polymer as it has moderate MDR reversal activity, which may provide additional benefits. The nanoprecipitation method was used to prepare PLGA nanoparticles with particle size below 150 nm, loaded with both drugs (RPM and PIP). Prepared nanoparticles showed sustained in vitro drug release for weeks, with initial release kinetics of zero order with non-Fickian transport, subsequently followed by Higuchi kinetics with Fickian diffusion. An everted gut sac method was used to study the effect of P-gp efflux on drug transport. This reveals that the uptake of the RPM (P-gp substrate) has been increased in the presence of chemosensitizer. Pharmacokinetic studies showed better absorption profile of RPM from polymeric nanoparticles compared to its suspension counterpart and improved bioavailability of 4.8-folds in combination with a chemosensitizer. An in vitro cell line study indicates higher efficacy of nanoparticles compared to free drug solution. Results suggest that the use of a combination of PIP with RPM nanoparticles would be a promising approach in the treatment of breast cancer.

Topics: Alkaloids; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Availability; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Lactic Acid; Nanoparticles; Piperidines; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polyunsaturated Alkamides; Sirolimus

Spices have been used for thousands of years, and recent studies suggest that certain spices confer beneficial effects on gastric disorders. The purpose of this study was to evaluate possible chemopreventive effects of spice-derived compounds on Helicobacter pylori (H. pylori)-induced gastritis.. We examined the inhibitory effects of curcumin, capsaicin, and piperine on H. pylori in vitro by determining the colony-forming units and real-time RT-PCR in H. pylori stimulated AGS gastric cancer cells. For in vivo analysis, 6-week-old SPF male Mongolian gerbils were infected with H. pylori, fed diets containing 5000 ppm curcumin, 100 ppm capsaicin, or 100 ppm piperine, and sacrificed after 13 weeks.. All three compounds inhibited in vitro proliferation of H. pylori, with curcumin being the most effective. Infiltration of neutrophils and mononuclear cells was suppressed by piperine both in the antrum and corpus of H. pylori-infected gerbils. Capsaicin also decreased neutrophils in the antrum and corpus and mononuclear cell infiltration and heterotopic proliferative glands in the corpus. mRNA expression of Tnf-α and formation of phospho-IκB-α in the antrum were reduced by both capsaicin and piperine. In addition, piperine suppressed expression of Il-1β, Ifn-γ, Il-6, and iNos, while H. pylori UreA and other virulence factors were not significantly attenuated by any compounds.. These results suggest that capsaicin and piperine have anti-inflammatory effects on H. pylori-induced gastritis in gerbils independent of direct antibacterial effects and may thus have potential for use in the chemoprevention of H. pylori-associated gastric carcinogenesis.

Topics: Alkaloids; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Benzodioxoles; Capsaicin; Chemoprevention; Colony Count, Microbial; Diet Therapy; Gastritis; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Male; Piperidines; Polyunsaturated Alkamides; Real-Time Polymerase Chain Reaction; Sequence Analysis, DNA; Stomach

Currently available treatment approaches for Parkinson׳s disease (PD) are limited in terms of variety and efficacy. Piper longum L. (PLL; Piperaceae) is used in traditional medicine in Asia and the Pacific Islands, with demonstrated anti-inflammatory and antioxidant activities in preclinical studies, and alkaloid extracts of PLL have shown protective effects in PD models. The present study investigated the mechanistic basis for the observed protective effects of PLL. Rats treated with PLL-derived alkaloids showed improvement in rotenone-induced motor deficits, while reactive oxygen species (ROS) production was decreased, mitochondrial membrane potential was stabilized, and the opening of the mitochondrial permeability transition pore (mPTP)-which is involved in ROS production-was inhibited. In addition, rotenone-induced apoptosis was abrogated in the presence of these alkaloids, while a pretreatment stimulated autophagy, likely mitigating neuronal injury by the removal of damaged mitochondria. These findings provide novel insight into the neuroprotective function of PLL as well as evidence in favor of its use in PD treatment. This article is part of a Special Issue entitled SI: Neuroprotection.

Topics: Alkaloids; Animals; Antiparkinson Agents; Apoptosis; Autophagy; Benzodioxoles; Brain; Cell Line; Dioxolanes; Drug Evaluation, Preclinical; Humans; Male; Mice; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Neurons; Neuroprotective Agents; Parkinsonian Disorders; Phytotherapy; Piper; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Random Allocation; Rats, Wistar; Rotenone

Piperine, one of the active components of black pepper, has been reported to have antioxidant and anti-inflammatory activities. However, the effects of piperine on lipolysaccharide (LPS)-induced acute lung injury (ALI) have not been reported. Thus, the protective effects of piperine against LPS-induced ALI were investigated in this study. LPS-induced lung injury was assessed by histological study, myeloperoxidase (MPO) activity, and inflammatory cytokine production. Our results demonstrated that piperine attenuated LPS-induced MPO activity, lung edema, and inflammatory cytokines TNF-α, IL-6, and IL-1β production. Histological studies showed that piperine obviously attenuated LPS-induced lung injury. In addition, piperine significantly inhibited LPS-induced NF-κB activation. In conclusion, our results demonstrated that piperine had a protective effect on LPS-induced ALI. The anti-inflammatory mechanism of piperine is through inhibition of NF-κB activation. Piperine may be a potential therapeutic agent for ALI.

Topics: Acute Lung Injury; Alkaloids; Animals; Anti-Inflammatory Agents; Antioxidants; Benzodioxoles; Enzyme Activation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lung Injury; Male; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; NF-kappa B; Peroxidase; Piperidines; Polyunsaturated Alkamides; Pulmonary Edema; Signal Transduction; Tumor Necrosis Factor-alpha

Black pepper is a source of effective antioxidants. It contains several powerful antioxidants and is thus one of the most important spices for preventing and curtailing oxidative stress. There is considerable interest in the development of a drug-delivery systems that would result in the selective delivery of antioxidants to tissues in sufficient concentrations to ameliorate oxidant-induced tissue injuries. Liposomes are biocompatible, biodegradable and nontoxic artificial phospholipid vesicles that offer the possibility of carrying hydrophilic, hydrophobic and amphiphilic molecules. This article focuses on the use of liposomes for the delivery of antioxidants in the prevention or treatment of pathological conditions related to oxidative stress. Liposome formulations of piperine were analyzed with various spectroscopic methods. The formulation with the highest entrapment efficiency (90.5%) was formulated with an L-α-phosphatidylcholine dipalmitoyl (DPPC):piperine, 30:1 molar ratio, and total lipid count of 19.47 mg/ml in the final liposomal preparation. The liposome formulation was found to be stable after storage at 4 °C, protected from light, for a minimum of 3 weeks. The incremental process of piperine penetration through the phospholipid membrane was analyzed using the FT-IR, UV-Vis and NMR methods. Temperature stability studies carried out at 37 °C showed the highest percentage of piperine release in the first 3 h of incubation.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Alkaloids; Antioxidants; Benzodioxoles; Liposomes; Nanocapsules; Piperidines; Polyunsaturated Alkamides

Piper nigrum (P. nigrum) is commonly used in traditional medicine. This current study aimed to investigate the anticancer and cancer preventive activity of a piperine-free P. nigrum extract (PFPE) against breast cancer cells and N-nitrosomethylurea (NMU)-induced mammary tumorigenesis in rats. The cytotoxic effects and the mechanism of action were investigated in breast cancer cells using the MTT assay and Western blot analysis, respectively. An acute toxicity study was conducted according to the Organization for Economic Co-operation and Development guideline. Female Sprague-Dawley rats with NMU-induced mammary tumors were used in preventive and anticancer studies. The results showed that PFPE inhibited the growth of luminal-like breast cancer cells more so than the basal-like ones by induction of apoptosis. In addition, PFPE exhibited greater selectivity against breast cancer cells than colorectal cancer, lung cancer, and neuroblastoma cells. In an acute toxicity study, a single oral administration of PFPE at a dose of 5,000 mg/kg body weight resulted in no mortality and morbidity during a 14-day observation period. For the cancer preventive study, the incidence of tumor-bearing rats was 10% to 20% in rats treated with PFPE. For the anticancer activity study, the growth rate of tumors in the presence of PFPE-treated groups was much slower when compared with the control and vehicle groups. The extract itself caused no changes to the biochemical and hematologic parameters when compared with the control and vehicle groups. In conclusion, PFPE had a low toxicity and a potent antitumor effect on mammary tumorigenesis in rats.

Topics: Alkaloids; Animals; Anticarcinogenic Agents; Apoptosis; Benzodioxoles; Body Weight; Cell Line, Tumor; Cell Proliferation; Female; Humans; Mammary Neoplasms, Experimental; MCF-7 Cells; Methylnitrosourea; Mice; Mice, Inbred ICR; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley

Piperine, a major alkaloid found in the fruits of black and long pepper plants, has anti-inflammatory properties; however, piperine's effect on dendritic cell (DC) migration and T cell-activating function has not been investigated. Bone marrow-derived mouse DCs that were matured in the presence of 100 μM piperine showed reduced in vitro migration in response to CCL21, as well as reduced in vivo migration to lymph nodes. In addition, piperine-treated DCs had reduced CCR7 expression and elevated CCR5 expression, as well as reduced expression of CD40 and class II major histocompatibility complex molecules and decreased nuclear accumulation of RelB. DC production of interleukin (IL)-6, tumor necrosis factor α, and monocyte chemoattractant protein-1 in response to lipopolysaccharide stimulation was also reduced following piperine treatment. Exposure to piperine during maturation therefore caused DCs to retain an immature phenotype, which was associated with a reduced capacity to promote T cell activation since co-culture of ovalbumin (OVA323-339)-specific T cells with OVA323-339-pulsed DCs that were previously matured in the presence of piperine showed reduced interferon-γ and IL-2 expression. OVA323-339-specific T cell proliferation was also reduced in vivo in the presence of piperine-treated DCs. Inhibition of DC migration and function by piperine may therefore be a useful strategy to down-regulate potentially harmful DC-driven T cell responses to self-antigens and transplantation antigens.

Topics: Alkaloids; Animals; Benzodioxoles; CD40 Antigens; Cell Proliferation; Cells, Cultured; Chemokines; Chemotaxis; Coculture Techniques; Cytokines; Dendritic Cells; Female; Histocompatibility Antigens Class II; Immunity, Cellular; Immunologic Factors; Lymphocyte Activation; Mice, Inbred C57BL; Ovalbumin; Peptide Fragments; Phenotype; Piperidines; Polyunsaturated Alkamides; Signal Transduction; T-Lymphocytes; Transcription Factor RelB

To date, the majority of research exploring associations with genetic variability in bitter taste receptors has understandably focused on compounds and foods that are predominantly or solely perceived as bitter. However, other chemosensory stimuli are also known to elicit bitterness as a secondary sensation. Here we investigated whether TAS2R variation explains individual differences in bitterness elicited by chemesthetic stimuli, including capsaicin, piperine and ethanol. We confirmed that capsaicin, piperine and ethanol elicit bitterness in addition to burning/stinging sensations. Variability in perceived bitterness of capsaicin and ethanol were significantly associated with TAS2R38 and TAS2R3/4/5 diplotypes. For TAS2R38, PAV homozygotes perceived greater bitterness from capsaicin and ethanol presented on circumvallate papillae, compared to heterozygotes and AVI homozygotes. For TAS2R3/4/5, CCCAGT homozygotes rated the greatest bitterness, compared to heterozygotes and TTGGAG homozygotes, for both ethanol and capsaicin when presented on circumvallate papillae. Additional work is needed to determine how these and other chemesthetic stimuli differ in bitterness perception across concentrations and presentation methods. Furthermore, it would be beneficial to determine which TAS2R receptors are activated in vitro by chemesthetic compounds.

Topics: Adult; Alkaloids; Benzodioxoles; Capsaicin; Ethanol; Female; Genetic Variation; Genotype; Humans; Male; Piperidines; Polymorphism, Single Nucleotide; Polyunsaturated Alkamides; Receptors, G-Protein-Coupled; Taste; Tongue

Quinolinic acid (QA) is an excitotoxin that induces Huntington's-like symptoms in animals and humans. Curcumin (CMN) is a well-known antioxidant but the major problem is its bioavailability. Therefore, the present study was designed to investigate the effect of CMN in the presence of piperine against QA-induced excitotoxic cell death in rats.. QA was administered intrastriatally at a dose of 200 nmol/2 µl saline, bilaterally. CMN (25 and 50 mg/kg/day, p.o.) and combination of CMN (25 mg/kg/day, p.o.) and with piperine (2.5 mg/kg/day, p.o.) was administered daily for the next 21 days. Body weight and behavioral parameters were observed on 1st, 7th, 14th and 21st day. On the 22nd day, animals were sacrificed and striatum was isolated for biochemical (LPO, nitrite and GSH), neuroinflammatory (interleukin (IL)-1β, IL-6 and TNF-α) and neurochemical (dopamine, norepinephrine, GABA, glutamate, 5-HT, 3,4-dihydroxyphenylacetic acid and homovanillic acid) estimation.. CMN treatment showed beneficial effect against QA-induced motor deficit, biochemical and neurochemical abnormalities in rats. Combination of piperine (2.5 mg/kg/day, p.o.) with CMN (25 mg/kg/day, p.o.) significantly enhanced its protective effect as compared to treatment with CMN alone.. This study has revealed that the combination of CMN and piperine showed strong antioxidant and protective effect against QA-induced behavioral and neurological alteration in rats.

Topics: Adenosine; Alkaloids; Animals; Antioxidants; Benzodioxoles; Brain; Catecholamines; Curcumin; Cytokines; Drug Therapy, Combination; gamma-Aminobutyric Acid; Glutamic Acid; Glutathione; Hand Strength; Huntington Disease; Lipid Peroxidation; Locomotion; Neuroprotective Agents; Nitrites; Piperidines; Polyunsaturated Alkamides; Quinolinic Acid; Rats, Wistar

The purpose of this investigation was to prepare and characterize acyclovir loaded floating microspheres by emulsification solvent evaporation method. Piperine was added to investigate its effect on acyclovir bioavailability. The microspheres were characterized for size, shape, entrapment efficiency, in vitro drug release, and in vivo pharmacokinetic parameters. The morphological characterization of microspheres was done using a scanning electron microscope. The microspheres were spherical and had particle size in the range of 400 to 525 μm. The percent drug entrapment efficiency varied between 56.12 ± 1.32 % to 87.32 ± 5.28 %. The drug release was decreased at higher polymer concentrations. Nearly two times higher AUC0-24 value of acyclovir-loaded piperine containing microspheres (15614.13 ± 6953.13 ng h ml(-1)) was observed as compared to the drug solution (7552.33 ± 3219.09 ng h ml(-1)). Under the accelerated storage conditions, the best selected formulation was found to be stable for 90 days. The preliminary results of this study suggest that the developed microspheres containing acyclovir could enhance drug entrapment efficiency, reduce initial burst release, and prolong the drug release with enhanced bioavailability.

Topics: Acyclovir; Alkaloids; Animals; Benzodioxoles; Biological Availability; Drug Delivery Systems; Drug Liberation; Drug Stability; Microscopy, Electron, Scanning; Microspheres; Particle Size; Piperidines; Polyunsaturated Alkamides; Rats; Solubility; Upper Gastrointestinal Tract

Stress can act as a precipitation factor in the onset of emotional disorders, particularly depression. Trans-resveratrol is a polyphenolic compound enriched in polygonum cuspidatum and has been found to exert antidepressant-like effects in our previous studies. In present study, we assessed the effects of trans-resveratrol used in combination with piperine, commonly known as a bioavailability enhancer, on chronic unpredictable mild stress-induced depressive-like behaviors and relevant molecular targets. Trans-resveratrol used alone reduced the immobility time of rats in the forced swimming test, with the maximal effects of trans-resveratrol around 60 % inhibition at the highest dose tested, 40 mg/kg. However, when a subthreshold dose of piperine, 2.5 mg/kg was used in combination with trans-resveratrol, the minimum effective dose of trans-resveratrol in reducing the immobility time was reduced to 20 mg/kg. Further evidence from neurochemical (monoamines in the frontal cortex and the hippocampus), biochemical (monoamine oxidase, MAO activities) and molecular biological (cAMP, PKA, CREB and BDNF) assays supported the findings in the behavioral studies. These results suggest that the co-treatment strategy with trans-resveratrol and piperine might be an alternative therapy that provides efficacious protection against chronic stress.

Topics: Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Cyclic AMP; Depression; Frontal Lobe; Hippocampus; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Stilbenes; Stress, Psychological

The aim of the present study was to investigate the protective effects of curcumin alone and in combination with piperine against lipopolysaccharide (LPS)-induced neurobehavioral and neurochemical deficits in the mice hippocampus. Mice were treated with curcumin (100, 200, and 400 mg/kg, p.o.) and piperine (20 mg/kg, p.o.) for 7 days followed by LPS (0.83 mg/kg, i.p.) administration. Animals exhibited anxiety and depressive-like phenotype after 3 and 24 h of LPS exposure, respectively. LPS administration increased the oxido-nitrosative stress as evident by elevated levels of malondialdehyde, nitrite, and depletion of glutathione level in the hippocampus. Furthermore, we found raised level of pro-inflammatory cytokines (IL-1β and TNF-α) in the hippocampus of LPS-treated mice. Pretreatment with curcumin alleviated LPS-induced neurobehavioral and neurochemical deficits. Furthermore, co-administration of curcumin with piperine significantly potentiated the neuroprotective effect of curcumin. These results demonstrate that piperine enhanced the neuroprotective effect of curcumin against LPS-induced neurobehavioral and neurochemical deficits.

Topics: Alkaloids; Animals; Benzodioxoles; Curcumin; Drug Synergism; Hippocampus; Lipopolysaccharides; Mice; Neurodegenerative Diseases; Neuroprotective Agents; Piperidines; Polyunsaturated Alkamides

The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by crossing the blood-brain barrier (BBB). We here evaluated piperine and five selected analogs (SCT-66, SCT-64, SCT-29, LAU397, and LAU399) regarding their BBB permeability. Data were obtained in three in vitro BBB models, namely a recently established human model with immortalized hBMEC cells, a human brain-like endothelial cells (BLEC) model, and a primary animal (bovine endothelial/rat astrocytes co-culture) model. For each compound, quantitative UHPLC-MS/MS methods in the range of 5.00-500ng/mL in the corresponding matrix were developed, and permeability coefficients in the three BBB models were determined. In vitro predictions from the two human BBB models were in good agreement, while permeability data from the animal model differed to some extent, possibly due to protein binding of the screened compounds. In all three BBB models, piperine and SCT-64 displayed the highest BBB permeation potential. This was corroborated by data from in silico prediction. For the other piperine analogs (SCT-66, SCT-29, LAU397, and LAU399), BBB permeability was low to moderate in the two human BBB models, and moderate to high in the animal BBB model. Efflux ratios (ER) calculated from bidirectional permeability experiments indicated that the compounds were likely not substrates of active efflux transporters.

Topics: Alkaloids; Benzodioxoles; Blood-Brain Barrier; Humans; In Vitro Techniques; Permeability; Piperidines; Polyunsaturated Alkamides; Receptors, GABA-A

We combine quantum chemical and molecular docking techniques to provide new insights into how piperine molecule in various forms of pepper enhances bioavailability of a number of drugs including curcumin in turmeric for which it increases its bioavailability by a 20-fold. We have carried out docking studies of quantum chemically optimized piperine structure binding to curcumin, CYP3A4 in cytochrome P450, p-Glycoprotein and UDP-glucuronosyltransferase (UGT), the enzyme responsible for glucuronosylation, which increases the solubility of curcumin. All of these studies establish that piperine binds to multiple sites on the enzymes and also intercalates with curcumin forming a hydrogen bonded complex with curcumin. The conjugated network of double bonds and the presence of multiple charge centers of piperine offer optimal binding sites for piperine to bind to enzymes such as UDP-GDH, UGT, and CYP3A4. Piperine competes for curcumin's intermolecular hydrogen bonding and its stacking propensity by hydrogen bonding with enolic proton of curcumin. This facilitates its metabolic transport, thereby increasing its bioavailability both through intercalation into curcumin layers through intermolecular hydrogen bonding, and by inhibiting enzymes that cause glucuronosylation of curcumin.

Topics: Alkaloids; Benzodioxoles; Biological Availability; Curcumin; Drug Discovery; Molecular Docking Simulation; Piper; Piperidines; Polyunsaturated Alkamides; Protein Conformation; Quantum Theory

Insecticide resistance carries the potential to undermine the efficacy of insecticide based malaria vector control strategies. Therefore, there is an urgent need for new insecticidal compounds. Black pepper (dried fruit from the vine, Piper nigrum), used as a food additive and spice, and its principal alkaloid piperine, have previously been shown to have larvicidal properties. The aim of this study was to investigate the larvicidal effects of ground black pepper and piperine against third and fourth instar Anopheles larvae drawn from several laboratory-reared insecticide resistant and susceptible strains of Anopheles arabiensis, An. coluzzii, An. gambiae, An. quadriannulatus and An. funestus.. Larvae were fed with mixtures of standard larval food and either ground black pepper or piperine in different proportions. Mortality was recorded 24 h after black pepper and 48 h after piperine were applied to the larval bowls.. Black pepper and piperine mixtures caused high mortality in the An. gambiae complex strains, with black pepper proving significantly more toxic than piperine. The An. funestus strains were substantially less sensitive to black pepper and piperine which may reflect a marked difference in the feeding habits of this species compared to that of the Gambiae complex or a difference in food metabolism as a consequence of differences in breeding habitat between species.. Insecticide resistant and susceptible strains by species proved equally susceptible to black pepper and piperine. It is concluded that black pepper shows potential as a larvicide for the control of certain malaria vector species.

Topics: Alkaloids; Animals; Anopheles; Benzodioxoles; Insecticide Resistance; Insecticides; Larva; Malaria; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Benzodioxoles; Biological Availability; Cell Survival; Chitosan; Curcumin; Drug Interactions; Drug Stability; Emulsions; Fibroblasts; HT29 Cells; Humans; Imidoesters; Male; Mice; Nanoparticles; NIH 3T3 Cells; Particle Size; Piperidines; Polyunsaturated Alkamides; Rats, Wistar; Surface Properties; Tissue Distribution

Nanotechnology-based drug products are emerging as promising agents to enhance the safety and efficacy of established chemotherapeutic molecules. Carbon nanotubes (CNTs), especially multiwalled CNTs (MWCNTs), have been explored for this potential owing to their safety and other desired attributes. Docetaxel (DTX) is an indispensable anticancer agent, which has wide applicability in variety of cancers. However, the potential of DTX is still not completely harvested due to problems like poor aqueous solubility, low tissue permeability, poor bioavailability, high first pass metabolism, and dose-related toxicity. Hence, it was proposed to attach DTX to MWCNTs and coadminister it along with piperine with an aim to enhance the tissue permeation, anticancer activity, and bioavailability. The Fourier transform infrared, UV, and NMR spectroscopic data confirmed successful conjugation of DTX to MWCNTs and adsorption of piperine onto MWCNTs. The codelivery MWCNT-based system offered drug release moderation and better cancer cell toxicity than that of plain DTX as well as DTX-CNT conjugate. The pharmacokinetic profile of DTX was exceptionally improved by the conjugation, in general, and coadministration with piperine, in specific vis-à-vis plain drug. Hence, the dual approach of MWCNTs conjugation and piperine coadministration can serve as a beneficial option for enhancement of the performance of DTX in cancer chemotherapy.

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Cell Line, Tumor; Docetaxel; Drug Delivery Systems; Humans; Magnetic Resonance Spectroscopy; MCF-7 Cells; Microscopy, Electron, Scanning; Nanomedicine; Nanotechnology; Nanotubes, Carbon; Piperidines; Polyunsaturated Alkamides; Spectroscopy, Fourier Transform Infrared; Taxoids

Hyperglycemia leads to elevation of oxidative stress and proinflammatory cytokines which are the main causes of diabetic nephropathy (DN). NLRP3 inflammasome and thioredoxin-interacting protein (TXNIP) are recently assumed to participate in the development of DN. We aimed to investigate the effects of Cepharanthine (CEP), Piperine (Pip) and their combination in streptozotocin (STZ)-induced DN focusing on their role to modulate NLRP3 and TXNIP induced inflammation.. Diabetic rats were treated with intraperitoneal (i.p.) injection of CEP (10mg/kg/day), Pip (30mg/kg/day) or their combination for 8weeks. Nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) were assessed by ELISA technique. TXNIP and NLRP3 genes expressions were evaluated by real time-PCR.. Diabetic rats showed significant increase in renal TXNIP and NLRP3 expression. CEP, Pip or their combination significantly decreased TXNIP and NLRP3 expression in diabetic kidneys. Hyperglycemia induced NF-κB activation leading to increased IL-1β and TNF-α levels. CEP, Pip or their combination showed significant inhibition of NF-κB together with decreased IL-1β and TNF-α levels in diabetic rats. Also, diabetic rats showed significant decrease in creatinine clearance and increase in blood glucose, serum creatinine, blood urea nitrogen, malondialdehyde, proteinuria, and kidney weight to body Weight ratio. All of these changes were reversed by CEP, Pip or their combination.. The antioxidant and anti-inflammatory effects of CEP and Pip which were accompanied by inhibition of NF-κB and NLRP3 activation might be helpful mechanisms to halt the progression of DN.

Topics: Alkaloids; Animals; Benzodioxoles; Benzylisoquinolines; Diabetic Nephropathies; Inflammasomes; Male; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley

We have recently proved the interactions of piperine with androgen receptor and androgen binding protein. The present study was aimed to evaluate the antifertility effect of piperine on male albino rats after the treatment period i. e., after 60 days and withdrawal period i. e., after 120 days.. Adult male rats were divided into 4 groups (n=12). Group I:. Rats were given vehicle p.o i. e., 0.5% carboxy methyl cellulose (CMC) in normal saline daily for 60 days, Group II: Rats were treated with piperine suspended in 0.5% CMC at a dose of 10 mg/kg daily/60 days. Group III: Rats were treated with piperine suspended in 0.5% CMC at a dose of 10 mg/kg on every 4(th) day for 60 days. Group IV: Rats were treated with piperine suspended in 0.5% CMC at a dose of 10 mg/kg on every 7(th) day for 60 days.. Piperine significantly altered the epididymal sperm count, motility, viability, weight of the epididymis, cauda, caput, corpus and seminal vesicles. It also exhibited negative impact on biochemical markers via decreasing epididymal sialic acid levels, seminal fructose content, epididymal anti-oxidant enzyme activities of super oxide dismutase (SOD), catalase (CAT) and by increasing the malondialdehyde content after the treatment period. Histopathological observations also supported the above findings. All the altered values were reinforced after the withdrawal period.. From the results of this study, we can conclude that piperine has the potential to become a good lead for the reversible male oral contraceptive research.

Topics: Alkaloids; Animals; Antispermatogenic Agents; Benzodioxoles; Epididymis; Male; Organ Size; Piperidines; Polyunsaturated Alkamides; Rats; Seminal Vesicles; Sperm Count; Sperm Motility; Spermatogenesis; Spermatozoa

The aims of the current research project were to investigate the efficiency of various polymers to enhance the solubility and increase the systemic absorption of piperine using hot melt extrusion technology.. Piperine 10-40% w/w and Eudragit(®) EPO/Kollidon(®) VA 64 or Soluplus(®) were mixed, and the resulting blends were extruded using a twin-screw extruder (Process 11, Thermo Fisher Scientific). Drug release profiles and piperine solubility studies of the extrudates were evaluated. A non-everted intestinal sac was employed for the most promising formulation, 10% w/w piperine/Soluplus(®) , and pure piperine to study the permeability characteristics.. Dissolution studies demonstrated enhancement in piperine per cent release of 10% and 20% w/w piperine/Soluplus(®) extrudates up to 95% and 74%, respectively. The solubility of 10% and 20% piperine/Soluplus(®) increased more than 160- and 45-fold in water, respectively. Furthermore, permeability studies demonstrated the enhancement in piperine absorption of 10% w/w piperine/Soluplus(®) extrudates up to 158.9 μg/5 ml compared with pure piperine at 1.3 μg/5 ml within 20 min.. These results demonstrated that increasing the bioavailability of piperine may be achieved as demonstrated by findings in this study.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Drug Compounding; Drug Liberation; Hot Temperature; Male; Permeability; Piperidines; Plant Extracts; Polyethylene Glycols; Polymethacrylic Acids; Polyunsaturated Alkamides; Polyvinyls; Povidone; Psychotropic Drugs; Rats, Sprague-Dawley; Solubility; Water

Piperine (PIP), the major alkaloid component from Piper longum L. and Piper nigrum L., could enhance the bioavailabilities of other drugs including rosuvastatin, peurarin and docetaxel (DOX) via inhibition of CYP3A and P-glycoprotein activity. Nevertheless, the effect of such drug combination usage on the in vivo exposure of PIP has not been investigated due to lack of assay for the simultaneous determination of PIP and other drugs such as DOX. Besides, the reported pharmacokinetics of PIP varied a lot without appropriate bioavailability determined from the same dose. In the current study, an LC/MS/MS method has been developed to simultaneously determine the plasma concentrations of PIP and DOX and further applied to investigate the pharmacokinetics properties of PIP after oral and intravenous administrations as well as the pharmacokinetics interactions between PIP and DOX after their co-administration. A simple protein precipitation method was employed for plasma sample treatment by adding a mixture of methanol and acetonitrile (1:1, v/v) with glibenclamide as internal standard (IS). The LC/MS/MS system consisted of Agilent 6430 series LC pumps and auto-sampler. The chromatographic separation was carried out in 15min on a Waters C18 column (150×3.9mm i.d., 4μm) with a mobile phase containing 0.2% formic acid and acetonitrile (1:1, v/v) at a flow rate of 0.4ml/min. The detection was performed using the positive ion electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode with precursor-to-product ion transitions at m/z 286.1→201.1 for PIP, m/z 830.3→548.9 for DOX and m/z 494.2→369.0 for IS. The method demonstrated good linearity for both PIP and DOX over the concentration range of 2.5-1280ng/ml with LLOD at 2.5ng/ml. The intra-day and inter-day precisions were less than 13.34% and relative error (R.E.) representing accuracy was in the range of -11.38 to 3.15%. The recoveries of PIP, DOX and IS were above 75% and there was no matrix effect. PIP and DOX exhibited good stabilities under various conditions. PIP was administrated via intravenous bolus at 3.5mg/kg and via oral administration at 35mg/kg and 3.5mg/kg, while DOX was intravenously administrated at 7mg/kg to Sprague-Daley rats. The plasma concentrations of PIP and DOX were determined using the above developed and validated method. At the dose of 3.5mg/kg, the bioavailability of PIP was calculated to be 25.36%. Its AUC0→t was unproportionally increased with doses, indicating a potenti

Topics: Administration, Intravenous; Administration, Oral; Alkaloids; Animals; Area Under Curve; Benzodioxoles; Chromatography, High Pressure Liquid; Docetaxel; Drug Stability; Herb-Drug Interactions; Male; Piper; Piperidines; Plant Preparations; Polyunsaturated Alkamides; Quality Control; Rats; Rats, Sprague-Dawley; Reference Standards; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Taxoids

Curcumin is a potential agent for both the prevention and treatment of cancers. Curcumin treatment alone, or in combination with piperine, limits breast stem cell self-renewal, while remaining non-toxic to normal differentiated cells. We paired fluorescence-activated cell sorting with RNA sequencing to characterize the genome-wide changes induced specifically in normal breast stem cells following treatment with these compounds. We generated genome-wide maps of the transcriptional changes that occur in epithelial-like (ALDH+) and mesenchymal-like (ALDH-/CD44+/CD24-) normal breast stem/progenitor cells following treatment with curcumin and piperine. We show that curcumin targets both stem cell populations by down-regulating expression of breast stem cell genes including ALDH1A3, CD49f, PROM1, and TP63. We also identified novel genes and pathways targeted by curcumin, including downregulation of SCD. Transient siRNA knockdown of SCD in MCF10A cells significantly inhibited mammosphere formation and the mean proportion of CD44+/CD24- cells, suggesting that SCD is a regulator of breast stemness and a target of curcumin in breast stem cells. These findings extend previous reports of curcumin targeting stem cells, here in two phenotypically distinct stem/progenitor populations isolated from normal human breast tissue. We identified novel mechanisms by which curcumin and piperine target breast stem cell self-renewal, such as by targeting lipid metabolism, providing a mechanistic link between curcumin treatment and stem cell self-renewal. These results elucidate the mechanisms by which curcumin may act as a cancer-preventive compound and provide novel targets for cancer prevention and treatment.

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Breast Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Separation; Curcumin; Female; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Piperidines; Polyunsaturated Alkamides; Sequence Analysis, RNA; Stearoyl-CoA Desaturase; Stem Cells

Curcumin is a nutraceutical obtained from the rhizomes of Curcuma longa with a significant medicinal value against numerous disorders. However, the potential cannot be completely exploited due to low in vivo bioavailability. Hence, in order to enhance the bioavailability of curcumin, we combined it with the bioavailability enhancers like piperine and quercetin.. The present study was targeted to explore the antidiabetic potential of combinatorial extract of curcumin with piperine and quercetin (CPQ) in streptozotocin- and nicotinamide-induced diabetic rats. Diabetes mellitus was induced by single intraperitoneal injection of streptozotocin (55 mg/kg) and nicotinamide (120 mg/kg-1). CPQ was orally administered at 100 mg kg-1 dose/day for a period of 28 days. At the end of 28 days, blood was analyzed for glucose, high density lipoprotein (HDL), low density lipoprotein (LDL) and total cholesterol level. Oral glucose tolerance test (OGTT) was also conducted at the end of 28 days.. Oral administration of CPQ at the dose of 100 mg kg-1 significantly (p<0.01) reduced plasma glucose at the end of 28 days, as compared to the diabetic control group. The reduction in the plasma glucose produced by the CPQ extract was equivalent to that of glibenclamide and significantly more compared to curcumin alone (p<0.01). Furthermore, a significant (p<0.01) reduction in the raised LDL, cholesterol and triglycerides and improvement was observed in the group fed with CPQ compared to diabetic control as well as the alone (p<0.05) curcumin group. There was a significant improvement in the body weight with CPQ compared to diabetes control group. OGTT revealed a significantly high glucose tolerance in CPQ fed rats compared to the diabetic control as well as the rats fed with curcumin alone.. Treatment with combinatorial extract of curcumin presented a significantly better therapeutic potential when compared with curcumin alone, which reveals that CPQ, with reduced dose of curcumin may serve as a therapeutic agent in the treatment of type 2 diabetes mellitus.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Blood Glucose; Body Weight; Curcuma; Curcumin; Diabetes Mellitus, Experimental; Drug Combinations; Female; Glucose Tolerance Test; Hypoglycemic Agents; Lipids; Male; Mice; Phytotherapy; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Quercetin; Rats, Wistar

Twelve methylenedioxy-containing compounds including piperine and 10 piperine-like synthetic compounds were assessed to determine their antifungal and antiaflatoxigenic activities against Aspergillus flavus ATCC 22546 in terms of their structure-activity relationships. Piperonal and 1,3-benzodioxole had inhibitory effects against A. flavus mycelial growth and aflatoxin B₁ production up to a concentration of 1000 μg/mL. Ten piperine-like synthetic compounds were synthesized that differed in terms of the carbon length in the hydrocarbon backbone and the presence of the methylenedioxy moiety. In particular, 1-(2-methylpiperidin-1-yl)-3-phenylprop-2-en-1-one had potent antifungal and antiaflatoxigenic effects against A. flavus up to a concentration of 1 μg/mL. This synthetic compound was remarkable because the positive control thiabendazole had no inhibitory effect at this concentration. Reverse transcription-PCR analysis showed that five genes involved in aflatoxin biosynthesis pathways were down-regulated in A. flavus, i.e., aflD, aflK, aflQ, aflR, and aflS; therefore, the synthetic compound inhibited aflatoxin production by down-regulating these genes.

Topics: Aflatoxin B1; Alkaloids; Aspergillus flavus; Benzodioxoles; Dose-Response Relationship, Drug; Fungicides, Industrial; Gene Expression Regulation, Fungal; Molecular Structure; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship

Parkinson's disease (PD) is the second most common neurodegenerative disorder, but there are few treatments currently available. The autophagy pathway plays an important role in the pathogenesis of PD; modulating this pathway is considered to be a promising treatment strategy. Piperine (PIP) is a Chinese medicine with anti-inflammatory and antioxidant effects. The present study investigated the neuroprotective effects of PIP on rotenone-induced neurotoxicity in SK-N-SH cells, primary rat cortical neurons, and in a mouse model. Mice were administered rotenone (10mg/kg) for 6 weeks; PIP (25mg/kg, 50mg/kg) was subsequently administered for 4 weeks. We found that PIP treatment attenuated rotenone-induced motor deficits, and rescued the loss of dopaminergic neurons in the substantia nigra. PIP increased cell viability and restored mitochondrial functioning in SK-N-SH cells and primary neurons. In addition, PIP induced autophagy by inhibiting mammalian target of rapamycin complex 1(mTORC1) via activation of protein phosphotase 2A (PP2A). However, inhibiting PP2A activity with okadaic acid reduced these protective effects, suggesting that PP2A is a target of PIP. These findings demonstrate that PIP exerts neuroprotective effects in PD models via induction of autophagy, and may be an effective agent for PD treatment.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Antioxidants; Autophagy; Benzodioxoles; Cell Survival; Dopaminergic Neurons; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mitochondria; Neuroprotective Agents; Parkinson Disease, Secondary; Piperidines; Polyunsaturated Alkamides; Protein Phosphatase 2; Rats; Rotenone; Substantia Nigra

Parkinson's disease (PD) is the most widespread form of dementia where there is an age related degeneration of dopaminergic neurons in the substantia nigra region of the brain. Accumulation of α-synuclein (αS) protein aggregate, mitochondrial dysfunction, oxidative stress, and neuronal cell death are the pathological hallmarks of PD. In this context, amalgamation of curcumin and piperine having profound cognitive properties, and antioxidant activity seems beneficial. However, the blood-brain barrier (BBB) is the major impediment for delivery of neurotherapeutics to the brain. The present study involves formulation of curcumin and piperine coloaded glyceryl monooleate (GMO) nanoparticles coated with various surfactants with a view to enhance the bioavailability of curcumin and penetration of both drugs to the brain tissue crossing the BBB and to enhance the anti-parkinsonism effect of both drugs in a single platform. In vitro results demonstrated augmented inhibition of αS protein into oligomers and fibrils, reduced rotenone induced toxicity, oxidative stress, and apoptosis, and activation of autophagic pathway by dual drug loaded NPs compared to native counterpart. Further, in vivo studies revealed that our formulated dual drug loaded NPs were able to cross BBB, rescued the rotenone induced motor coordination impairment, and restrained dopaminergic neuronal degeneration in a PD mouse model.

Topics: Alkaloids; alpha-Synuclein; Animals; Antiparkinson Agents; Benzodioxoles; Blood-Brain Barrier; Capillary Permeability; Curcumin; Drug Delivery Systems; Drug Therapy, Combination; Liposomes; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Nanoparticles; Neuroprotective Agents; Parkinsonian Disorders; PC12 Cells; Piperidines; Polyunsaturated Alkamides; Protein Aggregation, Pathological; Random Allocation; Rats; Rotenone; Surface-Active Agents

The present study investigated the comparative effects of piperine (PIP) - the active ingredient of black and long peppers - and simvastatin (SIM) on hepatic steatosis in hyperlipidemic rats. Male Wistar rats were fed a cholesterol mixture daily by intragastric gavage for 8 weeks. Piperine was given by oral gavage 8 h after cholesterol feeding. The animals were divided into 4 groups: control, high fat (HF), high fat plus 40 mg PIP/kg, and high fat plus 2 mg SIM/kg. At the end of the treatment, liver cholesterol, triglyceride, thiobaribituric reacting substances, superoxide dismutase (SOD), serum aminotransferase (AST), and alanine transferase (ALT) were measured. The result demonstrated that PIP and SIM significantly reduced the accumulation of cholesterol, triglyceride, and lipid peroxidation in the liver, while elevation of SOD was observed. The activities of AST and ALT significantly decreased in PIP when compared with the HF group. Our in vitro study of pancreatic lipase also showed the inhibitory effect of PIP higher than 30% at 5 mmol/L. These results demonstrate that PIP has beneficial effects in the treatment and (or) prevention of fat accumulation in the liver and that this mechanism is due to the inhibition of pancreatic lipase and the improvement of oxidative status.

Topics: Adipose Tissue; Alkaloids; Animals; Antioxidants; Benzodioxoles; Diet, High-Fat; Dietary Fats; Fatty Liver; Hyperlipidemias; Male; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Simvastatin

Many plant-derived chemicals have been studied for their potential benefits in ailments including inflammation, cancer, neurodegeneration, and cardiovascular disease. The health benefits of phytochemicals are often attributed to the targeting of reactive oxygen species (ROS). However, it is not always clear whether these agents act directly as antioxidants to remove ROS, or whether they act indirectly by blocking ROS production by enzymes such as NADPH oxidase (NOX) enzymes, or by influencing the expression of cellular pro- and anti- oxidants.. Here we evaluate the pro- and anti-oxidant and NOX-inhibiting qualities of four phytochemicals: celastrol, resveratrol, apigenin, and piperine.. This work was done using the H661 cell line expressing little or no NOX, modified H661 cells expressing NOX1 and its subunits, and an EBV-transformed B-lymphoblastoid cell line expressing endogenous NOX2. ROS were measured using Amplex Red and nitroblue tetrazolium assays. In addition, direct ROS scavenging of hydrogen peroxide or superoxide generated were measured using Amplex Red and methyl cypridina luciferin analog (MCLA).. Of the four plant-derived compounds evaluated, only celastrol displayed NOX inhibitory activities, while celastrol and resveratrol both displayed ROS scavenging activity. Very little impact on ROS was observed with apigenin, or piperine.. The results of this study reveal the differences that exist between cell-free and intracellular pro-oxidant and antioxidant activities of several plant-derived compounds.

Topics: Alkaloids; Antioxidants; Apigenin; Benzodioxoles; Cell Line; Humans; Hydrogen Peroxide; NADP; NADPH Oxidases; Oxidation-Reduction; Pentacyclic Triterpenes; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Reactive Oxygen Species; Resveratrol; Stilbenes; Triterpenes

We identify a target for treating obesity and type 2 diabetes, the consumption of calories by an increase in the metabolic rate of resting skeletal muscle. The metabolic rate of skeletal muscle can be increased by shifting myosin heads from the super-relaxed state (SRX), with a low ATPase activity, to a disordered relaxed state (DRX), with a higher ATPase activity. The shift of myosin heads was detected by a change in fluorescent intensity of a probe attached to the myosin regulatory light chain in skinned skeletal fibers, allowing us to perform a high-throughput screen of 2,128 compounds. The screen identified one compound, which destabilized the super-relaxed state, piperine (the main alkaloid component of black pepper). Destabilization of the SRX by piperine was confirmed by single-nucleotide turnover measurements. The effect was only observed in fast twitch skeletal fibers and not in slow twitch fibers or cardiac tissues. Piperine increased ATPase activity of skinned relaxed fibers by 66 ± 15%. The K

Topics: Adenosine Triphosphatases; Alkaloids; Animals; Basal Metabolism; Benzodioxoles; Diabetes Mellitus, Type 2; High-Throughput Screening Assays; Muscle Fibers, Fast-Twitch; Obesity; Piperidines; Polyunsaturated Alkamides; Rabbits; Skeletal Muscle Myosins; Up-Regulation

To study the efficacy and tolerability of Risorine Capsule (A fixed dose combination of Rifampicin 200 mg + INH 300 mg + Piperine 10 mg) therapy in the treatment of drug-susceptible pulmonary tuberculosis patients who developed GI intolerance with standard WHO anti TB regimen.. 33 patients with pulmonary tuberculosis were treated with one Risorine kit, daily consisting of one capsule of Risorine, one tablet of ethambutol (800 mg) and two tablets of Pyrazinamide 750 mg each, for first two months of therapy. All the patients received one capsule of Risorine daily for next four months. Symptomatic improvement, Sputum conversion and radiological improvement were monitored at regular intervals.. Out of 27 patients who were sputum positive at baseline, 24 patients became sputum negative during the first two months of treatment. Out remaining three patients, one became sputum negative at the end of third month of treatment and the other two became sputum negative at the end of sixth month of treatment. Out of 33 patients, only two patients developed mild nausea, which subsided spontaneously. One patient who was HIV positive, developed hepatitis.. Risorine, a novel formulation of rifampicin 200 mg with bioenhancer piperine 10mg, is found to be highly effective and well tolerated in the treatment of drug - susceptible pulmonary tuberculosis.

Topics: Adult; Alkaloids; Antitubercular Agents; Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Drug Combinations; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pilot Projects; Piperidines; Polyunsaturated Alkamides; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Young Adult

Piperine, a naturally occurring alkaloid, is well known as anti-oxidant, anti-mutagenic, anti-tumor and anti-proliferative agent. Piperine exerts such pharmacological activities by binding or interacting with various cellular targets. Recently, the first report for Piperine interaction with duplex DNA has been published last year but its interaction with G-quadruplex structures has not been studied yet. Herein, we report for the first time the interaction of Piperine with various DNA G-quadruplex structures. Comprehensive biophysical techniques were employed to determine the basis of interaction for the complex formed between Piperine and G-quadruplex DNA sequences. Piperine showed specificity for G-quadruplex DNA over double stranded DNA, with highest affinity for G-quadruplex structure formed at c-myc promoter region. Further, in-vitro studies show that Piperine causes apoptosis-mediated cell death that further emphasizes the potential of this natural product, Piperine, as a promising candidate for targeting G-quadruplex structure and thus, acts as a potent anti-cancer agent.

Topics: A549 Cells; Alkaloids; Antineoplastic Agents; Apoptosis; Benzodioxoles; Binding Sites; Circular Dichroism; Electrophoretic Mobility Shift Assay; G-Quadruplexes; Humans; Molecular Docking Simulation; Neoplasms; Nuclear Magnetic Resonance, Biomolecular; Nucleic Acid Conformation; Nucleic Acid Denaturation; Piperidines; Polyunsaturated Alkamides; Promoter Regions, Genetic; Proto-Oncogene Proteins c-myc; Spectrometry, Fluorescence; Temperature

The main purpose of this work was to develop and evaluate a self-emulsifying drug delivery system (SEDDS) of piperine to enhance its solubility and bioavailability. The formulation was optimized by solubility test and ternary phase diagrams. Then physiochemical properties and in vitro release of SEDDS were characterized. In vivo pharmacokinetics study and in situ single-pass intestinal perfusion were performed to investigate the effects of SEDDS on the bioavailability and intestinal absorption of piperine. The optimized formulation was composed of ethyl oleate, Tween 80 and Transcutol P (3:5.5:1.5, w/w), with the level of the piperine reached 2.5% (w/w). The in vitro dissolution rates of piperine SEDDS were significantly higher than the self-prepared capsules. In vivo pharmacokinetic study showed Cmax1, Cmax2 and area under the curve of piperine after oral administration of SEDDS in rats were 3.8-, 7.2- and 5.2-fold higher than the self-prepared capsules, respectively, and the relative bioavailability of SEDDS was 625.74%. The in situ intestinal absorption study revealed that the effective permeability and the effective absorption rate values of piperine for SEDDS were significantly improved comparing to solutions (p < 0.01). So SEDDS formulation could improve the oral bioavailability and intestinal absorption of piperine effectively.

Topics: Administration, Oral; Alkaloids; Animals; Area Under Curve; Benzodioxoles; Biological Availability; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Liberation; Emulsifying Agents; Emulsions; Intestinal Absorption; Lipids; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley

Piperine, a piperidine alkaloid present in black pepper, inhibits the growth of cancer cells, although the mechanism of action is not well understood. In this study, we show that piperine (75-150 µM) inhibited the growth of several colon cancer cell lines but had little effect on the growth of normal fibroblasts and epithelial cells. Piperine inhibited HT-29 colon carcinoma cell proliferation by causing G1 phase cell cycle arrest that was associated with decreased expression of cyclins D1 and D3 and their activating partner cyclin-dependent kinases 4 and 6, as well as reduced phosphorylation of the retinoblastoma protein and up-regulation of p21/WAF1 and p27/KIP1 expression. In addition, piperine caused hydroxyl radical production and apoptosis that was partially dependent on the production of reactive oxygen species. Piperine-treated HT-29 cells showed loss of mitochondrial membrane integrity and cleavage of poly (ADP-ribose) polymerase-1, as well as caspase activation and reduced apoptosis in the presence of the pan-caspase inhibitor zVAD-FMK. Increased expression of the endoplasmic reticulum stress-associated proteins inositol-requiring 1α protein, C/EBP homologous protein, and binding immunoglobulin protein, and activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, as well as decreased phosphorylation of Akt and reduced survivin expression were also observed in piperine-treated HT-29 cells. Furthermore, piperine inhibited colony formation by HT-29 cells, as well as the growth of HT-29 spheroids. Cell cycle arrest and endoplasmic reticulum stress-associated apoptosis following piperine treatment of HT-29 cells provides the first evidence that piperine may be useful in the treatment of colon cancer.

Topics: Alkaloids; Apoptosis; Benzodioxoles; Cell Cycle Checkpoints; Cell Proliferation; Colonic Neoplasms; Cyclin-Dependent Kinases; Cyclins; Endoplasmic Reticulum Stress; Epithelial Cells; Fibroblasts; G1 Phase; HT29 Cells; Humans; Inhibitor of Apoptosis Proteins; Mitochondria; p38 Mitogen-Activated Protein Kinases; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-jun; Reactive Oxygen Species; Survivin; Up-Regulation

Antibiotic resistance has stimulated the research for developing novel strategies that can prevent bacterial growth. Methicillin-resistant Staphylococcus aureus (MRSA), regarded as one of the most serious antibiotic-resistant bacteria which has been conventionally recognized as a nosocomial pathogen.. Nanoliposomal formulations of piperine and gentamicin were prepared by dehydration-rehydration (DRV) method and characterized for size, zeta potential and encapsulation efficiency. Antibactericidal activities of liposomal and free forms were evaluated against MRSA ATCC 43300 by the determination of minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and fractional inhibitory concentration index (FICI). The time-kill studies were carried out to evaluate the potency of antibacterial agents. The effect of piperine on bacterial efflux pumps was also investigated.. MIC values of gentamicin and piperine were 32 and 100 µg/mL, respectively. Synergetic effects were observed by the combination of gentamicin and piperine and FICI was determined to be 0.5. Following incorporation of gentamicin into liposomal gentamicin and liposomal combination, the MIC values were reduced 16- and 32-fold, respectively. MBC values of gentamicin reduced 4 and 8 times following incorporation into gentamicin and combination liposomes, respectively. In comparison with vancomycin, liposomal combination was more effective in bacterial inhibition and killing. Liposomal combination was the most effective preparations in time-kill study. Our findings indicated that liposomal piperine was able to inhibit the efflux pump sufficiently.. The results of this study revealed that liposomal combination is a powerful nano-antibacterial agent to eradicate MRSA infection. This dual-loaded formulation was an effective approach for eradication of MRSA.

Topics: Alkaloids; Anti-Bacterial Agents; Benzodioxoles; Chemistry, Pharmaceutical; Drug Combinations; Drug Compounding; Drug Synergism; Gentamicins; Liposomes; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Nanoparticles; Particle Size; Piperidines; Polyunsaturated Alkamides

Human serum albumin (HSA) and α-1-acid glycoprotein (AGP) (acute phase protein) are the plasma proteins in blood system which transports many drugs. To understand the pharmacological importance of piperine molecule, here, we studied the anti-inflammatory activity of piperine on mouse macrophages (RAW 264.7) cell lines, which reveals that piperine caused an increase in inhibition growth of inflammated macrophages. Further, the fluorescence maximum quenching of proteins were observed upon binding of piperine to HSA and AGP through a static quenching mechanism. The binding constants obtained from fluorescence emission were found to be K(piperine) = 5.7 ± .2 × 10(5) M(-1) and K(piperine) = 9.3± .25 × 10(4) M(-1) which correspond to the free energy of -7.8 and -6.71 kcal M(-1)at 25 °C for HSA and AGP, respectively. Further, circular dichrosim studies revealed that there is a marginal change in the secondary structural content of HSA due to partial destabilization of HSA-piperine complexes. Consequently, inference drawn from the site-specific markers (phenylbutazone, site I marker) studies to identify the binding site of HSA noticed that piperine binds at site I (IIA), which was further authenticated by molecular docking and molecular dynamic (MD) studies. The binding constants and free energy corresponding to experimental and computational analysis suggest that there are hydrophobic and hydrophilic interactions when piperine binds to HSA. Additionally, the MD studies have showed that HSA-piperine complex reaches equilibration state at around 3 ns, which prove that the HSA-piperine complex is stable in nature.

Topics: Algorithms; Alkaloids; Animals; Anti-Inflammatory Agents; Benzodioxoles; Binding Sites; Cell Line; Circular Dichroism; Humans; Hydrophobic and Hydrophilic Interactions; Macrophages; Mice; Models, Theoretical; Molecular Docking Simulation; Molecular Dynamics Simulation; Orosomucoid; Piperidines; Polyunsaturated Alkamides; Protein Binding; Protein Conformation; Protein Stability; Protein Structure, Secondary; Serum Albumin; Thermodynamics

The therapeutic agents for dementia are limited due to the complex system underlying the mechanisms. Taking a preventive point of view, we focused on the inhibition of β-secretase and acetylcholinesterase (AChE). In addition, plant resources including herbs and spices have been widely consumed, and further, may be consumed for a long period over a lifetime. Considering this background, we screened β-secretase and AChE inhibitors from curry spices. Amongst them, curry leaf, black pepper, and turmeric extracts were effective to inhibit β-secretase. Furthermore, black pepper and turmeric extracts were also effective to inhibit AChE. Having these results in hand, we focused on the investigation of β-secretase inhibitors since the inhibitor of this enzyme has not previously been well investigated. As a result, α- and β-caryophyllene, β-caryophyllene oxide (from curry leaf), piperine (from black pepper), curcumin, demethoxycurcumin, and bisdemethoxycurcumin (from turmeric) were successfully identified as low molecular inhibitors. This is the first report to determine α- and β-caryophyllene, β-caryophyllene oxide, and piperine as β-secretase inhibitors. These compounds may pass through the blood brain barrier since their molecular weights are relatively low.

Topics: Acetylcholinesterase; Alkaloids; Amyloid Precursor Protein Secretases; Benzodioxoles; Cholinesterase Inhibitors; Curcuma; Curcumin; Diarylheptanoids; Murraya; Piper nigrum; Piperidines; Plant Extracts; Polycyclic Sesquiterpenes; Polyunsaturated Alkamides; Sesquiterpenes

Piperine, a kind of natural alkaloid found in peppers, has been reported to exhibit anti-oxidative and anti-tumor activities, both in vitro and in vivo. Interleukin-6 (IL-6) is an important cytokine that activates the signal transduction, promotes tumor cell metastasis, and induces malignancy, including in gastric cancer. However, the effects of piperine on IL-6 expression in gastric cancer cells have not yet been well defined. In this study, we investigated the effects of piperine on the IL-6 expression, and examined the underlying signaling pathways via RT-PCR, promoter studies and Western blotting in human gastric cancer TMK-1 cells. Our results showed that piperine inhibited interleukin-1β (IL-1β)-induced IL-6 expression in a dose-dependent manner. In addition, piperine also inhibited IL-6 promoter activity. Experiments with mitogen-activated protein kinase (MAPK) inhibitors and dominant negative mutant p38 MAPK indicated that p38 MAPK was essential for IL-6 expression in the TMK-1 cells. Additionally, signal transducer and activator of transcription 3 (STAT3) was also involved in the IL-1β-induced IL-6 expression in gastric cancer cells. Piperine inhibited IL-1β-induced p38 MAPK and STAT3 activation and, in turn, blocked the IL-1β-induced IL-6 expression. Furthermore, gastric cancer cells pretreated with IL-1β showed markedly enhanced invasiveness, which was partially abrogated by treatment with IL-6 siRNA, piperine, and inhibitors of p38 MAPK and STAT3. These results suggest that piperine may exert at least part of its anti-cancer effect by controlling IL-6 expression through the suppression of p38 MAPK and STAT3.

Topics: Alkaloids; Benzodioxoles; Blotting, Western; Cell Line, Tumor; Cell Movement; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Interleukin-1beta; Interleukin-6; Mutation; Neoplasm Invasiveness; p38 Mitogen-Activated Protein Kinases; Piperidines; Polyunsaturated Alkamides; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; STAT3 Transcription Factor; Stomach Neoplasms; UDPglucose 4-Epimerase

Piperine is a secondary metabolite of black pepper. Its uses in medicine were already studied. However, its derivatives have not gained considerable attention. In the presented study, the Lipoxygenase (LOX) inhibitory activity of piperine and its derivatives, piperonylic acid, piperic acid, and piperonal have been assessed and compared by enzyme kinetics, ITC and molecular modeling experiments. The presented investigations expressed that all the studied compounds inhibited LOX by binding at its active site. The IC(50) values of these compounds were deduced from the kinetics data and found to be 85.79, 43.065, 45.17, and 50.78 μm for piperine, piperonylic acid, piperic acid, and piperonal, respectively. The binding free energies obtained from ITC experiments were -7.47, -8.33, -8.09, and -7.86 kcal/mol for piperine, piperonylic acid, piperic acid, and piperonal, respectively. Similarly, the glide scores obtained for piperine, piperonylic acid, piperic acid, and piperonal were -7.28, -10.32, -10.72, and -9.57 kcal/mol, respectively. The results of ITC and molecular modeling experiments suggested that piperonylic acid and piperonal exhibit stronger binding at the active site than piperine does. From the presented studies, it could be concluded that derivatives of piperine may be of higher significance than piperine for certain medicinal applications, implicating (Ayurvedic) fermented herbal drugs with piperine in them.

Topics: Alkaloids; Benzaldehydes; Benzoates; Benzodioxoles; Catalytic Domain; Computer Simulation; Fatty Acids, Unsaturated; Glycine max; Humans; Lipoxygenase; Lipoxygenase Inhibitors; Models, Molecular; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Protein Binding

The proliferation and migration of vascular smooth muscle cells (VSMCs) in blood vessels are important in the pathogenesis of vascular disorders such as atherosclerosis and restenosis. Piperine, a major component of black pepper, has antioxidant, anticancer, and anti-inflammatory activity. However, the antiatherosclerotic effects of piperine have not been investigated. In this study, the effects of piperine on platelet-derived growth factor (PDGF)-BB-induced proliferation and migration of VSMCs were investigated. The antiproliferative effects of piperine were determined using MTT assays, cell counting, real-time polymerase chain reaction, and western blots. Our results showed that piperine significantly attenuated the proliferation of VSMCs by increasing the expression of p27(kip1), regulating the mRNA expression of cell cycle enzymes (cyclin D, cyclin E, and PCNA), and decreasing the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in a noncytotoxic concentration-dependent manner (30-100 μM). Moreover, we examined the effects of piperine on the migration of PDGF-BB-stimulated VSMCs, as determined by the Boyden chamber assay, H2DCFDA staining, and western blots. Our results showed that 100 μM piperine decreased cell migration, the production of reactive oxygen species (ROS), and phosphorylation of the p38 mitogen-activated protein kinase (MAPK). Taken together, our results suggest that piperine inhibits PDGF-BB-induced proliferation and the migration of VSMCs by inducing cell cycle arrest and suppressing MAPK phosphorylation and ROS. These findings suggest that piperine may be beneficial for the treatment of vascular-related disorders and diseases.

Topics: Alkaloids; Animals; Becaplermin; Benzodioxoles; Blotting, Western; Cell Count; Cell Cycle Checkpoints; Cell Migration Assays; Cell Movement; Cell Proliferation; Cyclin D; Cyclin E; Cyclin-Dependent Kinase Inhibitor p27; Gene Expression Profiling; Male; MAP Kinase Signaling System; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; Piperidines; Polyunsaturated Alkamides; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-sis; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction

Piperine, the pungent alkaloid of black pepper, and several of its derivatives are modulators of γ-amino butyric acid type A (GABAA) receptors. Concomitantly, this natural product has also been reported to activate transient receptor potential vanilloid type 1 (TRPV1) receptors. We have developed a Heck cross-coupling reaction of conjugated dienamides enabling the rapid assembly of piperine derivatives containing a modified aromatic core. Upon assessment of a focussed compound library, key aromatic substituents were identified selectively affecting either the GABAA or the TRPV1 receptor.

Topics: Alkaloids; Alkenes; Benzodioxoles; Chemistry Techniques, Synthetic; Ligands; Piperidines; Polyunsaturated Alkamides; Receptors, GABA-A; TRPV Cation Channels

Piperine, an alkaloid from black pepper, is reported to have anticancer activities. In this study, we investigated the effect of piperine on the growth and motility of triple-negative breast cancer (TNBC) cells. Piperine inhibited the in vitro growth of TNBC cells, as well as hormone-dependent breast cancer cells, without affecting normal mammary epithelial cell growth. Exposure to piperine decreased the percentage of TNBC cells in the G2 phase of the cell cycle. In addition, G1- and G2-associated protein expression was decreased and p21(Waf1/Cip1) expression was increased in piperine-treated TNBC cells. Piperine also inhibited survival-promoting Akt activation in TNBC cells and caused caspase-dependent apoptosis via the mitochondrial pathway. Interestingly, combined treatment with piperine and γ radiation was more cytotoxic for TNBC cells than γ radiation alone. The in vitro migration of piperine-treated TNBC cells was impaired and expression of matrix metalloproteinase-2 and -9 mRNA was decreased, suggesting an antimetastatic effect by piperine. Finally, intratumoral administration of piperine inhibited the growth of TNBC xenografts in immune-deficient mice. Taken together, these findings suggest that piperine may be useful in the treatment of TNBC.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; Female; Humans; MCF-7 Cells; Mice; Mice, Inbred NOD; Mice, SCID; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

The anti-inflammatory effect of piperine has been largely investigated in macrophages, but its activity on epithelial cells in inflammatory settings is unclear. The present study aimed to investigate the effect of piperine on the expression of inflammatory cytokines in lipopolysaccharide (LPS)-stimulated human epithelial-like SW480 and HT-29 cells. Our data showed that although piperine inhibited the proliferation of SW480 and HT-29 cells in a dose-dependent manner, it had low cytotoxicity on these cell lines with 50 % inhibiting concentration (IC50) values greater than 100 μM. As epithelial-like cells, SW480 and HT-29 cells secreted high levels of the chemokine CXCL8 upon LPS stimulation. Importantly, piperine dose-dependently suppressed LPS-induced secretion of CXCL8 and the expression of CXCL8 messenger RNA (mRNA). Although piperine failed to affect the critical inflammatory nuclear factor-κB pathway, it attenuated the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling. Consistent with previous reports, p38 signaling seemed to play a more pronounced role on the CXCL8 expression than JNK signaling since inhibition of p38, instead of JNK, greatly suppressed LPS-induced CXCL8 expression. Collectively, our results indicated that piperine could attenuate the inflammatory response in epithelial cells via downregulating the MAPK signaling and thus the expression of CXCL8, suggesting its potential application in anti-inflammation therapy.

Topics: Alkaloids; Anti-Inflammatory Agents; Benzodioxoles; Cell Line; Cell Proliferation; Cell Survival; Down-Regulation; Epithelial Cells; HT29 Cells; Humans; Inflammation; Inflammatory Bowel Diseases; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Piperidines; Polyunsaturated Alkamides; RNA, Messenger

The piperidine alkaloid piperine, a major ingredient in black pepper, inhibits the growth and metastasis of cancer cells both in vivo and in vitro, although its mechanism of action is unclear. Furthermore, its anticancer activity against osteosarcoma cells has not been reported. In this study, we show that piperine inhibited the growth of HOS and U2OS cells in dose- and time-dependent manners but had a weaker effect on the growth of normal hFOB cells. Piperine inhibited osteosarcoma cell proliferation by causing G2/M phase cell cycle arrest associated with decreased expression of cyclin B1 and increased phosphorylation of Cyclin-dependent kinase-1(CDK1) and checkpoint kinase 2 (Chk2). In addition, piperine treatment inhibited phosphorylation of Akt and activated phosphorylation of c-Jun N-terminal kinase (c-JNK) and p38 mitogen-activated protein kinase (MAPK) in HOS and U2OS cells. Piperine induced colony formation in these two cell types. We proved that piperine could suppress the metastasis of osteosarcoma cells using scratch migration assays and Transwell chamber tests. Moreover, gelatin zymography showed that piperine inhibited the activity of matrix metalloproteinase (MMP)-2/-9 and increased the expression of tissue inhibitor of metalloproteinase (TIMP)-1/-2. Taken together, our results indicate that piperine inhibits proliferation, by inducing G2/M cell cycle arrest, and the migration and invasion of HOS and U2OS cells, via increased expression of TIMP-1/-2 and down-regulation of MMP-2/-9. These findings support further study of piperine as a promising therapeutic agent in the treatment of osteosarcoma.

Topics: Alkaloids; Benzodioxoles; Bone Neoplasms; CDC2 Protein Kinase; Cell Line, Tumor; Cell Movement; Cell Proliferation; Checkpoint Kinase 2; Cyclin B1; Down-Regulation; Gene Expression Regulation, Neoplastic; Growth Inhibitors; Humans; M Phase Cell Cycle Checkpoints; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Metastasis; Osteosarcoma; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Tissue Inhibitor of Metalloproteinase-1; Up-Regulation

Piperine is a simple alkaloid isolated from the seeds of Piper nigrum. Piperine and its derivatives exhibited a wide range of biological properties such as antitumor activity, antioxidant activity, antiinflammatory activity, antimycobacterial activity, insecticidal activity, etc. Although five excellent reviews have recently been described by Srinivasan in 2007, Mao in 2011, Butt in 2013, and Meghwal in 2013, respectively, their topics were mainly focused on the biological effects. Therefore, in the present review, the progress in the structural modifications on the aliphatic chain and the amide moiety of piperine was reported. Meanwhile, the biological activities and structure-activity relationship of piperine and its derivatives were also described.

Topics: Alkaloids; Benzodioxoles; Humans; Molecular Structure; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship

Spices are rich in natural antioxidants and have been shown to be potent inhibitors of lipid peroxidation during cooking of meat. Turmeric contains unique conjugated curcuminoids with strong antioxidant activity. Piperine, one of the main constituents of black pepper, is known to increase the bioavailability of curcuminoids in mouse and human studies when consumed with turmeric. We investigated whether adding black pepper to turmeric powder may further inhibit lipid peroxidation when added to meat patties prior to cooking. The addition of black pepper to turmeric significantly decreased the lipid peroxidation in hamburger meat. When investigating the antioxidant activity of the main chemical markers, we determined that piperine did not exhibit any antioxidant activity. Therefore, we conclude that other black pepper ingredients are responsible for the increased antioxidant activity of combining black pepper with turmeric powder.

Topics: Alkaloids; Antioxidants; Benzodioxoles; Cooking; Curcuma; Curcumin; Food Handling; Humans; Lipid Peroxidation; Meat; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Spices

Black pepper (Piper nigrum L.), the King of Spices is the most popular spice globally and its active ingredient, piperine, is reportedly known for its therapeutic potency. In this work, enzyme-assisted supercritical carbon dioxide (SC-CO2) extraction of black pepper oleoresin was investigated using α-amylase (from Bacillus licheniformis) for enhanced yield of piperine-rich extract possessing good combination of phytochemical properties. Optimization of the extraction parameters (without enzyme), mainly temperature and pressure, was conducted in both batch and continuous modes and the optimized conditions that provided the maximum yield of piperine was in the batch mode, with a sample size of 20 g of black pepper powder (particle diameter 0.42 ± 0.02 mm) at 60 °C and 300 bar at 2 L/min of CO2 flow. Studies on activity of α-amylase were conducted under these optimized conditions in both batch and continuous modes, with varying amounts of lyophilized enzyme (2 mg, 5 mg and 10 mg) and time of exposure of the enzyme to SC-CO2 (2.25 h and 4.25 h). The specific activity of the enzyme increased by 2.13 times when treated in the continuous mode than in the batch mode (1.25 times increase). The structural changes of the treated enzymes were studied by (1)H NMR analyses. In case of α-amylase assisted extractions of black pepper, both batch and continuous modes significantly increased the yields and phytochemical properties of piperine-rich extracts; with higher increase in batch mode than in continuous.

Topics: Alkaloids; alpha-Amylases; Bacillus; Benzodioxoles; Carbon Dioxide; Chromatography, Supercritical Fluid; Magnetic Resonance Spectroscopy; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides

Biliary cholesterol may contribute to the formation of cholesterol gallstones, and regulation of these levels could be a useful therapeutic strategy for gallstones disease. Piperine (PA) is a potential cholesterol lowering agent. In this study, we assessed the effect and mechanism of PA in preventing cholesterol gallstones formation induced by feeding lithogenic diet containing high cholesterol levels to mice. C57BL/6 inbred mice were fed lithogenic or chow diets for 10 weeks, with or without PA (15, 30 and 60 mg/kg) or ursodeoxycholic acid (UDCA, 60 mg/kg) administration. Cholesterol, phospholipids and crystals in bile, the lipid in serum, pathological changes and proteins expression in liver were analyzed. The results showed that PA could decrease the cholesterol potency and crystals in bile, reduce total cholesterol (TC), triglycerides (TG) and increase high-density lipoprotein/low-density lipoprotein (HDL/LDL) levels in serum. Furthermore, PA treatment reduced liver lipid peroxidation and protected hepatobiliary cells from liver injury by decreasing malondialdehyde (MDA) and increasing superoxide dismutase (SOD). In addition, PA inhibited the expression of ATP-binding cassette transporters G5/8 (ABCG5/8) and liver X receptor (LXR) in liver, and reduced cholesterol transport from the hepatocytes to the gallbladder. It may be the mechanism of PA in preventing cholesterol gallstones formation. PA as a potential drug for prevention cholesterol gallstones merits further investigation.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters; Benzodioxoles; Bile; Cholesterol; Diet; Gallstones; Gene Expression Regulation; Lipid Peroxidation; Lipoproteins; Liver; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; Piperidines; Polyunsaturated Alkamides

Piperine, a pungent alkaloid found in the fruits of black pepper plants, has diverse physiological effects, including the ability to inhibit immune cell-mediated inflammation. Since the cytokine interleukin-2 (IL-2) is essential for the clonal expansion and differentiation of T lymphocytes, we investigated the effect of piperine on IL-2 signaling in IL-2-dependent mouse CTLL-2 T lymphocytes. Tritiated-thymidine incorporation assays and flow cytometric analysis of Oregon Green 488-stained cells showed that piperine inhibited IL-2-driven T lymphocyte proliferation; however, piperine did not cause T lymphocytes to die or decrease their expression of the high affinity IL-2 receptor, as determined by flow cytometry. Western blot analysis showed that piperine blocked the IL-2-induced phosphorylation of signal transducer and activator of transcription (STAT) 3 and STAT5 without affecting the upstream phosphorylation of Janus kinase (JAK) 1 and JAK3. In addition, piperine inhibited the IL-2-induced phosphorylation of extracellular signal-regulated kinase 1/2 and Akt, which are signaling molecules that regulate cell cycle progression. Piperine also suppressed the expression of cyclin-dependent kinase (Cdk) 1, Cdk4, Cdk6, cyclin B, cyclin D2, and Cdc25c protein phosphatase by IL-2-stimulated T lymphocytes, indicating G0/G1 and G2/M cell cycle arrest. Piperine-mediated inhibition of IL-2 signaling and cell cycle progression in CTLL-2 T lymphocytes suggests that piperine should be further investigated in animal models as a possible natural source treatment for T lymphocyte-mediated transplant rejection and autoimmune disease.

Topics: Alkaloids; Animals; Benzodioxoles; Blotting, Western; Cell Cycle Checkpoints; Cell Line; Cell Proliferation; Cyclin-Dependent Kinases; Flow Cytometry; Interleukin-2; Janus Kinase 3; Mice; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; Signal Transduction; STAT3 Transcription Factor; STAT5 Transcription Factor; T-Lymphocytes

Deltamethrin (DLM), a well-known pyrethroid insecticide, is a potent immunotoxicant. In rodents, it is primarily characterized by marked thymic apoptosis. Mechanism of DLM induced thymic apoptosis in primary murine thymocytes has been recently explored. Oxidative stress and activation of caspase dependent pathways appear to be involved in the DLM induced thymic injury. Thus, for the amelioration of its effect, this study has been designed to first observe the binding affinity of piperine to immune cell receptors and its protective effects on the DLM induced immunotoxicity under in vitro condition. The docking results demonstrated that piperine has good binding affinity towards CD4 and CD8 receptors. In vitro study results have shown that piperine (1, 10 and 50 μg/ml) increased cell viability in a concentration dependent manner. The early activated markers of apoptosis such as enhanced reactive oxygen species (ROS) and caspase-3 activation by DLM was significantly reduced by piperine treatment. GSH depletion induced by DLM has been also restored by piperine treatment. At 18 h, all concentration of piperine (1, 10 and 50 μg/ml) significantly ameliorated the DLM induced apoptosis. Further, DLM induced phenotypic changes were mitigated by the piperine. In addition, piperine also restored the cytokine levels, which were suppressed by DLM treatment. These findings strongly indicate the anti-oxidative, anti-apoptotic and chemo-protective ability of piperine in the DLM induced thymic apoptosis.

Topics: Alkaloids; Animals; Antioxidants; Apoptosis; Benzodioxoles; Caspase 3; CD4 Antigens; Cell Survival; Glutathione; Immunologic Factors; Interferon-gamma; Interleukin-2; Interleukin-4; Male; Mice, Inbred BALB C; Molecular Docking Simulation; Nitriles; Piperidines; Polyunsaturated Alkamides; Pyrethrins; Reactive Oxygen Species; Receptors, Antigen, T-Cell; Thymocytes

Piperine, a main component of Piper longum Linn. and Piper nigrum Linn., is a plant alkaloid with a long history of medicinal use. Piperine exhibits antidepressant, hepatoprotective, anti-metastatic, anti-thyroid, immunomodulatory, antitumor and anti-inflammatory activities, However its therapeutic potential in amelioration of ulcerative colitis and the underlying mechanism for anti-inflammatory activity remains unknown.The objective of the present investigation was to unravel the therapeutic potential of piperine on amelioration of IBD using acetic acid induced experimental animal model for ulcerative colitis and to determine the role of TLR4 receptor in signalling pathway of inflammatory gene expression in ulcerative colitis.. We induced colitis using acetic acid (150µl of 5% once, intrarectally) in mice and estimated disease activity index (DAI), which took into account weight loss, stool consistency, and occult/gross bleeding. Colon length, spleen weights, ulcer area and ulcer index were measured; histological changes were observed by H&E staining. Effect of piperine on various antioxidant parameter of mice colon such as tissue myeloperoxidase (MPO) accumulation, SOD concentrations, reduced GSH and lipid peroxidation were determined. Pro-inflammatory mediators, namely, nitric oxide (NO), tumour necrosis factor-α (TNF-α) were determined by a TNF-α ELISA kit obtained from Thermo fisher scientific India Pvt. Ltd. Effect of piperine on haematological parameters of mice in acetic acid induced IBD was also determined which involves the estimation of FFA using a commercial free fatty acid fluorometric assay kit.. Piperine significantly attenuated acetic acid induced DAI score which implies that it suppresses weight loss, diarrhoea, gross bleeding and infiltration of immune cells. Piperine administration also effectively and dose dependently prevented shortening of colon length and enlargement of spleen size. Histological examination indicated that piperine reduces oedema in sub-mucosa, cellular infiltration, reduced haemorrhages and ulceration as compare to acetic acid induced colitis in mice. Furthermore piperine inhibited abnormal secretion of pro-inflammatory mediators namely NO, cytokines TNF-α and reduces FFA induced TLR4 mediated inflammation.. These results suggest that piperine has an anti-inflammatory effect at colorectal sites that is due to down- regulations of the productions and expression of inflammatory mediators and it also reduces FFA induced TLR4 mediated inflammation. Thus it may have therapeutic potential on amelioration of IBD.

Topics: Acetic Acid; Alkaloids; Animals; Anti-Inflammatory Agents; Benzodioxoles; Colitis, Ulcerative; Colon; Fatty Acids, Nonesterified; Glutathione; Lipid Peroxidation; Male; Malondialdehyde; Mice; Nitric Oxide; Piperidines; Polyunsaturated Alkamides; Superoxide Dismutase; Toll-Like Receptor 4; Toxicity Tests, Acute; Tumor Necrosis Factor-alpha

Piperine exhibits anti-inflammatory activity, and has a long history of medicinal use. The objective of this study was to investigate the protective effects of piperine on inflammation, alveolar bone and collagen fibers in experimental periodontitis. We evaluated the related expression of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, matrix metalloproteinase (MMP)-8 and MMP-13 to enhance insight into these effects.. Thirty-two Wistar rats were divided into four groups of eight animals each: control group, periodontitis group, periodontitis plus 50 mg/kg piperine group and periodontitis plus 100 mg/kg piperine group. Histopathologic changes were detected by hematoxylin and eosin staining. Alveolar bone loss and trabecula microstructures were evaluated by micro-computed tomography. Changes in collagen fibers were assessed by picrosirius red staining. Western blot analysis was conducted to determine the levels of IL-1β, TNF-α, MMP-8 and MMP-13.. Piperine clearly inhibited alveolar bone loss and reformed trabecula microstructures in a dose-dependent manner. Histological staining showed that piperine significantly reduced the infiltration of inflammation in soft tissues. Both doses of piperine limited the fractions of degraded areas in collagen fibers. Piperine (100 mg/kg) significantly downregulated the expressions of IL-1β, MMP-8 and MMP-13 in periodontitis, but not that of TNF-α.. Piperine displays significantly protective effects on inflammation, alveolar bone loss, bone microstructures and collagen fiber degradation in experimental periodontitis. The effects may be ascribed to its inhibitory activity on the expressions of IL-1β, MMP-8 and MMP-13.

Topics: Alkaloids; Alveolar Bone Loss; Animals; Benzodioxoles; Blotting, Western; Collagen; Cytochrome P-450 Enzyme Inhibitors; Disease Models, Animal; Histocytochemistry; Inflammation; Interleukin-1beta; Male; Matrix Metalloproteinase 13; Matrix Metalloproteinase 8; Periodontitis; Piperidines; Polyunsaturated Alkamides; Proteolysis; Rats, Wistar; Treatment Outcome; Tumor Necrosis Factor-alpha; X-Ray Microtomography

Allergic rhinitis (AR) is a global health problem that affects a large number of population. Piperine (PIP) has been reported to exhibit anti-inflammatory, anti-histaminic, and immunomodulatory activities; however, its antiallergic profile has not been studied.. The objective of the study was to investigate the antiallergic potential of PIP in ova-albumin (OVA)-induced AR, mast cell degranulation (MSD), and OVA-induced paw edema.. Mice were sensitized with OVA alternately on 1, 3, 5, 7, 9, 11, and 13th day. They were treated with either vehicle, PIP (10, 20, and 40 mg/kg, p.o.), or montelukast (10 mg/kg, p.o.) from the 14th to 20th day. On the 21st day, intranasal (OVA: 5% µl) challenge was done. Animals were evaluated for physiological parameters, biochemical parameters, spleen weight, expression of interleukins (IL-6 and IL-1β), and immunoglobin-E (IgE). Histopathology of nasal mucosa, lungs, and spleen was carried out. MSD and paw edema studies were made to understand the mechanism of action.. PIP (10, 20, and 40 mg/kg, p.o.) showed a significant dose-dependent protection with respect to nasal rubbing, redness of nose, and sneezing (p < 0.001) following nasal challenge. PIP dose dependently reduced histamine, NO concentration (p < 0.001), as well as reduced expression of IL-6, IL-1β, and IgE (p < 0.001) as compared with the control group. Histopathology showed inhibition of infiltration of eosinophils and hyperplasia. It dose dependently reduced MSD and paw edema (p < 0.001).. PIP acts by mast cell-stabilizing activity, exhibits immunomodulatory and anti-inflammatory activity, thereby providing an effective treatment for AR.

Topics: Acetates; Alkaloids; Animals; Anti-Allergic Agents; Benzodioxoles; Biomarkers; Cell Degranulation; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Eosinophils; Histamine; Immunoglobulin E; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Mast Cells; Nitric Oxide; Ovalbumin; Piperidines; Polyunsaturated Alkamides; Quinolines; Rhinitis, Allergic; Spleen; Sulfides; Time Factors

Deltamethrin (DLM) being a potent immunotoxicant affects both humoral and cell mediated immunity. Thus, for the amelioration of its effects, two different bioactive herbal extracts piperine and curcumin are evaluated and their efficacy has been compared. The docking results demonstrated that curcumin has good binding affinity towards CD28 and CD45 receptors as compared to piperine but in vitro studies revealed that piperine is more effective. DLM induced apoptotic markers such as oxidative stress and caspase 3 have been attenuated more significantly by piperine as compared to curcumin. Phenotypic and cytokine changes have also been mitigated best with piperine. Thus, these findings strongly demonstrate that piperine displays the more anti-oxidative, anti-apoptotic and chemo-protective properties in the DLM induced splenic apoptosis as compared to curcumin. So, piperine can be considered the drug of choice under immunocompromised conditions.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; CD28 Antigens; Curcumin; Humans; Immunity; Leukocyte Common Antigens; Male; Mice; Mice, Inbred BALB C; Nitriles; Piperidines; Polyunsaturated Alkamides; Pyrethrins; Spleen

Piperine is a major alkaloid component of black pepper (Piper nigrum Linn), which is a widely consumed spice. Here, we investigated the effect of piperine on mouse T lymphocyte activation. Piperine inhibited polyclonal and antigen-specific T lymphocyte proliferation without affecting cell viability. Piperine also suppressed T lymphocyte entry into the S and G2 /M phases of the cell cycle, and decreased expression of G1 -associated cyclin D3, CDK4, and CDK6. In addition, piperine inhibited CD25 expression, synthesis of interferon-γ, interleukin (IL)-2, IL-4, and IL-17A, and the generation of cytotoxic effector cells. The inhibitory effect of piperine on T lymphocytes was associated with hypophosphorylation of Akt, extracellular signal-regulated kinase, and inhibitor of κBα, but not ZAP-70. The ability of piperine to inhibit several key signaling pathways involved in T lymphocyte activation and the acquisition of effector function suggests that piperine might be useful in the management of T lymphocyte-mediated autoimmune and chronic inflammatory disorders.

Topics: Alkaloids; Animals; Benzodioxoles; Cell Cycle; Cell Proliferation; Gene Expression Regulation; Lymphocyte Activation; MAP Kinase Signaling System; Mice; Phosphorylation; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; T-Lymphocytes, Cytotoxic

Inflammatory bowel disease (IBD) is associated with chronic inflammation of the intestinal tract. Piperine (1-peperoylpiperidine), the primary lipophilic component in black pepper (Piper nigrum) and long pepper (Piper longum), has been reported to be effective for anti-inflammatory. Rencently, several ethnopharmacological purity compounds, such as baicalin and artemisinin, are reported to have potentially therapeutic role in treating IBD. In the present study, the effects of piperine on pregnane X receptor (PXR)-mediated CYP3A expression and its therapeutic role in IBD were investigated.. LS174T cells and C57BL/6J mice were treated by the piperine. Gene expressions were analyzed by real-time PCR, Western blot analysis, transient transfections assay and histological analysis.. Data indicated that treatment of LS174T cells with piperine markedly increased both CYP3A4 and PXR mRNA and protein. Transient transfection experiments indicated that transcriptional activation of the CYP3A4 gene via piperine was PXR-dependent. Data show that pre-administration of piperine decreased clinical hallmarks of colitis in DSS-treated PXR mice as measured by body weight loss and assessment of diarrhea, rectal bleeding, colon length, and histology. Inflammatory mediators (CCR2, ICAM-1, IL-1β, IL-6, IL-10, iNOS, MCP-1, and TNFα) after DSS treatment were significantly decreased in mice pretreated with piperine but corresponding conditions did not occur in mice with down-regulation of PXR by small interfering RNA (siRNA).. Piperine is a potential agonist of PXR and an inducer of PXR, which may induce CYP3A4 gene expression at the mRNA and protein levels. These results establish that piperine may contribute to prevention or reduction of colonic inflammation.

Topics: Alkaloids; Animals; Benzodioxoles; Cell Line; Dextran Sulfate; Hep G2 Cells; Humans; Inflammatory Bowel Diseases; Male; Mice; Mice, Inbred C57BL; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Pregnane X Receptor; Receptors, Steroid

Piperine is the main constituent of pepper, a commonly used kitchen spice and has been reported to possess various pharmacological activities. The structural features, an aromatic ring with a methylenedioxy bridge, a conjugated dienone system and a piperidine ring constituting an amide bond, possessed by the molecule have been considered important for the molecule to exhibit an array of bioactivities. Several modifications of above structural units have affected the biological properties of piperine, either enhancing or in some cases completely abolishing the activity. The present review emphasizes on the synthetic aspects of piperine along with the structure-activity relationships of its derivatives so as to rationalize the discovery of newer piperine based molecules.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Antiprotozoal Agents; Benzodioxoles; Molecular Structure; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship

The rod outer segments (OS) of the retina are specialized organelles where phototransduction takes place. The mitochondrial electron transport complexes I-IV, cytochrome c and Fo F1 -ATP synthase are functionally expressed in the OS disks. Here, we have studied the effect of some polyphenolic compounds acting as inhibitors of mitochondrial ATPase/synthase activity on the OS ectopic Fo F1 - ATP synthase. The mechanism of apoptosis in the OS was also investigated studying the expression of cytochrome c, caspase 9 and 3 and Apaf-1.. We prepared OS from fresh bovine retinae. Semi-quantitative Western blotting, confocal and electron microscopy, and cytofluorimetry were used along with biochemical analyses such as oximetry, ATP synthesis and hydrolysis.. Resveratrol and curcumin plus piperine inhibited ATP synthesis and oxygen consumption in the OS. Epigallocatechin gallate and quercetin inhibited ATP hydrolysis and oxygen consumption in the OS. Malondialdehyde and hydrogen peroxide were produced in respiring OS in the presence of substrates. Cytochrome c was located inside the disk membranes. Procaspase 9 and 3, as well as Apaf-1 were expressed in the OS.. These polyphenolic phytochemicals modulated the Fo F1 -ATP synthase activity of the the OS reducing production of reactive oxygen intermediates by the OS ectopic electron transport chain. Polyphenols decrease membrane peroxidation and cytochrome c release from disks, preventing the induction of caspase-dependent apoptosis in the OS Such effects are relevant in the design of protection against functional impairment of the OS following oxidative stress from exposure to intense illumination.

Topics: Adenosine Triphosphate; Alkaloids; Animals; Benzodioxoles; Caspase 3; Caspase 9; Catechin; Cattle; Curcumin; Cytochromes c; Hydrogen Peroxide; Malondialdehyde; Oxidative Phosphorylation; Oxygen Consumption; Phytochemicals; Piperidines; Polyunsaturated Alkamides; Quercetin; Resveratrol; Rod Cell Outer Segment; Stilbenes

Curcumin (CUR) is a poorly water-soluble drug and its absorption is very low. In this study, CUR and piperine (PIP) were co-encapsulated into the nanoformulation called self-microemulsifying drug delivery system (SMEDDS) to improve the stability and water-solubility of CUR and enhance its anti-colitis activity. The formulation of CUR-PIP-SMEDDS was prepared to encapsulate two hydrophobic components CUR and PIP, and then was characterized by assessing appearance, morphology, particle size, zeta potential and drug encapsulation efficiency. The appearance of CUR-PIP-SMEDDS remained clarified and transparent, and the microemulsion droplets appeared spherical without aggregation. The mean size of microemulsion droplet formed from CUR-PIP-SMEDDS was 15.87 ± 0.76 nm, and the drug encapsulation efficiency of SMEDDS for CUR and PIP were (94.34 ± 2.18)% and (90.78 ± 2.56)%, respectively. The vitro stability investigation of CUR-PIP-SMEDDS in colon tissue suggested that using SMEDDS as a delivery vehicle and co-encapsulated with PIP, CUR was more stable than drug solution in colons site. Meanwhile, the anti-inflammatory activity of CUR-PIP-SMEDDS was evaluated on DSS-induced colitis model. The results showed that CUR-PIP-SMEDDS exhibited definite anti-colitis activity by directing CUR-PIP-SMEDDS to inflammatory colon tissue through retention enema administration. Our study illustrated that the developed CUR-PIP-SMEDDS formulation was a potential carrier for developing colon-specific drug delivery system of CUR for ulcerative colitis treatment.

Topics: Alkaloids; Animals; Benzodioxoles; Chemistry, Pharmaceutical; Colitis, Ulcerative; Curcumin; Drug Delivery Systems; Drug Stability; Emulsions; Male; Mice; Mice, Inbred BALB C; Particle Size; Piperidines; Polyunsaturated Alkamides; Solubility

Understanding the molecular mechanism of action of traditional medicines is an important step towards developing marketable drugs from them. Piperine, an active constituent present in the Piper species, is used extensively in Ayurvedic medicines (practiced on the Indian subcontinent). Among others, piperine is known to possess a male contraceptive effect; however, the molecular mechanism of action for this effect is not very clear. In this regard, detailed docking and molecular dynamics simulation studies of piperine with the androgen-binding protein and androgen receptors were carried out. Androgen receptors control male sexual behavior and fertility, while the androgen-binding protein binds testosterone and maintains its concentration at optimal levels to stimulate spermatogenesis in the testis. It was found that piperine docks to the androgen-binding protein, similar to dihydrotestosterone, and to androgen receptors, similar to cyproterone acetate (antagonist). Also, the piperine-androgen-binding protein and piperine-androgen receptors interactions were found to be stable throughout 30 ns of molecular dynamics simulation. Further, two independent simulations for 10 ns each also confirmed the stability of these interactions. Detailed analysis of the piperine-androgen-binding protein interactions shows that piperine interacts with Ser42 of the androgen-binding protein and could block the binding with its natural ligands dihydrotestosterone/testosterone. Moreover, piperine interacts with Thr577 of the androgen receptors in a manner similar to the antagonist cyproterone acetate. Based on the in silico results, piperine was tested in the MDA-kb2 cell line using the luciferase reporter gene assay and was found to antagonize the effect of dihydrotestosterone at nanomolar concentrations. Further detailed biochemical experiments could help to develop piperine as an effective male contraceptive agent in the future.

Topics: Alkaloids; Androgen-Binding Protein; Benzodioxoles; Catalytic Domain; Cell Line; Computer Simulation; Contraceptive Agents, Male; Dihydrotestosterone; Humans; Hydrogen Bonding; Male; Metribolone; Molecular Docking Simulation; Molecular Dynamics Simulation; Piperidines; Polyunsaturated Alkamides; Protein Conformation; Receptors, Androgen; Serine

Cytotoxic amides have been isolated from the fruits of the endemic New Zealand medicinal plant kawakawa, Macropiper excelsum (Piperaceae). The main amide was piperchabamide A and this is the first report of this rare compound outside the genus Piper. Eleven other amides were purified including two new compounds with the unusual 3,4-dihydro-1(2H)-pyridinyl group. The new compounds were fully characterized by 2D NMR spectroscopy, which showed a slow exchange between two rotamers about the amide bond, and they were chemically synthesized. In view of the antitumor activity of the related piperlongumine, all of these amides plus four synthetic analogs were tested for cytotoxicity. The most active was the piperine homolog piperdardine, with an IC50 of 14 µM against HT 29 colon cancer cells.

Topics: Alkaloids; Amides; Benzodioxoles; Cell Survival; Fruit; HT29 Cells; Humans; Inhibitory Concentration 50; Molecular Structure; Piperaceae; Piperidines; Plant Extracts; Plants, Medicinal; Polyunsaturated Alkamides

Targeting Survivin, as an inhibitor of apoptosis and a regulator of cell division, has become a worldwide controversial issue. Piperine as a pungent alkaloid has been identified as the most potent adjuvant at enhancing the efficacy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based therapies in triple-negative breast cancer (TNBC) cells in vitro and in vivo, which might be mediated through inhibition of Survivin. In this work, the binding energies, inhibition constants and binding modes of a group of previously synthesized Piperine derivatives at the binding site of Survivin have been studied using molecular docking tools and the best compounds with minimum binding energies are proposed as potential drugs for the inhibition of Survivin. A comprehensive SAR analysis has been done on the results that can be used for designing new Piperine analogs with higher efficacy. Molecular docking computations also show that the studied compounds can bind to BIR domain of Survivin in the same binding site as that of Smac/DIABLO with a suitable binding energy. This binding may result in the segregation of Smac/DIABLO in the cytosol and subsequently free Smac/DIABLO molecules could be available for binding with inhibitors of apoptosis to initiate caspase mediated apoptosis.

Topics: Alkaloids; Benzodioxoles; Binding Sites; Breast Neoplasms; Female; Humans; Inhibitor of Apoptosis Proteins; Molecular Docking Simulation; Neoplasm Proteins; Piperidines; Polyunsaturated Alkamides; Survivin

Currently little is known as to how nutritionally derived compounds may affect dendritic cell (DC) maturation and potentially prevent inappropriate inflammatory responses that are characteristic of chronic inflammatory syndromes. Previous observations have demonstrated that two polyphenols quercetin and piperine delivered through reconstituted oil bodies (ROBs-QP) can influence DC maturation in response to LPS leading to a modulated inflammatory response. In the present study, we examined the molecular effects of ROBs-QP exposure on DC differentiation in mice and identified a unique molecular signature in response to LPS administration that potentially modulates DC maturation and activity in inflammatory conditions. Following LPS administration, ROBs-QP-exposed DCs expressed an altered molecular profile as compared with control DCs, including cytokine and chemokine production, chemokine receptor repertoire, and antigen presentation ability. In vivo ROBs-QP administration suppresses antigen-specific T-cell division in the draining lymph nodes resulting from a reduced ability to create stable immunological synapse. Our data demonstrate that polyphenols exposure can drive DCs toward a new anti-inflammatory molecular profile capable of dampening the inflammatory response, highlighting their potential as complementary nutritional approaches in the treatment of chronic inflammatory syndromes.

Topics: Alkaloids; Animals; Antigen Presentation; Benzodioxoles; Cell Differentiation; Cell Proliferation; Cytokines; Dendritic Cells; Gene Expression; Inflammation; Lipopolysaccharides; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Piperidines; Polyphenols; Polyunsaturated Alkamides; Primary Cell Culture; Quercetin; Receptors, Chemokine; T-Lymphocytes

Consumer health risk assessment for feed additives is based on the estimated human exposure to the additive that may occur in livestock edible tissues compared to its hazard. We present an approach using alternative methods for consumer health risk assessment. The aim was to use the fewest possible number of animals to estimate its hazard and human exposure without jeopardizing the safety upon use. As an example we selected the feed flavoring substance piperine and applied in silico modeling for residue estimation, results from literature surveys, and Read-Across to assess metabolism in different species. Results were compared to experimental in vitro metabolism data in rat and chicken, and to quantitative analysis of residues' levels from the in vivo situation in livestock. In silico residue modeling showed to be a worst case: the modeled residual levels were considerably higher than the measured residual levels. The in vitro evaluation of livestock versus rodent metabolism revealed no major differences in metabolism between the species. We successfully performed a consumer health risk assessment without performing additional animal experiments. As shown, the use and combination of different alternative methods supports animal welfare consideration and provides future perspective to reducing the number of animals.

Topics: Alkaloids; Animal Feed; Animals; Benzodioxoles; Chickens; Computer Simulation; Consumer Product Safety; Feasibility Studies; Female; Flavoring Agents; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Risk Assessment; Safety

Successful vascular healing after percutaneous coronary interventions is related to the inhibition of abnormal vascular smooth muscle cell proliferation and efficient re-endothelialization. In the search for vascular smooth muscle cell anti-proliferative agents from natural sources we identified piperine (1), the main pungent constituent of the fruits from Piper nigrum (black pepper). Piperine inhibited vascular smooth muscle cell proliferation with an IC50 of 21.6 µM, as quantified by a resazurin conversion assay. Investigations of ten piperamides isolated from black pepper fruits and 15 synthesized piperine derivatives resulted in the identification of three potent vascular smooth muscle cell proliferation inhibitors: the natural alkaloid pipertipine (4), and the two synthetic derivatives (2E,4E)-N,N-dibutyl-5-(3,5-dimethoxyphenyl)penta-2,4-dienamide (14) and (E)-N,N-dibutyl-3-(naphtho[2,3-d][1,3]dioxol-5-yl)acrylamide (20). They showed IC50 values of 3.38, 6.00, and 7.85 µM, respectively. Furthermore, the synthetic compound (2E,4E)-5-(4-fluorophenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one (12) was found to be cell type selective, by inhibiting vascular smooth muscle cell proliferation with an IC50 of 11.8 µM without influencing the growth of human endothelial cells.

Topics: Alkaloids; Benzodioxoles; Cell Proliferation; Fruit; Humans; Inhibitory Concentration 50; Molecular Structure; Muscle, Smooth, Vascular; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides

Piperine (PIP) is a phytopharmaceutical with reported neuroprotective potential in Alzheimer's disease (AD). Oral PIP delivery suffers from its hydrophobicity and pre-systemic metabolism. In this article, mono-disperse intranasal chitosan nanoparticles (CS-NPs) were elaborated for brain targeting of PIP. Formula optimization was based on particle size (PS), zeta potential (ZP), polydispersity index (PDI), % entrapment efficiency (% EE), release studies, and transmission electron microscopy. AD was induced in 48 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor for inflammation. Spherical NPs with optimum % EE (81.70), PS (248.50 nm), PDI (0.24), and ZP (+56.30 mV) were elaborated. PIP-NPs could significantly improve cognitive functions as efficient as standard drug (donpezil injection) with additional advantages of dual mechanism (Ach esterase inhibition and antioxidant effect). CS-NPs could significantly alleviate PIP nasal irritation and showed no brain toxicity. This work was the first to report additional mechanism of PIP in AD via anti-apoptosis and anti-inflammatory effects. To conclude, mucoadhesive CS-NPs were successfully tailored for effective, safe, and non-invasive PIP delivery with 20-folds decrease in oral dose, opening a gate for a future with lower AD morbidity.

Topics: Administration, Intranasal; Alkaloids; Alzheimer Disease; Animals; Antioxidants; Apoptosis; Benzodioxoles; Brain Diseases; Caspase 3; Chitosan; Cholinesterase Inhibitors; Cognition; Drug Delivery Systems; Male; Nanoparticles; Particle Size; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Piperine (P), a sensory stimulant in black pepper, is an agonist on TRPV1 receptors. Earlier work has showed capsaicin-sensitive and -insensitive mechanisms of the contractile action of P on the intestine. The current isolated organ study in the guinea-pig ileum, urinary bladder and trachea (a) confirms the presence of such components of effect (ileum and bladder); (b) indicates TRPV1 involvement in the effect of 5 or 30 µmol/l of P on the basis of an inhibitory action of the antagonist BCTC (ileum); (c) indicates that HC 030031-sensitive TRPA1 receptors and nifedipine-sensitive Ca(2+) channels contribute to the capsaicin-resistant contraction to 30 µmol/l P (ileum) and (d) shows that the contractile effect of P up to 100 µmol/l (guinea-pig trachea) or 30 µmol/l (guinea-pig urinary bladder) is capsaicin-sensitive and mediated by TRPV1 receptors/channels.

Topics: Acetanilides; Alkaloids; Animals; Benzodioxoles; Capsaicin; Dose-Response Relationship, Drug; Female; Guinea Pigs; Ileum; In Vitro Techniques; Male; Muscle Contraction; Nifedipine; Piperidines; Polyunsaturated Alkamides; Purines; Pyrazines; Pyridines; Trachea; TRPV Cation Channels; Urinary Bladder

3-Nitropropionic acid (3-NP) is a fungal toxin well established model used for inducing symptoms of Huntington's disease. Curcumin a natural polyphenol has been reported to possess neuroprotective activity by decreasing oxidative stress. The aim of present study was to investigate neuroprotective effect of curcumin with piperine (bioavailability enhancer) against 3-NP induced neurotoxicity in rats. Administration of 3-NP (10 mg/kg for 21 days) showed loss in body weight, declined motor function and changes in biochemical (LPO, nitrite and glutathione level), neuroinflammatory (TNF-α and IL-1β level) and neurochemical (DA, NE, 5-HT, DOPAC, 5-HIAA and HVA). Chronic treatment with curcumin (25 and 50 mg/kg) and curcumin (25 mg/kg) with piperine (2.5 mg/kg) once daily for 21 days prior to 3-NP administration. All the behavioral parameters were studied at 1st, 7th, 14th, and 21st day. On 22nd day all the animals was scarified and striatum was separated. Curcumin alone and combination (25 mg/kg) with piperine (2.5 mg/kg) showed beneficial effect against 3-NP induced motor deficit, biochemical and neurochemical abnormalities in rats. Piperine (2.5 mg/kg) with curcumin (25 mg/kg) significantly enhances its protective effect as compared with curcumin alone treated group. The results of the present study indicate that protective effect of curcumin potentiated in the presence of piperine (bioavailability enhancer) against 3-NP-induced behavioral and molecular alteration.

Topics: Alkaloids; Animals; Benzodioxoles; Curcumin; Drug Therapy, Combination; Male; Motor Activity; Neuroprotective Agents; Neurotransmitter Agents; Nitro Compounds; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Propionates; Rats; Rats, Wistar

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) has been widely used as a traditional medicine and was shown to possess a multitude of health-promoting properties in pre-clinical studies, but its bioavailability was low due to the extensive glucuronidation in liver and intestine, hindering the development of emodin as a feasible chemopreventive agent. In this study, piperine, as a bioenhancer, was used to enhance the bioavailability of emodin by inhibiting its glucuronidation. The pharmacokinetic profiles of emodin after oral administration of emodin (20mg/kg) alone and in combination with piperine (20mg/kg) to rats were investigated via a validated LC/MS/MS method. As the in vivo pharmacokinetic studies had indicated, the AUC and Cmax of emodin were increased significantly after piperine treatment, and the glucuronidation of emodin was markedly inhibited. Our study demonstrated that piperine significantly improved the in vivo bioavailability of emodin and the influence of piperine on the pharmacokinetics of emodin may be attributed to the inhibition of glucuronidation of emodin. Further research is needed to investigate the detailed mechanism of improved bioavailability of emodin via its combination with piperine.

Topics: Administration, Oral; Alkaloids; Animals; Area Under Curve; Benzodioxoles; Biological Availability; Chromatography, High Pressure Liquid; Drug Interactions; Emodin; Female; Glucuronides; Limit of Detection; Linear Models; Piperidines; Polyunsaturated Alkamides; Rats, Sprague-Dawley; Reproducibility of Results; Tandem Mass Spectrometry

Piperine is isolated from Piper nigrum popularly known as black pepper. Previous studies have demonstrated the beneficial effects of piperine in various health conditions. Additionally, it is a powerful bioenhancer for many drugs. Piperine extract is believed to potentiate the effect of drugs by several folds. The present study is focused on its individual effect on liver function.. A total of 30 CF-1 albino mice obtained from the animal house of faculty of Medicine, Benghazi University, Benghazi, Libya were included in the study. These mice were fed with high cholesterol diet and divided into 2 groups. Twenty mice were administered piperine at a dose of 5mg/kg body weight. Piperine was isolated in Department of Pharmacognosy, Faculty of Pharmacy, Benghazi University, Benghazi and 10 mice were not administered piperine but fed with high fat diet. These mice were anesthetized with ketamine and halothane and blood was drawn from each mouse before the study and after three weeks by cardiocentesis. Serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), alkaline phosphatase and total protein were measured by authenticated methods.. Serum alanine amino transferase was significantly elevated (p=0.0002) in group A mice after the administration of Piperine extract for three weeks compared to those of group B mice. Serum aspartate amino transferase was elevated significantly (p=0.046) and alkaline phosphatase (p= 0.0001) also was significantly increased after the administration of piperine. Serum total protein (p= 0.011) values were significantly decreased after the use of piperine for three weeks in group A mice.. This study showed that there might have been a considerable damage to liver with piperine extract. Further research may be required to prove this damage to liver function.

Topics: Alanine Transaminase; Alkaline Phosphatase; Alkaloids; Animals; Aspartate Aminotransferases; Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Diet, High-Fat; Liver; Liver Function Tests; Mice; Piper nigrum; Piperidines; Polyunsaturated Alkamides

The lifetime prevalence rate for major depressive disorder (MDD) is approximately 17 % for most developed countries around the world. Dietary polyphenols are currently used as an adjuvant therapy to accelerate the therapeutic efficacy on depression. Ferulic acid (FA) or 4-hydroxy-3-methoxy-cinnamic acid (Fig. 1a) is a main polyphenolic component of Chinese herb Radix Angelicae Sinensis, which is found to have antidepressant-like effects through regulating serotonergic and noradrenergic function. The present study examined the synergistic effect of low doses of FA combined with subthreshold dose of piperine, a bioavailability enhancer, on depression-like behaviors in mice, and investigated the possible mechanism. The administration of FA, even in the highest dose tested, reduced immobility time by 60 % in the tail suspension and forced swimming tests (TST and FST) in mice when compared to control. The maximal antidepressant-like effect of FA was obtained with 200 mg/kg. In addition, piperine only produced a weak antidepressant-like effect in the TST and FST. However, the evidence from the interaction analysis suggested a synergistic effect when low doses of FA were combined with a subthreshold dose of piperine. Further neurochemical evidence such as monoamine levels in the frontal cortex, hippocampus, and hypothalamus and measurements of monoamine oxidase activity also supported a synergistic effect of FA and piperine in the enhancement of monoaminergic function. This finding supports the concept that the combination strategy might be an alternative therapy in the treatment of psychiatric disorders with high efficacy and low side effects.

Topics: Alkaloids; Animals; Antidepressive Agents; Benzodioxoles; Biogenic Monoamines; Biological Availability; Brain Chemistry; Coumaric Acids; Depression; Drug Synergism; Hindlimb Suspension; Male; Mice; Mice, Inbred ICR; Monoamine Oxidase; Motor Activity; Neurotransmitter Agents; Piperidines; Polyunsaturated Alkamides; Swimming

Piperine is an exact of the active phenolic component from Black pepper. It has been reported to have many biological activities including anti-oxidant, anti-inflammatory and anti-tumor effects. Intervertebral disc degeneration (IDD) is a degenerative disease closely relate to inflammation of nucleus pulposus (NP) cells. This study aimed to assess the anti-inflammatory and anti-catabolic effects of piperine in rat intervertebral disc using in vitro and ex vivo analyzes. We demonstrated that piperine could inhibit LPS induced expression and production of inflammatory factors and catabolic proteases in NP cells culture model. It significantly inhibited multiple inflammatory factors and oxidative stress-associated genes (IL-1β, TNF-α, IL-6, iNOS), MMPs (MMP-3, MMP-13), ADAMTS (ADAMTS-4, ADAMTS-5) mRNA expression and NO production in a concentration-dependent manner. Moreover, piperine could reverse the LPS-induced inhibition of gene expression of aggrecan and collagen-II. Histologic and dimethylmethylene blue analysis indicated piperine could also against LPS induced proteoglycan (PG) depletion in a rat intervertebral disc culture model. Western blot results showed that piperine inhibited the LPS-mediated phosphorylation of JNK and activation of NF-κB. Finally, our results demonstrated the ability of piperine to antagonize LPS-mediated inflammation of NP cells and suppression of PG in rat intervertebral disc, suggesting a potential agent for treatment of IDD in future.

Topics: Aggrecans; Alkaloids; Animals; Anti-Inflammatory Agents; Benzodioxoles; Cell Survival; Cells, Cultured; Collagen Type II; Cytoprotection; Dose-Response Relationship, Drug; Gene Expression Regulation; Inflammation Mediators; Intervertebral Disc; Intervertebral Disc Degeneration; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Metalloendopeptidases; NF-kappa B; Organ Culture Techniques; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Time Factors

By structural modification of piperine, some piperine-based phenylsulfonylhydrazone derivatives exhibited an unprecedented and potent narcotic activity against the oriental armyworm, Mythimna separata (Walker). The ND50 values of compounds 6c and 6e against the third-instar larvae of M. separata, which were more potent than those of wilfortrine and wilforgine, were 0.0074 μmol (after 3.5 h), and 0.0075 μmol (after 7 h) per larvae, respectively. By transmission electron microscope, it demonstrated that mitochondria were vacuolated and swollen in the ganglion cell of M. separata after treatment with 6c. More importantly, 6c selectively displayed the inhibition activity on acetylcholine esterase (AchE) of M. separata. This work paved the way for further studying the insecticidal mechanism of 6c as a new and promising botanical narcotic agent.

Topics: Alkaloids; Animals; Benzodioxoles; Hydrazones; Insecticides; Larva; Lethal Dose 50; Moths; Narcotics; Piperidines; Polyunsaturated Alkamides; Sulfhydryl Compounds

Curcumin has been reported to suppress different types of clinical and experimentally-induced tumors, but due to less absorption and quick metabolism it show poor bioavailability. The present study was envisaged to investigate the possible synergistic effect of combined treatment of curcumin with piperine in suppression of diethylnitrosamine (DENA)-induced hepatocellular carcinoma (HCC) in rats, owing to permeability enhancing effect of latter. HCC was induced by supplying DENA (0.01%) in drinking water for 10 weeks. The rats were treated with curcumin (100mg/kg; p.o.) per se and curcumin along with piperine (20mg/kg; p.o.) for 4 weeks post HCC induction. The combined treatment significantly attenuated the morphological, histopathological, biochemical, apoptotic and proliferative changes in the liver and serum in comparison to curcumin per se and vehicle control group. The results of present study concluded that curcumin in combination with piperine shows better suppression of DENA-induced HCC in contrast to curcumin per se.

Topics: Alkaloids; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzodioxoles; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Diethylnitrosamine; Drug Administration Schedule; Drug Synergism; Lipid Peroxidation; Liver Neoplasms; Male; Neoplasms, Experimental; Piperidines; Polyunsaturated Alkamides; Rats

Piperine is the principal alkaloid in black peppers (Piper nigrum L.), which is a commonly included spice in anti-diarrheal formulations. Piperine has antispasmodic activities, but its anti-secretory effect is not known. Therefore, this study investigated the anti-secretory effect of piperine and its underlying mechanism. Piperine inhibited cAMP-mediated Cl- secretion in human intestinal epithelial (T84) cells, similar to black pepper extract. Intraluminal administration of piperine (2 μg/loop) suppressed cholera toxin-induced intestinal fluid accumulation by ∼85% in mice. The anti-secretory mechanism of piperine was investigated by evaluating its effects on the activity of transport proteins involved in cAMP-mediated Cl- secretion. Notably, piperine inhibited CFTR Cl- channel activity (IC50#8'6#10 μM) without affecting intracellular cAMP levels. The mechanisms of piperine-induced CFTR inhibition did not involve MRP4-mediated cAMP efflux, AMPK or TRPV1. Piperine also inhibited cAMP-activated basolateral K+ channels, but it had no effect on Na+-K+-Cl- cotransporters or Na+-K+ ATPases. Piperine suppressed Ca2+-activated Cl- channels (CaCC) without affecting intracellular Ca2+ concentrations or Ca2+-activated basolateral K+ channels. Collectively, this study indicates that the anti-secretory effect of piperine involves the inhibition of CFTR, CaCC and cAMP-activated basolateral K+ channels. Piperine represents a novel class of drug candidates for the treatment of diarrheal diseases caused by the intestinal hypersecretion of Cl-.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Transport; Caco-2 Cells; Cell Line, Tumor; Chlorides; Cholera Toxin; Cyclic AMP; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Intestinal Mucosa; Intestines; Male; Mice; Mice, Inbred CFTR; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Potassium Channel Blockers; Potassium Channels, Calcium-Activated; Sodium-Potassium-Exchanging ATPase

The dietary pigment curcumin is a natural polyphenol extracted from the Curcuma longa rhizomes native to South Asia. The antioxidative, antimicrobial, and anti-inflammatory activities besides its unknown side effects suggest that curcumin could be a promising antiresorptive agent to prevent replacement resorption in replanted teeth after traumatic avulsion. Piperine, an alkaloid present in black pepper, seems to enhance the bioavailability and activity of curcumin. Therefore, this study evaluated the biocompatibility of curcumin and piperine in cultures of periodontal ligament cells as well as their effects in an in vitro osteoclastogenesis model of RAW 264.7 macrophages.. The cytotoxicity in human periodontal ligament fibroblasts, human osteogenic sarcoma cells (SAOS-2), and murine osteoclastic precursors (RAW 264.7) was analyzed by using cell number determination and proliferation assays. The ability of curcumin and its conjugate to suppress the receptor activator of nuclear factor kappa B ligand-induced osteoclastogenesis was assessed by tartrate-resistant acid phosphatase (TRAP) staining and activity as well as real-time polymerase chain reaction.. Curcumin at concentrations ≥ 10 μmol/L was cytotoxic in all cell types tested, whereas piperine showed only slight cytotoxicity at 30 μmol/L in RAW and SAOS cultures. Although curcumin caused already significant effects, the combination with piperine completely suppressed the osteoclastogenesis by decreasing the TRAP activity and inhibiting the expression of the specific osteoclast markers TRAP, cathepsin K, and calcitonin receptor.. We demonstrated that curcumin combined with piperine suppressed the osteoclastogenesis in vitro without causing cytotoxic effects in periodontal ligament cells. These findings suggest its potential therapeutic application for the prevention and treatment of replacement resorption in replanted avulsed teeth.

Topics: Alkaloids; Animals; Benzodioxoles; Cells, Cultured; Curcumin; Fibroblasts; Humans; Mice; Osteogenesis; Periodontal Ligament; Piperidines; Polyunsaturated Alkamides; Postoperative Complications; RAW 264.7 Cells; Root Resorption; Tooth Avulsion; Tooth Replantation

Phyllanthin, a sparingly water-soluble hepatoprotective lignin obtained from Phyllanthus amarus Schum. et Thonn. (Euphorbiaceae) possesses low bioavailability. Phyllanthin along with piperine (a nutraceutical bioenhancer) was formulated as a mixed micellar lipid formulation (MMLF) in the present study and investigated to resolve the low bioavailability and enhance hepatoprotective effects on oral administration. Hepatoprotective, antioxidant and bioavailability studies of MMLF, a complex phosphatidylcholine formulation of phyllanthin (CP-PC), phyllanthin + piperine (CP-P-PC) and its corresponding non-formulated phyllanthin have been carried out. Phyllanthin (30 mg kg(-1) p.o.), CP-PC (30 mg kg(-1) p.o.), CP-P-PC (30 mg kg(-1) p.o.) and the reference drug silymarin (100 mg kg(-1), p.o.) were administered daily to rats for 10 days, followed by liver damage by administering a 1 : 1 (v/v) mixture of CCl4 and olive oil (1 ml kg(-1), i.p.) for 7 days from day 4 to day 10. The degree of protection was evaluated by determining the level of marker enzymes (SGOT and SGPT), bilirubin (TB) and total proteins (TP). Further, the effects of MMLF on lipid peroxidation (LPO), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GR) were estimated in liver homogenates to evaluate the antioxidant activity. Finally the concentration of phyllanthin was evaluated in plasma. EC50 values for the in vitro antioxidant assay with DPPH were found to be 19.99, 15.94 and 13.5 for phyllanthin, CP-PC and CP-P-PC, respectively. CP-P-PC (30 mg kg(-1) p.o.) showed significant (p < 0.05) hepatoprotective effect by reducing the levels of serum marker enzymes (SGOT, SGPT, and TB), whereas, elevated the levels of depleted total protein (TP), lipid peroxidation and antioxidant marker enzyme activities such as, GSH, SOD, CAT, GPX, and GR. The complex MMLF normalized adverse conditions of rat livers more efficiently than the non-formulated phyllanthin. The present findings indicate that the MMLF is helpful in solving the problem of low bioavailability of phyllanthin.

Topics: Administration, Oral; Alkaloids; Animals; Antioxidants; Benzodioxoles; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Chemistry, Pharmaceutical; Cytochrome P-450 Enzyme Inhibitors; Glutathione; Glutathione Peroxidase; Lignans; Lipid Peroxidation; Lipids; Liver; Male; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Protective Agents; Rats; Rats, Wistar; Silymarin

A disruption of cholesterol homeostasis characterized by the physical-chemical imbalance of cholesterol solubility in bile often results in formation of cholesterol gallstones. Our earlier studies revealed that curcumin (1000 mg/kg) could prevent formation of gallstones. It has been proved that curcumin is poorly absorbed while piperine is a bioavailability-enhancer. Nevertheless, whether curcumin combined with piperine could enhance the effect of curcumin in preventing gallstones is still awaited.. C57BL6 mice were fed on a lithogenic diet concomitant with curcumin at 500 or 1000 mg/kg and/or piperine at 20 mg/kg for 4 weeks. The ratio of gallbladder stone formation was recorded and samples of blood, bile, gallbladder, liver and small intestine were also collected. The volume of gallbladder and weight of liver were calculated, and blood and bile samples were analyzed through biochemical methods. Intestinal NPC1L1 and SREBP2 mRNA and protein expression were detected by real-time PCR and Western blot.. Combining with piperine can significantly enhance the effect of curcumin, thus preventing the development of gallbladder stones, lowering the saturation of blood lipids and cholesterol in bile, as well as decreasing the expression of NPC1L1 and SREBP2 in both mRNA and protein levels.. Curcumin can prevent the formation of cholesterol gallstones induced by high fat diet in mice and SREBP2 and NPC1L1 may participate in this process. Piperine can increase curcumin's bioavailability, thereby enhancing the effect of curcumin.

Topics: Alkaloids; Animals; Anticholesteremic Agents; Benzodioxoles; Bile; Biological Availability; Cholesterol, Dietary; Curcumin; Diet; Drug Combinations; Drug Synergism; Gallbladder; Gallstones; Gene Expression; Intestinal Mucosa; Intestines; Liver; Male; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Piperidines; Polyunsaturated Alkamides; Protective Agents; RNA, Messenger; Sterol Regulatory Element Binding Protein 2

Alzheimer's disease (AD) is one of the most patient devastating central nervous system diseases with no curative therapy. An effective oral therapy with brain-targeting potential is required that is hampered by blood-brain barrier. Piperine (PIP) is a natural alkaloid with memory enhancing potentials. Oral PIP delivery suffers from its hydrophobicity and first-pass metabolism. In this study, novel Tween-modified monoolein cubosomes (T-cubs) were elaborated as bioactive nanocarriers for brain-targeted oral delivery of PIP. Seven liquid crystalline nanoparticles (cubosomes) were prepared testing different bioactive surfactants (Tween 80, poloxamer, and Cremophor). Full in vitro characterization was carried out based on particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro release. Morphological examination and structure elucidation were performed using transmission and polarizing microscopes. Sporadic dementia of Alzheimer's type was induced in 42 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor-α for inflammation. Liver and kidney toxicity studies were conducted as well. Among others, T-cubs exhibited optimum particle size (167.00±10.49 nm), polydispersity index (0.18±0.01), and zeta potential (-34.60±0.47 mv) with high entrapment efficiency (86.67%±0.62%). Cubs could significantly sustain PIP in vitro release. In vivo studies revealed T-cubs potential to significantly enhance PIP cognitive effect and even restore cognitive function to the normal level. Superiority of T-cubs over others suggested brain-targeting effect of Tween. Toxicological studies contended safety of cubs on kidney, liver, and even brain. T-cubs exhibited potential anti-inflammatory and anti-apoptotic activity of loaded PIP, indicating potential to stop AD progression that was first suggested in this article. Novel oral nanoparticles elaborated possess promising in vitro and in vivo characteristics with high safety for effective chronic treatment of AD.

Topics: Administration, Oral; Alkaloids; Alzheimer Disease; Animals; Benzodioxoles; Blood-Brain Barrier; Brain; Caspase 3; Disease Models, Animal; Drug Delivery Systems; Glycerides; Humans; Inflammation; Kidney; Liquid Crystals; Liver; Male; Nanomedicine; Nanoparticles; Oxidative Stress; Particle Size; Piperidines; Poloxamer; Polyethylene Glycols; Polysorbates; Polyunsaturated Alkamides; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

The flagellate Trypanosoma brucei causes sleeping sickness in humans and nagana in animals. Only a few drugs are registered to treat trypanosomiasis, but those drugs show severe side effects. Also, because some pathogen strains have become resistant, new strategies are urgently needed to combat this parasitic disease. An underexplored possibility is the application of combinations of several trypanocidal agents, which may potentiate their trypanocidal activity in a synergistic fashion. In this study, the potential synergism of mutual combinations of bioactive alkaloids and alkaloids with a membrane-active steroidal saponin, digitonin, was explored with regard to their effect on T. b. brucei. Alkaloids were selected that affect different molecular targets: berberine and chelerythrine (intercalation of DNA), piperine (induction of apoptosis), vinblastine (inhibition of microtubule assembly), emetine (intercalation of DNA, inhibition of protein biosynthesis), homoharringtonine (inhibition of protein biosynthesis), and digitonin (membrane permeabilization and uptake facilitation of polar compounds). Most combinations resulted in an enhanced trypanocidal effect. The addition of digitonin significantly stimulated the activity of almost all alkaloids against trypanosomes. The strongest effect was measured in a combination of digitonin with vinblastine. The highest dose reduction indexes (DRI) were measured in the two-drug combination of digitonin or piperine with vinblastine, where the dose of vinblastine could be reduced 9.07-fold or 7.05-fold, respectively. The synergistic effects of mutual combinations of alkaloids and of alkaloids with digitonin present a new avenue to treat trypanosomiasis but one which needs to be corroborated in future animal experiments.

Topics: Alkaloids; Animals; Benzodioxoles; Benzophenanthridines; Berberine; Digitonin; Drug Combinations; Drug Synergism; Emetine; Harringtonines; Homoharringtonine; Models, Theoretical; Piperidines; Polyunsaturated Alkamides; Trypanocidal Agents; Trypanosoma brucei brucei; Vinblastine

Elevated plasma low-density lipoprotein (LDL) cholesterol is considered as a risk factor for atherosclerosis. Because the hepatic LDL receptor (LDLR) uptakes plasma lipoproteins and lowers plasma LDL cholesterol, the activation of LDLR is a promising drug target for atherosclerosis. In the present study, we identified the naturally occurring alkaloid piperine, as an inducer of LDLR gene expression by screening the effectors of human LDLR promoter. The treatment of HepG2 cells with piperine increased LDLR expression at mRNA and protein levels and stimulated LDL uptake. Subsequent luciferase reporter gene assays revealed that the mutation of sterol regulatory element-binding protein (SREBP)-binding element abolished the piperine-mediated induction of LDLR promoter activity. Further, piperine treatments increased mRNA levels of several SREBP targets and mature forms of SREBPs. However, the piperine-mediated induction of the mature forms of SREBPs was not observed in SRD-15 cells, which lack insulin-induced gene-1 (Insig-1) and Insig-2. Finally, the knockdown of SREBPs completely abolished the piperine-meditated induction of LDLR gene expression in HepG2 cells, indicating that piperine stimulates the proteolytic activation of SREBP and subsequent induction of LDLR expression and activity.

Topics: Alkaloids; Benzodioxoles; Hep G2 Cells; Humans; Liver; Piperidines; Polyunsaturated Alkamides; Proteolysis; Receptors, LDL

Pepper, a daily-used seasoning for promoting appetite, is widely used in folk medicine for treating gastrointestinal diseases. Piperine is the major alkaloid in pepper and possesses a wide range of pharmacological activities. However, the mechanism for linking metabolic and medicinal activities of piperine remains unknown. Here we report that piperine robustly boosts mTORC1 activity by recruiting more system L1 amino acid transporter (SLC7A5/SLC3A2) to the cell membrane, thus promoting amino acid metabolism. Piperine-induced increase of mTORC1 activity in resident peritoneal macrophages (pMΦs) is correlated with enhanced production of IL-6 and TNF-α upon LPS stimulation. Such an enhancement of cytokine production could be abrogated by inhibitors of the mTOR signaling pathway, indicating mTOR's action in this process. Moreover, piperine treatment protected resident pMΦs from bacterium-induced apoptosis and disappearance, and increased their bacterial phagocytic ability. Consequently, piperine administration conferred mice resistance against bacterial infection and even sepsis. Our data highlight that piperine has the capacity to metabolically reprogram peritoneal resident macrophages to fortify their innate functions against bacterial infection.

Topics: Alkaloids; Amino Acids; Animals; Anti-Bacterial Agents; Apoptosis; Benzodioxoles; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Female; Fusion Regulatory Protein 1, Heavy Chain; HeLa Cells; Humans; Immunity, Innate; Inflammation Mediators; Interleukin-6; Large Neutral Amino Acid-Transporter 1; Lipopolysaccharides; Macrophage Activation; Macrophages, Peritoneal; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Multiprotein Complexes; Phagocytosis; Piperidines; Polyunsaturated Alkamides; RAW 264.7 Cells; RNA Interference; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; Transfection; Tumor Necrosis Factor-alpha

Piperine, the bioactive phytochemical from black pepper (Piper nigrum L.), is a nontoxic natural compound exhibiting many physiological and pharmacological properties. They include antioxidant, anti-inflammatory, antimutagenic, antitumor, antiapoptotic, antigenotoxic, antiarthritic, antifungal, antimicrobial, antidepressant, anti-HBV, and gastro-protective activities. It also enhances the bioavailability of phytochemicals and drugs. The molecular mechanism of action of piperine with DNA has not yet been addressed, while its pharmacological activities have been reported. In this work we report for the first time the interaction of piperine molecule with DNA duplex. We have carried out UV-vis absorption and fluorescence spectroscopy to confirm the binding of piperine with calf thymus DNA (ctDNA). The energetics of interaction of piperine with ctDNA was monitored by isothermal titration calorimetry (ITC). Differential scanning calorimetry (DSC) and melting temperature (Tm) analysis were also performed, confirming a minor groove mode of binding of piperine with ctDNA. The binding free energy ΔG values obtained from molecular dynamics simulation studies agree well with ITC values and reveal a sequence dependent minor groove binding exhibiting a specificity toward AT rich sequences.

Topics: Alkaloids; Benzodioxoles; Calorimetry, Differential Scanning; DNA; Models, Molecular; Molecular Dynamics Simulation; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Thermodynamics; Water

Piperine, a natural compound isolated from the fruits of Piper, is known to modulate several neurotransmitter systems such as serotonin, norepinephrine, and GABA, all of which have been linked to the development of convulsions. Fruits of Piper species have been suggested as means for managing seizure disorders. The present study was designed to elucidate the anticonvulsant effect of piperine and its mechanisms of action using in-silico, in-vivo and in-vitro techniques.PASS software was used to determine its possible activity and mechanisms. Furthermore the latency for development of convulsions and mortality rate was recorded in different experimental mouse models of epilepsy (pentylenetetrazole, maximal electroshock, NMDA, picrotoxin, bicuculline, BAYK-8644, strychnine-induced convulsions) after administration of various doses of piperine (5, 10 and 20 mg/kg, i.p.). Finally, the effect of piperine on Na(+) and Ca(2+) channels were evaluated using the whole cell patch clamp techniqueOur results revealed that piperine decreased mortality in the MES-induced seizure model. Moreover, piperine (10 mg/kg) delayed the onset of tonic clonic convulsions in the pentylenetetrazole test and reduced associated mortality. Furthermore, an anticonvulsant dose of piperine also delayed the onset of tonic clonic seizures in strychnine, picrotoxin and BAY K-8644. Complete protection against mortality was observed in BAYK-8644 induced convulsions. Finally, whole cell patch clamp analysis suggested an inhibitory effect of piperine on Na(+) channels. Together, our data suggest Na(+) channel antagonist activity as a contributor to the complex anticonvulsant mechanisms of piperine.

Topics: Action Potentials; Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Calcium; Cell Line; Humans; Mice; Piperidines; Polyunsaturated Alkamides; Seizures; Sodium; Sodium Channel Blockers

Type 2 diabetes (T2DM) is a progressive insulin secretory defect accompanied by resistance to insulin, and thereby making glycemic control a major concern in the treatment of these patients. Oral drug administration, though a popular option for its non-invasiveness, suffer from poor bioavailability. It could be related to the efflux transport of intestinal P-glycoprotein (Pgp). In the present study, we explored the binding interactions of antidiabetic drugs i.e., sulfonylurea drugs (glimepiride, glipizide, glyburide) and rapid acting insulin secretagogues viz., nateglinide, repaglinide and rosiglitazone; and Pgp inhibitors i.e., Generation I (verapamil and tamoxifen), III (tetradrine and tariquidar), and natural inhibitors (fumagillin and piperine) in mouse Pgp model. Our results revealed that fumagillin piperine and verapamil possess maximum interaction energies with Pgp compared to antidiabetic drugs. These observations elucidate the role of fumagillin and piperine as potential natural compounds which could intervene in the efflux action of Pgp in extruding the antidiabetic drugs and may have implications for increasing efficacy of oral antidiabetic therapy.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Transport, Active; Cyclohexanes; Fatty Acids, Unsaturated; Hypoglycemic Agents; Intestinal Mucosa; Mice; Molecular Docking Simulation; Piperidines; Polyunsaturated Alkamides; Protein Binding; Sesquiterpenes; Tamoxifen; Verapamil

Parkinson's disease (PD) is second only to Alzheimer's disease as the most common and debilitating age-associated neurodegenerative disorder. Currently, no therapy has been shown to unequivocally retard or arrest the progression of the disease. The aim of the present study was to investigate the protective effect of piperine on the 1-methyl-4-phenyl-1,2,3,6‑tetrahydropyridine (MPTP)-induced Parkinson's mouse model. For MPTP treatment, the animals received repeated intraperitoneal injections (i.p.) of MPTP (30 mg/kg) solution for 7 days. Piperine (10 mg/kg) was administered orally for 15 days including 8 days of pretreatment. Motor behavior analysis was conducted with the rotarod test. The Morris water maze (MWM) was used to assess the cognitive learning ability of the mice. A histological examination was subsequently conducted. The results ddemonstrate that piperine treatment attenuated MPTP-induced deficits in motor coordination and cognitive functioning. Piperine also prevented MPTP-induced decreases in the number of tyrosine hydroxylase-positive cells in the substantia nigra. Additionally, piperine reduced the number of activated microglia, expression of cytokine IL-1β, and oxidative stress following MPTP treatment. An anti-apoptotic property of piperine was identified by maintaining the balance of Bcl-2/Bax. In conclusion, the results show that piperine exerts a protective effect on dopaminergic neurons via antioxidant, anti-apoptotic, and anti-inflammatory mechanisms in an MPTP-induced mouse model of PD. Thus, piperine is a potential therapeutic treatment for PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Alkaloids; Animals; Anti-Inflammatory Agents; Apoptosis; Benzodioxoles; Disease Models, Animal; Dopaminergic Neurons; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Motor Activity; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Piperidines; Polyunsaturated Alkamides; Rotarod Performance Test; Substantia Nigra; Tyrosine 3-Monooxygenase

In our previous study, piperlonguminine from the fruit of Piper chaba was reported to promote adipogenesis in 3T3-L1 cells like the peroxisome proliferator-activated receptor-γ (PPARγ) agonist, troglitazone. In the present study, the mode of action of piperlonguminine in cells was examined. Piperlonguminine increased mRNA levels of adiponectin, glucose transporter 4, and fatty acid-binding protein (aP2). It also increased mRNA levels of PPARγ2 but, unlike troglitazone, piperlonguminine did not activate PPARγ directly in a nuclear receptor cofactor assay. Analyses of plasma from mice treated with piperlonguminine, piperine, and retrofractamide A, and an extract of the fruit, showed that concentrations of piperlonguminine were higher than those of piperine and retrofractamide A, and that the "area-under-the-curve" of piperine increased following in vivo administration of the extract.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adiponectin; Alkaloids; Amides; Animals; Area Under Curve; Benzodioxoles; Deoxyglucose; Dioxolanes; DNA-Binding Proteins; Dose-Response Relationship, Drug; Fatty Acid-Binding Proteins; Fruit; Humans; Male; Mice; Phytotherapy; Piper; Piperidines; Plant Extracts; Plants, Medicinal; Polyunsaturated Alkamides; PPAR gamma; RNA, Messenger; Transcription Factors; Triglycerides

A simple and convenient method was established for simultaneous quantitative determination of piperine and piperlonguminine in dried fruits of Piper longum and allied plants. The average content of piperine in P. longum (18.26 mg/g, range 12.05-33.23 mg/g) was about one half that of P. nigrum (40.09 mg/g, range 29.57-54.23 mg/g), but the content of piperlonguminine in P. longum was in the range of 0.42-1.82 mg/g, and the average content of piperlonguminne (0.91 mg/g) was about seven times higher than that in P. nigrum (0.13 mg/g). A sample of P. longum from Vietnam and a sample of P. retrofractum collected in Ishigaki, Japan, showed high contents of piperine and piperlonguminine. On the other hand, a sample of P. betle collected in Taiwan showed low content of piperine, and piperlonguminine was not detected.

Topics: Alkaloids; Benzodioxoles; Chromatography, Liquid; Dioxolanes; Ethnobotany; Fruit; Japan; Phytotherapy; Piper; Piperidines; Plant Extracts; Plants, Medicinal; Polyunsaturated Alkamides; Species Specificity; Taiwan

Piper longum L. fruits have been traditionally used against snakebites in north-eastern and southern region of India. The aim of the study was to assess the production of antibody response against Russell's viper venom in mice after prophylactic immunization with ethanolic extract of fruits of Piper longum L. and piperine. The mice sera were tested for the presence of antibodies against Russell's viper venom by in vitro lethality neutralization assay and in vivo lethality neutralization assay. Polyvalent anti-snake venom serum (antivenom) manufactured by Haffkine Bio-Pharmaceutical Corporation Ltd. was used as standard. Further confirmation of presence of antibodies against the venom in sera of mice immunized with PLE and piperine was done using indirect enzyme-linked immunosorbent assay (ELISA) and double immunodiffusion test. Treatment with PLE-treated mice serum and piperine-treated mice serum was found to inhibit the lethal action of venom both in the in vitro lethality neutralization assay and in vivo lethality neutralization assay. ELISA testing indicated that there were significantly high (p<0.01) levels of cross reactions between the PLE and piperine treated mice serum and the venom antigens. In double immunodiffusion test, a white band was observed between the two wells of antigen and antibodies for both the PLE-treated and piperine-treated mice serum. Thus it can be concluded that immunization with ethanolic extract of fruits of Piper longum and piperine produced a high titre antibody response against Russell's viper venom in mice. The antibodies against PLE and piperine could be useful in antivenom therapy of Russell's viper bites. PLE and piperine may also have a potential interest in view of the development of antivenom formulations used as antidote against snake bites.

Topics: Alkaloids; Animals; Antibody Formation; Antivenins; Benzodioxoles; Daboia; Fruit; Immunization; Mice; Mice, Inbred Strains; Piper; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Snake Bites; Viper Venoms

Piperine had protective effects on oxidative stress damage of ventricular myocytes by hydrogen peroxide (H2O2). In this study we aimed to explore the protective effect of piperine on abnormalities of the cardiac action potential (AP) and several ion currents induced by hydrogen peroxide (H2O2) in single rabbit left atrial myocyte.. Conventional microelectrodes were used to record action potential duration (APD), resting membrane potential (RMP) and some ion currents (ICa,L,Ito,IK1 and Ikur,ect.), before and after H2O2 administration with or without piperine.. The piperine (7 μmol/L) had no significant effect on APD, ICa,L,Ito,IK1 and Ikur and their channel dynamics. In the presence of 50 μmol/L H2O2, APD50 and APD90 shortened (P<0.01), amplitude of RMP decreased (P<0.05), the peak of ICa,L reduced significantly (P<0.05). Piperine (7 μmol/L) significantly alleviated the inhibiting effect of H2O2 on APD and ICa,L (P<0.01) and protected the changes of ICa,L dynamics induced by H2O2. The peak current of Ito was reduced significantly (P<0.05); Piperine (7 μmol/L) significantly alleviated the inhibiting effect of H2O2 on Ito (P<0.01). In addition, piperine protected the changes of Ito dynamics induced by H2O2. The peak current of IK1 and IKUr was significantly reduced (P<0.05); Piperine (7 μmol/L) alleviated the inhibiting effect of H2O2 on IK1 and IKUr significantly (P<0.01). In addition, piperine protected the changes of IKUr dynamics induced by H2O2.. These results suggest that piperine effectively protects atrial myocytes from oxidative stress injury in atrial electrophysiology.

Topics: Action Potentials; Alkaloids; Animals; Atrial Function; Benzodioxoles; Heart Atria; Hydrogen Peroxide; Membrane Potentials; Microelectrodes; Myocytes, Cardiac; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Rabbits

The objective of this study was to develop the microspheres from gelatin (G) and silk fibroin (SF) aimed to be applied for the controlled release of curcumin and piperine. The glutaraldehyde-crosslinked G/SF microspheres at various weight blending ratios (100/0, 70/30, 50/50, and 30/70) were successfully fabricated by water in oil emulsion technique. The microspheres prepared from all compositions were in a round shape with homogeneous size distribution both in the dried (194-217 μm) and swollen states (297-367 μm). When subjected in collagenase solution at physiological condition, the G microspheres gradually degraded within 14 days while the blended G/SF microspheres, particularly at 50/50 and 30/70, were not degraded. For the release application, the microspheres were loaded with curcumin and/or piperine. It was found that the microspheres composed of SF tended to entrap curcumin and piperine with the high entrapment and loading efficiencies, possibly due to their hydrophobic interactions. The G/SF microspheres, particularly at the ratios of 50/50 and 30/70, released curcumin and piperine in a sustained manner both for the single and dual release systems. The controlled dual release of curcumin and piperine from the G/SF microspheres would prolong their half-life, provide the optimal concentrations for therapeutic effects at a target site, and improve the bioavailability of curcumin. These novel injectable microspheres dually releasing curcumin and piperine would be introduced for the treatment of diseases without the need of operation.

Topics: Alkaloids; Benzodioxoles; Biocompatible Materials; Curcumin; Drug Carriers; Fibroins; Gelatin; Microscopy, Electron, Scanning; Microspheres; Piperidines; Polyunsaturated Alkamides; Silk

Many endophytic fungi have been reported with the biosynthetic potential to produce same or similar metabolites present in host plants. The adaptations that might have acquired by these fungi as a result of the long-term association with their host plants can be the possible basis of their biosynthetic potential. The bioactive compounds originated from endophytes are currently explored for their potential applications in pharmaceutical, agriculture and food industries. Piper nigrum, a plant of the Piperaceae is very remarkable because of the presence of the alkaloid piperine. Piperine has been reported to have broad bioactive properties ranging from antimicrobial, antidepressant, anti-inflammatory, antioxidative to anticancer activities. Interestingly, piperine also plays a vital role in increasing the bioavailability of many drugs which again is a promising property. The current study was carried out to identify piperine producing endophytic fungus from Piper nigrum L. By screening various endophytic fungi, the isolate which was identified as member of Colletotrichum gloeosporioides was found to have the ability to form piperine and was confirmed by HPLC and LCMS. Considering the broad bioactive potential of piperine, the piperine producing fungi identified in the study can expect to have much industrial potential.

Topics: Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Colletotrichum; Endophytes; Piper nigrum; Piperidines; Polyunsaturated Alkamides

The aim of this study was to evaluate the cytotoxic and apoptotic effects of piperine on human lung cancer A549 cells and to explore its mechanisms. Piperine was found to exert the greatest cytotoxic effect against A549 cells in a dose-dependent manner, whereas it showed no effect on WI38 human lung fibroblasts. This cell growth-inhibitory effect might be attributed to cell DNA damage and cytotoxic effects. Besides, piperine had the ability to cause cell cycle arrest in G2/M phase and to activate caspase-3 and caspase-9 cascades in A549 cells. Furthermore, piperine-induced apoptosis could be blocked by the broad caspase inhibitor z-VAD-fmk in majority. In addition, piperine treatment decreased Bcl-2 protein expression, but increased Bax protein expression in A549 cells, which were positively correlated with an elevated expression of p53 compared to control. Taken together, these results suggested that piperine could induce p53-mediated cell cycle arrest and apoptosis via activation of caspase-3 and caspase-9 cascades, as well as increasing the Bax/Bcl-2 ratio. Thus, piperine could be developed as an effective antitumor agent in the prevention and treatment of lung cancer without toxicity to the host.

Topics: Alkaloids; Apoptosis; bcl-2-Associated X Protein; Benzodioxoles; Caspases; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Humans; Mitochondria; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tumor Suppressor Protein p53

Previous studies in our laboratory have demonstrated that piperine produced antidepressant-like action in various mouse models of behavioral despair. This study aimed to investigate the role of brain-derived neurotrophic factor (BDNF) signalling in the antidepressant-like effect of piperine in mice exposed to chronic unpredictable mild stress (CUMS). The results showed that CUMS caused depression-like behavior in mice, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. It was also found that BDNF protein expression in the hippocampus and frontal cortex were significantly decreased in CUMS-treated mice. Chronic treatment of piperine at the dose of 10mg/kg significantly ameliorated behavioural deficits of CUMS-treated mice in the sucrose preference test and forced swim test. Piperine treatment also significantly decreased immobility time in the forced swim test in naive mice. In parallel, chronic piperine treatment significantly increased BDNF protein expression in the hippocampus and frontal cortex of both naive and CUMS-treated mice. In addition, inhibition of BDNF signalling by injection of K252a, an inhibitor of the BDNF receptor TrkB, significantly blocked the antidepressant-like effect of piperine in the sucrose preference test and forced swim test of CUMS-treated mice. Taken together, this study suggests that BDNF signalling is an essential mediator for the antidepressant-like effect of piperine.

Topics: Alkaloids; Animals; Antidepressive Agents; Benzodioxoles; Brain-Derived Neurotrophic Factor; Carbazoles; Chronic Disease; Disease Models, Animal; Enzyme Inhibitors; Food Preferences; Indole Alkaloids; Male; Mice; Mice, Inbred ICR; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Stress, Psychological; Sucrose; Sweetening Agents; Time Factors

To isolate, fermentatively evaluate and identify black pepper (Piper nigrum L.)-associated bacteria for the microbial decortication of fresh ripened berries and dried black pepper for preparation of off-odour-free white pepper.. Among 45 bacterial isolates obtained from black pepper, seven of them were found to decorticate black pepper (>60%) and fresh pepper berries (98-100%) into white pepper within 5 days of immersion in bacterial suspension. The 16S rRNA genes (1500-bp amplicon) of these bacteria were sequenced, and species identity was established by closest match in GenBank. Superior-quality white pepper was obtained with Bacillus subtilis (IISR WP 33, 34, 38), Bacillus licheniformis (IISR WP 43), Acinetobacter baumanii (IISR WP 35), Klebsiella pneumoniae (IISR WP 19) and Microbacterium barkeri (IISR WP25). The bacterial isolates were found to secrete multiple hydrolytic enzymes such as cellulase, pectinase, amylase, protease and xylanase. Bacterial cultures were deposited with International Depository Authority at Microbial Type Culture Collection, India, as patent deposits as prescribed in Budapest Treaty for microbial deposits. The white pepper, thus obtained from bacterial decortication process, was free from off-odour compound, especially skatole. Other biochemical constituents such as oleoresin, piperine and essential oils were found in the acceptable range. The bacterial decortication did not affect inherent constituents of pepper such as essential oil constituents, oleoresin and piperine content.. One of the most significant findings of the work is identification of specific bacterial species for decortication of fresh berries or black pepper berries into value-added white pepper.. This work paved way for developing a technological process for microbial decortication of fresh/black pepper for the production of superior-quality white pepper.

Topics: Alkaloids; Bacteria; Benzodioxoles; Fermentation; Fruit; Molecular Sequence Data; Odorants; Oils, Volatile; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; RNA, Ribosomal, 16S

Previous studies in our laboratory have demonstrated that piperine produced antidepressant-like action in various mouse models of behavioral despair, which was related to the serotonergic system. The present study aimed to examine the behavioral and biochemical effects of piperine in rats exposed to chronic unpredictable mild stress (CUMS). The results showed that CUMS caused depression-like behavior in rats, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. In addition, it was found that serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) contents in the hippocampus and frontal cortex were significantly decreased in CUMS-treated rats. Treating the animals with piperine significantly suppressed behavioral and biochemical changes induced by CUMS. The results suggest that piperine produces an antidepressant-like effect in CUMS-treated rats, which is possibly mediated by increasing 5-HT and BDNF contents in selective brain tissues.

Topics: Alkaloids; Animals; Antidepressive Agents; Benzodioxoles; Brain-Derived Neurotrophic Factor; Chronic Disease; Male; Piperidines; Polyunsaturated Alkamides; Random Allocation; Rats; Rats, Sprague-Dawley; Serotonin; Stress, Psychological

In this study, a novel approach for in vitro regeneration of Piper nigrum L. has been applied in order to increase healthy biomass, phytochemicals and piperine production via reverse photoperiod (16hD/8hL). Leaf portions of the seed-derived plants were placed on an MS-medium fortified with different PGRs. Under 16hD/8hL, thidiazuron (TDZ; 4.0 mg L⁻¹) and BA (1.5 mg L⁻¹) was found to be the most effective (<90%) in callus induction. Two concentrations (1.5, 2.0 mg L⁻¹) of the IBA produced>80% shoots from callus cultures. Healthy shoots were transferred to rooting medium and higher percentage of rooting (<90%) was observed on IBA (1.5 mg L⁻¹). These in vitro tissues were subjected to amino acid analysis, spectrophotometry, and HPLC. ARG, SER, THR, and TYR were the most abundant components out of 17 amino acids. Higher amino acid production was observed under normal photoperiod (16hL/8hD) than under reverse photoperiod (16hD/8hL). The highest total phenolic content (TPC; 9.91 mg/g-DW) and flavonoid content (7.38 mg/g-DW) were observed in callus cultures incubated under 16hL/8hD than other tissues incubated under 16hD/8hL photoperiod. Higher DPPH and PoMo activities were observed in tissues incubated under 16hL/8hD photoperiod, while ABTS and Fe²⁺ chelating activities were found higher in tissues incubated under reverse photoperiod. Significant quantities of piperine content were observed in all tissues except callus cultures. These results suggest that reverse photoperiod is a promising approach for callus induction, phytochemicals and piperine production for commercial applications.

Topics: Alkaloids; Amino Acids; Antioxidants; Benzodioxoles; Biomass; Cells, Cultured; Chromatography, High Pressure Liquid; Flavonoids; Germination; Phenols; Photoperiod; Piper nigrum; Piperidines; Plant Bark; Plant Shoots; Polyunsaturated Alkamides; Regeneration; Seeds

Piperine is responsible for the hot taste of black pepper. Publications on genotoxicity of piperine are reported: negative Ames Tests and one in vitro micronucleus test (MNT). In vivo tests were mainly negative. In the majority of the data the administered dose levels did not follow the dose selection requirements of regulatory guidelines of having dose levels up to the maximum tolerated dose (MTD). The only oral high dose studies were a positive in vivo MNT in mice in contrast to a negative in vivo chromosome aberration test in rats. Thus, conflicting results in genotoxicity testing are published. To investigate this further, we administered piperine to mice up to the MTD and determined micronuclei-frequency. Piperine reduces core body temperature and interferes with blood cells both being known to result in irrelevant positive in vivo MNTs. Therefore we added mechanistic endpoints: core body temperature, haematology, erythropoietin level, and organ weights. Additionally an in vitro MNT in Chinese hamster ovary cells was performed. Piperine was negative in the in vitro MNT. It caused significant reduction of core body temperature, decrease of white blood cells and spleen weights but no increase in the micronucleus-frequency. Thus, in our studies piperine was not genotoxic.

Topics: Alkaloids; Animals; Benzodioxoles; CHO Cells; Cricetinae; Cricetulus; Female; In Vitro Techniques; Male; Mice; Mutagenicity Tests; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Polyphenols are natural compounds capable of interfering with the inflammatory pathways of several in vitro model systems. In this study, we developed a stable and effective strategy to administer polyphenols to treat in vivo models of acute intestinal inflammation. The in vitro suppressive properties of several polyphenols were first tested and compared for dendritic cells (DCs) production of inflammatory cytokines. A combination of the polyphenols, quercetin and piperine, were then encapsulated into reconstituted oil bodies (OBs) in order to increase their stability. Our results showed that administration of low dose reconstituted polyphenol OBs inhibited LPS-mediated inflammatory cytokine secretion, including IL-6, IL-23, and IL-12, while increasing IL-10 and IL-1Rα production. Mice treated with the polyphenol-containing reconstituted OBs (ROBs) were partially protected from dextran sodium sulfate (DSS)-induced colitis and associated weight loss, while mortality and inflammatory scores revealed an overall anti-inflammatory effect that was likely mediated by impaired DC immune responses. Our study indicates that the administration of reconstituted quercetin and piperine-containing OBs may represent an effective and potent anti-inflammatory strategy to treat acute intestinal inflammation.

Topics: Acute Disease; Alkaloids; Animals; Benzodioxoles; Capsules; Colitis; Dendritic Cells; Dextran Sulfate; Dose-Response Relationship, Drug; Drug Stability; Inflammation; Interleukin-6; Intestinal Diseases; Lipopolysaccharides; Liposomes; Mice; Peptidoglycan; Piperidines; Polyphenols; Polyunsaturated Alkamides; Quercetin; Tumor Necrosis Factor-alpha

In this study, curcumin was designed into the nanoformulation called cubosome with piperine in order to improve oral bioavailability and tissue distribution of curcumin.. The characteristic of the cubosome was studied by using scanning electron microscope (SEM), Infrared spectrum and small angle X-ray scattering (SAXS) techniques. Tissue distribution of cubosome was measured by liquid chromatography-mass spectrometry (LC-MS) method in mice.. The characteristic of the cubosome was demonstrated that the curcumin and piperine were encapsulated in the interior of the cubosome and the crystal form was Pn3m space. The pharmacokinetic test revealed that the cubosome could improve the oral bioavailability significantly compared to the suspension of curcumin with piperine and be mainly absorbed by the spleen.. These findings provide the reference to a preferable choice of the curcumin formulation and contribute to therapeutic application in clinical research.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Curcumin; Mice; Nanocapsules; Particle Size; Piperidines; Polyunsaturated Alkamides; Scattering, Small Angle; Spleen; Tissue Culture Techniques; X-Ray Diffraction

Novel antidepressants or treatment strategies that may offer a more rapid onset of action, improved efficacy, and greater tolerability are in desperate need. Because current clinically utilized antidepressants, which target high-affinity transporters for serotonin and norepinephrine, fail to provide satisfactory treatment outcomes for quite a portion of patients. In recent investigations, a low-affinity but high-capacity transporter organic cation transporter 2 (OCT2, SLC22A2) has been proposed as an important postsynaptic determinant of aminergic tonus and mood-related behaviors, a complementary system to the high-affinity transporters. In order to evaluate whether OCT2 inhibition may at least in part contribute to the pharmacological effects of antidepressants, several typical antidepressant compounds of various mechanism categories were employed to inhibit OCT2 activity in cells stably overexpressing OCT2. The tested antidepressant agents included selective serotonin reuptake inhibitors (SSRIs, fluoxetine, sertraline and paroxetine), tricyclic antidepressants (TCAs, amitriptyline, imipramine, desipramine), monoamine oxidase inhibitor (MAOI, moclobemide), serotonin-norepinephrine reuptake inhibitor (SNRI, venlafaxine) and reported antidepressant alkaloid piperine. Piperine was screened through synaptosomes before cell experiments, without the interference of monoamine oxidase. All of the nine antidepressant compounds showed moderate inhibitory effects on OCT2-mediated metformin, serotonin and/or norepinephrine uptake. Sertraline and desipramine tended to inhibit OCT2 activity via a competitive mechanism. The fact could be easily belied, since passive diffusion dominated the influx process. It remains to be seen whether OCT2 inhibition plays a role to the overall therapeutic effects in clinical practice.

Topics: Alkaloids; Animals; Antidepressive Agents; Benzodioxoles; Dogs; Madin Darby Canine Kidney Cells; Metformin; Norepinephrine; Organic Cation Transport Proteins; Organic Cation Transporter 2; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin; Synaptosomes; Transfection

Piperine has been shown to have anti-inflammatory properties. The molecular mechanisms by which it mediates anti-inflammatory activities remain elusive. Type II phosphatidylinositol 4-kinase(s) are key components in FcεRI receptor-mediated signaling leading to inflammatory mediators release in RBL-2H3 cells. The effects of piperine on IgE-mediated signaling and mast cell degranulation were investigated. Pretreatment of RBL-2H3 cells with piperine inhibited IgE-induced activation of type II PtdIns 4-kinase(s). In vitro lipid kinase assays showed piperine-inhibited type II PtdIns 4-kinase activity in a dose-dependent fashion with no effect on PtdIns 3-kinase activity. Concomitantly, pretreatment of RBL-2H3 cells with piperine also inhibited IgE-induced β-hexosaminidase release in RBL-2H3 cells. These results suggest that type II PtdIns 4-kinases are part of piperine-mediated anti-inflammatory signaling mechanisms.

Topics: Alkaloids; Benzodioxoles; Cell Line; Humans; Immunoglobulin E; Inflammation; Mast Cells; Minor Histocompatibility Antigens; Phosphatidylinositols; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Piperidines; Polyunsaturated Alkamides; Receptors, IgE; Signal Transduction

TRPV1 is a multimodal channel mainly expressed in sensory neurons. We aimed to explore the pharmacodynamics of the TRPV1 agonists, capsaicin, natural capsaicinoids, and piperine in an in vitro bioassay using human PC-3 cells and to examine desensitization and the effect of the specific antagonist SB366791.. PC-3 cells expressing TRPV1 were incubated with Fluo-4. Fluorescence emission changes following exposition to agonists with and without preincubation with antagonists were assessed and referred to maximal fluorescence following the addition of ionomycin. Concentration-response curves were fitted to the Hill equation.. Capsaicin and piperine had similar pharmacodynamics (E max 204.8 ± 184.3% piperine versus 176.6 ± 35.83% capsaicin, P = 0.8814, Hill coefficient 0.70 ± 0.50 piperine versus 1.59 ± 0.86 capsaicin, P = 0.3752). In contrast, capsaicinoids had lower E max (40.99 ± 6.14% capsaicinoids versus 176.6 ± 35.83% capsaicin, P < 0.001). All the TRPV1 agonists showed significant desensitization after the second exposition and their effects were strongly inhibited by SB366791.. TRPV1 receptor is successfully stimulated by capsaicin, piperine, and natural capsaicinoids. These agonists present desensitization and their effect is significantly reduced by a TRPV1-specific antagonist. In addition, PC-3 cell bioassays proved useful in the study of TRPV1 pharmacodynamics.

Topics: Alkaloids; Apoptosis; Benzodioxoles; Biological Assay; Capsaicin; Cell Line, Tumor; Cell Survival; Humans; Male; Metabolic Clearance Rate; Piperidines; Polyunsaturated Alkamides; Prostatic Neoplasms; TRPV Cation Channels

Piper nigrum is very remarkable for its medicinal properties due to the presence of metabolites like piperine. Emerging understanding on the biosynthetic potential of endophytic fungi suggests the possibility to have piperine producing fungi in P. nigrum. In the current study, endophytic fungi isolated from P. nigrum were screened for the presence of piperine by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This resulted in the identification of a Mycosphaerella sp. with the ability to produce piperine extracellularly. The biosynthesis of piperine (C17H19NO3) by the endophytic fungal isolate was confirmed by the presence of m/z 286.1 (M + H(+)) in the LC-MS/MS analysis using positive mode ionization. This was further supported by the presence of specific fragment ions with masses 135, 143, 171 and 201 formed due to the fragmentation of piperine present in the fungal extract.

Topics: Alkaloids; Ascomycota; Benzodioxoles; Chromatography, Liquid; Endophytes; Molecular Structure; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Tandem Mass Spectrometry

Triple-negative breast cancer (TNBC) is most the aggressive type of breast cancer and is poorly responsive to endocrine therapeutics; however, one of the most attractive treatments is tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based therapies. To identify compounds that enhance the efficacy of TRAIL-based therapies, we screened 55 compounds from natural products in combination with TRAIL in TNBC cells.. Human TNBC cells, MDA-MB-468 and MDA-MB-231, and murine TNBC cells, 4T1, were used. Cell viability, apoptotic cells, and cell cycle were quantified by the WST-1 assay, annexin-V/7-amino-actinomycinD (7-AAD) staining and Propidium iodide (PI) staining, respectively. In vivo effects of piperine were evaluated in the orthotopic-inoculated 4T1-luc mouse model.. After screening, we identified piperine as the most potent adjuvant at enhancing the efficacy of TRAIL-based therapies in TNBC cells in vitro and in vivo, which might be mediated through inhibition of survivin and p65 phosphorylation.. Piperine may enhance TRAIL-based therapeutics for TNBC.

Topics: Alkaloids; Animals; Antineoplastic Agents; Apoptosis; Benzodioxoles; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Drug Synergism; Female; Humans; Inhibitor of Apoptosis Proteins; Mice; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Survivin; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor RelA; Triple Negative Breast Neoplasms; Tumor Burden

Encapsulation in lipid particles is often proposed as a solution to improve curcumin bioavailability. This bioactive molecule has low water solubility and rapidly degrades during digestion. In the present study, the uptake of curcumin from oil in water emulsions, prepared with two different emulsifiers, Tween 20 and Poloxamer 407, was investigated to determine the effect of interfacial composition on absorption. Piperine was added to the curcumin to limit the degradation of curcumin because it is known to inhibit β-glucuronidase activity. The emulsions were administered to Caco-2 cell cultures, which is used as a model for intestinal uptake, and the recovery of curcumin was measured. The curcumin uptake was significantly affected by the type of interface, and the extent of curcumin uptake improved significantly by piperine addition only in the case of oil-in-water emulsions stabilized by Poloxamer 407. This work provides further evidence of the importance of interfacial composition on the delivery of bioactives.

Topics: Alkaloids; Benzodioxoles; Biological Availability; Caco-2 Cells; Cell Survival; Chemical Phenomena; Curcumin; Drug Stability; Emulsifying Agents; Emulsions; Glucuronidase; Humans; Hydrophobic and Hydrophilic Interactions; Particle Size; Piperidines; Poloxamer; Polysorbates; Polyunsaturated Alkamides

Although linarin possesses diverse pharmacological activities, its poor oral bioavailability has been a concern for further development. The present study aimed to demonstrate the feasibility of improving the oral absorption of linarin in rats with a bioenhancer‒piperine. First, the intestinal permeability of linarin in the presence and absence of verapamil or piperine was investigated using an in situ single-pass rat intestinal perfusion method. A significant increase in the Peff when co-perfused with verapamil or piperine indicated that piperine effectively inhibited P-glycoprotein mediated efflux of linarin. Then, the pharmacokinetic profiles of linarin in rats after oral administration of linarin (50 mg/kg) alone and in combination with piperine (20 mg/kg) were determined using a validated LC-MS/MS method. The results showed that piperine increased the plasma exposure (AUC) of linarin by 381% along with an increase in the Cmax by 346% and the Tmax from 0.05 h to 0.2 h. The present study revealed that piperine significantly enhanced the oral absorption of linarin in rats by inhibiting P-glycoprotein mediated cellular efflux during the intestinal absorption and likely simultaneously by inhibiting the metabolism of linarin.

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biological Availability; Glycosides; Humans; Intestinal Absorption; Permeability; Piperidines; Polyunsaturated Alkamides; Rats; Tandem Mass Spectrometry

Post natal exposure to VPA (valproic acid) in mice induces behavioral deficits, abnormal sensitivity to sensory stimuli and self-injurious behavior, observed in autism. Piperine has been reported to have protective effect on brain. The present study aimed at evaluating effect of piperine on VPA induced neurobehavioral and biochemical alterations in BALB/c mice. Young BALB/c mice 13 days old were procured from five different litters and segregated into five groups (n=6; 3 male, 3 female) i.e., Group I served as control group, received physiological saline on PND (Post natal day) 14 & Tween 80 p.o. from PND13-40. Group II served as normal treated group and received piperine (20mg/kg p.o.) from PND 13-40 and saline s.c. on PND 14. Group III served as valproate treated group received VPA (400mg/kg s.c.) on PND 14 and Tween 80 p.o. from PND 13-40. Group IV & V served as disease treated group received VPA (400mg/kg s.c.) on PND 14 & piperine (5 & 20mg/kg p.o.) from PND 13-40 respectively. BALB/c mice pups were subjected to behavioral testing to assess motor skill development, nociceptive response, locomotion, anxiety, and cognition on various postnatal days up to PND 40. At the end of behavioral evaluation, mice were sacrificed; brain was isolated for biochemical estimations (serotonin, glutathione, MDA and nitric oxide) and histopathological examination. Our study revealed that treatment with piperine significantly improved behavioral alterations, lowered oxidative stress markers, and restored histoarchitecture of cerebellum. This ameliorating effect of piperine is attributed to its anti-oxidant activity, cognition enhancing and neuroprotective activity.

Topics: Alkaloids; Animals; Anxiety; Autistic Disorder; Benzodioxoles; Biomarkers; Brain; Cognition; Disease Models, Animal; Locomotion; Mice; Mice, Inbred BALB C; Motor Skills; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Time Factors; Treatment Outcome; Valproic Acid

In this study, we determined the cytotoxic effects of piperine, a major constituent of black and long pepper in melanoma cells. Piperine treatment inhibited the growth of SK MEL 28 and B16 F0 cells in a dose and time-dependent manner. The growth inhibitory effects of piperine were mediated by cell cycle arrest of both the cell lines in G1 phase. The G1 arrest by piperine correlated with the down-regulation of cyclin D1 and induction of p21. Furthermore, this growth arrest by piperine treatment was associated with DNA damage as indicated by phosphorylation of H2AX at Ser139, activation of ataxia telangiectasia and rad3-related protein (ATR) and checkpoint kinase 1 (Chk1). Pretreatment with AZD 7762, a Chk1 inhibitor not only abrogated the activation of Chk1 but also piperine mediated G1 arrest. Similarly, transfection of cells with Chk1 siRNA completely protected the cells from G1 arrest induced by piperine. Piperine treatment caused down-regulation of E2F1 and phosphorylation of retinoblastoma protein (Rb). Apoptosis induced by piperine was associated with down-regulation of XIAP, Bid (full length) and cleavage of Caspase-3 and PARP. Furthermore, our results showed that piperine treatment generated ROS in melanoma cells. Blocking ROS by tiron protected the cells from piperine mediated cell cycle arrest and apoptosis. These results suggest that piperine mediated ROS played a critical role in inducing DNA damage and activation of Chk1 leading to G1 cell cycle arrest and apoptosis.

Topics: Alkaloids; Apoptosis; Benzodioxoles; Blotting, Western; Cell Line, Tumor; Cell Survival; Checkpoint Kinase 1; Enzyme Activation; G1 Phase Cell Cycle Checkpoints; Humans; Melanoma; Piperidines; Polyunsaturated Alkamides; Protein Kinases; Reactive Oxygen Species; RNA, Small Interfering

A mouse model of depression has been recently developed by exogenous corticosterone administration. The present study aimed to examine the antidepressant-like effect and the possible mechanisms of piperine, a major alkaloid of black pepper (Piper nigrum Linn.) and long pepper (Piper longum Linn.), in corticosterone-induced depression in mice. The results showed that 3-weeks corticosterone injections caused depression-like behavior in mice, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test and tail suspension test. Moreover, it was found that brain-derived neurotrophic factor protein and mRNA levels in the hippocampus were significantly decreased in corticosterone-treated mice. Treating the animals with piperine significantly suppressed behavioral and biochemical changes induced by corticosterone. The results suggest that piperine produces an antidepressant-like effect in corticosterone-treated mice, which is possibly mediated by increasing brain-derived neurotrophic factor expression in the hippocampus.

Topics: Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Brain-Derived Neurotrophic Factor; Corticosterone; Hippocampus; Male; Mice; Mice, Inbred ICR; Piperidines; Polyunsaturated Alkamides; RNA, Messenger

To study the pharmacokinetics and brain/plasma concentration ratio of nortriptyline at multiple doses in mice which were pre-treated with physiological saline, piperine and verapamil.. A total of 216 male Kun Ming mice [(25±3) g] were equally divided into 4 groups randomly. Each group was intragastrically administered physiological saline (B), piperine (170 μg/ kg), piperine (5 mg/kg) and verapamil (5 mg/kg) for 8 days. On the 8th day, 1 h after giving the above drugs, each mice was intraperitoneally injected nortriptyline (13 mg/kg). The mice were sacrificed by picking off eyeballs at the time intervals of 5, 15, 30 min, and 1, 2, 4, 6, 8 and 12 h, and the cerebra were collected and weighted. Nortriptyline in mouse plasma and brain was determined by HPLC-MS/MS. The pharmacokinetic properties of the plasma, brain and brain/plasma were calculated.. The AUC0-12 h of brain/plasma concentration ratio in the 170 μg/kg piperine group was significantly lower than that in the other groups (P<0.05), while the AUC0-12 h of brain/plasma concentration ratios in the 5 mg/kg piperine group and the verapamil group were not significantly different from those of untreated mice.. Piperine (170 μg/kg) may induce P-glycoprotein expression in the blood-brain barrier, while piperines at 5 mg/kg has no influence on P-glycoprotein expression in the bloodbrain barrier.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B; Benzodioxoles; Blood-Brain Barrier; Brain; Chromatography, High Pressure Liquid; Male; Mice; Nortriptyline; Piperidines; Polyunsaturated Alkamides; Tandem Mass Spectrometry; Verapamil

Piperine a trans-trans isomer of 1-piperoyl-piperidine was evaluated for its immunomodulatory activity to enhance the efficacy of rifampicin in a murine model of Mycobacterium tuberculosis infection. In-vitro immunomodulation of piperine was tested on mouse splenocytes for lymphocyte proliferation, cytokine production and macrophage activation. Protective efficacy of piperine was tested in a mice infection model of M. tuberculosis for the activation of Th-1 response and synergistic combination efficacy with rifampicin. Murine splenocytes exposed to piperine exhibited proliferation of T and B cell, increased Th-1 cytokines and enhanced macrophage activation. Piperine (1 mg/kg) in mice infected with M. tuberculosis activated the differentiation of T cells into Th-1 sub-population (CD4+ / CD8+ subsets). There was an increase in secretion of Th-1 cytokines (IFN-γ and IL-2) by these cells. The qRT-PCR studies revealed corresponding increases in the mRNA transcripts of IFN-γ and IL-2 in the infected lung tissues. Combination of piperine and rifampicin (1 mg/kg) exhibited better efficacy of and resulted in additional 1.4 to 0.8 log reduction in lung cfu as compared to rifampicin alone. The up-regulation of Th1 immunity by piperine can be synergistically combined with rifampicin to improve its therapeutic efficacy in immune-compromised TB patients.

Topics: Alkaloids; Animals; Antitubercular Agents; Benzodioxoles; Cell Proliferation; Cells, Cultured; Colony Count, Microbial; Drug Combinations; Drug Evaluation, Preclinical; Immunophenotyping; Interferon-gamma; Interleukin-2; Lung; Lymphocyte Activation; Macrophage Activation; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nitric Oxide; Piperidines; Polyunsaturated Alkamides; Rifampin; RNA, Messenger; Spleen; Th1 Cells; Tuberculosis

Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates γ-aminobutyric acid type A receptors (GABAAR). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABAAR by means of a two-microelectrode voltage-clamp technique. GABAAR were expressed in Xenopus laevis oocytes. Structure-activity relationships (SARs) were established to identify structural elements essential for efficiency and potency. Efficiency of piperine derivatives was significantly increased by exchanging the piperidine moiety with either N,N-dipropyl, N,N-diisopropyl, N,N-dibutyl, p-methylpiperidine, or N,N-bis(trifluoroethyl) groups. Potency was enhanced by replacing the piperidine moiety by N,N-dibutyl, N,N-diisobutyl, or N,N-bistrifluoroethyl groups. Linker modifications did not substantially enhance the effect on GABAAR. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABAA (maximal GABA-induced chloride current modulation (IGABA-max = 1673% ± 146%, EC50 = 51.7 ± 9.5 μM), while 25 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dibutyl-2,4-pentadienamide] displayed the highest potency (EC50 = 13.8 ± 1.8 μM, IGABA-max = 760% ± 47%). Compound 23 induced significantly stronger anxiolysis in mice than piperine and thus may serve as a starting point for developing novel GABAAR modulators.

Topics: Alkaloids; Animals; Anti-Anxiety Agents; Benzodioxoles; Male; Maze Learning; Mice; Oocytes; Patch-Clamp Techniques; Piperidines; Polyunsaturated Alkamides; Receptors, GABA-A; Structure-Activity Relationship; Xenopus laevis

Curcumin and piperine are proven for their potent medicinal benefits to treat various diseases and they are most commonly used combination in various Indian systems of medicine such as Ayurveda, Siddha and Unani. The objective of the present work is to develop a simultaneous estimation of curcumin and piperine by reverse phase Ultra-fast liquid chromatographic (RP-UFLC) method. The chromatographic separation was performed on a C8 column (250 x 4.6 mm, 5µ i.d.) stationary phase using a mobile phase of 25mM potassium dihydrogen ortho phosphate buffer (pH 3.5) and acetonitrile (30: 70 v/v) at a flow rate of lml/min at detection wave length of 280nm. The calibration curve was plotted in the concentration range of 0-2200ng/ml and found to be linear for both curcumin (r(2)=0.996) and piperine (r(2)=0.999). The method was validated for parameters such as accuracy, sensitivity, precision, linearity, specificity, ruggedness and robustness as per ICH guidelines. The developed simple, precise and specific method can be used as a quality control tool for qualitative and quantitative estimation of curcumin and piperine in various food products, herbal medicines and nutraceuticals.

Topics: Alkaloids; Benzodioxoles; Chromatography, Reverse-Phase; Curcumin; Limit of Detection; Piperidines; Polyunsaturated Alkamides

Piperine, the main alkaloid of black pepper, Piper nigrum Linn., is an important Indian spice used in traditional food and medicine in India. In the present study, we investigated the antioxidant activities of piperine against copper-ascorbate induced toxic injury to mitochondria obtained from a goat heart, in vitro. Incubation of isolated cardiac mitochondria with copper-ascorbate resulted in elevated levels of lipid peroxidation and protein carbonylation of the mitochondrial membrane, a reduced level of mitochondrial GSH and altered status of antioxidant enzymes as well as decreased activities of pyruvate dehydrogenase and the Kreb's cycle enzymes, altered mitochondrial morphology, mitochondrial swelling, di-tyrosine level and mitochondrial DNA damage. All these changes were found to be ameliorated when the cardiac mitochondria were co-incubated with copper-ascorbate and piperine, in vitro. Piperine, in our in vitro experiments, was found to scavenge hydrogen peroxide, superoxide anion free radicals, hydroxyl radicals and DPPH radicals, in a chemically defined system, indicating that this compound may provide protection to cardiac mitochondria against copper-ascorbate induced toxic injury through its antioxidant activities. The results of this study suggest that piperine may be considered as a future therapeutic antioxidant and may be used singly or as a co-therapeutic in the treatment of diseases associated with mitochondrial oxidative stress.

Topics: Alkaloids; Animals; Ascorbic Acid; Benzodioxoles; Copper; Glutathione; Goats; Heart; Heart Injuries; Humans; In Vitro Techniques; Lipid Peroxidation; Mitochondria; Myocardium; Oxidative Stress; Piper; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Protective Agents; Reactive Oxygen Species

An increased risk of obesity has become a common public health concern as it is associated with hypertension, diabetes, osteoarthritis, heart diseases, liver steatosis etc. Pharmacological intervention with natural product-based drugs is considered a healthier alternative to treat obesity. This study was aimed to evaluate anti-obesity effects of piperine on high fat diet (HFD) induced obesity in rats. Piperine was isolated from methanolic extract of Piper nigrum by using column chromatography and confirmed by LC-MS analysis. Male SD rats were fed HFD initially for 15weeks to induce obesity. After induction of obesity, piperine was supplemented in different doses (20, 30 and 40mg/kgb.wt) through HFD for 42days to experimental rats. HFD induced changes in body weight, body composition, fat percentage, adiposity index, blood pressure, plasma levels of glucose, insulin resistance, leptin, adiponectin, plasma and tissue lipid profiles, liver antioxidants were explained. The activities of lipase, amylase and lipid metabolic marker enzymes such as HMG-CoA reductase, carnitine palmitoyl transferase (CPT), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), lecithin-cholesterol acyl transferase (LCAT) and lipoprotein lipase (LPL) were assessed in experimental rats. Supplementation of piperine at a dose of 40mg/kgb.wt has significantly (p<0.05) reversed the HFD-induced alterations in experimental rats in a dose dependant manner, the maximum therapeutic effect being noted at a dose of 40mg/kgb.wt. Our study concludes that piperine can be well considered as an effective bioactive molecule to suppress of body weight, improve insulin and leptin sensitivity, ultimately leading to regulate obesity.

Topics: Alkaloids; Animals; Anti-Obesity Agents; Benzodioxoles; Body Weight; Diet, High-Fat; Male; Obesity; Organ Size; Piperidines; Polyunsaturated Alkamides; Rats, Sprague-Dawley

An investigation was made to explore the possibility of anxiolytic activity of piperine in unstressed and stressed mice along with the underlying role of nitriergic and GABAergic modulation for the noted activity of piperine.. Piperine (5, 10 and 20mg/kg, ip) was administered to unstressed mice. In another groups of animals, piperine was administered 30 min before subjecting them to immobilization stress for 6h. Antianxiety activity was evaluated by employing elevated plus maze, light-dark box and social interaction test. Diazepam was employed as standard anxiolytic drug.. Piperine produced significant antianxiety-like activity in unstressed and stressed mice. The anxiolytic-like activity of piperine was comparable to diazepam. In unstressed mice, piperine significantly increased brain GABA levels, but could not produce any change in plasma nitrite levels. Meanwhile, in stressed mice, piperine did not produce any significant change in GABA levels, but significantly decreased nitrite levels. Pre-treatment with aminoguanidine (50mg/kg, ip), an inducible nitric oxide synthase (NOS) inhibitor, significantly potentiated the anxiolytic-like activity of piperine, as compared to piperine and aminoguanidine alone in stressed mice. On the other hand, pretreatment with 7-nitroindazole (20mg/kg, ip), a neuronal NOS inhibitor significantly potentiated the antianxiety-like activity of piperine, as compared to piperine and 7-nitroindazole alone in unstressed mice.. These data suggest that the piperine produced significant anxiolytic activity in unstressed mice possibly through increase in GABA levels and inhibition of neuronal NOS. On the other hand, antianxiety activity in stressed mice might be through inhibition of inducible NOS.

Topics: Alkaloids; Animals; Anti-Anxiety Agents; Anxiety; Benzodioxoles; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Guanidines; Indazoles; Male; Maze Learning; Mice; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitrites; Piperidines; Polyunsaturated Alkamides; Stress, Psychological

Piperine, a major alkaloid of black pepper (Piper nigrum) and long pepper (Piper longum), was shown to have anti-inflammatory activity through the suppression of cyclooxygenase (COX)-2 gene expression and enzyme activity. It is also reported to exhibit anti-platelet activity, but the mechanism underlying this action remains unknown. In this study, we investigated a putative anti-platelet aggregation mechanism involving arachidonic acid (AA) metabolism and how this compares with the mechanism by which it inhibits macrophage inflammatory responses;. Rabbit platelets and murine macrophage RAW264.7 cells were treated with piperine, and the effect of piperine on the activity of AA-metabolizing enzymes, including cytosolic phospholipase A2 (cPLA2), COX-1, COX-2, and thromboxane A2 (TXA2) synthase, as well as its effect on AA liberation from the plasma membrane components, were assessed using isotopic labeling methods and enzyme immunoassay kit;. Piperine significantly suppressed AA liberation by attenuating cPLA2 activity in collagen-stimulated platelets. It also significantly inhibited the activity of TXA2 synthase, but not of COX-1, in platelets. These results suggest that piperine inhibits platelet aggregation by attenuating cPLA2 and TXA2 synthase activities, rather than through the inhibition of COX-1 activity. On the other hand, piperine significantly inhibited lipopolysaccharide-induced generation of prostaglandin (PG)E2 and PGD2 in RAW264.7 cells by suppressing the activity of COX-2, without effect on cPLA2;. Our findings indicate that piperine inhibits platelet aggregation and macrophage inflammatory response by different mechanisms.

Topics: Alkaloids; Animals; Arachidonic Acid; Benzodioxoles; Blood Platelets; Cell Line, Tumor; Cyclooxygenase 1; Cyclooxygenase 2; Macrophages; Male; Mice; Phospholipase A2 Inhibitors; Phospholipases A2; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Polyunsaturated Alkamides; Rabbits; Thromboxane-A Synthase

Piperine is an important active component of the Chinese herb Large leaf moss. The aim of this study was to investigate the effects of piperine on oxidative stress. An oxidative stress model was developed in rabbit atrial cells treated with low concentrations of hydrogen peroxide (H2O2). A primary cell culture of the atrial cells was established and the cells were randomly divided into three groups: A piperine group, an H2O2 group and a control group. The results demonstrated that the cell viability and superoxide dismutase activity in the piperine group were significantly higher than in the H2O2 group (P<0.05), and the expression levels of malondialdehyde and glutathione were significantly reduced in the piperine group compared with the H2O2 group (P<0.05). The intracellular free calcium concentration and the expression level of mitochondrial mRNA in the piperine group were also significantly lower than in the H2O2 group (P<0.05). In conclusion, piperine was important in protecting the primary rabbit atrial cells from oxidative stress.

Topics: Alkaloids; Animals; Animals, Newborn; Benzodioxoles; Calcium; Cardiotonic Agents; Cell Survival; Cells, Cultured; Drug Evaluation, Preclinical; Glutathione; Heart Atria; Hydrogen Peroxide; Malondialdehyde; Myocytes, Cardiac; Oxidation-Reduction; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Rabbits; Superoxide Dismutase

Allergy is an abnormal immune response to an allergen. Type I hypersensitivity is an immunoglobulin (Ig) E-mediated allergic disorder. Fructus piperis is derived from the ripe fruit of the pepper, which is widely used as a spice in human diets and is also administered as a medicine in many countries. Piperine has been shown to have anti-oxidant, anti-depressant, anti-tumor, and anti-inflammatory activities. However, the effect of piperine on IgE-mediated allergic responses has not been reported. Here, the rat basophilic leukemia cells by membrane chromatography (RBL-2H3/CMC) coupled to high performance liquid chromatography/mass spectrometry (HPLC/MS) to discover and identify piperine can bind to RBL-2H3 cell membranes. Piperine inhibited the expression of cytokines, and the release of both β-hexosaminidase and histamine, which could be stimulated by antigen in RBL-2H3 mast cells. We found that the levels of intracellular Ca(2+) also decreased. Furthermore, RT-PCR showed that the mRNA expression levels of IL-4, IL-13, and TNF-α were significantly suppressed by piperine. The inhibitory effect of piperine on IgE-mediated degranulation and cytokine production by RBL-2H3 cells may be caused by the inhibition of IgE-mediated signaling pathways, including the phosphorylation of Lyn, p38, Erk, and Ras. In summary, piperine can inhibit antigen-induced allergic reactions that control degranulation.

Topics: Alkaloids; Animals; Benzodioxoles; beta-N-Acetylhexosaminidases; Calcium; Cell Degranulation; Cell Line, Tumor; Cytokines; Histamine; Hypersensitivity; Immunoglobulin E; Mast Cells; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Rats; Signal Transduction

Alkaloid-containing natural compounds have shown promise in the treatment of microbial infections. However, practical application of many of these compounds is pending a mechanistic understanding of their mode of action. We investigated the effect of two alkaloids, piperine (found in black pepper) and reserpine (found in Indian snakeroot), on the ability of the uropathogenic bacterium Escherichia coli CFT073 to colonize abiotic surfaces. Sub-inhibitory concentrations of both compounds (0.5 to 10 µg/mL) decreased bacterial swarming and swimming motilities and increased biofilm formation. qRT-PCR revealed a decrease in the expression of the flagellar gene (fliC) and motility genes (motA and motB) along with an increased expression of adhesin genes (fimA, papA, uvrY). Interestingly, piperine increased penetration of the antibiotics ciprofloxacin and azithromycin into E. coli CFT073 biofilms and consequently enhanced the ability of these antibiotics to disperse pre-established biofilms. The findings suggest that these alkaloids can potentially affect bacterial colonization by hampering bacterial motility and may aid in the treatment of infection by increasing antibiotic penetration in biofilms.

Topics: Adhesins, Bacterial; Alkaloids; Anti-Bacterial Agents; Bacterial Adhesion; Benzodioxoles; Biofilms; Escherichia coli Proteins; Flagella; Flagellin; Gene Expression Regulation, Bacterial; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Reserpine; Uropathogenic Escherichia coli

Knowing that curcumin has low bioavailability when administered orally, and that piperine has bioenhancer activity by inhibition of hepatic and intestinal biotransformation processes, the aim of this study was to investigate the antidiabetic and antioxidant activities of curcumin (90 mg/kg) and piperine (20 or 40 mg/kg), alone or co-administered, incorporated in yoghurt, in streptozotocin (STZ)-diabetic rats. The treatment for 45 days of STZ-diabetic rats with curcumin-enriched yoghurt improved all parameters altered in this experimental model of diabetes: the body weight was increased in association with the weight of skeletal muscles and white adipose tissues; the progressive increase in the glycemia levels was avoided, as well as in the glycosuria, urinary urea, dyslipidemia, and markers of liver (alanine and aspartate aminotransferases and alkaline phosphatase) and kidney (urinary protein) dysfunction; the hepatic oxidative stress was decreased, since the activities of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase were increased, and the levels of malondialdehyde and protein carbonyl groups were reduced. The dose of 20 mg/kg piperine also showed antidiabetic and antioxidant activities. The treatment of STZ-diabetic rats with both curcumin and 20 mg/kg piperine in yoghurt did not change the antidiabetic and antioxidant activities of curcumin; notably, the treatment with both curcumin and 40 mg/kg piperine abrogated the beneficial effects of curcumin. In addition, the alanine aminotransferase levels were further increased in diabetic rats treated with curcumin and 40 mg/kg piperine in comparison with untreated diabetic rats. These findings support that the co-administration of curcumin with a bioenhancer did not bring any advantage to the curcumin effects, at least about the antidiabetic and antioxidant activities, which could be related to changes on its biotransformation.

Topics: Alanine Transaminase; Alkaloids; Animals; Antioxidants; Benzodioxoles; Blood Glucose; Body Weight; Catalase; Curcumin; Diabetes Mellitus, Experimental; Drug Interactions; Glutathione Peroxidase; Hypoglycemic Agents; Lipid Peroxidation; Liver; Male; Malondialdehyde; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Rats, Wistar; Superoxide Dismutase; Treatment Outcome

Benjakul, a Thai traditional herbal preparation, comnprises five plants: Piper chaba, Piper sarmentosum, Piper interruptum, Plumbago indica, and Zingiber officinale. It has widely been used to treat cancer patients in folk medicine in Thailand. Benjakul extract, and its isolated compounds should be investigated for cytotoxic activity and analysis isolated compounds from chemical fingerprinting.. To study cytotoxicity ofBenjakul extract and its isolatedpure compounds against human small cell lung cancer cell line (NCI-HI 688) and in normal human lungfibroblast cell line (MRC-5) and analysis the content ofisolated compounds for quality control of Benjakul extract.. Bioassay-guided fractionation was used for isolated active compounds from ethanolic extract of Benjakul. Cytotoxic activity was carried using the SRB assay. HPLC method was applied to analyze six isolated compound contentfrom Benjakul extract.. The ethanolic extract ofBenjakul showed cytotoxicity against NCI-H1688 with IC50 value = 36.15±4.35 μg/ml. Hexane fraction as semi-separation by VLC showed the best cytotoxic activity (21.1 7±7.42 μg/ml). Six isolated compounds were identified as myristicin, plumbagin, methyl piperate, 6-shogaol, 6-gingerol and piperine. Plumbagin exhibited the highest cytotoxic activity and 6-shogaol was the second most effective cytotoxic constituent (IC50 values = 1.41±0.01 and 6.45±0.19 μg/ml, respectively). Piperine showed the highest content in both ofHPLC analysis and column chromatography separation.. Benjakul extract exhibited cytotoxicity against NCI-HI 688. Plumbagin and 6-shogaol are bioactive markers for cytotoxicity against this small cell lung cancer cell line. Chromatographic fingerprinting can be used to analyze six cytotoxic compounds isolatedfrom the ethanolic extract ofBenjakul.

Topics: Alkaloids; Benzodioxoles; Catechols; Cell Line, Tumor; Chromatography, High Pressure Liquid; Drug Screening Assays, Antitumor; Ethanol; Fatty Alcohols; Humans; Lung Neoplasms; Medicine, Traditional; Naphthoquinones; Piper; Piperidines; Plant Extracts; Plumbaginaceae; Polyunsaturated Alkamides; Small Cell Lung Carcinoma; Thailand; Zingiber officinale

The present study was aimed to investigate the effect of piperine, a major active ingredient of black pepper, on the pharmacokinetics of domperidone in rats. Animals were given oral (p.o.) or intraperitoneal (i.p.) domperidone (20 mg/kg) alone or together with piperine (20 mg/kg, p.o.). Plasma samples were collected at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0 and 12 hours after drug administration. The concentration of domperidone in the plasma was measured using a HPLC method. The concomitant administration of piperine with oral or intraperitoneal domperidone resulted in a significant (P<0.05) increase in the maximum plasma concentration (Cmax), the mean area under the plasma concentration-time curve (AUC), and the elimination half-life (t1/2) of domperidone as compared to those obtained for domperidone alone. These results suggest that an important pharmacokinetic interaction may occur if piperine is administered concurrently with domperidone.

Topics: Administration, Oral; Alkaloids; Animals; Antiemetics; Area Under Curve; Benzodioxoles; Domperidone; Dopamine Antagonists; Drug Interactions; Half-Life; Injections, Intraperitoneal; Male; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats, Wistar

The objective of the study was to prepare and evaluate the quality of curcumin-piperinedual drug loaded self-microemulsifying drug delivery system(Cur-PIP-SMEDDS). Simplex lattice design was constructed using optimal oil phase, surfactant and co-surfactant concentration as independent variables, and the curcumin and piperine were used as model drugs to optimize Cur-PIP-SMEDDS formulation. In the present study, the drug loadings of curcumin and piperine, mean particle size of Cur-PIP-SMEDDS were made as indicators, and the experiment design, model building and response surface analysis were established using Design Expert 8. 06 software to optimize and verify the composition of SMEDDS formulation. The quality of Cur-PIP-SMEDDS was evaluated by observing the appearance status, transmission electron microscope micrographs and determining particle diameter, electric potential, drug entrapment efficiency and drug loading of it. As a result, the optimal formulation of SMEDDS was CapryoL 90-Cremophor RH40-TranscutoL HP (10:60:30). The appearance of Cur-PIP-SMEDDS remained clarified and transparent, and the microemulsion droplets appeared spherical without aggregation with uniform particle size distribution. The mean size of microemulsion droplet formed from Cur-PIP-SMEDDS was 15.33 nm, the drug loading of SMEDDS for Cur and PIP were 40.90 mg · g(-1) and 0.97 mg · g(-1), respectively, the drug entrapment efficiency were 94.98% and 90.96%, respectively. The results show that Cur-PIP-SMEDDS can increase the solubility and stability of curcumin significantly, in the expectation of enhancing the bioavailability of it. Taken together, these findings can provide the reference to a preferable choice of the Cur formulation and contribute to therapeutic application in clinical research.

Topics: Alkaloids; Benzodioxoles; Chemistry, Pharmaceutical; Curcumin; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drugs, Chinese Herbal; Emulsions; Methylmethacrylates; Particle Size; Piperidines; Polystyrenes; Polyunsaturated Alkamides

20(S)-protopanaxadiol (PPD), similar to several other anticancer agents, has low oral absorption and is extensively metabolized. These factors limit the use of PPD for treatment of human diseases.. In this study, we used cubic nanoparticles containing piperine to improve the oral bioavailability of PPD and to enhance its absorption and inhibit its metabolism. Cubic nanoparticles loaded with PPD and piperine were prepared by fragmentation of glyceryl monoolein (GMO)/poloxamer 407 bulk cubic gel and verified using transmission electron microscopy and differential scanning calorimetry. We evaluated the in vitro release of PPD from these nanoparticles and its absorption across the Caco-2 cell monolayer model, and subsequently, we examined the bioavailability and metabolism of PPD and its nanoparticles in vivo.. The in vitro release of PPD from these nanoparticles was less than 5% at 12 hours. PPD-cubosome and PPD-cubosome loaded with piperine (molar ratio PPD/piperine, 1:3) increased the apical to basolateral permeability values of PPD across the Caco-2 cell monolayer from 53% to 64%, respectively. In addition, the results of a pharmacokinetic study in rats showed that the relative bioavailabilities of PPD-cubosome [area under concentration-time curve (AUC)(0-∞)] and PPD-cubosome containing piperine (AUC(0-∞)) compared to that of raw PPD (AUC(0-∞)) were 166% and 248%, respectively.. The increased bioavailability of PPD-cubosome loaded with piperine is due to an increase in absorption and inhibition of metabolism of PPD by cubic nanoparticles containing piperine rather than because of improved release of PPD. The cubic nanoparticles containing piperine may be a promising oral carrier for anticancer drugs with poor oral absorption and that undergo extensive metabolism by cytochrome P450.

Topics: Absorption; Administration, Oral; Alkaloids; Animals; Area Under Curve; Benzodioxoles; Biological Availability; Caco-2 Cells; Humans; Male; Nanoparticles; Particle Size; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Sapogenins

Piper longum L. fruits have been traditionally used against snakebites in north-eastern and southern region of India.. To examine the ability of ethanolic extract of fruits of Piper longum L., Piperaceae (PLE) and piperine, one of the main active principles of Piper longum, to inhibit the Russell's viper (Doboia russelii, Viperidae) snake venom activities.. Anti-snake venom activities of ethanolic extract of fruits of Piper longum L. (Piperaceae) and piperine against Russell's viper venom was studied in embryonated fertile chicken eggs, mice and rats by using various models as follows: inhibition of venom lethal action, inhibition of venom haemorrhagic action (in vitro), inhibition of venom haemorrhagic action (in vivo), inhibition of venom necrotizing action, inhibition of venom defibrinogenating action, inhibition of venom induced paw edema, inhibition of venom induced mast cell degranulation, creatine kinase assay and assay for catalase activity.. PLE was found to inhibit the venom induced haemorrhage in embryonated fertile chicken eggs. Administration of PLE and piperine significantly (p<0.01) inhibited venom induced lethality, haemorrhage, necrosis, defibrinogenation and inflammatory paw edema in mice in a dose dependent manner. PLE and piperine also significantly (p<0.01) reduced venom induced mast cell degranulation in rats. Venom induced decrease in catalase enzyme levels in mice kidney tissue and increase in creatine kinase enzyme levels in mice serum were significantly (p<0.01) reversed by administration of both PLE and piperine.. PLE possesses good anti-snake venom properties and piperine is one of the compounds responsible for the effective venom neutralizing ability of the plant.

Topics: Alkaloids; Animals; Antivenins; Benzodioxoles; Catalase; Cell Degranulation; Creatine Kinase; Daboia; Edema; Ethanol; Female; Fruit; Male; Mast Cells; Mice; Necrosis; Piper; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Rats; Rats, Wistar; Solvents; Viper Venoms

Only one kind of synthesized alkaloid, piperlonguminine, was used to understand the interference of the other alkaloids in pharmacokinetic study using HPLC/UV in rat plasma after oral administration. Compared with the previous report, it was clarified that mixed alkaloids such as piperine and the other extract from Piper longum Linn did not interfere with the results.

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Chromatography, High Pressure Liquid; Dioxolanes; Linear Models; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Reproducibility of Results; Sensitivity and Specificity; Spectrophotometry, Ultraviolet

The present study was aimed to characterize the anticonvulsant effects of piperine in combination with well established antiepileptic drug (AED) phenytoin, in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of phenytoin with piperine at the fixed-ratio of 1:1 from the MES test with respect to long-term memory and skeletal muscular strength were evaluated along with free plasma concentration of piperine and phenytoin. Parameters of oxidative stress (glutathione, malondialdehyde), brain serotonin and serum calcium levels were also determined to probe the mechanism involved in the interaction. Test of parallelism revealed that 2 drugs were associated with non-parallel dose response effects, hence only one fixed ratio combination (1:1) was evaluated which displayed additive interaction between the 2 drugs with a slight tendency towards superadditivity. Free plasma concentrations of piperine and phenytoin revealed no significant changes in their concentrations when the drugs were combined at the fixed-ratio of 1:1. In combination, neither long-term memory nor skeletal muscular strength was impaired. Analysis of biochemical parameters showed that the piperine alone or in combination with phenytoin successfully reversed the parameters of oxidative stress and increased brain serotonin levels as compared to MES group. However, no significant alteration in the serum calcium levels was observed by any treatment. In conclusion, the combination displayed additive interaction and slight tendency towards synergistic potential with protection towards side effects associated with AED therapy and is worthy of consideration for further investigations.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Calcium; Disease Models, Animal; Drug Therapy, Combination; Electroshock; Lipid Peroxidation; Male; Memory, Long-Term; Mice; Muscle Strength; Phenytoin; Piperidines; Polyunsaturated Alkamides; Seizures

Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC50 values of 1.2 and 1.5mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC50=0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

Topics: Acrolein; Action Potentials; Acyclic Monoterpenes; Alkaloids; Amides; Animals; Benzodioxoles; Female; Isothiocyanates; Male; Monoterpenes; Neural Conduction; Piperidines; Polyunsaturated Alkamides; Ranidae; Sciatic Nerve; Transient Receptor Potential Channels

Cerebellar atrophy during ageing can produce neurobehavioural changes characterized by cognitive and motor impairment. Chronic exposure to D-galactose, a reducing sugar can accelerate ageing by producing an unprecedented rise in oxidative load. This can enhance neuronal damage by promoting the oxidation of protein and lipids. We perceived that the simultaneous administration of piperine and curcumin, two powerful antioxidants can exert neuroprotective effect by inhibiting damage caused by the chronic exposure to D-galactose. Young Wistar rats treated with D-galactose (150 mg/kg, s.c.) were simultaneously treated with piperine alone, curcumin separately; and in combination for a period of 56 days by the oral route. A vehicle control, D-galactose alone and naturally aged control were also evaluated. Cognitive changes, motor impairment, protein carbonyls, protein thiols, advanced oxidation protein products, 4 hydroxynonenol and nitric oxide levels were determined in the brain homogenate. In order to ascertain the impact of cerebellum on motor performance, histopathological changes in the cerebellum were also established. Results obtained from our studies reflect a marked improvement in memory, sensorimotor performance, reduced oxidative and nitrosative burden on simultaneous treatment with piperine and curcumin. Furthermore, alterations produced in the Purkinje cells were minimized on treatment with the combination. Our studies demonstrated the influence of protein and lipid oxidation products on behavioural changes in D-galactose induced ageing model. Incorporation of these antioxidants might reduce the risk of developing neurodegenerative disorders, an important counterpart of advancing age.

Topics: Aging; Alkaloids; Animals; Antioxidants; Benzodioxoles; Brain; Curcumin; Drug Combinations; Galactose; Lipid Peroxidation; Oxidation-Reduction; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Random Allocation; Rats; Rats, Wistar

The present work was undertaken to determine the effects of Amaranthus roxburghianus Nevski. (Amaranthaceae) root alone and in combination with piperine in treating ulcerative colitis (UC) in mice.. Swiss albino mice were divided into seven groups (n = 6). Standard group received prednisolone (5 mg/kg, intraperitoneally). Treatment groups received hydroalcoholic extract of roots of A. roxburghianus (50 and 100 mg/kg, per oral) and a combination of hydroalcoholic extract of roots of A. roxburghianus (50 and 100 mg/kg, per oral) and piperine (5 mg/kg, per oral). Ulcer index, colitis severity, myeloperoxidase (MPO), malondialdehyde and glutathione were estimated from blood and tissue. Column chromatography of the extract was done and purified fractions were analyzed by gas chromatography-mass spectroscopy (GC-MS).. Treatment with the combination of hydroalcoholic extract of A. roxburghianus and piperine showed minimal ulceration, hemorrhage, necrosis and leucocyte infiltration by histopathological observation. Acetic acid increased MPO levels in blood and colon tissue to 355 U/mL and 385 U/mg, respectively. The combination of hydroalcoholic extract of A. roxburghianus (100 mg/kg) and piperine (5 mg/kg) significantly decreased MPO in blood and tissue to 182 U/mL and 193 U/mg, respectively (P < 0.05). Similarly, this combination significantly reduced malondialdehyde levels and increased glutathione levels in blood and tissue. Various phytoconstituents were detected by GC-MS.. The combination of hydroalcoholic extract of A. roxburghianus and piperine is effective in the treatment of UC and the effects are comparable with the standard drug prednisolone. 4H-pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6-methyl, eugenol and benzene, and 1-(1,5-dimethyl-4-hexenyl)-4-methyl are reported having analgesic, anti-inflammatory, and antioxidant properties; they may play a role in the biological activity of A. roxburghianus root.

Topics: Alkaloids; Amaranthus; Animals; Benzodioxoles; Colitis, Ulcerative; Colon; Drug Therapy, Combination; Glutathione; Humans; Male; Malondialdehyde; Mice; Peroxidase; Piperidines; Plant Extracts; Plant Roots; Polyunsaturated Alkamides

Bilateral destruction of the olfactory bulbs is known to cause behavioral changes analogous to symptoms of depression. Curcumin, a traditional Indian spice is currently being investigated in different psychiatric problems including depression. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study is an attempt to elucidate the neuroprotective mechanism of curcumin and its co-administration with piperine against olfactory bulbectomy induced depression in rats.. Rats undergone olfactory bulbs ablations were analyzed after post-surgical rehabilitation period of 2 weeks. Animals were then treated with different doses of curcumin (100, 200 and 400 mg/kg; p.o.), piperine (20 mg/kg; p.o.) and their combination daily for another 2 weeks. Imipramine (10 mg/kg; i.p.) served as a standard control. Various behavioral tests like forced swim test (FST), open field behaviour and sucrose preference test (SPT) were performed, followed by estimation of biochemical, mitochondrial, molecular and histopathological parameters in rat brain.. Ablation of olfactory bulbs caused depression-like symptoms as evidenced by increased immobility time in FST, hyperactivity in open field arena, and anhedonic like response in SPT along with alterations in mitochondrial enzyme complexes, increased serum corticosterone levels and oxidative damage. These deficits were integrated with increased inflammatory cytokines (TNF-α) and apoptotic factor (caspase-3) levels along with a marked reduction in neurogenesis factor (BDNF) in the brain of olfactory bulbectomized (OBX) rats. Curcumin treatment significantly and dose-dependently restored all these behavioral, biochemical, mitochondrial, molecular and histopathological alterations associated with OBX induced depression. Further, co-administration of piperine with curcumin significantly potentiated their neuroprotective effects as compared to their effects alone.. The present study highlights that curcumin along with piperine exhibits neuroprotection against olfactory bulbectomy induced depression possibly by modulating oxidative-nitrosative stress induced neuroinflammation and apoptosis.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Brain; Brain-Derived Neurotrophic Factor; Caspase 3; Corticosterone; Curcumin; Depression; Disease Models, Animal; Drug Therapy, Combination; Electron Transport Chain Complex Proteins; Food Preferences; Immobilization; Inflammation; Lipid Peroxidation; Male; Mitochondria; Olfactory Bulb; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Signal Transduction; Sucrose; Tumor Necrosis Factor-alpha

The action of piperine (the pungent component of pepper) and its derivative SCT-66 ((2E,4E)-5-(1,3-benzodioxol-5-yl))-N,N-diisobutyl-2,4-pentadienamide) on different gamma-aminobutyric acid (GABA) type A (GABA(A)) receptors, transient-receptor-potential-vanilloid-1 (TRPV1) receptors and behavioural effects were investigated. GABA(A) receptor subtypes and TRPV1 receptors were expressed in Xenopus laevis oocytes. Modulation of GABA-induced chloride currents (I(GABA)) by piperine and SCT-66 and activation of TRPV1 was studied using the two-microelectrode-voltage-clamp technique and fast perfusion. Their effects on explorative behaviour, thermoregulation and seizure threshold were analysed in mice. Piperine acted with similar potency on all GABA(A) receptor subtypes (EC₅₀ range: 42.8±7.6 μM (α₂β₂)-59.6±12.3 μM (α₃β₂). I(GABA) modulation by piperine did not require the presence of a γ(2S)-subunit, suggesting a binding site involving only α and β subunits. I(GABA) activation was slightly more efficacious on receptors formed from β(2/3) subunits (maximal I(GABA) stimulation through α₁β₃ receptors: 332±64% and α₁β₂: 271±36% vs. α₁β₁: 171±22%, p<0.05) and α₃-subunits (α₃β₂: 375±51% vs. α₅β₂:136±22%, p<0.05). Replacing the piperidine ring by a N,N-diisobutyl residue (SCT-66) prevents interactions with TRPV1 and simultaneously increases the potency and efficiency of GABA(A) receptor modulation. SCT-66 displayed greater efficacy on GABA(A) receptors than piperine, with different subunit-dependence. Both compounds induced anxiolytic, anticonvulsant effects and reduced locomotor activity; however, SCT-66 induced stronger anxiolysis without decreasing body temperature and without the proconvulsive effects of TRPV1 activation and thus may serve as a scaffold for the development of novel GABA(A) receptor modulators.

Topics: Alkaloids; Animals; Benzodioxoles; GABA Modulators; Male; Mice; Mice, Inbred C57BL; Motor Activity; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Protein Binding; Receptors, GABA-A; TRPV Cation Channels

Activation of the pregnane X receptor (PXR) and subsequently its target genes, including those encoding drug transporters and metabolizing enzymes, while playing substantial roles in xenobiotic detoxification, might cause undesired drug-drug interactions. Recently, an increased awareness has been given to dietary components for potential induction of diet-drug interactions through activation of PXR. Here, we studied, whether piperine (PIP), a major component extracted from the widely-used daily spice black pepper, could induce PXR-mediated expression of cytochrome P450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1). Our results showed that PIP activated human PXR (hPXR)-mediated CYP3A4 and MDR1 expression in human hepatocytes, intestine cells, and a mouse model; PIP activated hPXR by recruiting its coactivator SRC-1 in both cellular and cell-free systems; PIP bound to the hPXR ligand binding domain in a competitive ligand binding assay in vitro. The dichotomous effects of PIP on induction of CYP3A4 and MDR1 expression observed here and inhibition of their activity reported elsewhere challenges the potential use of PIP as a bioavailability enhancer and suggests that caution should be taken in PIP consumption during drug treatment in patients, particularly those who favor daily pepper spice or rely on certain pepper remedies.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Binding, Competitive; Cell Line; Chimera; Cytochrome P-450 CYP3A; Hemodynamics; Humans; Male; Mice; Mice, Inbred C57BL; Models, Molecular; Nuclear Receptor Coactivator 2; Piperidines; Plasmids; Polyunsaturated Alkamides; Pregnane X Receptor; Real-Time Polymerase Chain Reaction; Receptors, Steroid; RNA; RNA, Small Interfering; Transcriptional Activation

The effects of effective part group on hyperlipidemia in animal were studied. The SD rats, hamsters and Kunming mouse were divided into blank group, model group. The positive control group and test group were fed with normal diet, blank and other groups were fed with high fat diet (mouse only a single intraperitoneal injection of egg yolk ). The corresponding concentration of solvent, simvastatin, effective part group of emulsion were given gavage once daily. The animal serum total cholesterol (TC) , triglyceride (TG) , low density lipoprotein (LDL) , high density lipoprotein (HDL) and liver TC, TG contents were determined to observe the effects of the effective fractions on blood lipid regulating function. Comparing with control group, the animial hyperlipidemia models of the SD rat (TC increase), mouse (TC, TG, LDL increase), hamsters ( TC, TG, LDL increase, HDL decrease) (P <0. 05, P < 0. 001) were successfully established. Piper longum effective part group could decrease the serum TC, TG, LDL (P <0.05, P < 0. 001) and liver TC, TG content, and elevate serum HDL levels (P <0.05, P <0.001). The golden hamster is ideal for hyperlipidemia model.

Topics: Alkaloids; Animals; Benzodioxoles; Cholesterol; Cricetinae; Drugs, Chinese Herbal; Female; Hyperlipidemias; Lipid Metabolism; Lipoproteins, HDL; Lipoproteins, LDL; Liver; Male; Mice; Piper; Piperidines; Polyunsaturated Alkamides; Rats; Triglycerides

The work reported herein describes the synthesis and the assessment of the trypanocidal activity of thirteen new 1,2,4-triazole-3-thiones obtained from natural piperine, the main constituent of the dry fruits of Piper nigrum. It is part of a research program aiming to use abundant and easily available natural products as starting materials for the design and synthesis of new molecules potentially useful as antiparasitic drugs. The variously substituted triazole derivatives were synthesized from the natural amide in four steps with the use of microwave irradiation on overall yields ranging from 32% to 51%. The cyclohexyl substituted derivative showed the best trypanocidal profile on proliferative forms of Trypanosoma cruzi (Y strain), with IC₅₀s = 18.3 and 8.87 mM against epimastigotes and amastigotes, respectively.

Topics: Alkaloids; Benzodioxoles; Drug Design; Inhibitory Concentration 50; Molecular Structure; Parasitic Sensitivity Tests; Piperidines; Polyunsaturated Alkamides; Thiones; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

It has been reported that piperine (PIP) and deoxyschizandrin (DS) can modulate synchronized Ca²⁺ oscillations in cultured hippocampal neuronal networks. We investigated the modulation effects of four different combinations of piperine and deoxyschizandrin on synchronized Ca²⁺ oscillations in cultured hippocampal neuronal networks. The results showed that all four combinations (PIP:DS 4.9:1.9, 2.45:2.85, 7.35:0.95, and 2.45:0.95 mg/L) inhibit Ca²⁺ oscillation intensity to a similar extent. However, the first three combinations had strong inhibitory effects on the frequency of Ca²⁺ oscillations whereas the last combination (2.45:0.95 mg/L) only slightly enhanced the frequency of Ca²⁺ oscillations. We propose an improved Chay's model to explain the mechanism of the effects of piperine and deoxyschizandrin on synchronized Ca²⁺ oscillations in cultured hippocampal neuronal cells. We concluded that deoxyschizandrin modulated synchronized Ca²⁺ oscillations in cultured hippocampal neuronal networks bidirectionally and the effect depended on concentration. Deoxyschizandrin reduced voltage-gated sodium channel conductance and ATP-sensitive potassium channel conductance, and affected the rate of exchange of intracellular calcium and the pump activity of Ca²⁺-ATPase in the endoplasmic reticulum (ER). Piperine reduced the activity of calcium release in the ER, and reduced the pump activity of calcium in the cytomembrane or enhanced the pump activity of Ca²⁺-ATPase in the ER.

Topics: Alkaloids; Animals; Benzodioxoles; Calcium Channels; Calcium Signaling; Cells, Cultured; Cyclooctanes; Drug Synergism; Hippocampus; Lignans; Models, Biological; Neurons; Piperidines; Polycyclic Compounds; Polyunsaturated Alkamides; Rats

Prostate cancer is the most common solid malignancy in men, with 32,000 deaths annually. Piperine, a major alkaloid constituent of black pepper, has previously been reported to have anti-cancer activity in variety of cancer cell lines. The effect of piperine against prostate cancer is not currently known. Therefore, in this study, we investigated the anti-tumor mechanisms of piperine on androgen dependent and androgen independent prostate cancer cells. Here, we show that piperine inhibited the proliferation of LNCaP, PC-3, 22RV1 and DU-145 prostate cancer cells in a dose dependent manner. Furthermore, Annexin-V staining demonstrated that piperine treatment induced apoptosis in hormone dependent prostate cancer cells (LNCaP). Using global caspase activation assay, we show that piperine-induced apoptosis resulted in caspase activation in LNCaP and PC-3 cells. Further studies revealed that piperine treatment resulted in the activation of caspase-3 and cleavage of PARP-1 proteins in LNCaP, PC-3 and DU-145 prostate cancer cells. Piperine treatment also disrupted androgen receptor (AR) expression in LNCaP prostate cancer cells. Our evaluations further show that there is a significant reduction of Prostate Specific Antigen (PSA) levels following piperine treatment in LNCaP cells. NF-kB and STAT-3 transcription factors have previously been shown to play a role in angiogenesis and invasion of prostate cancer cells. Interestingly, treatment of LNCaP, PC-3 and DU-145 prostate cancer cells with piperine resulted in reduced expression of phosphorylated STAT-3 and Nuclear factor-κB (NF-kB) transcription factors. These results correlated with the results of Boyden chamber assay, wherein piperine treatment reduced the cell migration of LNCaP and PC-3 cells. Finally, we show that piperine treatment significantly reduced the androgen dependent and androgen independent tumor growth in nude mice model xenotransplanted with prostate cancer cells. Taken together, these results support further investigation of piperine as a potential therapeutic agent in the treatment of prostate cancer.

Topics: Alkaloids; Androgens; Animals; Apoptosis; Benzodioxoles; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Humans; Male; Mice; Mice, Nude; Piperidines; Polyunsaturated Alkamides; Prostate-Specific Antigen; Prostatic Neoplasms

Black pepper (Piper nigrum) is a common remedy in Traditional Chinese Medicine and possesses diverse biological activities including anti-inflammatory properties. Osteoarthritis (OA) is a degenerative joint disease with an inflammatory component that drives the degradation of cartilage extracellular matrix. The present study aimed to assess the effects of piperine, the active phenolic component in black pepper extract, on human OA chondrocytes. In this study, human OA chondrocytes were pretreated with piperine at 10, 50 or 100μg/ml and subsequently stimulated with IL-1β (5ng/ml) for 24h. Production of PGE2 and NO was evaluated by the Griess reaction and an ELISA. Gene expression of MMP-3, MMP-13, iNOS and COX-2 was measured by real-time PCR. MMP-3 and MMP-13 proteins in culture medium were determined using cytokine-specific ELISA. Western immunoblotting was used to analyze the iNOS and COX-2 protein production in the culture medium. The regulation of NF-kB activity and the degradation of IkB were explored using luciferase and Western immunoblotting, respectively. We found that piperine inhibited the production of PGE2 and NO induced by IL-1β. Piperine significantly decreased the IL-1β-stimulated gene expression and production of MMP-3, MMP-13, iNOS and COX-2 in human OA chondrocytes. Piperine inhibited the IL-1β-mediated activation of NF-κB by suppressing the degradation of its inhibitory protein IκBα in the cytoplasm. The present report is first to demonstrate the anti-inflammatory activity of piperine in human OA chondrocytes. Piperine can effectively abrogate the IL-1β-induced over-expression of inflammatory mediators; suggesting that piperine may be a potential agent in the treatment of OA.

Topics: Aged; Alkaloids; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Cells, Cultured; Chondrocytes; Cyclooxygenase 2; Dinoprostone; Female; Gene Expression Regulation; Humans; Inflammation Mediators; Interleukin-1beta; Male; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; Medicine, Chinese Traditional; Middle Aged; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Osteoarthritis; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Piperine is a bioactive component of black pepper, Piper nigrum Linn, commonly used for daily consumption and in traditional medicine. Here, the molecular mechanisms by which piperine exerts antitumor effects in HER2-overexpressing breast cancer cells was investigated. The results showed that piperine strongly inhibited proliferation and induced apoptosis through caspase-3 activation and PARP cleavage. Furthermore, piperine inhibited HER2 gene expression at the transcriptional level. Blockade of ERK1/2 signaling by piperine significantly reduced SREBP-1 and FAS expression. Piperine strongly suppressed EGF-induced MMP-9 expression through inhibition of AP-1 and NF-κB activation by interfering with ERK1/2, p38 MAPK, and Akt signaling pathways resulting in a reduction in migration. Finally, piperine pretreatment enhanced sensitization to paclitaxel killing in HER2-overexpressing breast cancer cells. Our findings suggest that piperine may be a potential agent for the prevention and treatment of human breast cancer with HER2 overexpression.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Apoptosis; Benzodioxoles; Breast Neoplasms; Caspase 3; Female; Gene Expression Regulation, Neoplastic; Humans; p38 Mitogen-Activated Protein Kinases; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Receptor, ErbB-2; Signal Transduction

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia and other symptoms like polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger) which ultimately causes various other complications like retinopathy, neuropathy, nephropathy and microangiopathy.. The antidiabetic and antihyperlipidemic potential of oil from Piper longum (PLO) and piperine was investigated with their possible mechanism using α-glucosidase, aldose reductase (AR), and pancreatic lipase inhibitory activity.. The biochemical parameters, viz. glucose level, insulin level, liver glycogen content, glycosylated hemoglobin, total plasma cholesterol, triglyceride, and antioxidant parameters, were estimated for all treated groups in acute and chronic antihyperglycemic animal models.. PLO (100 and 200 mg/kg), piperine (25 and 50 mg/kg), and glibenclamide (0.6 mg/kg) in respective groups of diabetic animals administered for 28 days reduced the blood glucose level in streptozotocin-induced diabetic rats. There was significant increase in body weight, liver glycogen content, plasma insulin, and high-density lipoprotein and decrease in glycosylated hemoglobin, triglyceride, and total plasma cholesterol in PLO-administered groups as compared to control group. The IC50 value of PLO for α-glucosidase, AR, and pancreatic lipase was found to be 150 ± 2.5, 120 ± 1.2, and 175 ± 1.2 μg/ml, respectively, which was found comparable with the standard drugs acarbose (90 ± 2.3 μg/ml), quercetin (80 ± 2.3 μg/ml), and orlistat (25 ± 0.5 μg/ml), respectively.. The investigation done reveals that PLO has significant antidiabetic and antihyperlipidemic activity.

Topics: Aldehyde Reductase; Alkaloids; alpha-Glucosidases; Animals; Benzodioxoles; Blood Glucose; Cholesterol; Diabetes Mellitus, Experimental; Glutathione; Glycogen; Hyperlipidemias; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Lipase; Liver; Piper; Piperidines; Plant Oils; Polyunsaturated Alkamides; Rats; Rats, Wistar; Triglycerides

The antigenotoxic effects of curcumin alone and with piperine on benzo(a)pyrene-diol (BaP) epoxide DNA adducts (BaPDE-DNA adducts), and carcinogen biotransformation enzymes was investigated in liver and lung of mice. Male Swiss albino mice received curcumin (100 mgkg(-1) body weight) and piperine (20 mgkg(-1) body weight) separately as well as in combination orally in corn oil for 7 days as pretreatments and thereafter 2 h, BaP (125 mgkg(-1) body weight) was administered orally in corn oil. A single dose of BaP to normal mice increased the activities of ethoxyresorufin o-deethylase (EROD), pentoxyresorufin o-depentylase (PROD) and levels of BaPDE-DNA adducts in both the tissues. Quinone reductase (QR) activity was also elevated in the BaP-treated group in both liver and lung when compared with normal control group. Pretreatment of curcumin and curcumin plus piperine before administration of BaP significantly decreased the activities of EROD, PROD, and the level of BaPDE-DNA adducts with consequent increase in QR activities. The study clearly indicates that curcumin, when given in combination with piperine, is more effective in modulating BaPDE-DNA adducts (liver and lung), and activity of EROD (liver).

Topics: Alkaloids; Animals; Benzo(a)pyrene; Benzodioxoles; Biotransformation; Carcinogens; Curcumin; Cytochrome P-450 CYP1A1; DNA Adducts; Liver; Lung; Male; Mice; Piperidines; Polyunsaturated Alkamides

The mechanisms involved in the anti-seizure property of piperine (1-[5-(1,3-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]-(E,E)-piperidine, C17H19NO3) are still unclear. Piperine could activate transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor, and the rapid activation of whole-cell currents is antagonized by the competitive TRPV1 antagonist capsazepine. Interestingly, recent studies have reported that TRPV1 may be a novel anti-epileptogenic target which led us to hypothesize that the anti-seizure property of piperine involves the TRPV1 receptor. To test this hypothesis, we examined the effect of piperine on seizures induced in mice and identified the receptors involved in the suppression of seizure caused by maximal electroshock (MES) and pentylenetetrazol (PTZ) models. Piperine, administered at doses of 40 and 80 mg/kg, significantly delayed the onset of myoclonic jerks and generalized clonic seizures, and decreased the seizure stage and mortality compared with the vehicle-treated animals. Piperine also significantly reduced the incidence of MES-induced tonic hindlimb extension (THE) and PTZ-induced Fos immunoreactivity in the dentate gyrus. The anti-seizure effects of piperine were blocked by a TRPV1-selective antagonist capsazepine. Taken together, these data support the further investigation of piperine as a TRPV1 agonist for anti-seizure therapy.

Topics: Alkaloids; Animals; Anticonvulsants; Behavior, Animal; Benzodioxoles; Electroshock; Gene Expression Regulation; Hippocampus; Male; Mice; Pentylenetetrazole; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-fos; Seizures; TRPV Cation Channels

Piperine, an alkaloid from black and long peppers (Piper nigrum Linn & Piper longum Linn), has been reported to exhibit antitumor activities in vitro and in vivo. To further understand the antitumor mechanism of piperine, we investigated the growth inhibitory effects of piperine on human prostate cancer DU145, PC-3 and LNCaP cells. Piperine treatment resulted in a dose-dependent inhibition of the proliferation of these cell lines. Cell cycle arrest at G₀/G₁ was induced and cyclin D1 and cyclin A were downregulated upon piperine treatment. Notably, the level of p21(Cip1) and p27(Kip1) was increased dose-dependently by piperine treatment in both LNCaP and DU145 but not in PC-3 cells, in line with more robust cell cycle arrest in the former two cell lines than the latter one. Although piperine induced low levels of apoptosis, it promoted autophagy as evidenced by the increased level of LC3B-II and the formation of LC3B puncta in LNCaP and PC-3 cells. The piperine-induced autophagic flux was further confirmed by assaying LC3-II accumulation and LC3B puncta formation in the presence of chloroquine, a well-known autophagy inhibitor. Taken together, these results indicated that piperine exhibited anti-proliferative effect in human prostate cancer cells by inducing cell cycle arrest and autophagy.

Topics: Alkaloids; Autophagy; Benzodioxoles; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin A1; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Dose-Response Relationship, Drug; Down-Regulation; G1 Phase; Humans; Male; Piperidines; Polyunsaturated Alkamides; Prostatic Neoplasms; Up-Regulation

Major depression is characterized by dysfunction of neuroendocrine and immune networks. Trans-resveratrol, a phenolic compound presented in polygonum cuspidatum, was demonstrated previously to exert antidepressant-like effects through regulating monoaminergic system, oxidative/antioxidant defense and inflammatory response. The present study investigated the synergistic antidepressant-like effect of trans-resveratrol and piperine, a bioavailability enhancer, in mice and explored the possible mechanism. Trans-resveratrol was shown to reduce the immobility time both in the tail suspension and forced swimming tests (TST and FST). But the maximal inhibition was nearly 60% even if the doses were increased by 160 mg/kg; while piperine produced weak antidepressant-like effects in these two models. The interaction between trans-resveratrol and piperine was shown a clear-cut synergistic effect as evidenced by an isobolographic analysis. The further study suggested that the anti-immobility response from the subthreshold dose of piperine (2.5 mg/kg) and low doses of trans-resveratrol (10 and 20 mg/kg) was abolished by pretreatment with para-chlorophenylalanine (PCPA, 300 mg/kg, i.p.) in TST and FST, indicating the involvement of serotonergic system. Moreover, treatment with the subthreshold dose of piperine and low doses of trans-resveratrol attenuated reserpine-induced hypothermia and ptosis arguing for the relevance of noradrenaline. Additional evidence from neurochemical (monoamines in the frontal cortex, hippocampus, and hypothalamus) and biochemical (monoamine oxidase, MAO activity) assays corroborated the synergistically elevated monoaminergic system after co-treatment with trans-resveratrol and piperine. The present results indicate the effect of trans-resveratrol combined with piperine on depressive-like behaviors may be partly due to the potentiated activation of monoaminergic system in the brain. Further studies are necessary to elucidate the involvement of the oxidative/nitrosative stress, inflammatory and neuroprotective pathway in the antidepressant-like effect of this combination. The synergistic effect obtained from the combination may provide innovative clues for designing novel antidepressants with high efficacy and low side effects.

Topics: Alkaloids; Animals; Antidepressive Agents; Behavior, Animal; Benzodioxoles; Brain; Depression; Drug Synergism; Hindlimb Suspension; Mice; Monoamine Oxidase; Motor Activity; Piperidines; Polyunsaturated Alkamides; Resveratrol; Serotonin; Stilbenes; Swimming

This study examined the effect of piperine on hepatic steatosis and insulin resistance induced in mice by feeding a high-fat diet (HFD) for 13 weeks and elucidated potential underlying molecular mechanisms. Administration of piperine (50 mg/kg body weight) to mice with HFD-induced hepatic steatosis resulted in a significant increase in plasma adiponectin levels. Also, elevated plasma concentrations of insulin and glucose and hepatic lipid levels induced by feeding a HFD were reversed in mice when they were administered piperine. However, piperine did not reduce body weight and other biochemical markers to an extent where they became equal to the levels found in the CD-fed mice. Piperine reversed HFD-induced down-regulation of adiponecitn-AMP-activated protein kinase (AMPK) signalling molecules which play an important role in mediating lipogenesis, fatty acid oxidation and insulin signalling in the livers of mice. The expressions of lipogenic target genes were decreased, whereas the expression of carnitine palmitoyltransferase 1 (CPT1) gene involved in fatty acid oxidation was increased in the livers of the Pin50 group. Piperine significantly decreased the phosphorylation of insulin receptor substrate-1 (IRS-1) compared with the HFD-fed mice. Administration of piperine appeared to reverse preexisting HFD-induced hepatic steatosis and insulin resistance, probably by activation of adiponectin-AMPK signalling in mice.

Topics: Adiponectin; Alkaloids; AMP-Activated Protein Kinases; Animals; Benzodioxoles; Diet, High-Fat; Fatty Liver; Humans; Insulin Resistance; Lipogenesis; Male; Mice; Mice, Inbred C57BL; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Triglycerides

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, twenty-six new piperine-based hydrazone derivatives were synthesized from piperine, an alkaloid isolated from Piper nigrum Linn. The single-crystal structures of 6c, 6q and 6w were unambiguously confirmed by X-ray crystallography. Their insecticidal activity was evaluated against the pre-third-instar larvae of Mythimna separata Walker in vivo. Especially compounds 6b, 6i and 6r, the final mortality rates of which, at the concentration of 1 mg/mL, were 62.1%, 65.5% and 65.5%, respectively, exhibited more pronounced insecticidal activity compared to toosendanin at 1 mg/mL, a commercial botanical insecticide isolated from Melia azedarach. It suggested that introduction of the substituents at the C-2 position on the phenyl ring of the hydrazone derivatives was important for their insecticidal activity.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Products; Crystallography, X-Ray; Hydrazones; Insecticides; Larva; Melia; Molecular Conformation; Moths; Piper; Piperidines; Polyunsaturated Alkamides

Piperine is a spice principle, and its protective role against oxidative damage and lipid peroxidation has been reported. In this study, we aimed to investigate the effects of piperine in the prevention of ischemia-reperfusion injury to the small intestine.. Rats were allocated to three groups of 8 rats each. Rats in the sham group underwent laparotomy and observation only. Animals in the control and study groups underwent 45 minutes ischemia followed by 60 minutes reperfusion. In the study group, 10 mg/kg piperine was administered intraperitoneally just before the reperfusion procedure. Blood samples were obtained for measurement of lactate levels, and resection of the terminal ileum was performed to evaluate the histopathologic specimens and tissue malondialdehyde, superoxide dismutase, and glutathione activities. All results were expressed as mean±SD. Comparisons between groups were made by using the one way analysis of variance (ANOVA).. Lactate and malondialdehyde levels were significantly higher in the control group than the study and sham groups (p<0.001). In the study group, superoxide dismutase, and glutathione activities were significantly higher than in the control group (p<0.001). The sham group had the highest activities. Histopathologic examination showed disruption of villous pattern and lamina propria in the control group.. Intraperitoneal administration of 10 mg/kg piperine just before the reperfusion may reduce ischemia-reperfusion injury to the small intestine.

Topics: Alkaloids; Animals; Benzodioxoles; Disease Models, Animal; Glutathione; Ileum; Injections, Intraperitoneal; Ischemic Preconditioning; Lipid Peroxidation; Male; Malondialdehyde; Piperidines; Polyunsaturated Alkamides; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase; Torsion Abnormality

Piperine, is the major active principal of black pepper. In traditional medicine, black pepper has been used as an analgesic, anti-inflammatory agent and in the treatment of epilepsy. This study was conducted to evaluate the in vivo analgesic and anticonvulsant effects of piperine in mice. The analgesic and anticonvulsant effects of piperine were studied in mice using acetic acid-induced writhing, tail flick assay, pentylenetetrazole (PTZ)- and picrotoxin (PIC)-induced seizures models. The intraperitoneal (i.p.) administration of piperine (30, 50 and 70 mg/kg) significantly inhibited (P<0.01) the acetic acid-induced writhing in mice, similar to the effect of indomethacin (20 mg/kg i.p.). In the tail flick assay, piperine (30 and 50 mg/kg, i.p.) and morphine (5 mg/kg, i.p.) caused a significant increase (P<0.01) in the reaction time of mice. Pre-treatment of animals with naloxone (5 mg/kg i.p.), reversed the analgesic effects of both piperine and morphine in the tail flick assay. Piperine (30, 50 and 70 mg/kg, i.p.) and standard drugs, valproic acid (200 mg/kg, i.p.), carbamazepine (30 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) significantly (P<0.01) delayed the onset of PTZ-and PIC-induced seizures in mice. These findings indicate that piperine exhibits analgesic and anticonvulsant effects possibly mediated via opioid and GABA-ergic pathways respectively. Moreover, piperine being the main constituent of black pepper, may be contributing factor in the medicinal uses of black pepper in pain and epilepsy.

Topics: Acetic Acid; Alkaloids; Analgesics; Animals; Anticonvulsants; Benzodioxoles; Hot Temperature; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pentylenetetrazole; Picrotoxin; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Seizures

This study is to explore the amelioration of piperine on chronic acute combining stress rat with depression-like behavior, visceral sensitivity, and its effect on the expression of serotonin (5-HT) and synaptophysin. Forty two SD rats were divided into seven groups: blank group, model group, piperine (12.5, 25, 50 and 100 mgkg-1, ig) and imipramine (10 mgkg-1, ip) groups. The rat model of irritable bowel syndrome was established by chronic acute combining stress, and then to evaluate depression-like behavior and visceral sensitivity. The expressions of 5-HT and synaptophysin in the hippocampus and colon were determined by high performance liquid chromatography (HPLC) and Western blotting, respectively. The duration of immobility of IBS rat in the forced swimming test had been significantly increased, the sucrose consumption of IBS rat had been reduced and visceral sensitivity was obviously elevated in the IBS model group as compared with those in the normal control group (P<0.05, P<0.01). As compared with those in the normal control group, the expression of 5-HT significantly decreased, 5-HIAA/5-HT ratio significantly increased in the hippocampus of IBS model group (P<0.05), but opposite presentations were noted in the colon (P<0.05). As compared with that in the normal control group, the synaptophysin expression in the hippocampus decreased significantly but obviously increased in the colon (P<0.05). Piperine improved the behavior of IBS rats, and reversed the levels of 5-HT and 5-HIAA, and 5-HIAA/5-HT proportion in the hippocampus and colon (P<0.05); besides, they significantly reverse the synaptophysin level in the hippocampus and colon (P<0.05). The presence of depression and visceral sensitivity had been changed in IBS rats, with abnormal expression of 5-HT and synaptophysin in the brain-gut system. Piperine can ameliorate the changes of the behavior and regulation of serotonin and synaptophysin expression in IBS rat model.

Topics: Alkaloids; Animals; Benzodioxoles; Colon; Hippocampus; Hydroxyindoleacetic Acid; Irritable Bowel Syndrome; Male; Motor Activity; Piper nigrum; Piperidines; Plants, Medicinal; Polyunsaturated Alkamides; Random Allocation; Rats; Rats, Sprague-Dawley; Serotonin; Synaptophysin

Black pepper is used worldwide to enhance food flavor. We investigated dietary supplementation with piperine, the active principle of black pepper, to high carbohydrate, high fat (HCHF) diet-fed rats as a model of human metabolic syndrome. Rats were fed with either HCHF diet (carbohydrate, 52%; fat, 24%; 25% fructose in drinking water) or cornstarch (CS) diet for a total of 16 weeks. Diets of the treatment groups (CS + piperine and HCHF + piperine) were supplemented with piperine for the last 8 weeks of this protocol. After 16 weeks, rats fed with HCHF diet developed hypertension, elevated oxidative stress and inflammation-induced cardiac changes (infiltration of inflammatory cells in heart, increase in count and degranulation of mast cells in heart, cardiac fibrosis and increase in ventricular stiffness), reduced responsiveness of aortic rings, impaired glucose tolerance, abdominal obesity together with liver fibrosis, fat deposition and increased plasma liver enzymes. Supplementation with piperine (375 mg/kg food; approximately 30 mg/kg/day) in HCHF-fed rats normalized blood pressure, improved glucose tolerance and reactivity of aortic rings, reduced plasma parameters of oxidative stress and inflammation, attenuated cardiac and hepatic inflammatory cell infiltration and fibrosis and improved liver function. These changes clearly suggest that piperine reduces symptoms of human metabolic syndrome in HCHF-fed rats by reducing inflammation and oxidative stress.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Antioxidants; Benzodioxoles; Cardiovascular System; Diet, High-Fat; Dietary Carbohydrates; Dietary Supplements; Liver; Male; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Black pepper (Piper nigrum L.) lowers blood lipids in vivo and inhibits cholesterol uptake in vitro, and piperine may mediate these effects. To test this, the present study aimed to compare actions of black pepper extract and piperine on (1) cholesterol uptake and efflux in Caco-2 cells, (2) the membrane/cytosol distribution of cholesterol transport proteins in these cells, and (3) the physicochemical properties of cholesterol micelles. Piperine or black pepper extract (containing the same amount of piperine) dose-dependently reduced cholesterol uptake into Caco-2 cells in a similar manner. Both preparations reduced the membrane levels of NPC1L1 and SR-BI proteins but not their overall cellular expression. Micellar cholesterol solubility of lipid micelles was unaffected except by 1 mg/mL concentration of black pepper extract. These data suggest that piperine is the active compound in black pepper and reduces cholesterol uptake by internalizing the cholesterol transporter proteins.

Topics: Alkaloids; Benzodioxoles; Biological Transport; Caco-2 Cells; Cholesterol; Humans; Membrane Proteins; Membrane Transport Proteins; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Protein Transport; Scavenger Receptors, Class B

In the present study, we examined the molecular mechanism by which Piperine (bioactive compound of Piper nigrum) inhibits neuronal cell apoptosis. We further investigated the anti-inflammatory effect of Piperine on 6-OHDA induced Parkinson's disease. Consistent with its antioxidant properties, Piperine (10 mg/kg bwt) reduced 6-OHDA-induced lipid peroxidation and stimulated glutathione levels in striatum of rats. Furthermore, Piperine treatment diminished cytochrome-c release from mitochondria and reduced caspase-3 and caspase-9 activation induced by 6-OHDA. Treatment with Piperine markedly inhibited poly(ADP-ribose) polymerase activation, pro-apoptotic Bax levels and elevation of Bcl-2 levels. Piperine reduces contralateral rotations induced by apomorphine. Further narrow beam test and rotarod also showed improvement in motor coordination and balance behavior in rats treated with Piperine. In addition Piperine depletes inflammatory markers, TNF-α and IL-1β in 6-OHDA-induced Parkinson's rats. We propose that, in addition to its antioxidant properties Piperine exerts a protective effect via anti-apoptotic and anti-inflammatory mechanism on 6-OHDA induced Parkinson's disease.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Apomorphine; Apoptosis; Behavior, Animal; Benzodioxoles; Disease Models, Animal; Male; Oxidative Stress; Oxidopamine; Parkinson Disease; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

P-glycoprotein (P-gp) has a major role to play in drug pharmacokinetics and pharmacodynamics, since it effluxes many cytotoxic hydrophobic anticancer drugs from gastrointestinal tract, brain, liver and kidney. Piperine is known to enhance the bioavailability of curcumin, as a substrate of P-gp by at least 2000%. Besides these at least 50 other substrates and inhibitors of P-gp have been reported so far. All P-gp inhibitors have diverse structures. Although little is known about binding of some flavonoids and steroids at the NBD (nucleotide binding domain) of P-gp in the vicinity of ATP binding site inhibiting its hydrolysis, a valid explanation of how P-gp accommodates such a diverse set of inhibitors is still awaited. In the present study, piperine up to 100 μM has not shown observable cytotoxic effect on MDCK cell line, and it has been shown to accumulate rhodamine by fluorescence microscopy and fluorescent activated cell sorter in MDCK cells. Computational simulation for piperine and some first and second generation P-gp inhibitors has shown that these dock at the NBD site of P-gp. A comparative simulation study has been carried out regarding their docking and binding energies. Binding conformation of P-gp co-crystallized complexes with ADP, AMP-PNP (Adenylyl-imidodiphosphate), and ATP were compared with piperine. The receptor based E-pharmacophore of docked piperine has been simulated to find common features amongst P-gp inhibitors. Finally it has been concluded that piperine could be utilized as base molecule for design and development of safe non-toxic inhibitor of P-gp in order to enhance the bioavailability of most of its substrates.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Adenylyl Imidodiphosphate; Alkaloids; Amino Acids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Binding Sites; Biological Availability; Cell Survival; Computer Simulation; Dogs; Flow Cytometry; Humans; Madin Darby Canine Kidney Cells; Models, Molecular; Piperidines; Polyunsaturated Alkamides; Protein Structure, Tertiary; Rhodamines; Structural Homology, Protein; Substrate Specificity

Angiogenesis plays an important role in tumor progression. Piperine, a major alkaloid constituent of black pepper, has diverse physiological actions including killing of cancer cells; however, the effect of piperine on angiogenesis is not known. Here we show that piperine inhibited the proliferation and G(1)/S transition of human umbilical vein endothelial cells (HUVECs) without causing cell death. Piperine also inhibited HUVEC migration and tubule formation in vitro, as well as collagen-induced angiogenic activity by rat aorta explants and breast cancer cell-induced angiogenesis in chick embryos. Although piperine binds to and activates the cation channel transient receptor potential vanilloid 1 (TRPV1), its effects on endothelial cells did not involve TRPV1 since the antiproliferative effect of piperine was not affected by TRPV1-selective antagonists, nor did HUVECs express detectable TRPV1 mRNA. Importantly, piperine inhibited phosphorylation of Ser 473 and Thr 308 residues of Akt (protein kinase B), which is a key regulator of endothelial cell function and angiogenesis. Consistent with Akt inhibition as the basis of piperine's action on HUVECs, inhibition of the phosphoinositide-3 kinase/Akt signaling pathway with LY-294002 also inhibited HUVEC proliferation and collagen-induced angiogenesis. Taken together, these data support the further investigation of piperine as an angiogenesis inhibitor for use in cancer treatment.

Topics: Alkaloids; Angiogenesis Inhibitors; Animals; Aorta; Benzodioxoles; Breast Neoplasms; Cell Movement; Cell Proliferation; Chick Embryo; Chromones; Drug Screening Assays, Antitumor; Female; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; Male; Morpholines; Neovascularization, Pathologic; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; Rats, Wistar; S Phase; Serine; Threonine; TRPV Cation Channels

Depression is a mental disease causing large personal and socio-economic problems, and new improved drugs are therefore needed. Selective monoamine oxidase A (MAO-A) inhibitors are potential anti-depressants, but discovering new MAO-A inhibitors from natural sources by bioassay-guided approaches are a lengthy and time-consuming process. New analytical technologies that allow simultaneously chemical and biological screening of extracts are therefore urgently needed.. In the present study we describe coupling of a photometric microplate-based high-resolution MAO-A inhibitor assay with a hyphenated system consisting of high-performance liquid chromatography, solid-phase extraction and tube transfer nuclear magnetic resonance (HPLC-SPE-ttNMR). The standard compound clorgyline, and an extract of black pepper (Piper nigrum L.), representing a complex plant matrix, were used for proof-of-concept.. The work with clorgyline showed that the microplate-based high-resolution assay produced MAO-A inhibition profiles that easily allowed detection of submicrogram amounts of this selective MAO-A inhibitor. Furthermore, the HPLC-SPE-ttNMR/high-resolution MAO-A inhibition assay platform allowed identification of piperine and two piperine analogues as the main MAO-A inhibitors in the black pepper petroleum ether extract.. The HPLC-SPE-ttNMR/high-resolution MAO-A inhibition assay platform is a powerful tool for fast and efficient identification of new MAO-A inhibitors from complex extracts, and promise future advancement in the search for new anti-depressants from natural sources.

Topics: Alkaloids; Benzodioxoles; Biocatalysis; Chromatography, High Pressure Liquid; Chromogenic Compounds; Clorgyline; Dose-Response Relationship, Drug; Enzyme Assays; Magnetic Resonance Spectroscopy; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Photometry; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Reproducibility of Results; Solid Phase Extraction; Tyramine

Piperine, an alkaloid phytochemical found in the fruit of black and long pepper plants, is reported to inhibit the growth of cancer cells; however, the mechanism of action in human cancer cells is not clear. In this study we investigated the effect of piperine on the growth of HRT-18 human rectal adenocarcinoma cells. MTT assays showed that piperine inhibited the metabolic activity of HRT-18 cells in a dose- and time-dependent fashion, suggesting a cytostatic and/or cytotoxic effect. Flow cytometric analysis of Oregon Green 488-stained and propidium iodide-stained HRT-18 cells showed that piperine inhibited cell cycle progression. Piperine also caused HRT-18 cells to die by apoptosis, as determined by Annexin-V-FLUOS staining and characteristic changes in cell morphology. Flow cytometric analysis of dihydroethidium- and 2',7'-dichlorofluorescein diacetate-stained HRT-18 cells showed increased production of reactive oxygen species in piperine-treated cells. Furthermore, the antioxidant N-acetylcysteine reduced apoptosis in cultures of piperine-treated HRT-18 cells, indicating that piperine-induced cytotoxicity was mediated at least in part by reactive oxygen species. The cytostatic and cytotoxic effects of piperine on rectal cancer cells suggest that this dietary phytochemical may be useful in cancer treatment.

Topics: Acetylcysteine; Adenocarcinoma; Alkaloids; Apoptosis; Benzodioxoles; Cell Cycle; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cytochrome P-450 Enzyme Inhibitors; Free Radical Scavengers; Humans; Mitochondria; Piperidines; Polyunsaturated Alkamides; Reactive Oxygen Species; Rectal Neoplasms; Succinate Dehydrogenase

Aging is associated with progressive decline in mental abilities and functional capacities. Postmitotic tissues are most vulnerable to alteration due to oxidative damage leading to behavioral and biochemical changes. We hypothesized that the anatomical and functional facets of the brain could be protected with powerful antioxidants such as piperine and curcumin by examining their effects individually and in combination in delaying senescence induced by d-galactose. Young adult male Wistar rats were treated with piperine (12 mg/kg) alone, and curcumin (40 mg/kg) alone; and in combination for a period of 49 days by the oral route with treatment being initiated a week prior to d-galactose (60 mg/kg, i.p.). A control group, d-galactose alone and naturally aged control were also evaluated. Behavioral tests, hippocampal volume, CA1 neuron number, oxidative parameters, formation of lipofuscin like autofluorescent substances, neurochemical estimation, and histopathological changes in CA1 region of hippocampus were established. Our results suggest that the combination exerted a superior response compared to monotherapy as evidenced by improved spatial memory, reduced oxidative burden, reduced accumulation of lipofuscin; improvement in signaling, increase in hippocampal volume and protection of hippocampal neurons. We speculate that the powerful antioxidant nature of both, augmented response of curcumin in the presence of piperine and enhanced serotoninergic signaling was responsible for improved cognition and prevention in senescence.

Topics: Aging; Alkaloids; Animals; Antioxidants; Benzodioxoles; Brain; Catalase; Curcumin; Drug Synergism; Galactose; Glutathione; Male; Malondialdehyde; Maze Learning; Piperidines; Polyunsaturated Alkamides; Pyramidal Cells; Rats; Rats, Wistar; Serotonin; Superoxide Dismutase

The purpose of this study was to investigate the potential pharmacokinetic interactions with natural products (such as piperine (PIP), gallic acid (GA) and cinnamic acid (CA)) and rosuvastatin (RSV) (a specific breast cancer resistance protein, BCRP substrate) in rats. In Caco2 cells, the polarized transport of RSV was effectively inhibited by PIP, CA and GA at concentration of 50 μM. After per oral (p.o.) coadministration of PIP, CA and GA (10 mg/kg) significantly increased intravenous exposure (AUC(last)) of RSV (1 mg/kg) by 73.5%, 62.9% and 53.3% (p < 0.05), respectively than alone group (control). Compared with the control (alone) group, p.o. coadministration of PIP, CA and GA (10 mg/kg) significantly increased the oral exposure (AUC(last)) of RSV (5 mg/kg) by 2.0-fold, 1.83-fold (p < 0.05) and 2.34 -fold (p < 0.05), respectively. Moreover, the cumulative biliary excretion of RSV (5 mg/kg, p.o.) was significantly decreased by 53.3, 33.4 and 39.2% at the end of 8 h after p.o. co-administration of PIP, CA and GA (10 mg/kg), respectively. Taken together, these results indicate that the natural products such as PIP, CA and GA significantly inhibit RSV transport in to bile and increased the plasma exposure (AUC(last)) of RSV.

Topics: Administration, Oral; Alkaloids; Animals; Area Under Curve; Benzodioxoles; Bile; Cinnamates; Dogs; Drug Interactions; Fluorobenzenes; Gallic Acid; Madin Darby Canine Kidney Cells; Male; Piperidines; Polyunsaturated Alkamides; Pyrimidines; Rats; Rats, Sprague-Dawley; Rosuvastatin Calcium; Sulfonamides

Piperine, an alkaloid present in the Piper genus, was shown to have an anticonvulsant activity, evaluated by the pilocarpine-induced model, in mice. Pilocarpine (350mg/kg, i.p.) was administered 30min after piperine (2.5, 5, 10 and 20mg/kg, i.p.) which significantly increased latencies to 1st convulsion and to death, and percentage of survivals. These parameters were also increased in the pilocarpine groups pretreated with atropine plus piperine (10 and 2.5mg/kg, respectively), as related to the pilocarpine group. However, they were not altered in the pilocarpine groups pretreated with memantine (a NMDA-type glutamate receptors blocker, 2mg/kg, p.o.) or nimodipine (a calcium channel blocker, 10mg/kg, p.o.), both associated with piperine (1 or 2.5mg/kg), as compared to the piperine plus pilocarpine group. Moreover, the pilocarpine group pretreated with diazepam (which binds to the GABAA receptor, 0.2 and 0.5mg/kg, i.p.) plus piperine (1 and 2.5mg/kg) significantly increased latency to the 1st convulsion, as related to the pilocarpine group, suggesting that the GABAergic system is involved with the piperine action. Furthermore, the piperine effect was blocked by flumazenil (2mg/kg, i.p.), a benzodiazepine antagonist. Untreated P350 animals showed decreased striatal DA and increased DOPAC and HVA levels that were not affected in the piperine plus pilocarpine groups. Piperine increased striatal levels of GABA, glycine and taurine, and reversed pilocarpine-induced increases in nitrite contents in sera and brain. Hippocampi from the untreated pilocarpine group showed an increased number of TNF-α immunostained cells in all areas, as opposed to the pilocarpine group pretreated with piperine. Taken together, piperine anticonvulsant effects are the result of its anti-inflammatory and antioxidant actions, as well as TNF-α reduction. In addition, piperine effects on inhibitory amino acids and on the GABAergic system may certainly contribute to the drug anticonvulsant activity.

Topics: Alkaloids; Amino Acids; Animals; Anticonvulsants; Antioxidants; Atropine; Benzodioxoles; Biogenic Monoamines; Brain; Diazepam; Disease Models, Animal; Epilepsy; Flumazenil; gamma-Aminobutyric Acid; Humans; Male; Memantine; Mice; Nimodipine; Nitrites; Pilocarpine; Piperidines; Polyunsaturated Alkamides; Seizures; Tumor Necrosis Factor-alpha

In view of the wide-spread deficiency of iron and zinc in populations dependent on plant foods, it is desirable to improve the bioavailability of the same. Specific dietary spices may alter the ultrastructure and permeability characteristics of intestines. Groups of Wistar rats were fed piperine, capsaicin and ginger containing diets for 8 weeks in order to examine their possible influence on intestinal absorption of iron, zinc and calcium. Everted segments of duodenum, jejunum and ileum portions of small intestines isolated from these rats were examined for ex vivo uptake of iron, zinc and calcium from incubations containing digesta of finger millet. Higher uptake of iron, zinc and calcium by the intestinal segments from spice-fed animals was observed. The increase in the mineral uptake was the highest for calcium with >100% in some cases. The positive influence of dietary capsaicin was more pronounced on zinc uptake as compared to that of iron. Uptake of the glutamic acid standard was 87% and 62% higher in the case of jejunal segments of rats fed piperine and ginger. The higher intestinal uptake of iron and zinc as a result of consumption of pungent spices could encourage a strategy to reduce deficiency of these trace elements prevalent in population dependent on plant based foods.

Topics: Alkaloids; Animals; Benzodioxoles; Calcium; Capsaicin; Intestinal Absorption; Intestinal Mucosa; Intestines; Iron; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Zinc; Zingiber officinale

A reliable in vitro regeneration system for the economical and medicinally important Piper nigrum L. has been established. Callus and shoot regeneration was encouraged from leaf portions on Murashige and Skoog (MS) medium augmented with varied concentrations of plant growth regulators. A higher callus production (90 %) was observed in explants incubated on MS medium incorporated with 1.0 mg L(-1) 6-benzyladenine (BA) along with 0.5 mg L(-1) gibberellic acid after 4 weeks of culture. Moreover, a callogenic response of 85 % was also recorded for 1.0 mg L(-1) BA in combination with 0.25 mg L(-1) α-naphthalene acetic acid (NAA) and 0.25 mg L(-1) 2,4-dichlorophenoxyacetic acid or 0.5 mg L(-1) indole butyric acid (IBA) along with 0.25 mg L(-1) NAA and indole acetic acid. Subsequent sub-culturing of callus after 4 weeks of culture onto MS medium supplemented with 1.5 mg L(-1) thiodiazoran or 1.5 mg L(-1) IBA induced 100 % shoot response. Rooted plantlets were achieved on medium containing varied concentrations of auxins. The antioxidative enzyme activities [superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX)] revealed that significantly higher SOD was observed in regenerated plantlets than in other tissues. However, POD, CAT, and APX were higher in callus than in other tissues. A high-performance liquid chromatography (HPLC) fingerprint analysis protocol was established for quality control in different in vitro-regenerated tissues of P. nigrum L. During analysis, most of the common peaks represent the active principle "piperine." The chemical contents, especially piperine, showed variation from callus culture to whole plantlet regeneration. Based on the deviation in chromatographic peaks, the in vitro-regenerated plantlets exhibit a nearly similar piperine profile to acclimated plantlets. The in vitro regeneration system and HPLC fingerprint analysis established here brought a novel approach to the quality control of in vitro plantlets, producing metabolites of interest with substantial applications for the conservation of germplasm.

Topics: Alkaloids; Antioxidants; Ascorbate Peroxidases; Benzodioxoles; Biotechnology; Catalase; Chromatography, High Pressure Liquid; Peroxidase; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Quality Control; Superoxide Dismutase

To prepare curcumin-piperine (Cu-Pi) nanoparticles by various methods and to study the effect of various manufacturing parameters on Cu-Pi nanoparticles and to identify a suitable method for the preparation of Cu-Pi nanoparticles to overcome oral bioavailability and cancer cell targeting limitations in the treatment of cancer.. Cu-Pi nanoparticles were prepared by thin film hydration method, solid dispersion method, emulsion polymerization method and Fessi method. Optimization was carried out to study the effect of various manufacturing parameter on the Cu-Pi nanoparticles.. Out of four methods, Fessi method produced a minimum average particle size of 85.43 nm with a polydispersity index of 0.183 and zeta potential of 29.7 mV. Change of organic solvent (acetone or ethanol) did not have any significant effect on Cu-Pi nanoparticles. However, increase in sonication time, stirring speed, viscosity, use of 1:10:10 ratio of drug/polymer/surfactant, and use of anionic surfactant or combination of anionic surfactant with cationic polymer or combination of non-ionic surfactant with cationic polymer had a significant effect on Cu-Pi nanoparticles.. Cu-Pi nanoparticles coated with PEG containing copolymer produced by Fessi method had a minimum average particle size, excellent polydispersity index and optimal zeta potential which fall within the acceptable limits of the study. This dual nanoparticulate drug delivery system appears to be promising to overcome oral bioavailability and cancer cell targeting limitations in the treatment of cancer.

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Curcumin; Drug Carriers; Drug Combinations; Nanoparticles; Particle Size; Piperidines; Polyunsaturated Alkamides

Benjakul [BEN], a Thai Traditional medicine preparation, is composed of five plants: Piper chaba fruit [PC], Piper sarmentosum root [PS], Piper interruptum stem [PI], Plumbago indica root [PL] and Zingiber officinale rhizome [ZO]. From selective interviews of folk doctors in Southern Thailand, it was found that Benjakul has been used for cancer patients.. To investigate cytotoxicity activity of Benjakul preparation [BEN] and its ingredients against three human cancer cell lines, large lung carcinoma cell line (COR-L23), cervical cancer cell line (Hela) liver cancer cell line (HepG2) as compared with normal lungfibroblast cell (MRC-5) by using SRB assay.. The extraction as imitated the method used by folk doctors was done by maceration in ethanol and boiling in water Bioassay guided isolation was used isolated cytotoxic compound.. The ethanolic extracts of PL, ZO, PC, PS, BEN and PS showed specific activity against lung cancer cell (IC50 = 3.4, 7.9, 15.8, 18.4, 19.8 and 32.91 microg/ml) but all the water extracts had no cytotoxic activity. Three active ingredients [6-gingerol, plumbagin and piperine as 0.54, 4.18 and 7.48% w/w yield of crude extract respectively] were isolated from the ethanolic extract of BEN and they also showed cytotoxic activity with plumbagin showing the highest cytotoxic activity against COR-L23, HepG2, Hela and MRC-5 (IC50 = 2.55, 2.61, 4.16 and 11.54 microM respectively).. These data results may support the Thai traditional doctors who are using Benjakul to treat cancer patients and three of its constituents (6-gingerol, plumbagin and piperine) are suggested to be used as biomarkers for standardization of this preparation.

Topics: Alkaloids; Benzodioxoles; Catechols; Cell Line, Tumor; Fatty Alcohols; Female; Humans; Liver Neoplasms; Lung Neoplasms; Medicine, East Asian Traditional; Naphthoquinones; Phytotherapy; Piper; Piperidines; Plant Extracts; Plants, Medicinal; Plumbaginaceae; Polyunsaturated Alkamides; Thailand; Uterine Cervical Neoplasms; Zingiber officinale

Novel chemotypes with carbonic anhydrase (CA; EC 4.2.1.1) inhibitory action, in addition to the sulphonamide and sulphamate were discovered, many of which are based on natural products. Caffeine and piperine were extracted and tested for inhibition of the human (h) cytosolic isoforms hCA I and II. The IC(50) values of caffeine against hCA I was of 55 mM, whereas that of piperine of 60 mM. The IC(50) values of caffeine and piperine against hCA II were of 2 mM. Although these are quite weak inhibitors they may constitute leads for developing tighter binding compounds.

Topics: Alkaloids; Benzodioxoles; Biological Products; Caffeine; Carbonic Anhydrase I; Carbonic Anhydrase II; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fruit; Humans; Piperaceae; Piperidines; Plant Leaves; Polyunsaturated Alkamides; Structure-Activity Relationship; Theaceae

Docetaxel is the mainline treatment approved by the FDA for castration-resistant prostate cancer (CRPC) yet its administration only increases median survival by 2-4 months. Docetaxel is metabolized in the liver by hepatic CYP3A4 activity. Piperine, a major plant alkaloid/amide, has been shown to inhibit the CYP3A4 enzymatic activity in a cell-free system. Thus, we investigated whether the co-administration of piperine and docetaxel could increase docetaxel's pharmacokinetic activity in vitro and in vivo.. Liver CYP3A4 enzymatic activity was measured by fluorescence. In vivo docetaxel pharmacokinetic activity was analyzed by liquid chromatography. An in vivo xenograft model of human CRPC was utilized to assess the anti-tumor effect of docetaxel when co-administered with piperine.. Inhibition of hepatic CYP3A4 activity resulted in an increased area under the curve, half-life and maximum plasma concentration of docetaxel when compared to docetaxel alone administration. The synergistic administration of piperine and docetaxel significantly improved the anti-tumor efficacy of docetaxel in a xenograft model of human CRPC.. Docetaxel is one of the most widely used cytotoxic chemotherapeutic agents and is currently the mainstay treatment for metastatic CRPC. Dietary constituents are important agents modifying drug metabolism and transport. In our studies, dietary consumption of piperine increases the therapeutic efficacy of docetaxel in a xenograft model without inducing more adverse effects on the treated mice.

Topics: Alkaloids; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzodioxoles; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Docetaxel; Drug Interactions; Male; Mice; Piperidines; Polyunsaturated Alkamides; Prostatic Neoplasms; Taxoids; Xenograft Model Antitumor Assays

The objective of the present study was to evaluate the effects of curcumin alone and with adjuvant piperine against benzo(a)pyrene (BaP) induced oxidative stress in lungs of male Swiss albino mice. Mice were pretreated either with curcumin (100 mg/kg body weight), or piperine (20 mg/kg body weight), and in combination of both for one week, followed by single dose of benzo(a)pyrene (125 mg/kg body weight) treatment. Treatment with benzo(a)pyrene resulted in increased levels of lipid peroxides (LPO), protein carbonyl content (PCC) and with consequent decrease in the levels of tissue antioxidants like superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and reduced glutathione (GSH), which however, were increased significantly following curcumin treatment, but the increase was more pronounced when piperine was used as an adjuvant. BaP treatment alone did not alter significantly the GST activity. Pretreatment with curcumin increased the GST activity in BaP treated group, which was enhanced further upon synergistic treatment with piperine and curcumin. Therefore, combined administration of curcumin and piperine shall prove to be more effective in attenuating BaP induced toxicity.

Topics: Alkaloids; Animals; Antioxidants; Benzo(a)pyrene; Benzodioxoles; Curcumin; Drug Synergism; Lipid Peroxides; Lung; Male; Mice; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Protein Carbonylation

Baicalein (B), a bioactive flavone isolated from the root of a traditional Chinese medicinal herb Scutellaria baicalensis Georgi, was found to undergo extensive intestinal Phase II metabolism during its absorption process. Compounds sharing the same metabolic pathways with B or being inhibitors of enzymes UGT and SULT are expected to interfere with the metabolism of B leading to alteration of the absorption of B. The present study aims to identify potential intestinal absorption and metabolism interactions between B and four selected compounds, namely acetaminophen (APAP), (-)-epicatechin (EC), piperine (PIP) and curcumin (CUR) using in vitro and in situ models.. Three in vitro and one in situ methods were employed to investigate the effect of selected compounds on the metabolism and absorption on B. Incubation studies using rat intestinal s9 and Caco-2 cell lysate were used to study the effect of selected compounds on glucuronidation and sulfation of B. Sigmoidal dose-response curves were plotted and IC(50) values were estimated. Apical to basolateral absorption study using Caco-2 cell monolayer model was also employed to study the effect of selected compounds on absorption of B. The most potent inhibitor identified was selected to further investigate its potential herb-drug interaction with B using in situ rat intestinal perfusion model. LC/MS/MS was used for the analysis of B and its metabolites in collected samples.. It was found that all the four selected compounds could produce a dose-dependent inhibition on the glucuronidation and sulfation of B. Moreover, the presence of CUR and high-dose EC demonstrated a subsequent increase in the absorption of B. In general, the order of potency on glucuronidation inhibition is: CUR>PIP>EC>APAP; while the potency order on sulfation inhibition is: CUR>EC>PIP>APAP. CUR was selected to further study its in vivo effect on B using in situ rat intestinal perfusion model. It was found that CUR could significantly increase the absorption of B via the inhibition on formation of its metabolites.. Our findings indicated that the intestinal metabolism of B could be inhibited by all the selected compounds with CUR being the most potent inhibitor, which could result in subsequent increase of absorption of B. The current study had significant implications for further investigation on the in vivo evaluations of the herb-drug and herb-herb interactions between B and selected compounds, especially CUR.

Topics: Acetaminophen; Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biotransformation; Caco-2 Cells; Catechin; Chromatography, Liquid; Curcumin; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Flavanones; Glucuronides; Herb-Drug Interactions; Humans; Intestinal Absorption; Jejunum; Male; Medicine, Chinese Traditional; Perfusion; Piperidines; Plant Roots; Plants, Medicinal; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Scutellaria baicalensis; Sulfates; Tandem Mass Spectrometry

A few common spices are known to stimulate secretion of bile with higher amount of bile acids which play a major role in digestion and absorption of dietary lipids. It would be appropriate to verify if these spices enable efficient digestion and absorption during high-fat intake. In this context, dietary ginger (0.05%), piperine (0.02%), capsaicin (0.015%), and curcumin (0.5%) were examined for their influence on bile secretion, digestive enzymes of pancreas and absorption of dietary fat in high-fat (30%) fed Wistar rats for 8 weeks.. These spices enhanced the activity of pancreatic lipase, amylase, trypsin and chymotrypsin by 22-57%, 32-51%, 63-81% and 12-38%, respectively. Dietary intake of spices along with high-fat enhanced fat absorption. These dietary spices increased bile secretion with higher bile acid content. Stimulation of lipid mobilisation from adipose tissue was suggested by the decrease in perirenal adipose tissue weight by dietary capsaicin and piperine. This was also accompanied by prevention of the accumulation of triglyceride in liver and serum in high-fat fed rats. Activities of key lipogenic enzymes in liver were reduced which was accompanied by an increased activity of hormone-sensitive lipase.. Thus, dietary ginger and other spice compounds enhance fat digestion and absorption in high-fat fed situation through enhanced secretion of bile salts and a stimulation of the activity pancreatic lipase. At the same time, the energy expenditure is facilitated by these spices to prevent the accumulation of absorbed fat.

Topics: Adiposity; Alkaloids; Animals; Benzodioxoles; Bile; Bile Acids and Salts; Capsaicin; Curcumin; Diet, High-Fat; Dietary Fats; Digestion; Hydrolases; India; Intestinal Absorption; Lipid Metabolism; Liver; Male; Pancreas; Piperidines; Polyunsaturated Alkamides; Rats, Wistar; Rhizome; Spices; Up-Regulation; Zingiber officinale

The insecticidal activity of Piper nigrum fruit-derived piperidine alkaloid (piperine) and N-isobutylamide alkaloids (pellitorine, guineensine, pipercide and retrofractamide A) against female adults of Culex pipiens pallens and Aedes aegypti was examined. On the basis of 24-h LD(50) values, the compound most toxic to female C. pipiens pallens was pellitorine (0.4 µg/♀) followed by guineensine (1.9 µg/♀), retrofractamide A (2.4 µg/♀) and pipercide (3.2 µg/♀). LD(50) value of chlorpyrifos was 0.03 µg/♀. Against female A. aegypti, the insecticidal activity was more pronounced in pellitorine (0.17 µg/♀) than in retrofractamide A (1.5 µg/♀), guineensine (1.7 µg/♀), and pipercide (2.0 µg/♀). LD(50) value of chlorpyrifos was 0.0014 µg/♀.

Topics: Aedes; Alkaloids; Alkenes; Amides; Animals; Benzodioxoles; Culex; Fatty Acids, Unsaturated; Female; Heterocyclic Compounds, 2-Ring; Insecticides; Male; Piper nigrum; Piperidines; Polyunsaturated Alkamides

In the present study, the antioxidative and anticlastogenic effects of curcumin and piperine separately and in combination have been investigated against benzo(a)pyrene (BaP)-mediated toxicity in mice. Male Swiss albino mice were pretreated with curcumin (100 mg kg(-1) body weight) and piperine (20 mg kg(-1) body weight) separately as well as in combination orally in corn oil for 7 days; and subsequently, after 2 h of pretreatment, BaP was administered orally in corn oil (125 mg kg(-1) body weight). A single dose of BaP in normal mice increased the levels of lipid peroxidation (LPO), protein carbonyl content (PCC), and frequency of bone marrow micronucleated polychromatic erythrocytes (MNPCEs) but decreased significantly the levels of endogenous antioxidants such as superoxide dismutases (SODs), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT) and reduced glutathione (GSH) in the liver. Pretreatments with curcumin and curcumin plus piperine before administration of single dose of BaP significantly decreased the levels of LPO, PCC, and incidence of MNPCEs but elevated the level of GSH and enzyme activities of GPx, GR, SOD, CAT, and glutathione-S-transferase (GST) when compared to the BaP-treated group. The effect of curcumin plus piperine is more pronounced as compared to curcumin in attenuating BaP-induced oxidative insult and clastogenicity.

Topics: Alkaloids; Animals; Antimutagenic Agents; Antioxidants; Benzo(a)pyrene; Benzodioxoles; Carcinogens; Catalase; Curcumin; Drug Combinations; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Liver; Male; Mice; Micronuclei, Chromosome-Defective; Piperidines; Polyunsaturated Alkamides; Protein Carbonylation; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Hyperactivation of the hypothalamic-pituitary-adrenal axis and the associated hippocampal atrophy were observed in patients with depression, which could be ameliorated by the treatment with antidepressants. Therefore, neuroprotection has been proposed to be one of the acting mechanisms of antidepressant. Our previous studies have showed that treating mice with piperine produced antidepressant-like effect in animal models of behavioral despair. This study aimed to examine the protective effect of piperine treatment on corticosterone-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. The results showed that piperine co-treatment revealed a differential effect on the cytotoxicity of corticosterone and had its maximum inhibitory effect at 1 μM. Piperine (1 μM) co-treatment also significantly decreased intracellular reactive oxygen species level, and enhanced superoxide dismutase activity and total glutathione level in corticosterone-treated PC12 cells. In addition, piperine (1 μM) co-treatment was found to reverse the decreased brain-derived neurotrophic factor (BDNF) mRNA level caused by corticosterone in PC12 cells. The results suggest that piperine exerts a neuroprotective effect on corticosterone-induced neurotoxicity in PC12 cells, at least in part, via the inhibition of oxidative stress and the upregulation of BDNF mRNA expression. This neuroprotective effect may be one of the acting mechanisms accounts for the in vivo antidepressant activity of piperine.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Antidepressive Agents; Benzodioxoles; Corticosterone; Depression; Mice; Neuroprotective Agents; PC12 Cells; Piperidines; Polyunsaturated Alkamides; Rats

An attempt has been made to develop and validate a simultaneous HPLC method for novel approach of drug release via oil-in-water (o/w) nanoemulsion formulation and Habb-e-Khardal Unani tablet containing piperine and guggul sterones E and Z as main ingredients. Nanoemulsion was prepared by titration method using sefsol-218 as an oily phase, cremophor-EL as a surfactant, transcutol as a co-surfactant and distilled water as an aqueous phase. The formulation was optimized on the basis of thermodynamic stability and dispersibilty test. The nanoformulation was evaluated for particle size, surface morphology, electrical conductivity and viscosity determination. The in vitro dissolution was carried out by dialysis bag method. Drugs were quantified using an HPLC method developed in-house with a C(18) column as stationary phase and acetonitrile and water as mobile phase at λ(max) of 240 nm. The optimized formulation showed higher drug release, lower droplet size and less viscosity as compared with the conventional Habb-e-Khardal Unani tablet. The present study illustrated the potential of nanoemulsion dosage form in improving biopharmaceutic performance of piperine and guggul sterone. The HPLC method was also found to be quite sufficient for the routine quality control of formulations containing piperine and guggul sterone E and Z as ingredients and also for in vitro drug release studies.

Topics: Alkaloids; Benzodioxoles; Calibration; Chromatography, High Pressure Liquid; Drug Stability; Emulsions; India; Medicine, Unani; Nanostructures; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Pregnenediones; Reproducibility of Results; Solubility; Tablets

Leukocyte infiltration, up-regulation of proinflammatory cytokines and severe oxidative stress caused by increased amounts of reactive oxygen species are characteristics of inflammatory bowel disease. The catechin (2R,3R)-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol-3-(3,4,5-trihydroxybenzoate), named epigallocatechin-3-gallate, EGCG, has been demonstrated to exert anti-inflammatory and antioxidative properties, reducing reactive oxygen species in the inflamed tissues. The aim of this study was to evaluate the therapeutic effects of EGCG in a murine model of colitis induced by oral administration of dextran sodium sulfate.. Mice received a daily oral administration of 6.9 mg/kg body weight EGCG or Piper nigrum (L.) alkaloid (2E,4E)-5-(1,3-benzodioxol-5-yl)-1-piperidin-1-ylpenta-2,4-dien-1-one, named piperine (2.9 mg/kg body weight) or the combination of the both - piperine was used in this combination to enhance the bioavailability of EGCG.. In vivo data revealed the combination of EGCG and piperine to significantly reduce the loss of body weight, improve the clinical course and increase overall survival in comparison to untreated groups. The attenuated colitis was associated with less histological damages to the colon and reduction of tissue concentrations of malondialdehyde, the final product of lipid peroxidation. Neutrophils accumulation indicator myeloperoxidase was found to be reduced in colon tissue, while antioxidant enzymes like superoxide dismutase and glutathione peroxidase showed an increased activity. In vitro, the treatment with EGCG plus piperine enhanced the expression of SOD as well as GPO and also reduced the production of proinflammatory cytokines.. These data support the concept of anti-inflammatory properties of EGCG being generally beneficial in the DSS-model of colitis, an effect that may be mediated by its strong antioxidative potential.

Topics: Alkaloids; Analysis of Variance; Animals; Antioxidants; Benzodioxoles; Catechin; Colitis; Dextran Sulfate; Female; Glutathione Peroxidase; HT29 Cells; Humans; Interleukin-8; Malondialdehyde; Mice; Mice, Inbred C57BL; Oxidative Stress; Peroxidase; Piperidines; Polyunsaturated Alkamides; Reactive Oxygen Species; Superoxide Dismutase; Weight Loss

To gain a more comprehensive knowledge on whether, besides the well-known piperine, other compounds are responsible for the pungent and tingling oral impression imparted by black pepper, an ethanol extract prepared from black pepper (Piper nigrum L.) was screened for its key sensory-active nonvolatiles by application of taste dilution analysis (TDA). Purification of the compounds perceived with the highest sensory impact, followed by LC-MS and 1D/2D NMR experiments as well as synthesis, led to the structure determination of 25 key pungent and tingling phytochemicals, among which the eight amides 1-(octadeca-2E,4E,13Z-trienyl)piperidine, 1-(octadeca-2E,4E,13Z-trienyl)pyrrolidine, (2E,4E,13Z)-N-isobutyl-octadeca-2,4,13-trienamide, 1-(octadeca-2E,4E,12Z-trienoyl)-pyrrolidine, 1-(eicosa-2E,4E,15Z-trienyl)piperidine, 1-(eicosa-2E,4E,15Z-trienyl)pyrrolidine, (2E,4E,15Z)-N-isobutyl-eicosa-2,4,15-trienamide, and 1-(eicosa-2E,4E,14Z-trienoyl)-pyrrolidine were not yet reported in literature. Sensory studies by means of a modified half-tongue test revealed recognition thresholds ranging from 3.0 to 1150.2 nmol/cm² for pungency and from 520.6 to 2162.1 nmol/cm² for the tingling orosensation depending on their chemical structure.

Topics: Adult; Alkaloids; Benzodioxoles; Female; Humans; Male; Molecular Structure; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Taste; Young Adult

To investigate the effects of piperine, a major pungent alkaloid present in Piper nigrum and Piper longum, on the tumor growth and metastasis of mouse 4T1 mammary carcinoma in vitro and in vivo, and elucidate the underlying mechanisms.. Growth of 4T1 cells was assessed using MTT assay. Apoptosis and cell cycle of 4T1 cells were evaluated with flow cytometry, and the related proteins were examined using Western blotting. Real-time quantitative PCR was applied to detect the expression of matrix metalloproteinases (MMPs). A highly malignant, spontaneously metastasizing 4T1 mouse mammary carcinoma model was used to evaluate the in vivo antitumor activity. Piperine was injected into tumors every 3 d for 3 times.. Piperine (35-280 μmol/L) inhibited the growth of 4T1 cells in time- and dose-dependent manners (the IC(50) values were 105 ± 1.08 and 78.52 ± 1.06 μmol/L, respectively, at 48 and 72 h). Treatment of 4T1 cells with piperine (70-280 μmol/L) dose-dependently induced apoptosis of 4T1 cells, accompanying activation of caspase 3. The cells treated with piperine (140 and 280 μmol/L) significantly increased the percentage of cells in G(2)/M phase with a reduction in the expression of cyclin B1. Piperine (140 and 280 μmol/L) significantly decreased the expression of MMP-9 and MMP-13, and inhibited 4T1 cell migration in vitro. Injection of piperine (2.5 and 5 mg/kg) dose-dependently suppressed the primary 4T1 tumor growth and injection of piperine (5 mg/kg) significantly inhibited the lung metastasis.. These results demonstrated that piperine is an effective antitumor compound in vitro and in vivo, and has the potential to be developed as a new anticancer drug.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Benzodioxoles; Breast; Breast Neoplasms; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 13; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Piper; Piperidines; Polyunsaturated Alkamides

The present study was undertaken to investigate the anti-inflammatory effect of piperine against adjuvant-induced arthritis in rats, an experimental model for rheumatoid arthritis and compared it with that of the non-steroidal anti-inflammatory drug indomethacin. Administration of heat-killed Mycobacterium tuberculosis (0. 1 ml) intradermally into the right hind paw of rats resulted in increased paw volume, lysosomal enzymes, glycoproteins and tissue marker enzymes and decreased body weight. However, these changes were reverted to near normal levels upon piperine (30 mg/kg body weight, i.p.) treatment. Histopathological analysis of joints also revealed that synovial hyperplasia and mononuclear infiltration observed in arthritic rats were alleviated by piperine. Thus, the present study clearly indicated that piperine possesses promising anti-inflammatory effect against adjuvant-induced arthritis by suppressing inflammation and cartilage destruction.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Benzodioxoles; Edema; Female; Glycoproteins; Indomethacin; Inflammation; Joints; Male; Mycobacterium tuberculosis; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Piperine, one of the main components of Piper longum Linn. and P. nigrum Linn., is a plant alkaloid with a long history of medicinal use. Piperine has been shown to modulate the immune response, but the mechanism underlying this modulation remains unknown. Here, we examined the effects of piperine on lipopolysaccharide (LPS)-induced inflammatory responses in bone-marrow-derived dendritic cells (BMDCs). Piperine significantly inhibited the expression of major histocompatibility complex class II, CD40 and CD86 in BMDCs in a dose-dependent manner. Furthermore, piperine treatment led to an increase in fluorescein-isothiocyanate-dextran uptake in LPS-treated dendritic cells and inhibited the production of tumour necrosis factor alpha and interleukin (IL)-12, but not IL-6. The inhibitory effects of piperine were mediated via suppression of extracellular signal-regulated kinases and c-Jun N-terminal kinases activation, but not p38 or nuclear factor-κB activation. These findings provide insight into the immunopharmacological role of piperine.

Topics: Alkaloids; Animals; Benzodioxoles; Bone Marrow Cells; Cell Differentiation; Dendritic Cells; Inflammation; Interleukin-12; Interleukin-6; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Tumor Necrosis Factor-alpha

This study investigated the antiadipogenic activity of black pepper extract and its constituent piperine in 3T3-L1 preadipocytes as well as the underlying molecular mechanisms. Both black pepper extract and piperine, without affecting cytotoxicity, strongly inhibited the adipocyte differentiation of 3T3-L1 cells. The mRNA expression of the master adipogenic transcription factors, PPARγ, SREBP-1c, and C/EBPβ, was markedly decreased. Intriguingly, mRNA levels of PPARγ target genes were also down-regulated. Moreover, a luciferase reporter assay indicated that pipierine significantly represses the rosiglitazone-induced PPARγ transcriptional activity. Finally, GST-pull down assays demonstrated that piperine disrupts the rosiglitazone-dependent interaction between PPARγ and coactivator CBP. Genome-wide analysis using microarray further supports the role of piperine in regulating genes associated with lipid metabolism. Overall, these results suggest that piperine, a major component of black pepper, attenuates fat cell differentiation by down-regulating PPARγ activity as well as suppressing PPARγ expression, thus leading to potential treatment for obesity-related diseases.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Alkaloids; Animals; Benzodioxoles; Cell Differentiation; Down-Regulation; Mice; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; PPAR gamma

A series of piperine derivates (1-19) have been designed, synthesized and evaluated in vitro for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. It is worth noting that most of the small amine moieties substituted on the piperidine ring proved to be potent and selective inhibitors of MAO-B rather than of MAO-A. 5-(3,4-methylenedioxyphenyl)-2E,4E-pentadienoic acid n-propyl amide (3) showed the greatest MAO-B inhibitory activity (IC(50)(MAO-B)=0.045 μM) and good selectivity (IC(50)(MAO-A)=3.66 μM). The conjugated double bond and carbonyl group of piperine are proved to be an essential feature for piperine and related alkylamides to exhibit MAO-inhibitory activity. Binding mode of the titled compounds was predicted using FlexX algorithm. The design and optimization of novel small molecule monoamine oxidase inhibitors will be guided by the results of this report.

Topics: Alkaloids; Benzodioxoles; Humans; Inhibitory Concentration 50; Models, Molecular; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Polyunsaturated Alkamides; Protein Binding; Protein Structure, Tertiary; Structure-Activity Relationship

The use of ionizing radiation (IR) is essential for treating many human cancers. However, radioresistance markedly impairs the efficacy of tumor radiotherapy. IR enhances the production of reactive oxygen species (ROS) in a variety of cells which are determinant components in the induction of apoptosis. Much interest has developed to augment the effect of radiation in tumors by combining it with radiosensitizers to improve the therapeutic ratio. In the current study, the radiosensitizing effects of resveratrol and piperine on cancer cells were evaluated. Cancer cell lines treated with these natural products exhibited significantly augmented IR-induced apoptosis and loss of mitochondrial membrane potential, presumably through enhanced ROS generation. Applying natural products as sensitizers for IR-induced apoptotic cell death offers a promising therapeutic approach to treat cancer.

Topics: Alkaloids; Anticarcinogenic Agents; Apoptosis; Benzodioxoles; Blotting, Western; Colonic Neoplasms; Humans; Melanoma, Experimental; Membrane Potential, Mitochondrial; Oxidation-Reduction; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Radiation Tolerance; Radiation-Sensitizing Agents; Radiation, Ionizing; Reactive Oxygen Species; Resveratrol; Stilbenes; Tumor Cells, Cultured

Piperine, an amide isolated from Piper species (Piperaceae), has been reported to exhibit central nervous system depression, anti-pyretic and anti-inflammatory activity. Immunomodulatory and anti-tumor activity of piperine has been demonstrated in mouse carcinomas. However, there is little information available concerning the effect of piperine on humans. We evaluated the immunopharmacological activity of this compound in human immune cells. Human peripheral blood mononuclear cells (PBMCs) were exposed to piperine, and cell proliferation was determined by the MTS assay. Piperine significantly inhibited phytohemagglutinin-stimulated human PBMC proliferation after exposure for 72 h. This compound inhibited PBMC activity, with an IC(50) of 100.73 ± 11.16 μg/mL. Production of interleukin-2 (IL-2) and interferon-γ (IFN-γ) was measured using an ELISA assay and RT-PCR. Piperine inhibited IL-2 and IFN-γ production in the PBMCs. RT-PCR data indicated that IL-2 and IFN-γ mRNA expression in PBMCs is suppressed by piperine. This compound significantly inhibited the production of these two cytokines by activated PBMCs in a dose-dependent manner. In conclusion, piperine appears to have potential as an immunomodulatory agent for immune system suppression.

Topics: Alkaloids; Benzodioxoles; Cell Proliferation; Cytokines; Humans; Immunologic Factors; Interferon-gamma; Interleukin-2; Leukocytes, Mononuclear; Lymphocyte Activation; Phytohemagglutinins; Piperidines; Polyunsaturated Alkamides; RNA, Messenger

Piperine is a major component of black (Piper nigrum Linn) and long (Piper longum Linn) peppers, and is widely used as a traditional food and medicine. It also exhibits a variety of biological activities, which include antioxidant, anti-tumor and anti-pyretic properties. In the present study, we investigated the inhibitory effects of piperine on phorbol 12-myristate 13-acetate (PMA)-induced cyclooxygenase-2 (COX-2) gene expression and analyzed the molecular mechanism of its activity in murine RAW 264.7 macrophages. Piperine dose-dependently decreased PMA-induced COX-2 expression and PGE(2) production, as well as COX-2 promoter-driven luciferase activity. Transient transfections utilizing COX-2 promoter deletion constructs and COX-2 promoter constructs, in which specific enhancer elements were mutagenized, revealed that the nuclear factor-κB (NF-κB), CCAAT/enhancer binding protein (C/EBP) and activator protein-1 (AP-1), were the predominant contributors to the effects of piperine. In addition, piperine inhibited PMA-induced NF-κB, C/EBP and c-Jun nuclear translocation. Furthermore, piperine significantly inhibited PMA-induced activation of the Akt and ERK. These findings demonstrate that piperine effectively attenuates COX-2 production, and provide further insight into the signal transduction pathways involved in the anti-inflammatory effects of piperine.

Topics: Alkaloids; Animals; Benzodioxoles; Blotting, Western; CCAAT-Enhancer-Binding Proteins; Cell Line; Cyclooxygenase 2; Dinoprostone; Down-Regulation; Enzyme Activation; Humans; Macrophages; Mice; NF-kappa B; Piperidines; Polyunsaturated Alkamides; Protein Kinases; Real-Time Polymerase Chain Reaction; Signal Transduction; Tetradecanoylphorbol Acetate; Transcription Factor AP-1

The pathophysiological mechanisms leading to neuronal injury in middle cerebral artery occlusion (MCAO) model of cerebral stroke are complex and multifactorial that form the bases of behavioral deficits and inflammation mediated damage. The present study demonstrates the effect of piperine pretreatment (10 mg/kg b wt, once daily p.o. for 15 days) on cerebral ischemia-induced inflammation in male Wistar rats. The right middle cerebral artery was occluded for 2 h followed by reperfusion for 22 h. A maximum infarct volume (57.80 %) was observed in ischemic MCAO group. However, piperine administration prior to ischemia showed a significant reduction in infarct volume (28.29 %; p < 0.05) and neuronal loss (12.72 %; p < 0.01). As a result of piperine pretreatment, a significant improvement in behavioral outputs of MCAO rats (p < 0.05-0.01) was observed. Piperine successfully reduced the level of proinflammatory cytokines IL-1β, IL-6 and TNF-α, in ischemic group (p < 0.01). Ischemic group brain has shown edematous morphology with vacuolated architecture and pyknotic nuclei in H & E staining which was successfully ameliorated by piperine administration. Moreover, piperine also succeeded in lowering the expression of COX-2, NOS-2, and NF-κB (p < 0.01). Both cytosolic and nuclear NF-κB were down-regulated in ischemic group pre-administered with piperine (p < 0.01). The present study suggests that piperine is able to salvage the ischemic penumbral zone neurons by virtue of its anti-inflammatory property, thereby limiting ischemic cell death.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Benzodioxoles; Cyclooxygenase 2; Cytokines; Down-Regulation; Infarction, Middle Cerebral Artery; Inflammation Mediators; Male; Motor Activity; Muscle Strength; Neuroprotective Agents; NF-kappa B; Nitric Oxide Synthase Type II; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Reperfusion Injury

Piperine (CAS no: 94-62-2), an alkaloid obtained from Piper nigrum and P. longum is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent anti-hyperglycemic activity of nateglinide (CAS no: 105816-04-4) as evaluated by glucose challenged and alloxan-induced diabetic models, when it was administered with nateglinide. Nateglinide plasma concentrations were also increased, when administered with piperine. The synergistic anti-hyperglycemic activity of nateglinide when administered with piperine can be attributed to increased plasma concentration of nateglinide. The results of this study demonstrate that piperine could be used as a potential bioenhancer along with nateglinide.

Topics: Alkaloids; Alloxan; Animals; Benzodioxoles; Cyclohexanes; Diabetes Mellitus, Experimental; Drug Interactions; Drug Synergism; Glucose Tolerance Test; Hypoglycemic Agents; Male; Nateglinide; Phenylalanine; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Curcumin, a principal component from Curcuma longa, with antioxidant and anti-inflammatory activities was proposed as a potential candidate for the preventation and/or treatment of cancer and chronic diseases. However, curcumin could not achieve its expected therapeutic outcome in clinical trials due to its low solubility and poor bioavailability. The actual intestinal physiological barriers limiting curcumin absorption after oral administration have not been fully investigated. To identify the main barriers curtailing its absorption, in vitro permeability of curcumin and flux of its glucuronide were monitored in rat jejunum and Transwell grown Caco-2 cells. Curcumin was more permeable under acidic conditions, but the permeability was substantially below the permeability of highly permeable standards. Its efflux could not be inhibited by specific Pgp and MRP inhibitors. BCRP was found to participate in curcumin transport, but the Organic Anion Transporting Polypeptide (OATP) did not. The permeability of curcumin significantly increased when the structure of mucus was compromised. The inhibitor of curcumin metabolism, piperin, failed to act as a permeability enhancer. Piperin inhibited Pgp and MRP transporters and decreased the amount of glucuronide transported back into the intestine. Inclusion of piperin in curcumin-containing formulations is highly recommended as to inhibit curcumin glucuronidation and to increase the transport of formed glucuronides into the plasma, therefore increasing the probability of glucuronide distribution into target tissue and inter-convertion to curcumin. It would also be beneficial, if curcumin delivery systems could reversibly compromise the mucous integrity to minimize the non-specific binding of curcumin to its constituents.

Topics: Algorithms; Alkaloids; Animals; Benzodioxoles; Buffers; Caco-2 Cells; Chromatography, High Pressure Liquid; Curcumin; Drug Stability; Glucuronides; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Intestinal Mucosa; Jejunum; Mass Spectrometry; Membrane Potentials; Patch-Clamp Techniques; Permeability; Piperidines; Polyunsaturated Alkamides; Rats; Solubility

Argulus are common aquatic ectoparasites that create one of the major threats to aquaculture due to absence of suitable therapy. Piperine, a bioactive component of Piper longum, has medicinal properties and acts as anti-inflammatory, antibacterial, and antifungal, considering eco-friendliness and cost-effectiveness. The present study aimed to evaluate antiparasitic effect of piperine against an ectoparasite Argulus spp. on Carassius auratus. Artificial Argulus infection was carried out by cohabitation method, and the fishes were selected for in vivo study when intensity of Argulus infestation was observed to be 15-20 Argulus per fish. In vitro and in vivo studies were performed at different concentration 1.0 (T (1)), 3.0 (T (2)), 5.0 (T (3)), 7.0 (T (4)), and 9.0 mg l(-1) (T (5)) of piperine solution to treat Argulus for 3 and 72 h, respectively. The acute toxicity test for piperine EC 97 % against goldfish was performed for 96 h. The 96 h median lethal concentration (LC(50)) for piperine was found to be 52.64 mg l(-1). In vitro effect of piperine solution led to 100 % mortality of Argulus at 9.0 mg l(-1) in 3 h whereas, under in vivo test, the 100 % antiparasitic efficacy of piperine solution was found at 9.0 mg l(-1) in 48 h. The EC(50) for 48 h was 9.0 mg l(-1), and thus, therapeutic index is 5.8. The results revealed that piperine at a concentration of 9.0 mg l(-1) can be used as a potential natural agent for controlling Argulus parasite.

Topics: Alkaloids; Animals; Antiparasitic Agents; Arguloida; Benzodioxoles; Disease Models, Animal; Ectoparasitic Infestations; Goldfish; Piper; Piperidines; Polyunsaturated Alkamides; Survival Analysis; Treatment Outcome

This study investigated the effect of piperine on the gene expression of P-glycoprotein (P-gp) as well as pregnane-X-receptor (PXR) activity and also its implication on the bioavailability of diltiazem, a P-gp substrate. The effect of piperine on the systemic exposure of diltiazem was examined in rats after the intravenous and oral administration of diltiazem with/without 2 week pretreatment with piperine. Compared with the control group given diltiazem (20 mg/kg) alone, the pretreatment with piperine (10 or 20 mg/kg, once daily for 2 weeks) decreased the oral exposure of diltiazem by 36-48% in rats. Consequently, the bioavailability of oral diltiazem was significantly lower (p < 0.05) after the 2 week pretreatment with piperine. The pretreatment with piperine for 2 weeks also reduced the systemic exposure of desacetyldiltiazem, a major active metabolite of diltiazem by approximately 73%, accompanied by a significant decrease in the metabolite-parent ratio. In contrast to the oral pharmacokinetics, piperine did not affect the intravenous pharmacokinetics of diltiazem in rats. Immunoblot analysis indicated that the protein expression level of intestinal P-gp was significantly enhanced after the 2 week pretreatment with piperine in rats. In addition, piperine increased the PXR reporter activity in human hepatoma cells. Taken together, the 2 week pretreatment with piperine significantly induced intestinal P-gp expression in conjunction with stimulated PXR activity and decreased the oral exposure of diltiazem and desacetyldiltiazem in rats.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Availability; Calcium Channel Blockers; Diltiazem; Food-Drug Interactions; Gene Expression; Hep G2 Cells; Humans; Male; Piperidines; Polyunsaturated Alkamides; Pregnane X Receptor; Rats; Rats, Sprague-Dawley; Receptors, Steroid

This study investigated the role of piperine in the transcriptional regulation of liver X receptor α (LXRα) and the effects of dietary piperine on high-fat diet (HFD)-induced hepatic steatosis and insulin resistance in mice. Furthermore, we explored the potential molecular mechanisms through which the protective effects of piperine may work. In the present study, piperine significantly reduced ligand-induced LXRα activity in a dose-dependent manner and gradually disrupted the interaction between ligand-bound LXRα and GST-CBP. In mice, an HFD supplemented with 0.05% piperine (PSD) significantly decreased body and liver weight as well as plasma and hepatic lipid levels. In agreement with our in vitro study, in mice fed an HFD, dietary piperine markedly decreased LXRα mRNA expression and its lipogenic target genes (i.e., SREBP1c, ChREBPα, FAS, and CD36). Piperine also significantly decreased plasma insulin and glucose concentrations, while increasing insulin sensitivity in mice fed an HFD. In addition, piperine downregulated the expression of genes involved in ER stress, including GRP78, activating transcription factor 6, and eukaryotic translation initiation factor 2α, and upregulated GLUT2 translocation from the cytosol to the plasma membrane in the livers of PSD mice. Piperine antagonized LXRα transcriptional activity by abolishing the interaction of ligand-bound LXRα with the co-activator CBP. The effects of piperine on hepatic lipid accumulation were likely regulated via alterations in LXRα-mediated lipogenesis in mice fed an HFD. Dietary piperine also led to reduced ER stress and increased insulin sensitivity and prevented hepatic insulin resistance in mice fed the HFD.

Topics: Alkaloids; Animals; Base Sequence; Benzodioxoles; Blotting, Western; Dietary Fats; DNA Primers; Endoplasmic Reticulum Chaperone BiP; Fatty Liver; HEK293 Cells; Humans; Insulin; Mice; Piperidines; Polymerase Chain Reaction; Polyunsaturated Alkamides; Signal Transduction

Life event stressors are the major vulnerability factors for the development of cognitive disorders. A vital therapeutic for stress related disorders is curcumin, derived from curry spice turmeric. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study was designed to investigate the effect of curcumin and its co-administration with piperine against chronic unpredictable stress (CUS)-induced cognitive impairment and oxidative stress in mice. Male Laca mice were subjected to undergo a battery of stressors for a period of 28 days. Vehicle/drugs were administered daily 30mins before CUS procedure. Chronic stress significantly impaired memory performance (delayed latency time to reach platform in Morris water maze as well as to reach closed arm in elevated plus maze test) and decreased locomotor activity along with sucrose consumption. Further, there was a significant impairment in oxidative parameters (elevated malondialdehyde, nitrite concentration and decreased reduced glutathione, catalase levels) and mitochondrial enzyme complex activities, along with raised acetylcholinesterase and serum corticosterone levels. Chronic treatment with curcumin (200 and 400mg/kg, p.o.) significantly improved these behavioral and biochemical alterations, restored mitochondrial enzyme complex activities and attenuated increased acetylcholinesterase and serum corticosterone levels. In addition, co-administration of piperine (20mg/kg; p.o.) with curcumin (100 and 200mg/kg, p.o.) significantly elevated the protective effect as compared to their effects alone. The results clearly suggest that piperine enhanced the bioavailability of curcumin and potentiated its protective effects against CUS induced cognitive impairment and associated oxidative damage in mice.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Chronic Disease; Cognition Disorders; Corticosterone; Curcumin; Cytochrome P-450 Enzyme Inhibitors; Dietary Sucrose; Drug Synergism; Food Preferences; Male; Maze Learning; Mice; Mice, Inbred Strains; Mitochondria; Motor Activity; Neuroprotective Agents; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Stress, Psychological; Uncertainty

A series of compounds related to piperine and antiepilepsirine was screened in a monoamine oxidase A and B assay. Piperine is an alkaloid from the source plant of both black and white pepper grains, Piper nigrum. Piperine has been shown to have a wide range of activity, including MAO inhibitory activity. The z-factor for the screening assay was found to be greater than 0.8 for both assays. Notably, the compounds tested were selective towards MAO-B, with the most potent compound having an IC(50) of 498 nM. To estimate blood-brain barrier (BBB) permeability, we used a PAMPA assay, which suggested that the compounds are likely to penetrate the BBB. A fluorescent bovine serum albumin (BSA) high-throughput screening (HTS) binding assay showed an affinity of 8 μM for piperine, with more modest binding for other test compounds. Taken together, the data described here may be useful in gaining insight towards the design of selective MAO-B inhibitory compounds devoid of MAO-A activity.

Topics: Alkaloids; Animals; Benzodioxoles; Binding Sites; Blood-Brain Barrier; Cattle; Humans; Hydrogen Bonding; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Protein Binding; Protein Structure, Tertiary; Serum Albumin, Bovine

The effect of piperine on the pharmacokinetics and pharmacodynamics of glimepiride in normal as well as diabetic rats was studied. In normal and streptozotocin induced diabetic rats the combination of glimepiride with piperine increased all the pharmacokinetic parameters, such as Cmax, AUC0-n, AUCtotal, t1/2, and MRT, and decreased the clearance, Vd, markedly as compared with the control group. In pharmacodynamic studies, the combination of glimepiride with piperine provided significant protection against the diabetes induced alterations in the biochemical parameters. In addition, the combination of glimepiride with piperine also improved the total antioxidant status significantly in diabetic rats compared with piperine and glimepiride treated groups. The results revealed that a combination of glimepiride with piperine led to the enhancement of the bioavailability of glimepiride by inhibiting the CYP2C9 enzyme, which suggested that piperine might be beneficial as an adjuvant to glimepiride in a proper dose, in diabetic patients.

Topics: Alanine Transaminase; Alkaloids; Animals; Antioxidants; Area Under Curve; Aspartate Aminotransferases; Benzodioxoles; Blood Glucose; Body Weight; Cholesterol; Chromatography, High Pressure Liquid; Diabetes Mellitus, Experimental; Hypoglycemic Agents; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Sulfonylurea Compounds; Triglycerides

In the present study, the anti-inflammatory effect of piperine was investigated on monosodium urate crystal-induced inflammation in mice, an experimental model for gouty arthritis, and compared it with that of the nonsteroidal anti-inflammatory drug, indomethacin. The levels of lysosomal enzymes, lipid peroxidation, tumor necrosis factor-α, and paw volume were increased significantly, and the activities of antioxidant status were in turn decreased in monosodium urate crystal-induced mice, whereas these changes were reverted to near normal levels upon piperine (30 mg/kg b.wt, i.p.) treatment. In vitro, piperine (50/100 ug/ml) suppressed the level of β-glucuronidase and lactate dehydrogenase in monosodium urate crystal-incubated polymorphonuclear leucocytes in concentration-dependent manner when compared to control cells. Thus, the present study clearly indicated that piperine inhibit the monosodium urate crystal-induced inflammation and can be regarded as therapeutic drug for the treatment of acute gouty arthritis.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Arthritis, Gouty; Benzodioxoles; Disease Models, Animal; Female; Humans; In Vitro Techniques; Indomethacin; Lipid Peroxidation; Lysosomes; Male; Mice; Neutrophils; Piperidines; Polyunsaturated Alkamides; Tumor Necrosis Factor-alpha; Uric Acid

Although spice compounds have several pharmacological and biochemical actions such as antioxidant activity, their physiological effects on neuropeptides related to feeding regulation are not well known. The aim of the present study was to identify the pharmacological activities of spice compounds on appetite regulation using a goldfish (Carassius auratus) model with emphasis on the role of neuropeptides. The spice compounds used in this study were curcumin, piperine, and ursolic acid. Goldfish were injected intraperitoneally with test solutions containing each spice or vehicle (including 10% dimethyl sulfoxide in saline), and the changes in food intake were measured every 15 min for 60 min. Among the tested spice compounds, curcumin was found to reduce cumulative food intake and was thus selected for further experiments. Pretreatment with capsaicin, a neurotoxin of afferent nerves, abolished the curcumin-induced decrease of food intake. Curcumin-induced anorexigenic action was also attenuated by intracerebroventricular injection of the corticotropin-releasing hormone (CRH) receptor antagonist α-helical CRH((9-41)). We also examined the expression levels of mRNA for CRH, which is a potent anorexigenic neuropeptide in goldfish, in the diencephalon at 1 h after treatment with curcumin, and found that they were increased. Therefore, the reduction of appetite induced by curcumin treatment in goldfish was suggested to be mediated by the vagal afferent and subsequently through the CRH/CRH receptor pathway.

Topics: Alkaloids; Animals; Appetite Depressants; Appetite Regulation; Benzodioxoles; Capsaicin; Corticotropin-Releasing Hormone; Curcumin; Eating; Enzyme Inhibitors; Feeding Behavior; Goldfish; Hormone Antagonists; Humans; Injections, Intraperitoneal; Molecular Structure; Peptide Fragments; Piperidines; Polyunsaturated Alkamides; Receptors, Corticotropin-Releasing Hormone; Sensory System Agents; Triterpenes; Ursolic Acid

Piperine, a major plant alkaloid found in black pepper (Piper nigrum) and long pepper (Piper longum), has shown potential for inhibiting the efflux pump (EP) of Staphylococcus aureus. In this study, a modulation assay showed that piperine could decrease the MIC of ethidium bromide (EtBr) twofold at 32 μg ml(-1) and fourfold at 64 μg ml(-1) against Mycobacterium smegmatis mc(2) 155 ATCC 700084. A real-time, 96-well plate fluorometric method was employed to evaluate the EP inhibition ability of piperine in M. smegmatis. Reserpine, chlorpromazine, verapamil and carbonyl cyanide m-chlorophenylhydrazone were used as positive controls. Piperine significantly enhanced accumulation and decreased the efflux of EtBr in M. smegmatis, which suggests that it has the ability to inhibit mycobacterial EPs.

Topics: Alkaloids; Anti-Bacterial Agents; Benzodioxoles; Biological Transport; Enzyme Inhibitors; Ethidium; Microbial Sensitivity Tests; Mycobacterium smegmatis; Piper; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Long-term treatment with haloperidol is associated with a number of extrapyramidal side effects, particularly the irregular movements of chorionic type. This limitation presents a marked therapeutic challenge. The present study investigates the molecular etiology of haloperidol neurotoxicity and the role of curcumin, a well-known anti-oxidant, in ameliorating these adverse effects. The redox status of haloperidol-treated brains along with NO, TNF-α, NF-kappaB p65 subunit, caspase-3, and monoamine neurotransmitters were measured in the striatum of rat brain. Chronic treatment with haloperidol (5 mg/kg, i.p., 21 days) produced orofacial dyskinetic movements which were coupled with marked increase in oxidative stress parameters, TNF-α, caspase-3 activity in cytoplasmic lysate and active p65 sub unit of NF-kappaB in nuclear lysates of the striatum. Neurochemically, chronic administration of haloperidol resulted in a significant decrease in the levels of norepinephrine, dopamine, and serotonin. The prototype atypical anti-psychotic, clozapine (10 mg/kg, i.p., 21 days) produced mild oxidative stress but did not alter any other parameters. Interestingly, co-administration of curcumin (25 and 50 mg/kg, i.p., 21 days) dose-dependently prevented all the behavioral, cellular, and neurochemical changes associated with the chronic administration of haloperidol. Curcumin per se (50 mg/kg) did not show any side effects. Co-administration of piperine significantly enhanced the effect of curcumin (25 mg/kg) but not of curcumin (50 mg/kg). Collectively, the data indicated the potential of curcumin as an adjunct to haloperidol treatment and provided initial clues to the underlying molecular mechanisms in haloperidol neurotoxicity. This study also provides a rationale for the combination of piperine and curcumin.

Topics: Alkaloids; Analysis of Variance; Animals; Apoptosis; Behavior, Animal; Benzodioxoles; Caspase 3; Colorimetry; Curcumin; Cytokines; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Haloperidol; Inflammation; Male; Neuroprotective Agents; Neurotoxicity Syndromes; Neurotransmitter Agents; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Statistics as Topic; Thiobarbituric Acid Reactive Substances

Ethyl piperate is an effective lipid-lowering drug candidate synthesized from piperine. However, its pharmacokinetic characteristics and oral absorption process remain unclear. A liquid chromatography-tandem mass spectrometry method was applied to determine the oral bioavailability of ethyl piperate. Simulated gastrointestinal pH conditions and intestinal washings were prepared to investigate their contributions to the loss of ethyl piperate. Hydrolysis by carboxylesterase (CES) was evaluated in vitro using microsomes and S9 fractions. In situ intestinal single-pass perfusion experiments were performed to estimate the role of CES in ethyl piperate absorption. The bioavailability of ethyl piperate was extremely low (0.47%) in hamster independent of gastrointestinal environmental effects. Ethyl piperate was a typical substrate of CES with kinetic parameters K(m) and V(max) of 7.56 ± 1.491 μM and 0.16 ± 0.008 nmol · min(-1) · mg protein(-1), respectively. CES was responsible for 85.8% of the intestinal hydrolysis of ethyl piperate. Specific inhibition of CES with bis-p-nitrophenyl phosphate (BNPP), decreased degradation clearance to 36% of control with no significant change in absorption clearance. This contrasted with the results of Caco-2 monolayer experiments, which showed a dramatic increase in the apparent permeability coefficient after BNPP treatment. mRNA levels for the CES isozyme, CES2A3, were similar among the three regions of hamster intestine and 60% less than those in liver; CES1B1 mRNA levels were even lower in the intestine and showed a proximal-to-distal decrease. In conclusion, CES markedly contributes to intestinal first-pass hydrolysis of ethyl piperate that is sufficient, but not necessary, to cause the observed extremely low bioavailability.

Topics: Alkaloids; Animals; Anticholesteremic Agents; Benzodioxoles; Caco-2 Cells; Carboxylesterase; Cricetinae; Drug Stability; Fatty Acids, Unsaturated; Humans; Hydrolysis; Intestinal Absorption; Intestinal Mucosa; Male; Nitrophenols; Piperidines; Polyunsaturated Alkamides; RNA, Messenger

Piperine is a major component of black pepper, Piper nigrum Linn, used widely in traditional medicine. Several previous studies reported that piperine possesses various beneficial biological activities including antioxidant, anti-tumor and anti-inflammation properties. In the present study, we investigated the inhibitory effects of piperine on tumor invasion and migration and the possible mechanisms involved using human fibrosarcoma HT-1080 cells. We found that piperine suppresses PMA-enhanced matrix metalloproteinase-9 (MMP-9) expression at the protein, mRNA, and transcriptional levels through the suppression of NF-κB and AP-1 activation without changing the level of tissue inhibitor of metalloproteinase (TIMP)-1. Piperine also inhibits PMA-enhanced membrane-type 1 MMP expression without changing the level of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Piperine inhibited PMA-induced NF-κB and c-Jun nuclear translocation, which are upstream of PMA-induced MMP-9 expression and invasion. Furthermore, piperine strongly repressed the PMA-induced phosphorylation of ERK, which are dependent on the PKCα pathway. In conclusion, we demonstrated that the anti-invasive effects of piperine may occur through inhibition of PKCα and ERK phosphorylation and reduction of NF-κB and AP-1 activation, leading to down-regulation of MMP-9 expression. Thus, piperine has potential as a potent anti-cancer drug in therapeutic strategies for fibrosarcoma metastasis.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Benzodioxoles; Cell Line, Tumor; Cell Movement; Dose-Response Relationship, Drug; Down-Regulation; Fibrosarcoma; Gene Expression Regulation, Enzymologic; Humans; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasm Invasiveness; NF-kappa B; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Protein Kinase C-alpha; Proto-Oncogene Proteins c-jun; RNA, Messenger; Signal Transduction; Tetradecanoylphorbol Acetate; Time Factors; Transcription Factor AP-1; Transcription, Genetic; Transfection

Piperine is a major alkaloid of black pepper (Piper nigrum Linn.) and long pepper (P. longum Linn.), and its antidepressant-like effect has been previously demonstrated. The purpose of this study was to explore the possible contribution of the serotonergic system in the antidepressant-like effect of piperine in mice. The results showed that piperine significantly reduced the immobility time in the forced swim test and tail suspension test in mice. The anti-immobility effect of piperine in the forced swim test and tail suspension test was completely abolished by pre-treating the mice with pCPA (an inhibitor of 5-HT synthesis). Piperine treatment also significantly potentiated the number of head-twitches of mice induced by 5-HTP (a metabolic precursor to 5-HT). In addition, the neurochemical assays showed that piperine produced a marked increase of 5-HT level in both the hippocampus and frontal cortex of mice. Taken together, these results clearly suggest that the antidepressant-like effect of piperine is mediated via the serotonergic system by enhancing 5-HT content in mouse brain.

Topics: 5-Hydroxytryptophan; Alkaloids; Analysis of Variance; Animals; Antidepressive Agents; Behavior, Animal; Benzodioxoles; Brain Chemistry; Cerebral Cortex; Fenclonine; Fluoxetine; Hindlimb Suspension; Hippocampus; Male; Mice; Mice, Inbred ICR; Piperidines; Polyunsaturated Alkamides; Selective Serotonin Reuptake Inhibitors; Serotonin; Swimming

The endophytic fungus Periconia sp. produces piperine (5-(3, 4-methylenedioxyphenyl)-1-piperidinopent-2, 4-dien-1-one) under liquid culture. This is the first report of the alternative source for this chemical other than its host, Piper longum. The highly functionalized fungus-derived piperine exhibits strong antimycobacterial activity against Mycobacterium tuberculosis and M. smegmetis with minimum inhibitory concentrations of 1.74 and 2.62 μg ml(-1), respectively. The compound was crystallized and the structure was elucidated by single-crystal X-ray crystallography. This finding is of significance as piperine is a potential cancer preventative agent. It is reaffirmed by this report that important pharmaceuticals can be produced by endophytic microbes, and these molecules appear to be mimetic to their host origin. Therefore, we can enhance the bioactive principles of medicinal plants by isolating and identifying the endophytes, thereby showing the importance of preserving the biodiversity of these plants.

Topics: Alkaloids; Anti-Bacterial Agents; Ascomycota; Benzodioxoles; Crystallization; Crystallography, X-Ray; Culture Media; Microbial Sensitivity Tests; Mycobacterium smegmatis; Mycobacterium tuberculosis; Piper; Piperidines; Polyunsaturated Alkamides

The present study was carried out to determine the effects of lyophilized dried fruit extracts of Piper nigrum and pure piperine on the tadpole melanophores of frog Rana tigerina which offer excellent in vitro opportunities for studying the effects of pharmacological and pharmaceutical agents. The nature of specific cellular receptors present on the neuro-melanophore junction and their involvement in pigmentary responses has been explored.. Effects of lyophilized extracts of P. nigrum and pure piperine were studied on the isolated tail melanophores of tadpoles of the frog R. tigerina as per the modified method.. The extract of P. nigrum and its active ingredient piperine caused significant melanin dispersal responses leading to darkening of the tail melanophores, which were completely antagonized by atropine and hyoscine. These per se melanin dispersal effects were also found to be markedly potentiated by neostigmine an anticholinesterase agent.. It appears that the melanin dispersal effects of the extracts of P. nigrum and pure piperine leading to skin darkening are mediated by cholinergic muscarinic or piperine-like receptors having similar properties.

Topics: Acetylcholine; Alkaloids; Animals; Atropine; Benzodioxoles; Butylscopolammonium Bromide; Cholinesterase Inhibitors; Larva; Melanins; Melanophores; Molecular Structure; Muscarinic Antagonists; Neostigmine; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Ranidae; Receptors, Cholinergic

Piperine is a phenolic component of black pepper (Piper nigrum) and long pepper (Piper longum), fruits used in traditional Asian medicine. Our previous study showed that piperine inhibits lipopolysaccharide-induced inflammatory responses. In this study, we investigated whether piperine reduces the severity of cerulein-induced acute pancreatitis (AP). Administration of piperine reduced histologic damage and myeloperoxidase (MPO) activity in the pancreas and ameliorated many of the examined laboratory parameters, including the pancreatic weight (PW) to body weight (BW) ratio, as well as serum levels of amylase and lipase and trypsin activity. Furthermore, piperine pretreatment reduced the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 during cerulein-induced AP. In accordance with in vivo results, piperine reduced cell death, amylase and lipase activity, and cytokine production in isolated cerulein-treated pancreatic acinar cells. In addition, piperine inhibited the activation of mitogen-activated protein kinases (MAPKs). These findings suggest that the anti-inflammatory effect of piperine in cerulein-induced AP is mediated by inhibiting the activation of MAPKs. Thus, piperine may have a protective effect against AP.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Benzodioxoles; Ceruletide; Enzyme Activation; Interleukin-1beta; Interleukin-6; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Pancreatitis; Piperidines; Polyunsaturated Alkamides; Tumor Necrosis Factor-alpha

To measure the interactions of diacylglycerol acyltransferase (DGAT) by surface plasmon resonance (SPR), we immobilized Saccharomyces cerevisiae DGAT2 encoded by DGA1 on a BIACORE sensor chip surface. We used N-terminally truncated Dga1p with a FLAG tag at the C-terminus, which was purified to apparent homogeneity, maintaining significant DGAT activity (Kamisaka et al., Appl. Microbiol. Biotechnol., 88, 105-115 (2010)). Truncated Dga1p with a FLAG tag was immobilized with an anti-FLAG antibody that had been coupled with an L1 chip surface consisting of a carboxymethyl dextran matrix with additional hydrophobic alkane groups. The Dga1p-immobilized chip surface was analyzed for interactions of Dga1p with oleoyl-CoA, its substrate, and anti-Dga1p IgG, its interacting protein, by SPR. The binding of these analytes with the Dga1p-immobilized chip surface was specific, because butyryl-CoA, which cannot be used as a substrate for DGAT, and anti-glyceraldehyde-3-phosphate dehydrogenase IgG, did not induce any signals on SPR. Furthermore, injection of organic compounds such as xanthohumol, a DGAT inhibitor, into the Dga1p-immobilized chip surface induced significant SPR signals, probably due to interaction with DGAT. Another DGAT inhibitor, piperine, did not induce SPR signals on application, but induced them due to piperine on application together with oleoyl-CoA, in which piperine can be incorporated into the micelles of oleoyl-CoA. The results indicate that the Dga1p-immobilized L1 chip surface recognized DGAT inhibitors. Taking all this together, SPR measurement using the Dga1p-immobilized L1 chip surface provided a useful system to elucidate the structure-function relationships of DGAT and screen DGAT inhibitors.

Topics: Acyl Coenzyme A; Alkaloids; Alkanes; Antibodies; Benzodioxoles; Dextrans; Diacylglycerol O-Acyltransferase; Enzyme Inhibitors; Enzymes, Immobilized; Flavonoids; High-Throughput Screening Assays; Lab-On-A-Chip Devices; Oligopeptides; Peptides; Piperidines; Polyunsaturated Alkamides; Propiophenones; Protein Binding; Saccharomyces cerevisiae; Structure-Activity Relationship; Substrate Specificity; Surface Plasmon Resonance

Piperine, a trans-trans-isomer of 1-piperoyl-piperidine, was tested in combination with mupirocin for antimicrobial activity against Staphylococcus aureus strains including meticillin-resistant S. aureus. The combination markedly reduced the MIC of mupirocin and also lowered the mutation frequency. Enhanced accumulation and efflux of ethidium bromide from wild-type and mutant (Mup(r)-1) strains in the presence of piperine indicated that inhibition of efflux could be a possible mechanism of potentiation of mupirocin activity by piperine. The combination of piperine with mupirocin in a dermal infection model of mice showed better in vivo efficacy when compared with the commercially available formulation of 2 % mupirocin.

Topics: Alkaloids; Animals; Anti-Bacterial Agents; Bacterial Proteins; Benzodioxoles; Disease Models, Animal; Drug Synergism; Enzyme Inhibitors; Ethidium; Female; Membrane Transport Proteins; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Mupirocin; Piperidines; Polyunsaturated Alkamides; Rodent Diseases; Staphylococcal Infections; Treatment Outcome

We examined the effects of TRPV1 agonists olvanil and piperine on glutamatergic spontaneous excitatory transmission in the substantia gelatinosa (SG) neurons of adult rat spinal cord slices with the whole-cell patch-clamp technique. Bath-applied olvanil did not affect the frequency and amplitude of spontaneous excitatory postsynaptic current (sEPSC), and unchanged holding currents at -70 mV. On the other hand, superfusing piperine reversibly and concentration-dependently increased sEPSC frequency (half-maximal effective concentration: 52.3 μM) with a minimal increase in its amplitude. This sEPSC frequency increase was almost repetitive at an interval of more than 20 min. Piperine at a high concentration produced an inward current in some neurons. The facilitatory effect of piperine was blocked by TRPV1 antagonist capsazepine. It is concluded that piperine but not olvanil activates TRPV1 channels in the central terminals of primary-afferent neurons, resulting in an increase in the spontaneous release of l-glutamate onto SG neurons.

Topics: Alkaloids; Animals; Benzodioxoles; Capsaicin; Excitatory Amino Acid Agents; Glutamates; Neurons; Patch-Clamp Techniques; Piperidines; Polyunsaturated Alkamides; Rats; Substantia Gelatinosa; Synaptic Transmission; TRPV Cation Channels

Resveratrol (3,5,4'-trihydroxystilbene) is a phytoalexin shown to possess a multitude of health-promoting properties in pre-clinical studies. However, the poor in vivo bioavailability of resveratrol due to its rapid metabolism is being considered as a major obstacle in translating its effects in humans. In this study, we examined the hypothesis that piperine will enhance the pharmacokinetic parameters of resveratrol via inhibiting its glucuronidation, thereby slowing its elimination.. Employing a standardized LC/MS assay, we determined the effect of piperine co-administration with resveratrol on serum levels resveratrol and resveratrol-3-O-β-D-glucuronide in C57BL mice. Mice were administered resveratrol (100 mg/kg; oral gavage) or resveratrol (100 mg/kg; oral gavage)+piperine (10 mg/kg; oral gavage), and the serum levels of resveratrol and resveratrol-3-O-β-D-glucuronide were analyzed at different times. We found that the degree of exposure (i.e. AUC) to resveratrol was enhanced to 229% and the maximum serum concentration (C(max)) was increased to 1544% with the addition of piperine.. Our study demonstrated that piperine significantly improves the in vivo bioavailability of resveratrol. However, further detailed research is needed to study the mechanism of improved bioavailability of resveratrol via its combination with piperine as well as its effect on resveratrol metabolism.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Drug Interactions; Glucuronides; Mice; Mice, Inbred C57BL; Piperidines; Polyunsaturated Alkamides; Resveratrol; Stilbenes

Over-expression of P-gp, MRP1 and BCRP in tumor cells is one of the important mechanisms leading to multidrug resistance (MDR), which impairs the efficacy of chemotherapy. P-gp, MRP1 and BCRP are ABC (ATP-Binding Cassette) transporters, which can expel a variety of lipophilic anti-cancer drugs and protect tumor cells. During a screening of MDR reversal agents among alkaloids of various structural types, a piperidine alkaloid, piperine (a main piperidine alkaloid in Piper nigurm) was identified as an inhibitor. Piperine can potentiate the cytotoxicity of anti-cancer drugs in resistant sublines, such as MCF-7/DOX and A-549/DDP, which were derived from MCF-7 and A-549 cell lines. At a concentration of 50 μM piperine could reverse the resistance to doxorubicin 32.16 and 14.14 folds, respectively. It also re-sensitized cells to mitoxantrone 6.98 folds. In addition, long-term treatment of cells by piperine inhibits transcription of the corresponding ABC transporter genes. These results suggest that piperine can reverse MDR by multiple mechanisms and it may be a promising lead compound for future studies.

Topics: Alkaloids; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Benzodioxoles; Cell Line, Tumor; Down-Regulation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Piper nigrum; Piperidines; Polyunsaturated Alkamides

To develop an HPLC method for determination of gallic acid, hydroxysafflor yellow A, cinnamic aldehyde and piperine in Tibetan medicine Dangzuo, and to compare the content of four active components in Dangzuo of different Tibetan regions.. The separation was carried out on a Waters XTerra RP-C18 column ( 4.6 mm x 250 mm, 5 microm). The mobile phases were methanol and water, all contained 0.1% glacial acetic acid, for gradient elution. The gradient program was as follows: 0-22.5 min, methanol was changed from 5% to 50%; 22.5-40 min, changed to 80% 80:20. The flow rate was 1.0 mL x min(-1). The detection wavelength was 270 nm. The reference wavelength was 500 nm.. The linear ranges of gallic acid, hydroxysafflor yellow A, cinnamic aldehyde and piperine were 0.040-0.640 microg (r = 0.999 8), 0.090-1.440 microg (r = 0.999 9), 0.031-0.500 microg (r = 0.999 9 ) and 0.092-41.477 microg (r = 0.998 9), respectively. The average recoveries (n = 6) were 97.42% (RSD 1.9%), 97.55% (RSD 2.9%), 98.69% (RSD 0.96%) and 96.72% (RSD 4.0%), respectively. The content ranges of gallic acid, hydroxysafflor yellow A, cinnamic aldehyde and piperine in Dangzuo samples of different Tibetan regions were 0.11341.69 mg x g(-1), 0.889-1.51 mg x g(-1), 0.000-40.606 mg x g(-1) and 1.96-2.73 mg x g(-1), respectively.. The method is a simple and effective for quality control of Tibetan medicine Dangzuo.

Topics: Acrolein; Alkaloids; Benzodioxoles; Chalcone; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Gallic Acid; Medicine, Tibetan Traditional; Piperidines; Plant Components, Aerial; Plant Extracts; Polyunsaturated Alkamides; Quality Control; Quinones; Reference Standards; Spectrophotometry, Ultraviolet

The present study was planned to investigate the antigenotoxic effects of curcumin and piperine separately and in combination against benzo(a)pyrene (BaP) induced DNA damage in lungs and livers of mice. Male Swiss albino mice received curcumin (100 mg kg(-1) body weight) and piperine (20 mg kg(-1) body weight) separately as well as in combination orally in corn oil for 7 days as pretreatments and subsequently, 2h after, BaP was administered orally in corn oil (125 mg kg(-1) body weight). A single dose of BaP to normal mice increased the level of 8-oxo-2'-deoxyguanosine (8-oxo-dG) content and % DNA in the comet tail in the lungs and liver. Pretreatments of curcumin and curcumin plus piperine before administration of single dose of BaP significantly decreased the levels of 8-oxo-dG content and % DNA in the comet tail in both the tissues. Moreover, the genoprotective potential of curcumin plus piperine was significantly higher as compared to curcumin alone against BaP induced DNA damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alkaloids; Animals; Benzo(a)pyrene; Benzodioxoles; Comet Assay; Curcumin; Deoxyguanosine; DNA Damage; Drug Synergism; Enzyme-Linked Immunosorbent Assay; Hepatocytes; Liver; Lung; Male; Mice; Piperidines; Polyunsaturated Alkamides

The antioxidant effect and potential mechanism of nitroxide radical-containing nanoparticles (RNPs) coupled with piperine (PI) were investigated in human neuroblastoma SH-SY5Y cells. The effects of RNP/PI on SH-SY5Y cell lines was determined by WST assay for cell viability, nitroblue tetrazolium and deoxyribose assay for reactive oxygen species generation, ELISA assay for reactive oxygen species products and apoptotic cell death, and biochemical techniques for catalase and glutathione peroxidase activity. The RNP/PI significantly reduced the reactive oxygen species level and reactive oxygen species products compared with those of cells treated with RNPs alone. The RNP/PI treatment enhanced catalase and glutathione peroxidase activity. The combination of RNP/PI has been found to have an augmented antioxidant effect on an Alzheimer's model in vitro. The mechanism of the protective effect of this combination therapy was correlated in this study with its ability to reduce the generation of reactive oxygen species and prevent apoptosis via scavenging enzyme action pathways.

Topics: Alkaloids; Amyloid beta-Peptides; Apoptosis; Benzodioxoles; Cell Line, Tumor; Humans; Nanoparticles; Neuroblastoma; Nitrogen Oxides; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Reactive Oxygen Species

Leishmaniasis is a tropical disease caused by protozoan parasites of the genus Leishmania which affects 12 million people worldwide. The discovery of drugs for the treatment of leishmaniasis is a pressing concern in global health programs. The aim of this study aim was to evaluate the leishmanicidal effect of piperine and its derivatives/analogues on Leishmania amazonensis. Our results showed that piperine and phenylamide are active against promastigotes and amastigotes in infected macrophages. Both drugs induced mitochondrial swelling, loose kinetoplast DNA, and led to loss of mitochondrial membrane potential. The promastigote cell cycle was also affected with an increase in the G1 phase cells and a decrease in the S-phase cells, respectively, after piperine and phenylamide treatment. Lipid analysis of promastigotes showed that piperine reduced triglyceride, diacylglycerol, and monoacylglycerol contents, whereas phenylamide only reduced diacylglycerol levels. Both drugs were deemed non toxic to macrophages at 50 μM as assessed by XTT (sodium 2,3,-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl]-2H-tetrazolium inner salt), Trypan blue exclusion, and phagocytosis assays, whereas low toxicity was noted at concentrations higher than 150 μM. None of the drugs induced nitric oxide (NO) production. By contrast, piperine reduced NO production in activated macrophages. The isobologram analysis showed that piperine and phenylamide acted synergistically on the parasites suggesting that they affect different target mechanisms. These results indicate that piperine and its phenylamide analogue are candidates for development of drugs for cutaneous leishmaniasis treatment.

Topics: Alkaloids; Amides; Benzodioxoles; Cell Cycle; Fruit; Glycerides; Leishmania; Leishmaniasis; Leishmaniasis, Cutaneous; Lipid Metabolism; Macrophages; Mitochondria; Nitric Oxide; Phytotherapy; Piper; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Trypanocidal Agents

The alkaloids from Piper longum L. showed protective effects on Parkinson's disease models in our previous study and piperine and piperlonguminine were the two main constituents in the alkaloids. The present study aimed at developing a rapid, sensitive, and accurate UFLC-ESI-MS/MS method and validating it for the simultaneous determination of piperine and piperlonguminine in rat plasma using terfenadine as the internal standard. The analytes and internal standard (IS) were extracted from rat plasma using a simple protein precipitation by adding methanol/acetonitrile (1:1, v/v). A Phenomenex Gemini 3 u C18 column (20 mm × 2.00 mm, 3 μm) was used to separate the analytes and IS using a gradient mode system with a mobile phase consisting of water with 0.1% formic acid (mobile phase A) and acetonitrile with 0.1% formic acid (mobile phase B) at a flow rate of 0.4 mL/min and an operating column temperature of 25°C. The total analytical run time was 4 min. The detection was performed using the positive ion electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode with transitions at m/z 286.1-201.1 for piperine, m/z 274.0-201.1 for piperlonguminine, and m/z 472.4-436.4 for the IS. The calibration curves were both linear (r>0.995) over a concentration range of 1.0 to 1000 ng/mL; the lower limit of quantification (LLOQ) was 1.0 ng/mL for both piperine and piperlonguminine. The intra-day and inter-day precisions (RSD %) were <12.1%, accuracies ranged from 86.6 to 120%, and recoveries ranged from 90.4 to 108%. The analytes were proven stable in the short-term, long-term, and after three freeze-thaw cycles. The method was successfully applied to pharmacokinetic studies of piperine and piperlonguminine in rats after oral administration of alkaloids from P. longum L.

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Chromatography, High Pressure Liquid; Dioxolanes; Drug Stability; Least-Squares Analysis; Male; Piper; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

Our previous studies have showed that treating mice with piperine significantly decreased the immobility time of the animals in the forced swim test and tail suspension test, which was related to up-regulation of serotonin (5-HT) level in the brain. The purpose of this study is to explore the contribution of 5-HT receptors in the antidepressant-like effect of piperine. The results showed that pre-treating mice with methiothepin (a non-selective 5-HT receptor antagonist, 0.1mg/kg, intraperitoneally), 4-(2'-methoxy-phenyl)-1-[2'-(n-2″-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (a selective 5-HT(1A) receptor antagonist, 1mg/kg, subcutaneously) or 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (a 5-HT(1B) receptor antagonist, 2.5mg/kg, intraperitoneally) was found to abolish the anti-immobility effect of piperine (10mg/kg, intraperitoneally) in the forced swim test. On the other hand, a sub-effective dose of piperine (1mg/kg, intraperitoneally) produced a synergistic antidepressant-like effect with (+)-8-hydroxy-2-(di-n-propylamino)tetralin (a 5-HT(1A) receptor agonist, 1mg/kg, intraperitoneally) or anpirtoline (a 5-HT(1B) receptor agonist, 0.25mg/kg, intraperitoneally). Taken together, these results suggest that the antidepressant-like effect of piperine in the mouse forced swim test may be mediated, at least in part, by the activation of 5-HT(1A) and 5-HT(1B) receptors.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Alkaloids; Aminopyridines; Animals; Antidepressive Agents; Benzodioxoles; Data Interpretation, Statistical; Male; Methiothepin; Mice; Mice, Inbred ICR; Motor Activity; Piperazines; Piperidines; Polyunsaturated Alkamides; Propanolamines; Pyridines; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT1B; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Swimming

Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of ibuprofen evaluated by both acetic acid writhing and formalin test, when it was administered with ibuprofen. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of ibuprofen when administered with piperine can be attributed to increased plasma concentration of ibuprofen. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen.

Topics: Acetic Acid; Alkaloids; Analgesics; Animals; Benzodioxoles; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Enzyme Inhibitors; Formaldehyde; Fruit; Ibuprofen; Indicators and Reagents; Male; Mice; Pain Measurement; Piper nigrum; Piperidines; Polyunsaturated Alkamides

In patients with epilepsy, a common comorbidity diagnosed is depression. Temporal lobe epilepsy or post status epilepticus (SE) animal model establish and validate the co morbidity and common pathogenesis of depression and epilepsy. Elevation in serotonin concentration gives an inhibitory response to epileptic discharge and stabilizes the depressed mood disorder. Piperine is a potent monoaminooxidase inhibitor and stimulates the synthesis of serotonin. So the present work is undertaken to investigate the effect of piperine on depression associated with by status epilepticus induced by pilocarpine in rats.. Status epilepticus was induced in the rats by administration of pilocarpine 350 mg/kg i.p.. Behaviour tests like forced swimming test (FST), saccharin consumption test, actophotometer test and rotarod test were conducted. Antidepressant effect and neuroprotective effect of piperine (25 mg/kg, p.o. for 10 days) in post status epilepticus animal model was evaluated. Brain serotonin concentration was also estimated. Fluoxetine (20 mg/kg p.o.) was used as standard.. Only piperine but not fluoxetine significantly increased the decrease in number of rotations of wheel in FST, and decrease volume of saccharine consumption caused by pilocarpine. Both fluoxetine and piperine significantly increase the pilocarpine induced decrease in activity score in actophotometer, time taken to fall in rotarod and concentration of serotonin in brain.. The underlying mechanism behind depression in epilepsy may be alteration in monoaminergic pathways and GABAergic pathways. The antidepressant activity of piperine in post-SE rats may be attributed to its MAO inhibitor activity and neuroprotective activity.

Topics: Alkaloids; Anhedonia; Animals; Anticonvulsants; Behavior, Animal; Benzodioxoles; Biogenic Monoamines; Brain Chemistry; Chromatography, Thin Layer; Convulsants; Depression; Epilepsy; Female; Fluoxetine; Male; Motor Activity; Pilocarpine; Piperidines; Polyunsaturated Alkamides; Postural Balance; Rats; Serotonin; Spectrophotometry, Infrared; Status Epilepticus; Swimming

In this study we examined the antioxidant effect of curcumin on lipid oxidation in vitro and in vivo. In vitro, curcumin at 5 microgM concentration completely prevented low-density lipoprotein (LDL) oxidation by CuS0(4), indicating that curcumin is an effective antioxidant in vitro. In vivo, feeding a pure cholesterol (PC)-rich diet to rabbits significantly increased the plasma and liver lipids as well as thiobarbituric acid reactive substances (TBARS) levels. Addition of curcumin to the PC diet did not show any effect on either plasma lipid and TBARS or liver lipids. Liver TBARS tended to decrease but that decrease was not significant. Erythrocyte glutathione peroxidase (GSH-Px) activity was significantly decreased while catalase activity was significantly increased in rabbits fed a PC diet. The addition of curcumin to a PC diet did not show any significant effect on erythrocyte enzyme activities compared to the rabbits fed a PC diet. The liver GSH-Px and catalase activities were significantly decreased in rabbits fed a PC diet, but the addition of curcumin to the PC diet enhanced the liver GSH-Px activity, which became nonsignificantly different from the control group. These results were discussed considering that curcumin may not be well absorbed and it did not reach a level high enough in vivo to overcome the severe hypercholesterolemia and oxidative stress produced by the PC-rich diet.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Catalase; Cholesterol, Dietary; Curcumin; Glutathione Peroxidase; Hypercholesterolemia; Lipid Peroxidation; Lipids; Lipoproteins, LDL; Liver; Male; Oxidation-Reduction; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Rabbits

The cancer stem cell hypothesis asserts that malignancies arise in tissue stem and/or progenitor cells through the dysregulation or acquisition of self-renewal. In order to determine whether the dietary polyphenols, curcumin, and piperine are able to modulate the self-renewal of normal and malignant breast stem cells, we examined the effects of these compounds on mammosphere formation, expression of the breast stem cell marker aldehyde dehydrogenase (ALDH), and Wnt signaling. Mammosphere formation assays were performed after curcumin, piperine, and control treatment in unsorted normal breast epithelial cells and normal stem and early progenitor cells, selected by ALDH positivity. Wnt signaling was examined using a Topflash assay. Both curcumin and piperine inhibited mammosphere formation, serial passaging, and percent of ALDH+ cells by 50% at 5 microM and completely at 10 microM concentration in normal and malignant breast cells. There was no effect on cellular differentiation. Wnt signaling was inhibited by both curcumin and piperine by 50% at 5 microM and completely at 10 microM. Curcumin and piperine separately, and in combination, inhibit breast stem cell self-renewal but do not cause toxicity to differentiated cells. These compounds could be potential cancer preventive agents. Mammosphere formation assays may be a quantifiable biomarker to assess cancer preventive agent efficacy and Wnt signaling assessment can be a mechanistic biomarker for use in human clinical trials.

Topics: Aldehyde Dehydrogenase; Alkaloids; Antineoplastic Combined Chemotherapy Protocols; Benzodioxoles; Breast; Breast Neoplasms; Cell Differentiation; Cell Proliferation; Cells, Cultured; Curcumin; Female; Humans; Immunoenzyme Techniques; Neoplastic Stem Cells; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Wnt Proteins

Chemosensory signaling by the tongue is a primary determinant of ingestive behavior and is mediated by specific interactions between tastant molecules and G protein-coupled and ion channel receptors. The functional relationship between tastant and receptor should be amenable to pharmacologic methods and manipulation. We have performed a pharmacologic characterization of the taste-directed licking of mice presented with solutions of capsaicin and other transient receptor potential vanilloid-1 (TRPV1) agonists using a brief access taste aversion assay. Dose-response functions for lick-rate suppression were established for capsaicin (EC(50) = 0.5 microM), piperine (EC(50) = 2 muM), and resiniferatoxin (EC(50) = 0.02 microM). Little or no effect on lick rate was observed in response to the full TRPV1 agonist olvanil. Capsaicin lick rates of wild-type and transient receptor potential melastatin-5 (TRPM5) knockout mice were equivalent, indicating that TRPM5, a critical component of aversive signaling for many bitter tastants, did not contribute to the capsaicin taste response. The selective TRPV1 antagonists N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (10 microM) and (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide (AMG9810) (10 microM) effectively blocked capsaicin- and piperine-mediated lick suppression. However, (E)-3-(4-chlorophenyl)-N-(3-methoxyphenyl)-N-phenylprop-2-enamide (SB 366791) and capsazepine, also TRPV1 antagonists, were without effect at test concentrations of up to 30 and 100 microM, respectively. Our results demonstrate that TRPV1-mediated oral aversiveness presents a pharmacologic profile differing from what has been reported previously for TRPV1 pain signaling and, furthermore, that aversive tastes can be evaluated and controlled pharmacologically.

Topics: Acrylamides; Administration, Oral; Alkaloids; Anilides; Animals; Avoidance Learning; Benzodioxoles; Bridged Bicyclo Compounds, Heterocyclic; Capsaicin; Cinnamates; Diterpenes; Dose-Response Relationship, Drug; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines; Polyunsaturated Alkamides; Pyrazines; Pyridines; Taste; TRPM Cation Channels; TRPV Cation Channels

Several studies have revealed piperine and a few related compounds as potent inhibitors of monoamine oxidases without delineating the underlying mechanism. Using in silico modelling, we propose a structural basis of such activity by showing that these compounds can successfully dock into the inhibitor binding pockets of human monoamine oxidase isoforms with predicted affinities comparable to some known inhibitors. The results therefore suggest that piperine can be a promising lead for developing novel monoamine oxidase inhibitors.

Topics: Alkaloids; Animals; Benzodioxoles; Binding Sites; Brain; Computer Simulation; Drug Design; Humans; Mice; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Polyunsaturated Alkamides; Rats; Structure-Activity Relationship

Recently, numerous medicinal plants possessing profound central nervous system effects and antioxidant activity have received much attention as food supplement to improve cognitive function against cognitive deficit condition including in Alzheimer's disease condition. Based on this information, the effect of piperine, a main active alkaloid in fruit of Piper nigrum, on memory performance and neurodegeneration in animal model of Alzheimer's disease have been investigated. Adult male Wistar rats (180-220 g) were orally given piperine at various doses ranging from 5, 10 and 20mg/kg BW at a period of 2 weeks before and 1 week after the intracerebroventricular administration of ethylcholine aziridinium ion (AF64A) bilaterally. The results showed that piperine at all dosage range used in this study significantly improved memory impairment and neurodegeneration in hippocampus. The possible underlying mechanisms might be partly associated with the decrease lipid peroxidation and acetylcholinesterase enzyme. Moreover, piperine also demonstrated the neurotrophic effect in hippocampus. However, further researches about the precise underlying mechanism are still required.

Topics: Acetylcholinesterase; Alkaloids; Alzheimer Disease; Animals; Aziridines; Benzodioxoles; Choline; Cognition Disorders; Donepezil; Hippocampus; Indans; Injections, Intraventricular; Lipid Peroxidation; Male; Malondialdehyde; Maze Learning; Nerve Degeneration; Neuromuscular Blocking Agents; Neuroprotective Agents; Nootropic Agents; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Space Perception; Thailand

A plant extract library was screened for GABA(A) receptor activity making use of a two-microelectrode voltage clamp assay on Xenopus laevis oocytes. An ethyl acetate extract of black pepper fruits [Piper nigrum L. (Piperaceae) 100 microg/mL] potentiated GABA-induced chloride currents through GABA(A) receptors (composed of alpha(1), beta(2), and gamma(2S) subunits) by 169.1 +/- 2.4%. With the aid of an HPLC-based activity profiling approach, piperine (5) was identified as the main active compound, together with 12 structurally related less active or inactive piperamides (1-4, 6-13). Identification was achieved by on-line high-resolution mass spectrometry and off-line microprobe 1D and 2D NMR spectroscopy, using only milligram amounts of extract. Compound 5 induced a maximum potentiation of the chloride currents by 301.9 +/- 26.5% with an EC(50) of 52.4 +/- 9.4 microM. A comparison of the modulatory activity of 5 and other naturally occurring piperamides enabled insights into structural features critical for GABA(A) receptor modulation. The stimulation of chloride currents through GABA(A) receptors by compound 5 was not antagonized by flumazenil (10 microM). These data show that piperine (5) represents a new scaffold of positive allosteric GABA(A) receptor modulators targeting a benzodiazepine-independent binding site.

Topics: Alkaloids; Animals; Benzodiazepines; Benzodioxoles; Binding Sites; Chloride Channels; Chromatography, High Pressure Liquid; Female; Flumazenil; Fruit; GABA Modulators; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Oocytes; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Receptors, GABA-A; Xenopus laevis

In the present investigation, a UPLC-qTOF-MS/MS method has been developed for the simultaneous determination of etoposide and a piperine analogue, namely, 4-ethyl 5-(3,4-methylenedioxyphenyl)-2E,4E-pentadienoic acid piperidide (PA-1). The analytes were separated on a reverse phase C18 column using methanol-water (72:28, v/v) mobile phase with a flow rate of 250 microL/min. The qTOF-MS was operated under multiple reaction monitoring mode using electro-spray ionization (ESI) technique with positive ion polarity. The major product ions for etoposide and PA-1 were at m/z 185.1350 and 164.1581, respectively. The recovery of the analytes from mouse plasma was optimized using solid phase extraction technique. The total run time was 6 min and the elution of etoposide and PA-1 occurred at 1.24 and 2.84 min, respectively. The calibration curves of etoposide as well as PA-1 were linear over the concentration range of 2-1000 ng/mL (r(2), 0.9829), and 1-1000 ng/mL (r(2), 0.9989), respectively. For etoposide intra-assay and inter-assay accuracy in terms of % bias was in between -7.65 to +6.26, and -7.83 to +5.99, respectively. For PA-1 intra-assay and inter-assay accuracy in terms of % bias was in between -7.01 to +9.10, and -7.36 to +6.71, respectively. The lower limit of quantitation for etoposide and PA-1 were 2.0 and 1.0 ng/mL, respectively. Analytes were stable under various conditions (in autosampler, during freeze-thaw, at room temperature, and under deep-freeze conditions). The method was used for a pharmacokinetic study which showed that PA-1 enhanced the oral bioavailability of etoposide in mice by 2.32-fold.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Benzodioxoles; Biological Availability; Chromatography, High Pressure Liquid; Drug Carriers; Etoposide; Mice; Piperidines; Polyunsaturated Alkamides; Tandem Mass Spectrometry

The beneficial influence of three common spices was examined in experimental rats on: (i) the membrane fluidity of intestinal brush-border membranes (BBM), (ii) the activity of intestinal membrane-bound enzymes, and (iii) ultrastructural alterations in the intestinal epithelium. Groups of male Wistar rats were maintained on dietary black pepper (0.5 %), red pepper (3.0 %), ginger (0.05 %) and spice bioactive compounds piperine (0.02 %) and capsaicin (0.01 %) for 8 weeks. A membrane fluidity study using an apolar fluorescent probe showed increased BBM fluidity in all the spice-fed animals. This was corroborated by a decreased cholesterol:phospholipid ratio in the jejunal and ileal regions of the intestine. These dietary spices stimulated the activities of BBM enzymes (glycyl-glycine dipeptidase, leucine amino peptidase and gamma-glutamyl transpeptidase) in the jejunal mucosa, suggesting a modulation in membrane dynamics due to the apolar spice bioactive compounds interacting with surrounding lipids and hydrophobic portions in the protein vicinity, which may decrease the tendency of membrane lipids to act as steric constraints to enzyme proteins and thus modify enzyme conformation. Scanning electronic microscopy of the intestinal villi in these spice treatments revealed alterations in the ultrastructure, especially an increase in microvilli length and perimeter which would mean a beneficial increase in the absorptive surface of the small intestine, providing for an increased bioavailability of micronutrients. Thus, dietary spices (black pepper, red pepper and ginger) were evidenced to induce alterations in BBM fluidity and passive permeability property, associated with the induction of an increased microvilli length and perimeter, resulting in an increased absorptive surface of the small intestine.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Capsaicin; Capsicum; Cell Membrane; Cholesterol; Diet; Enterocytes; Enzymes; Gastrointestinal Agents; Hydrophobic and Hydrophilic Interactions; Intestinal Absorption; Intestinal Mucosa; Intestine, Small; Lipid Metabolism; Magnoliopsida; Male; Membrane Fluidity; Microscopy, Electron, Scanning; Microvilli; Phospholipids; Piper nigrum; Piperidines; Plant Preparations; Polyunsaturated Alkamides; Protein Conformation; Rats; Rats, Wistar; Spices; Zingiber officinale

A series of natural and synthetic piperine amides were evaluated for activity on the human TRPV1 expressed in HEK293 cells. The agonistic effect of piperine amides was mainly dependent on the length of the carbon chain. Structural changes of double bonds and stereochemistry in the aliphatic chain of these compounds did not change their potency or efficacy, indicating that increased rigidity or planarity of the piperine structure does not affect the activity. The opening of the methylenedioxy ring or changes in the heterocyclic ring of the piperine molecule reduced or abolished activity. Furthermore, inactive compounds did not display functional antagonistic activity.

Topics: Alkaloids; Amides; Benzodioxoles; Capsaicin; Cell Line; Dose-Response Relationship, Drug; Humans; Molecular Structure; Piperidines; Polyunsaturated Alkamides; Spectrometry, Fluorescence; TRPV Cation Channels

Spices are traditionally known to have digestive stimulant action and to cure digestive disorders. In this study, the protective effect of dietary spices with respect to activities of antioxidant enzymes in gastric and intestinal mucosa was examined. Groups of Wistar rats were fed for 8 weeks with diets containing black pepper (0.5%), piperine (0.02%), red pepper (3.0%), capsaicin (0.01%), and ginger (0.05%). All these spices significantly enhanced the activities of antioxidant enzymes--superoxide dismutase, catalase, glutathione reductase, and glutathione-S-transferase--in both gastric and intestinal mucosa, suggesting a gastrointestinal protective role for these spices. In a separate study, these dietary spices were found to alleviate the diminished activities of antioxidant enzymes in gastric and intestinal mucosa under conditions of ethanol-induced oxidative stress. The gastroprotective effect of the spices was also reflected in their positive effect on mucosal glycoproteins, thereby lowering mucosal injury. The amelioration of the ethanol-induced decrease in the activities of antioxidant enzymes in gastric and intestinal mucosa by dietary spices suggests their beneficial gastrointestinal protective role. This is the first report on the gastrointestinal protective potential of dietary spices.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Capsaicin; Capsicum; Catalase; Cytoprotection; Diet; Disease Models, Animal; Ethanol; Gastric Mucosa; Gastrointestinal Agents; Gastrointestinal Diseases; Glutathione Reductase; Glutathione Transferase; Glycoproteins; Intestinal Mucosa; Male; Mucus; Oxidative Stress; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Spices; Superoxide Dismutase; Zingiber officinale

It was previously reported that piperine (PIP) significantly blocks convulsions induced by intracerebroventricular injection of threshold doses of kainate, but had no or only slight effects on convulsions induced by L-glutamate, N-methyl-D-aspartate and guanidinosuccinate. In traditional Chinese medicine, black pepper has been used for epileptic treatment; however, the exact mechanism is still unclear. We reported here in that appropriate concentration of PIP effectively inhibites the synchronized oscillation of intracellular calcium in rat hippocampal neuronal networks and represses spontaneous synaptic activities in terms of spontaneous synaptic currents (SSC) and spontaneous excitatory postsynaptic currents (sEPSC). Moreover, pretreatment with PIP expects protective effect on glutamate-induced decrease of cell viability and apoptosis of hippocampal neurons. These data suggest that the neuroprotective effects of PIP might be associated with suppression of synchronization of neuronal networks, presynaptic glutamic acid release, and Ca(2+) overloading.

Topics: Alkaloids; Animals; Anticonvulsants; Apoptosis; Benzodioxoles; Calcium; Calcium Signaling; Cell Survival; Drugs, Chinese Herbal; Epilepsy; Glutamic Acid; Hippocampus; Neurons; Neuroprotective Agents; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Signal Transduction; Synapses; Synaptic Transmission

Pellitorine (1), which was isolated from the roots of Piper nigrum, showed strong cytotoxic activities against HL60 and MCT-7 cell lines. Microbial transformation of piperine (2) gave a new compound 5-[3,4-(methylenedioxy)phenyl]-pent-2-ene piperidine (3). Two other alkaloids were also found from Piper nigrum. They are (E)-1-[3',4'-(methylenedioxy)cinnamoyl]piperidine (4) and 2,4-tetradecadienoic acid isobutyl amide (5). These compounds were isolated using chromatographic methods and their structures were elucidated using MS, IR and NMR techniques.

Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Cell Line, Tumor; Fatty Acids, Unsaturated; Humans; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Synthetic metalloporphyrins, in the presence of monooxygen donors, are known to mimetize various reactions of cytochrome P450 enzymes systems in the oxidation of drugs and natural products. The oxidation of piperine and piplartine by iodosylbenzene using iron(III) and manganese(III) porphyrins yielded mono- and dihydroxylated products, respectively. Piplartine showed to be a more reactive substrate towards the catalysts tested. The structures of the oxidation products were proposed based on electrospray ionization tandem mass spectrometry.

Topics: Alkaloids; Benzodioxoles; Biological Products; Biomimetics; Catalysis; Cytochrome P-450 Enzyme System; Ferric Compounds; Inactivation, Metabolic; Iodobenzenes; Iron; Manganese; Oxidation-Reduction; Piperidines; Piperidones; Polyunsaturated Alkamides; Porphyrins; Singlet Oxygen; Spectrometry, Mass, Electrospray Ionization

A robust and sensitive ultra-low flow liquid chromatography (UFLC) method that can reproducibly, at reasonable cost, detect low concentrations of piperine from human plasma is necessary. Piperine in plasma was separated and quantified by a gradient method using ultraviolet detection at a maximal absorbance wavelength of 340 nm. An aliquot was injected onto a reversed-phase column Waters SymmetryShield, 2.1 x 100 mm, 3.5 microm, C(18) column, attached to a Waters absorbosphere, 4.6 x 30 mm, C(18) guard column and eluted with a mobile phase containing a mixture of acetonitrile/water/acetic acid (25:74.9:0.1, v/v/v) on line A and acetonitrile/acetic acid (99.9:0.1, v/v) on line B. The flow rate was 0.3 mL/min. The gradient method consisted of an opening condition of 20% pump B, with a linear increase to 37% pump B over 8 min, then a linear increase to 100% pump B at 11 min, 2 min at 100% pump B, and then a return to the opening condition (20% pump B) via a linear gradient over 2 min, followed by 5 min re-equilibration at opening conditions. The total run time was 20 min for each sample. All samples were processed protected from ambient light to avoid isomerization of piperine. The plasma assay was linear with R = 0.9995, with a lower limit of detection [signal-to-noise (S/N) > 5:1] of 100 pg of piperine loaded into the analytical system with acceptable accuracy and precision. Extraction recoveries of piperine from human plasma were 88% for quality control high (QCH), 93% for quality control medium (QCM), and 90% for quality control low (QCL), and the matrix effect was <12%. Piperine was quantifiable from a 50 mg oral dose given to human volunteers. A UFLC method for the rapid assay of human plasma with sensitivity to detect as low as 5 ng/mL piperine was developed. The method sensitivity equals that of liquid chromatography/tandem mass spectrometry (LC/MSMS) methods with much less cost.

Topics: Alkaloids; Benzodioxoles; Chromatography, Liquid; Humans; Piperidines; Polyunsaturated Alkamides

The present study aimed to investigate the effect of piperine, a major component of black pepper, on the oral exposure of fexofenadine in rats. Pharmacokinetic parameters of fexofenadine were determined in rats following an oral (10 mg/kg) or intravenous (5 mg/kg) administration of fexofenadine in the presence and absence of piperine (10 or 20 mg/kg, given orally). Compared to the control group given fexofenadine alone, the combined use of piperine increased the oral exposure (AUC) of fexofenadine by 180% to 190% while there was no significant change in C(max) and T(1/2) of fexofenadine in rats. The bioavailability of fexofenadine was increased by approximately 2-folds via the concomitant use of piperine. Furthermore, T(max) tends to be increased which might be attributed to the delayed gastric emptying in the presence of piperine. In contrast, piperine did not alter the intravenous pharmacokinetics of fexofenadine, implying that piperine may increase mainly the gastrointestinal absorption of fexofenadine rather than reducing hepatic extraction. In conclusion, piperine significantly enhanced the oral exposure of fexofenadine in rats likely by the inhibition of P-glycoprotein-mediated cellular efflux during the intestinal absorption, suggesting that the combined use of piperine or piperine-containing diet with fexofenadine may require close monitoring for potential drug-diet interactions.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Availability; Chromatography, High Pressure Liquid; Enzyme Inhibitors; Food-Drug Interactions; Gastric Emptying; Half-Life; Histamine H1 Antagonists, Non-Sedating; Intestinal Absorption; Male; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Terfenadine

Pentylenetetrazol (PTZ)-induced oxidative stress results in disturbance of the antioxidant enzyme status accompanied by neuronal injury and the development of epilepsy in rats. The present study evaluated the antioxidant effects of curcumin against PTZ-induced convulsions. Over a period of 30 days, i.p. injections of subconvulsive doses of PTZ on alternate days resulted in the development of a well-known kindling model of epilepsy. Spectrophotometric analysis revealed a markedly elevated activity of the antioxidant enzymes malondialdehyde (MDA), catalase and glutathione S-transferase (GST) in the cerebrum and cerebellum of epileptic rats due to PTZ-induced oxidative stress. Oral supplementation of curcumin at a dose of 2 g/kg for 30 days resulted in a transient decrease in MDA, catalase and GST levels in the rat cerebrum and cerebellum. Piperine (20 mg/kg orally) was administered along with curcumin to enhance the bioavailability of the latter up to 20-fold more. Combined treatment with curcumin and carbamazepine (3.6 mg/kg orally) also gave similar results, indicating that the potent antioxidant curcumin can be used as an adjuvant in antiepileptic therapy.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Biological Availability; Carbamazepine; Catalase; Curcumin; Disease Models, Animal; Drug Therapy, Combination; Epilepsy; Glutathione Transferase; Injections, Intraperitoneal; Male; Malondialdehyde; Oxidative Stress; Pentylenetetrazole; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Curcumin, capsaicin and piperine--the bioactive compounds present in spices--turmeric (Curcuma longa), red pepper (Capsicum annuum) and black pepper (Piper nigrum) respectively, have a considerable portion of structural homology. Tissue distribution and elimination of these three structurally similar bioactive compounds was examined following their oral intake in rats.. Separate sets of animals (150-160 g) were orally administered the three spice principles at dosages of 30 mg (capsaicin), 170 mg (piperine) and 500 mg (curcumin) / kg body weight. The tissue concentrations of administered spice compounds were determined by HPLC.. Maximum distribution of 24.4 per cent of administered capsaicin was seen at 1 h, while no intact capsaicin was detectable after 4 days. Absorption of capsaicin was about 94 per cent and very rapid relative to other two compounds. A maximum of 10.8 per cent of administered piperine was seen in tissues at 6 h. Absorption of the administered piperine was about 96 per cent. Curcumin concentration was maximum in the intestine at 1 h; maximum in blood at 6 h and remained at significantly higher level even at 24 h. About 63.5 per cent of the curcumin dose was absorbed. Only a small portion of the administered dose of capsaicin (< 0.1%) and curcumin (0.173 %) was excreted in urine, whereas piperine was not detectable in urine. Enhanced bioavailability of curcumin was evidenced when the same was orally administered concomitant with piperine. Intestinal absorption of curcumin was relatively higher when administered concomitantly with piperine, and it stayed significantly longer in the body tissues. Intact curcumin was detected in brain at 24, 48 and 96 h with a maximum at 48 h.. Considerable difference exists in the bioavailability of the three test compounds. Curcumin could be traced in the brain following its administration. Bioavailability of curcumin can be improved by co-administration with piperine.

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biological Availability; Capsaicin; Chromatography, High Pressure Liquid; Curcumin; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Spectrophotometry, Ultraviolet; Tissue Distribution

To evaluate the role of piperine as an inhibitor of Rv1258c of Mycobacterium tuberculosis.. Rifampicin, in combination with piperine, was tested against M. tuberculosis H37Rv and rifampicin-resistant (rif(r)) M. tuberculosis. A laboratory-generated rifampicin-resistant mutant (rif(r)) of M. tuberculosis was tested for drug susceptibility and the expression level of the putative efflux protein (Rv1258c) by real-time PCR. The three-dimensional (3D) structure of Rv1258c was also predicted using an in silico approach.. In the present study, rifampicin in combination with piperine, a trans-trans isomer of 1-piperoyl-piperidine, reduced the MIC and mutation prevention concentration (MPC) of rifampicin for M. tuberculosis H37Rv, including multidrug-resistant (MDR) M. tuberculosis and clinical isolates. Moreover, piperine effectively enhanced the bactericidal activity of rifampicin in time-kill studies and also significantly extended its post-antibiotic effect (PAE). In the presence of rifampicin, M. tuberculosis rif(r) showed a 3.6-fold overexpression of Rv1258c. The 3D structure of Rv1258c, using in silico modelling, was analysed to elucidate the binding of piperine to the active site.. The results of this study are suggestive of piperine's involvement in the inhibition of clinically overexpressed mycobacterial putative efflux protein (Rv1258c). Piperine may be useful in augmenting the antimycobacterial activity of rifampicin in a clinical setting.

Topics: Alkaloids; Antitubercular Agents; ATP-Binding Cassette Transporters; Bacterial Proteins; Benzodioxoles; Drug Synergism; Enzyme Inhibitors; Gene Expression Profiling; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Piperidines; Polymerase Chain Reaction; Polyunsaturated Alkamides; Protein Structure, Tertiary; Rifampin

Based on reported antileishmanial activity of naturally occurring alkaloid piperine and amino acid esters, their conjugates were synthesized by the hydrolysis of piperine to piperic acid followed by reaction with amino acid methyl esters. These conjugates were further converted to compounds with free carboxyl group and those with reduced double bonds. The synthesized compounds were evaluated for activity against promastigote and amastigote forms of L. donovani in vitro. All the compounds showed better activity than either piperine or the amino acid methyl esters. Piperoyl-valine methyl ester was the most active compound showing an IC50 of 0.075 mM against the amastigotes. Two active compounds were evaluated for in vivo activity in golden hamster model of leishmaniasis.

Topics: Alkaloids; Amino Acids; Animals; Antiprotozoal Agents; Benzodioxoles; Catalytic Domain; Cricetinae; Esters; Humans; Inhibitory Concentration 50; Leishmania donovani; Leishmaniasis; Male; Models, Molecular; Piperidines; Polyunsaturated Alkamides

TRPV1 (transient receptor potential vanilloid 1) is a ligand-gated ion channel expressed predominantly in nociceptive primary afferents that plays a key role in pain processing. In vivo activation of TRPV1 receptors by natural agonists like capsaicin is associated with a sharp and burning pain, frequently described as pungency. To elucidate the mechanisms underlying pungency we investigated a series of TRPV1 agonists that included both pungent and non-pungent compounds covering a large range of potencies. Pungency of capsaicin, piperine, arvanil, olvanil, RTX (resiniferatoxin) and SDZ-249665 was evaluated in vivo, by determining the increase in the number of eye wipes caused by direct instillation of agonist solutions into the eye. Agonist-induced calcium fluxes were recorded using the FLIPR technique in a recombinant, TRPV1-expressing cell line. Current-clamp recordings were performed in rat DRG (dorsal root ganglia) neurons in order to assess the consequences of TRPV1 activation on neuronal excitability. Using the eye wipe assay the following rank of pungency was obtained: capsaicin>piperine>RTX>arvanil>olvanil>SDZ-249665. We found a strong correlation between kinetics of calcium flux, pungency and lipophilicity of TRPV1 agonists. Current-clamp recordings confirmed that the rate of receptor activation translates in the ability of agonists to generate action potentials in sensory neurons. We have demonstrated that the lipophilicity of the compounds is directly related to the kinetics of TRPV1 activation and that the latter influences their ability to trigger action potentials in sensory neurons and, ultimately, pungency.

Topics: Action Potentials; Alkaloids; Animals; Benzodioxoles; Capsaicin; Diterpenes; Ganglia, Spinal; Kinetics; Lipid Metabolism; Male; Neurons, Afferent; Pain; Patch-Clamp Techniques; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sensory Receptor Cells; Solubility; TRPV Cation Channels; Urea

Piperine, a main component of Piper longum Linn. and Piper nigrum Linn., is a plant alkaloid with a long history of medical use. Piperine exhibits anti-inflammatory activity; however, the underlying mechanism remains unknown. We examined the effects of piperine on lipopolysaccharide (LPS)-induced inflammatory responses. Administration of piperine inhibited LPS-induced endotoxin shock, leukocyte accumulation and the production of tumor necrosis factor-alpha (TNF-alpha), but not of interleukin (IL)-1beta and IL-6. In peritoneal macrophages, piperine inhibited LPS/poly (I:C)/CpG-ODN-induced TNF-alpha production. Piperine also inhibited LPS-induced endotoxin shock in TNF-alpha knockout (KO) mice. To clarify the inhibitory mechanism of LPS-induced endotoxin shock, type 1 interferon (IFN) mRNA expression was determined. Piperine inhibited LPS-induced expression of type 1 IFN mRNA. Piperine inhibited the levels of interferon regulatory factor (IRF)-1 and IRF-7 mRNA, and the phosphorylation and nuclear translocation of IRF-3. Piperine also reduced activation of signal transducer and activator of transcription (STAT)-1. In addition, activation of STAT-1 was inhibited in IFN-alpha/beta-treated cells by piperine. These results suggest that piperine inhibits LPS-induced endotoxin shock through inhibition of type 1 IFN production.

Topics: Alkaloids; Animals; Benzodioxoles; Female; Gene Knockout Techniques; Inflammation; Interferon Type I; Lipopolysaccharides; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Piperidines; Polyunsaturated Alkamides; Shock, Septic; STAT1 Transcription Factor; Tumor Necrosis Factor-alpha

We investigated energy metabolism enhancement by pepper by examining suppression of body fat accumulation in mice due to piperine (PIP) and black pepper (BP) intake. To induce adiposity, mice were fed a high-fat, high-sucrose (HFS) diet as a control diet for 4 weeks. Visceral fat weights decreased significantly in the mice fed diets of 0.03% and of 0.05% PIP. Body weight in the 0.05% PIP group also decreased significantly. In the mice fed a diet of 1.0% BP, body weight and visceral fat weights decreased significantly. For all parameters tested, the 1.0% BP group tended to show values slightly lower than those of the 0.03% PIP group. Expression of thermogenic protein uncoupling protein 1 tended to increase in the mice on the 1.0% BP diet. These results indicate that BP suppresses the effect of body fat accumulation mainly through the action of PIP.

Topics: Adipose Tissue; Adiposity; Alkaloids; Animals; Benzodioxoles; Body Weight; Eating; Mice; Mice, Inbred C57BL; Odorants; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Dried fruits of Piper nigrum (black pepper) are commonly used in gastrointestinal disorders. The aim of this study was to rationalize the medicinal use of pepper and its principal alkaloid, piperine, in constipation and diarrhea using in vitro and in vivo assays. When tested in isolated guinea pig ileum, the crude extract of pepper (Pn.Cr) (1–10 mg/mL) and piperine (3–300 μM) caused a concentration-dependent and atropine-sensitive stimulant effect. In rabbit jejunum, Pn.Cr (0.01–3.0 mg/mL) and piperine (30–1,000 μM) relaxed spontaneous contractions, similar to loperamide and nifedipine. The relaxant effect of Pn.Cr and piperine was partially inhibited in the presence of naloxone (1 μM) similar to that of loperamide, suggesting the naloxone-sensitive effect in addition to the Ca(2+) channel blocking (CCB)-like activity, which was evident by its relaxant effect on K+ (80 mM)-induced contractions. The CCB activity was confirmed when pretreatment of the tissue with Pn.Cr (0.03–0.3 mg/mL) or piperine (10–100 μM) caused a rightward shift in the concentration–response curves of Ca(2+), similar to loperamide and nifedipine. In mice, Pn.Cr and piperine exhibited a partially atropine-sensitive laxative effect at lower doses, whereas at higher doses it caused antisecretory and antidiarrheal activities that were partially inhibited in mice pretreated with naloxone (1.5 mg/kg), similar to loperamide. This study illustrates the presence of spasmodic (cholinergic) and antispasmodic (opioid agonist and Ca(2+) antagonist) effects, thus providing the possible explanation for the medicinal use of pepper and piperine in gastrointestinal motility disorders.

Topics: Alkaloids; Animals; Antidiarrheals; Benzodioxoles; Calcium Channel Blockers; Cholinergic Agents; Constipation; Diarrhea; Dose-Response Relationship, Drug; Female; Gastrointestinal Diseases; Guinea Pigs; Ileum; Jejunum; Laxatives; Male; Mice; Mice, Inbred BALB C; Muscle Contraction; Naloxone; Phytotherapy; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rabbits; Receptors, Opioid

The presented study is aimed on exploring the effects of black pepper on blood pressure in the rat model of experimental hypertension induced by chronic NO synthesis inhibition.. Piperine, the compound of black pepper, can cause a significant decrease of blood pressure in normotensive rats possibly via calcium channel blockade, a pathway that is known to be effective in prevention of L-NAME (N(G)-nitro-L-arginine methyl ester) induced hypertension.. Wistar rats were administered clear water (C), L-NAME (40 mg/kg/day, L), piperine (20 mg/kg/day) in corn oil by oral gavage with L-NAME (LP) or without it (P) for 6 weeks. The systolic blood pressure was measured weekly. Specimens of thoracic aorta were processed in paraffin and histological slices were stained with hematoxylin and eosin, Mallory's phosphotungstic acid hematoxylin (PTAH), orcein, antibodies against inducible NO synthase (iNOS) and smooth muscle cells actin (SMCA). Microscopic pictures were digitally processed and morphometrically evaluated.. L-NAME increased the blood pressure, cross-sectional area of aorta, media thickness, elastin and SMCA synthesis and PTAH positive myofibrils relative and absolute content in the aortic media, wheras it decreased percentual content of iNOS, elastin and SMCA. Piperine decreased the blood pressure rise from the third week of treatment, synthesis of elastin and the percentual and absolute content of PTAH positive myofibrils, however, it did not affect other parameters.. Oral administration of piperine is able to partially prevent the increase of blood pressure caused by chronic L-NAME administration. This effect is probably caused by the blockage of voltage-dependent calcium channels and supported by filamentous actin disassembly (Tab. 1, Fig. 2, Ref. 35).

Topics: Alkaloids; Animals; Antibodies; Aorta, Thoracic; Benzodioxoles; Blood Pressure; Elastin; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Dietary supplements have been extensively studied for their beneficial effects on cognition and AD neuropathology. The current study examines the effect of a medical food cocktail consisting of the dietary supplements curcumin, piperine, epigallocatechin gallate, α-lipoic acid, N-acetylcysteine, B vitamins, vitamin C, and folate on cognitive functioning and the AD hallmark features and amyloid-beta (Aβ) in the Tg2576 mouse model of the disease.. The study found that administering the medical food cocktail for 6 months improved cortical- and hippocampal- dependent learning in the transgenic mice, rendering their performance indistinguishable from non-transgenic controls. Coinciding with this improvement in learning and memory, we found that treatment resulted in decreased soluble Aβ, including Aβ oligomers, previously found to be linked to cognitive functioning.. In conclusion, the current study demonstrates that combination diet consisting of natural dietary supplements improves cognitive functioning while decreasing AD neuropathology and may thus represent a safe, natural treatment for AD.

Topics: Acetylcysteine; Alkaloids; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Ascorbic Acid; Benzodioxoles; Brain; Catechin; Cerebral Cortex; Cognition; Curcumin; Dietary Supplements; Folic Acid; Hippocampus; Humans; Immunoblotting; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Piperidines; Polyunsaturated Alkamides; Thioctic Acid; Vitamin B Complex; Vitamins

Benjakul is a Thai traditional medicine preparation, used for balanced health. From selective interviews of folk doctors in southern Thailand, it was used as the adaptogen drug for cancer patients. In our previous study, the ethanolic extract of Benjakul preparation exhibited high cytotoxic activity against lung cancer cell lines (COR-L23). Piperine has been identified as the main compound in the extract. In addition, plumbagin was found as the most cytotoxic compound. In this study, a reversed-phase high performance liquid chromatography (HPLC) method for quality control such as chemical fingerprint, quantification and stability of the ethanolic extract of Benjakul preparation was developed. The reversed-phase HPLC was performed with a gradient mobile phase composed of water and acetronitrile, and peaks were detected at 256 nm. Based on validation results, this analytical method is precise, accurate and stable for quantitative determination of piperine and plumbagin which are cytotoxic compounds isolated from the ethanolic extract of Benjakul preparation. This method could be suitable for analysis of Benjakul extract.

Topics: Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Drug Stability; Drugs, Chinese Herbal; Humans; Medicine, Traditional; Naphthoquinones; Pharmaceutical Preparations; Piperaceae; Piperidines; Plant Extracts; Plants, Medicinal; Plumbaginaceae; Polyunsaturated Alkamides; Quality Control; Reproducibility of Results; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Thailand; Zingiber officinale

To research the absorbed character of piperine in Erxiekang plaster, and piperine by transdermal absorption was determined.. The percutaneous absorption of piperine in vitro at different times was conducted by Franz osmosis and diffusion apparatus as well as high-performance liquid chromatography.. It showed that the piperine through skins of mice gradually increased within the experiment time. After 52 h, the penetration of piperine was 78.51%, and remained basically unchanged.. The method is reliable, and can be used for Erxiekang plaster of determination of transdermal absorption.

Topics: Alkaloids; Animals; Benzodioxoles; Linear Models; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Skin Absorption

Curcumin, a yellow pigment extracted from rhizomes of the plant Curcuma longa (turmeric), has been widely used as food additive and also as a herbal medicine throughout Asia. The present study was designed to study the pharmacological, biochemical and neurochemical effects of daily administration of curcumin to rats subjected to chronic unpredictable stress. Curcumin treatment (20 and 40 mg/kg, i.p., 21 days) significantly reversed the chronic unpredictable stress-induced behavioral (increase immobility period), biochemical (increase monoamine oxidase activity) and neurochemical (depletion of brain monoamine levels) alterations. The combination of piperine (2.5 mg/kg, i.p., 21 days), a bioavailability enhancer, with curcumin (20 and 40 mg/kg, i.p., 21 days) showed significant potentiation of its anti-immobility, neurotransmitter enhancing (serotonin and dopamine) and monoamine oxidase inhibitory (MAO-A) effects as compared to curcumin effect per se. This study provided a scientific rationale for the use of curcumin and its co-administration with piperine in the treatment of depressive disorders.

Topics: Alkaloids; Animals; Antidepressive Agents; Behavior, Animal; Benzodioxoles; Biogenic Amines; Biological Availability; Biomarkers; Brain Chemistry; Chronic Disease; Cold Temperature; Curcumin; Depressive Disorder; Female; Light; Monoamine Oxidase; Motor Activity; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Stress, Psychological; Swimming

Nitrergic myenteric neurons co-innervating motor endplates were previously shown to inhibit vagally induced contractions of striated muscle in the rodent oesophagus. Immunohistochemical demonstration of putative co-transmitters, e.g. galanin, in enteric neurons prompted us to study a possible role of galanin in modulating vagally mediated contractions in an in vitro vagus nerve-oesophagus preparation of the mouse. Galanin (1-16) (1-100 nmol L(-1)), in the presence of the peptidase inhibitor, phenanthroline monohydrate, inhibited vagally induced contractions in a concentration-dependent manner (control: 100%; galanin 1 nmol L(-1): 95.6 +/- 1.6%; galanin 10 nmol L(-1): 57.3 +/- 6.5%; galanin 100 nmol L(-1): 31.2 +/- 8.1%, n = 5). The non-selective galanin receptor antagonist, galantide (100 nmol L(-1)), blocked the inhibitory effect of galanin (10 nmol L(-1)) while the selective non-galanin receptor 1 and galanin receptor 3 antagonists, M871 (1 micromol L(-1)) and SNAP37889 (100 nmol L(-1)), respectively, and the nitric oxide synthase inhibitor, NG-nitro-l-arginine methyl ester (L-NAME) (200 micromol L(-1)), failed to affect this galanin-induced response. Simultaneous application of galantide (100 nmol L(-1)) and L-NAME (200 micromol L(-1)) significantly reduced the inhibitory effect of capsaicin (30 mumol L(-1)) on vagally induced contractions when compared with its effect in the presence of L-NAME alone or in combination with the selective galanin receptor 2 or 3 antagonists. An inhibitory effect of piperine on vagally induced contractions was reduced neither by galantide nor by L-NAME. Immunohistochemistry revealed galanin immunoreactive myenteric neurons and nerve fibres intermingling with cholinergic vagal terminals at motor endplates. These data suggest that galanin from co-innervating enteric neurons co-operates with nitric oxide in modulating vagally induced contractions in the mouse oesophagus.

Topics: Alkaloids; Animals; Benzodioxoles; Capsaicin; Electric Stimulation; Enzyme Inhibitors; Esophagus; Female; Galanin; Indoles; Male; Mice; Muscle Contraction; NG-Nitroarginine Methyl Ester; Phenanthrolines; Piperidines; Polyunsaturated Alkamides; Receptors, Galanin; Sensory System Agents; Substance P; Vagus Nerve

A bioassay-guided isolation of an ethanol extract of the fruit of Piper longum L. yielded piperlonguminine, piperine and pipernonaline, as the main antihyperlipidemic constituents. They exhibit appreciable antihyperlipidemic activity in vivo, which is comparable to that of the commercial antihyperlipidemic drug, simvastatin.

Topics: Alkaloids; Animals; Benzodioxoles; Dioxolanes; Fruit; Hypolipidemic Agents; Male; Molecular Structure; Piper; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Simvastatin

Chemical characterization and acute and sub-acute toxicity study of Trikatu, a generic herbal formulation of Indian system of medicine, was carried out in Charles Foster (CF) rats for safety profiling. In acute toxicity experiment, Trikatu at 2,000 mg/kg body weight once orally was well tolerated by the experimental animals (both male and female) and no changes were observed in mortality, morbidity, gross pathology, gain in weight, vital organ weight, hematological (total white blood cells (WBC) and red blood cells (RBC) count), biochemical parameters such as serum creatinine, serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), serum lipid profile and tissue biochemical parameters such as reduced glutathione and malonaldehyde content as oxidative stress markers. In sub-acute experiment, Trikatu was administered at 5, 50 and 300 mg/kg body weight once daily for 28 days in female CF rats, and non-significant changes were found in most of the parameters studied such as acute experiment except significant increase in low density lipoprotein (LDL) cholesterol level at 50 and 300 mg/kg body weight, decrease in high density lipoprotein (HDL) cholesterol level at 300 mg/kg body weight, increase in SGPT activity at 50 mg/kg body weight and decrease in WBC count at 300 mg/kg body weight on 28(th) day post treatment.

Topics: Administration, Oral; Alanine Transaminase; Alkaloids; Alkenes; Animals; Benzodioxoles; Body Weight; Cholesterol, HDL; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Female; Glutathione; Lipoproteins, LDL; Male; Medicine, Ayurvedic; Motor Activity; Piper; Piperidines; Plant Preparations; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Sex Factors; Sleep Stages; Time Factors; Toxicity Tests, Acute; Zingiber officinale

This study aimed to investigate the effect of piperine on airway hyperresponsiveness, pulmonary eosinophilic infiltration, various immune cell phenotypes, Th2 cytokine production, immunoglobulin E and histamine production in a murine model of asthma.. Asthma was induced in Balb/c mice by ovalbumin sensitization and inhalation. Piperine (4.5 and 2.25 mg/kg) was orally administered 5 times a week for 8 weeks. At 1 day after the last ovalbumin exposure, airway hyperresponsiveness was determined and samples of bronchoalveolar lavage fluid, lung cells and serum were collected for further analysis.. Piperine-treated groups had suppressed eosinophil infiltration, allergic airway inflammation and airway hyperresponsiveness, and these occurred by suppression of the production of interleukin-4, interleukin-5, immunoglobulin E and histamine. Moreover, polymerase chain reaction products for thymus and activation regulated chemokine from lung cell RNA preparations were decreased in the piperine-treated group compared with control groups, although transforming growth factor-beta products were increased in the piperine-treated group.. The results suggest that the therapeutic mechanism by which piperine effectively treats asthma is based on a reduction of Th2 cytokines (interleukin-4, interleukin-5), eosinophil infiltration, and by marked reduction of thymus and activation regulated chemokine, eotaxin-2 and interleukin-13 mRNA expression (especially transcription of nuclear factor-kappaB dependent genes) in lung tissue, as well as reduced interleukin-4, interleukin-5 and eotaxin levels in bronchoalveolar lavage fluid, and histamine and ovalbumin-specific immunoglobulin E production in serum.

Topics: Alkaloids; Animals; Asthma; Benzodioxoles; Bronchial Hyperreactivity; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophils; Female; Histamine; Immunoglobulin E; Mice; Mice, Inbred BALB C; Ovalbumin; Piperidines; Polyunsaturated Alkamides; RNA, Messenger; T-Lymphocytes; Th2 Cells

Oral carcinoma accounts for 40-50 percent of all cancers in India. Tobacco chewing, smoking and alcohol consumption are the major risk factors associated with the high incidence of oral cancer in India. Our aim was to investigate the chemopreventive potential of curcumin and piperine during 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis.. Oral squamous cell carcinoma was developed in the buccal pouch of Syrian golden hamsters, by painting them with 0.5 percent DMBA in liquid paraffin, three times a week for 14 weeks. The tumour incidence, tumour volume and burden were determined in the buccal pouches. The status of phase II detoxification agents, lipid peroxidation and antioxidants were estimated by specific colorimetric methods.. We observed 100 percent tumour formation in DMBA-alone painted hamsters. Disturbances in the status of lipid peroxidation, antioxidants and phase II detoxification agents were noticed in DMBA-alone painted hamsters. Oral administration of curcumin (80 mg/kg body weight) and piperine (50 mg/kg body weight) to DMBA-painted hamsters on alternate days to DMBA painting for 14 weeks completely prevented the formation of oral carcinoma. Also, curcumin and piperine restored the status of lipid peroxidation, antioxidants and detoxifying agents in DMBA-painted hamsters.. The chemopreventive efficacy of curcumin and piperine is probably due to their antilipidperoxidative and antioxidant potential as well as their modulating effect on the carcinogen detoxification process.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Alkaloids; Animals; Anticarcinogenic Agents; Antioxidants; Benzodioxoles; Carcinogens; Carcinoma, Squamous Cell; Cheek; Colorimetry; Cricetinae; Curcumin; Humans; Lipid Peroxidation; Mesocricetus; Mouth Neoplasms; Piperidines; Polyunsaturated Alkamides

The objective of this study was to determine the anti-inflammatory, nociceptive, and antiarthritic effects of piperine, the active phenolic component in black pepper extract.. The in vitro anti-inflammatory activity of piperine was tested on interleukin 1beta (IL1beta)-stimulated fibroblast-like synoviocytes derived form patients with rheumatoid arthritis. The levels of IL6, matrix metalloproteinase (MMPs), cyclo-oxygenase 2 (COX-2), and prostaglandin E2 (PGE2) were investigated by ELISA and RT-PCR analysis. The analgesic and antiarthritic activities of piperine were investigated on rat models of carrageenan-induced acute paw pain and arthritis. The former were evaluated with a paw pressure test, and the latter by measuring the squeaking score, paw volume, and weight distribution ratio. Piperine was administrated orally to rats at 20 and 100 mg/kg/day for 8 days.. Piperine inhibited the expression of IL6 and MMP13 and reduced the production of PGE2 in a dose dependant manner at concentrations of 10 to 100 microg/ml. In particular, the production of PGE2 was significantly inhibited even at 10 microg/ml of piperine. Piperine inhibited the migration of activator protein 1 (AP-1), but not nuclear factor (NF)kappaB, into the nucleus in IL1beta-treated synoviocytes. In rats, piperine significantly reduced nociceptive and arthritic symptoms at days 8 and 4, respectively. Histological staining showed that piperine significantly reduced the inflammatory area in the ankle joints.. These results suggest that piperine has anti-inflammatory, antinociceptive, and antiarthritic effects in an arthritis animal model. Thus, piperine should be further studied with regard to use either as a pharmaceutical or as a dietary supplement for the treatment of arthritis.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Benzodioxoles; Cyclooxygenase 2; Dinoprostone; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Humans; Hyperalgesia; Inflammation; Interleukin-1beta; Interleukin-6; Male; Matrix Metalloproteinases; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Synovial Membrane

An ionic liquid-based ultrasonic-assisted extraction (ILUAE) method has been developed for the effective extraction of piperine from white pepper powder. A series of 1-alkyl-3-methylimidazolium ionic liquids differing in composition of alkyl chain and anion were evaluated for extraction efficiency. The results indicate that both the characteristics of anions and cations have remarkable effects on the extraction efficiency. In addition, the ILUAE procedure was also optimized on some ultrasonic parameters, such as ultrasonic power, extraction time and solid-liquid ratio. Compared with the conventional heat-reflux extraction (HRE) and regular UAE, the optimized approach gained the highest extraction efficiency (from 1.950% to 3.577%) within the shortest extraction time (from 2 h to 30 min). Furthermore, the developed method was validated by the recovery, correlation coefficient (R(2)), and reproducibility (relative standard deviation (RSD), n=3). Average recoveries of piperine were between 93.5% and 98.7% at spiking levels 0.05, 0.1 and 0.2 mg mL(-1) with RSD lower than 5%. The developed method is linear at concentrations within the tested interval, with R(2) at 0.9994.

Topics: Alkaloids; Benzodioxoles; Chemical Fractionation; Ionic Liquids; Linear Models; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Reproducibility of Results; Sensitivity and Specificity; Time Factors; Ultrasonics

The fluorescence characteristics of the complex of piperine with cation in micellar system were studied. At the same time, the influence of experimental condition on the fluorescence intensity was also studied. The experiments indicated that piperine had very low fluorescence signal itself. But in pH 8.77 Na2 HPO4-NaH2PO4 buffer solution, both Mn(II) and cationic surfactant cetyltrimethylammonium bromide can enhance the fluorescence intensity and stability of piperine. Based on this, a sensitive method has been developed for the quantitative determination of piperine in Mn(II)-piperine-cetyltrimethylammonium bromide ternary system. Under the optimum conditions, there is a linear relationship between the enhancement of fluorescence intensity and the concentration of Mn(II). The optimal conditions are as follows: the concentration of Mn(II) is 2.5 x 10(-4) mol x L(-1) and the concentration of cetyltrimethylammonium bromide is 5 x 10(-4) mol x L(-1). The fluorescence intensity was determined by a 1 cm quartz cell with the excitation wavelength of 352 nm and the emission wavelength of 452 nm. The linear range of concentration of piperine was 2.02-10.1 microg x mL(-1) with the relative coefficient of 0.9985 and the detection limit of 0.0602 microg x mL(-1). The relative standard deviation (RSD) was 1.10%. The proposed method has been successfully applied to the quantitative determination of piperine in the Mongolian medicine Piper longum L, and the recovery was within the range of 97.6%-102.0%. The results were very satisfactory.

Topics: Alkaloids; Benzodioxoles; Cetrimonium; Cetrimonium Compounds; Limit of Detection; Manganese; Piperidines; Polyunsaturated Alkamides

Curcumin, a derived product from common spice turmeric that is safe and beneficial in several aliments was formulated into biodegradable nanoparticles with a view to improve its oral bioavailability. The curcumin encapsulated nanoparticles prepared by emulsion technique were spherical in shape with particle size of 264nm (polydispersity index 0.31) and 76.9% entrapment at 15% loading. The curcumin encapsulated nanoparticles were able to withstand the International Conference on Harmonisation (ICH) accelerated stability test conditions for refrigerated products for the studied duration of 3 months. X-ray diffraction analysis revealed the amorphous nature of the encapsulated curcumin. The in vitro release was predominantly by diffusion phenomenon and followed Higuchi's release pattern. The in vivo pharmacokinetics revealed that curcumin entrapped nanoparticles demonstrate at least 9-fold increase in oral bioavailability when compared to curcumin administered with piperine as absorption enhancer. Together the results clearly indicate the promise of nanoparticles for oral delivery of poorly bioavailable molecules like curcumin.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Biological Availability; Curcumin; Drug Compounding; Electrochemistry; Excipients; Freeze Drying; Intestinal Absorption; Lactic Acid; Male; Microscopy, Atomic Force; Nanoparticles; Particle Size; Piperidines; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Solubility; Tissue Distribution; X-Ray Diffraction

Spice active principles are reported to have anti-diabetic, anti-hypercholesterolemic, antilithogenic, anti-inflammatory, anti-microbial and anti-cancer properties. In our previous report we have shown that spices and their active principles inhibit 5-lipoxygenase and also formation of leukotriene C4. In this study, we report the modulatory effect of spice active principles viz., eugenol, capsaicin, piperine, quercetin, curcumin, cinnamaldehyde and allyl sulphide on in vitro human platelet aggregation. We have demonstrated that spice active principles inhibit platelet aggregation induced by different agonists, namely ADP (50microM), collagen (500microg/ml), arachidonic acid (AA) (1.0mM) and calcium ionophore A-23187 (20microM). Spice active principles showed preferential inhibition of arachidonic acid-induced platelet aggregation compared to other agonists. Among the spice active principles tested, eugenol and capsaicin are found to be most potent inhibitors of AA-induced platelet aggregation with IC50 values of 0.5 and 14.6microM, respectively. The order of potency of spice principles in inhibiting AA-induced platelet aggregation is eugenol>capsaicin>curcumin>cinnamaldehyde>piperine>allyl sulphide>quercetin. Eugenol is found to be 29-fold more potent than aspirin in inhibiting AA-induced human platelet aggregation. Eugenol and capsaicin inhibited thromboxane B2 (TXB2) formation in platelets in a dose-dependent manner challenged with AA apparently by the inhibition of the cyclooxygenase (COX-1). Eugenol-mediated inhibition of platelet aggregation is further confirmed by dose-dependent decrease in malondialdehyde (MDA) in platelets. Further, eugenol and capsaicin inhibited platelet aggregation induced by agonists-collagen, ADP and calcium ionophore but to a lesser degree compared to AA. These results clearly suggest that spice principles have beneficial effects in modulating human platelet aggregation.

Topics: Acrolein; Adenosine Diphosphate; Alkaloids; Allyl Compounds; Arachidonic Acid; Benzodioxoles; Calcimycin; Capsaicin; Collagen Type III; Curcumin; Eugenol; Humans; Malondialdehyde; Piperidines; Platelet Aggregation; Platelet Aggregation Inhibitors; Polyunsaturated Alkamides; Quercetin; Spices; Sulfides; Thromboxanes

Quantitative structure activity relationship (QSAR) analysis of piperine analogs as inhibitors of efflux pump NorA from Staphylococcus aureus has been performed in order to obtain a highly accurate model enabling prediction of inhibition of S. aureus NorA of new chemical entities from natural sources as well as synthetic ones. Algorithm based on genetic function approximation method of variable selection in Cerius2 was used to generate the model. Among several types of descriptors viz., topological, spatial, thermodynamic, information content and E-state indices that were considered in generating the QSAR model, three descriptors such as partial negative surface area of the compounds, area of the molecular shadow in the XZ plane and heat of formation of the molecules resulted in a statistically significant model with r(2)=0.962 and cross-validation parameter q(2)=0.917. The validation of the QSAR models was done by cross-validation, leave-25%-out and external test set prediction. The theoretical approach indicates that the increase in the exposed partial negative surface area increases the inhibitory activity of the compound against NorA whereas the area of the molecular shadow in the XZ plane is inversely proportional to the inhibitory activity. This model also explains the relationship of the heat of formation of the compound with the inhibitory activity. The model is not only able to predict the activity of new compounds but also explains the important regions in the molecules in quantitative manner.

Topics: Alkaloids; Anti-Bacterial Agents; Bacterial Proteins; Benzodioxoles; Computer Simulation; Models, Chemical; Models, Molecular; Multidrug Resistance-Associated Proteins; Piperidines; Polyunsaturated Alkamides; Quantitative Structure-Activity Relationship; Software; Staphylococcus aureus

To study the antidepressant effects of piperine in chronic unpredictable mild stress (CUMS) rats and to explore the underlying mechanisms in the hypothalamic-pituitary-adrenal (HPA) axis.. Fifty rats were housed alone and exposed to an unpredicted sequence of mild stressors to induce CUMS, and then were divided into untreated group, desipramine group and low-, medium- and high-dose piperine groups. Another 10 normal rats were used as normal control. The behavior of the rats was detected by body weight and sucrose preference test, and the serum levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in different groups were observed by radioimmunoassay.. The results indicated that after 21-day administration, piperine at concentrations of 10 and 20 mg/kg could significantly improve the behavioral disorder by increasing sucrose consumption. Piperione at concentrations of 5, 10 and 20 mg/kg could remarkably reduce serum ACTH and CRH levels in the CUMS rats, but had little effect on the content of CORT.. Piperine can relieve depression in CUMS rats by modulating the function of HPA axis.

Topics: Alkaloids; Animals; Antidepressive Agents; Benzodioxoles; Hypothalamo-Hypophyseal System; Male; Neuroprotective Agents; Piperidines; Pituitary-Adrenal System; Polyunsaturated Alkamides; Random Allocation; Rats; Rats, Wistar

Piperine is one of the most promising bioenhancers to date. Methods used for its extraction suffer from drawbacks such as use of organic solvents, poor extraction efficiency, tedious and expensive methodology. These methods are not encouraged with a view to reducing global warming. The objective was therefore to develop an alternative solvent-free extraction method.. An aqueous extract of long pepper fruits was prepared using hydrophilic lipid Gelucire 44/14 as the extracting aid and this was compared with an alcoholic extract. Extracts were characterized using high-performance thin layer chromatography and differential scanning calorimetry. P-glycoprotein (P-gp) inhibitory activity of the aqueous and alcoholic extracts and pure piperine was compared using an in-vitro everted rat intestinal model using ornidazole as the model drug. The study was performed using two oral pretreatment dose levels (10 and 20 mg/kg) and durations (1 and 3 days). Exsorption of ornidazole from serosal to mucosal surface was monitored.. P-gp inhibitory activity of the aqueous extract was comparable with that of pure piperine (P > 0.05) and was significantly higher than the alcoholic extract (P < 0.05). Pure piperine and the aqueous extract exhibited significant P-gp inhibitory activity compared with control, which was irrespective of oral pretreatment dose and duration levels. No significant effect of oral pretreatment duration of the aqueous extract was observed. The observed enhancement in P-gp inhibitory activity of the aqueous extract may have been attributed to the P-gp inhibitory potential of Gelucire 44/14 and its efficient extraction and solubility enhancement ability.. In the field of phytopharmaceuticals efficient and eco-friendly extraction processes are still a goal to be achieved. Extraction with Gelucire 44/14 could be a potential method of extraction for phytopharmaceuticals. Compared with conventional methods of extraction it is more efficient, easier to prepare, eco-friendly and scalable.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Chromatography, High Pressure Liquid; Intestines; Male; Ornidazole; Piper; Piperidines; Plant Extracts; Polyethylene Glycols; Polyunsaturated Alkamides; Rats; Rats, Wistar; Solvents

The present study is designed to investigate the effect of piperine in modifying the carcinogenic process, as well as biochemical alterations at the molecular level during DMBA-induced hamster buccal pouch carcinogenesis by FT-IR spectroscopy. Specific changes were noticed in the FT-IR spectral features of DMBA-induced hamster buccal pouch carcinoma. These alterations include structural changes of proteins and possible increase of its content, an increase in the nuclear-to-cytoplasm ratio, an increase in the relative amount of DNA, an enhancement in the phosphorylation of proteins, a loss of hydrogen bonding of the C-OH groups in the amino acid residues of proteins and diminished lipid peroxidation which were accompanied by a significant reduction in the relative amount of lipids compared to untreated control animals. Administration of piperine significantly increased the levels of lipid peroxidation and decreased the levels of proteins and nucleic acid content that were found to increase in oral cancer bearing animals. In conclusion, the results of the present study suggest that piperine may exert its chemopreventive effect by modulating the biochemical changes at the molecular level during DMBA-induced hamster buccal pouch carcinogenesis which can be detected using FT-IR spectroscopic technique.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Alkaloids; Animals; Antineoplastic Agents; Benzodioxoles; Cricetinae; Male; Mouth Mucosa; Piperidines; Polyunsaturated Alkamides; Skin Neoplasms

To observe the antidepressant effect of piperine and its neuroprotective mechanism.. The behavioral studies were performed in forced swimming test (FST) and tail suspension test (TST). To further explore the mechanisms underlying their antidepressant-like activities, CORT-induced neuroblastoma SH-SY5Y cells and isolated and cultured neural progenitor cells. By using MTT assay, the effect of piperine on neural cells proliferation was observed.. The research results indicated that after a week of administration, piperine (10, 20 mg x kg(-1)) could significantly reduce the duration of immobility in both FST and TST. Piperine has the protective effect on neuroblastoma cells and increased proliferation of hippocampus neural progenitor cells.. In the present study, we demonstrated that the antidepressant-like effects of piperine and its mechanisms might be involved by up-regulation of the progenitor cell proliferation of hippocampus and cytoprotective activity.

Topics: Alkaloids; Animals; Antidepressive Agents; Benzodioxoles; Cell Line; Cell Proliferation; Cells, Cultured; Female; Mice; Motor Activity; Neurons; Neuroprotective Agents; Piperidines; Polyunsaturated Alkamides; Random Allocation; Stem Cells

Detailed chemical studies on the roots of Piper sarmentosum and Piper nigrum have resulted in several alkaloids. The roots of P. sarmentosum gave a new aromatic compound, 1-nitrosoimino-2,4,5-trimethoxybenzene (1). Piper nigrum roots gave pellitorine (2), (E)-1-[3',4'-(methylenedioxy)cinnamoyl]piperidine (3), 2,4-tetradecadienoic acid isobutyl amide (4), piperine (5), sylvamide (6), cepharadione A (7), piperolactam D (8) and paprazine (9). Structural elucidation of these compounds was achieved through NMR and MS techniques. Cytotoxic activity screening of the plant extracts indicated some activity.

Topics: Alkaloids; Aporphines; Benzodioxoles; Cell Survival; Fatty Acids, Unsaturated; HeLa Cells; HL-60 Cells; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Piper; Piper nigrum; Piperidines; Plant Roots; Polyunsaturated Alkamides

Topics: Alkaloids; Anticarcinogenic Agents; Benzodioxoles; Breast; Breast Neoplasms; Clinical Trials as Topic; Curcumin; Diet; Estrogen Antagonists; Humans; Piperidines; Polyunsaturated Alkamides; Stem Cells

An alkaloid piperine isolated from the Piper Nigrum was found to inhibit lipid droplet accumulation in mouse macrophages, and especially inhibited cholesteryl ester (CE) synthesis (IC50: 25 microM). The metabolism of cholesterol from lysosome to lipid droplet was inhibited with a similar IC50 (18 microM), indicating that the site of inhibition is one of the steps between the lysosomes and the endoplasmic reticulum. Therefore, effects of piperine on acyl-CoA:cholesterol acyltransferase (ACAT) activity in the microsomes prepared from mouse macrophage and liver were studied, to show that the compounds inhibited the activity in both cases (IC50: 9.1, 7.0 microM, respectively). Furthermore, piperine was found to inhibit both ACAT1 and ACAT2 isozymes to a similar extent (IC50: 16, 18 microM, respectively) in cell-based assays using ACAT1- or ACAT2-expressing cells. Thus, it was suggested that piperine inhibited macrophage ACAT to decrease CE synthesis, leading to a reduction of lipid droplets.

Topics: Alkaloids; Animals; Benzodioxoles; Cholesterol; Enzyme Inhibitors; In Vitro Techniques; Isoenzymes; Lipid Metabolism; Lipids; Lysosomes; Macrophages; Mice; Microscopy, Confocal; Piperidines; Polyunsaturated Alkamides; Sterol O-Acyltransferase

The effects of steam and irradiation treatments on the physicochemical properties (moisture content, pH, extractable yield, reducing sugar, soluble pigment, antioxidant activity, piperine, Hunter's color, and sensory attributes) and microbiological quality (total aerobic bacteria, coliforms, and yeasts and molds) of ground black pepper stored at refrigerated and room temperatures for 6 months were compared and evaluated. Irradiation resulted in a higher microbial reduction in pepper, with minimal effects on the proximate composition, functional components, color, and sensory attributes of the spice. Steamed peppers appeared darker, and a considerable decrease in the piperine content was observed after treatment and storage. This study illustrates that irradiation is a better decontamination method than steam treatment in eliminating microorganisms without apparently affecting the quality of the powdered spice. Storage at 4 degrees C enhanced the microbial quality and minimized the loss of piperine content in ground black peppers.

Topics: Alkaloids; Antioxidants; Benzodioxoles; Chemical Phenomena; Chemistry, Physical; Cold Temperature; Decontamination; Food Irradiation; Food Preservation; Humans; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Sensation; Steam

The purpose of this study was to estimate the pharmacokinetic parameters and tissue distribution of positively charged stearylamine (LN-P-SA) and pegylated lipid nanospheres (LN-P-PEG) of piperine in BALB/c mice. Lipid nanospheres of piperine (LN-P), LN-P-PEG and LN-P-SA were prepared by homogenization followed by ultrasonication. The pharmacokinetics and tissue distribution of different lipid nanosphere formulations (piperine, LN-P, LN-P-PEG and LN-P-SA) were studied in male BALB/c mice. The pharmacokinetic parameters of LN-P-PEG and LN-P-SA were: AUC(0-24): 372.1 +/- 71.6 and 162.2 +/- 36.4 microg h(-1) ml(-1), clearance 13 +/- 2.5 and 32 +/- 7.5 ml h(-1), Cmax: 24.7 +/- 1.5 and 22.3 +/- 1.0 microg ml(-1), Vd: 0.45 +/- 0.02 and 0.66 +/- 0.06 l Kg(-1)). Pharmacokinetics of piperine in lipid nanospheres showed a biexponential decline with significantly high AUC, a lower rate of clearance and a smaller volume of distribution than piperine.

Topics: Alkaloids; Amines; Animals; Antiparasitic Agents; Benzodioxoles; Brain Chemistry; Chromatography, High Pressure Liquid; Drug Carriers; Lipids; Mice; Mice, Inbred BALB C; Nanospheres; Piperidines; Polyethylene Glycols; Polyunsaturated Alkamides; Spectrophotometry, Ultraviolet; Spleen; Tissue Distribution

Cadmium (Cd), a well known environmental carcinogen, is a potent immunotoxicant. In rodents, it is primarily characterized by marked thymic atrophy and splenomegaly. Cadmium induces apoptosis in murine lymphocytes and alters the immune functions. Thus, for the amelioration of its effect, three structurally different bioactive herbal extracts such as piperine-alkaloid, picroliv-glycosides and curcumin-polyphenols were evaluated and their efficacy compared. For ascertaining their immunomodulatory role, various biochemical indices of cell damage such as cytotoxicity, oxidative stress (ROS, GSH), apoptosis (mitochondrial membrane potential, caspase-3 activity, phosphatidylserine externalization, apoptotic DNA) along with lymphocyte phenotyping, blastogenesis and cytokine secretion were assessed in thymic and splenic cell suspensions. Of the three herbals examined, piperine displayed maximum efficacy. All the three doses of piperine (1, 10 and 50 microg/ml) increased cell viability in a dose dependent manner, whereas curcumin and picroliv were also effective, but to a lesser degree. Only the two higher doses exhibited cell viability efficacy. The median doses ie 10 microg/ml, were therefore selected, for comparison of their antioxidant, anti-apoptotic and immune function modulation. Restoration of ROS and GSH was most prominent with piperine. The anti-apoptotic potential was directly proportional to their antioxidant nature. In addition, Cd altered blastogenesis, T and B cell phenotypes and cytokine release were also mitigated best with piperine. The ameliorative potential was in order of piperine > curcumin > picroliv and former could be considered the drug of choice under immunocompromised conditions.

Topics: Alkaloids; Animals; Apoptosis; B-Lymphocytes; Benzodioxoles; Cadmium Chloride; Caspase 3; Cell Survival; Cinnamates; Curcumin; DNA Damage; Glutathione; Glycosides; Interferon-gamma; Interleukin-2; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Reactive Oxygen Species; Vanillic Acid

The most common haematological malignancy is leukaemia. Differentiation induction is considered as one of the effective therapies for leukemia. Piperine, an alkaloid extracted from piperaceae, has been reported to display a variety of pharmacological activities, including sedation, anti-inflammation and antitumor effects. This study was to investigate the effect of piperine on proliferation, differentiation and apoptosis of erythroleukemia K562 cells.. Inhibition of cell growth was determined by trypan blue exclusion test; cell cycle and cell apoptosis were analyzed by FACS; induction of cell differentiation was confirmed by morphological observation, nitroblue tetrazolium (NBT) reduction assay and measurements of CD33 and CD14 expressions.. Piperine induced K562 cells to differentiate into macrophages/monocytes at 20 micromol/L or 40 micromol/L. After incubation with 40 mumol/L piperine for 3 d, the NBT reduction rate of K562 cells increased from (8.5+/-1.9)% to (76.7+/-5.3)%; after incubation with 20 mumol/L piperine for 3 d, the mean fluorescence intensity (MFI) of CD33 in K562 cells was decreased by 42.05% (P<0.01), whereas the MFI of CD14 was doubled (P<0.01). Piperine inhibited the proliferation of K562 cells in a dose-and time-dependent manner at a concentration of above 20 micromol/L.. Piperine can induce K562 cells to differentiate into macrophages/monocytes.

Topics: Alkaloids; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Apoptosis; Benzodioxoles; Cell Cycle; Cell Differentiation; Cell Proliferation; Humans; K562 Cells; Lipopolysaccharide Receptors; Piperidines; Polyunsaturated Alkamides; Sialic Acid Binding Ig-like Lectin 3

The effect of piperine, the main alkaloid from piper nigrum, on the central nervous system is not clearly known until now. In the present study, male Wistar rats were administered piperine at various doses ranging from 5, 10 and 20mg/kg BW once daily for 4 weeks and the animals were determined the neuropharmacological activity after single, 1, 2, 3 and 4 weeks of treatment. The results showed that piperine at all dosage range used in this study possessed anti-depression like activity and cognitive enhancing effect at all treatment duration. Therefore, piperine may be served as the potential functional food to improve brain function. However, further investigations about precise underlying mechanism are still required.

Topics: Alkaloids; Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Benzodioxoles; Cognition Disorders; Food Analysis; Male; Maze Learning; Mood Disorders; Motor Activity; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Swimming

Curcumin is a major active principle of Curcuma longa, one of the widely used preparations in the Indian system of medicine. It is known for its diverse biological actions.. The present study was designed to investigate the involvement of monoaminergic system(s) in the antidepressant activity of curcumin and the effect of piperine, a bioavailability enhancer, on the bioavailability and biological effects of curcumin.. Behavioral (forced swim test), biochemical (monoamine oxidase (MAO) enzyme inhibitory activity), and neurochemical (neurotransmitter levels estimation) tests were carried out. Curcumin (10-80 mg/kg, i.p.) dose dependently inhibited the immobility period, increased serotonin (5-hydroxytryptamine, 5-HT) as well as dopamine levels (at higher doses), and inhibited the monoamine oxidase enzymes (both MAO-A and MAO-B, higher doses) in mice. Curcumin (20 mg/kg, i.p.) enhanced the anti-immobility effect of subthreshold doses of various antidepressant drugs like fluoxetine, venlafaxine, or bupropion. However, no significant change in the anti-immobility effect of imipramine and desipramine was observed. Furthermore, combination of subthreshold dose of curcumin and various antidepressant drugs resulted in synergistic increase in serotonin (5-HT) levels as compared to their effect per se. There was no change in the norepinephrine levels. The coadministration of piperine (2.5 mg/kg, i.p.), a bioavailability enhancing agent, with curcumin (20 and 40 mg/kg, i.p.) resulted in potentiation of pharmacological, biochemical, and neurochemical activities.. The study provides evidences for mechanism-based antidepressant actions of curcumin. The coadministration of curcumin along with piperine may prove to be a useful and potent natural antidepressant approach in the management of depression.

Topics: Alkaloids; Animals; Antidepressive Agents; Behavior, Animal; Benzodioxoles; Biogenic Monoamines; Biological Availability; Curcumin; Dopamine; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Immobility Response, Tonic; Injections, Intraperitoneal; Male; Mice; Mice, Inbred Strains; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Polyunsaturated Alkamides; Reserpine; Selegiline; Serotonin; Swimming; Time Factors; Tranylcypromine

Based on our recent findings that piperine is a potent Staphylococcus aureus NorA efflux pump inhibitor (EPI), 38 piperine analogs were synthesized and bioevaluated for their EPI activity. Twenty-five of them were found active with potentiating activity equivalent or more than known EPIs like reserpine, carsonic acid and verapamil. The inhibitory mechanism of the compounds was confirmed by efflux inhibition assay using ethidium bromide as NorA substrate. The present communication describes the synthesis, bioevaluation and structure related activity of these efflux pump inhibitors.

Topics: Alkaloids; Anti-Bacterial Agents; Bacterial Proteins; Benzodioxoles; Ciprofloxacin; Enzyme Inhibitors; Ethidium; Microbial Sensitivity Tests; Multidrug Resistance-Associated Proteins; Nucleic Acid Synthesis Inhibitors; Piperidines; Polyunsaturated Alkamides; Staphylococcus aureus

This study was aimed to explore underlying mechanism(s) of cardiovascular effects of piperine. Intravenous administration of piperine caused a dose-dependent (1 to 10 mg/kg) decrease in mean arterial pressure (MAP) in normotensive anesthetized rats; the next higher dose (30 mg/kg) did not cause any further change in MAP. The fall in blood pressure (BP) was followed by small increase in MAP after each dose. In Langendorrf's rabbit heart preparation, piperine caused partial inhibition and verapamil caused complete inhibition of force and rate of ventricular contractions and coronary flow. In rabbit aortic rings, piperine inhibited high K+ (80 mM) precontractions and partially inhibited phenylephrine (PE), suggesting Ca2+ channel blockade (CCB), which was further confirmed when pretreatment of tissues with piperine caused rightward shift in Ca2+ concentration-response curves, similar to verapamil. In Ca2+-free medium, piperine (1 to 30 microM) exhibited vasoconstrictor effect. In rat aorta, piperine demonstrated endothelium-independent vasodilator effect and was more potent against high K+ precontractions than PE. In bovine coronary artery preparations, piperine inhibited high K+ precontractions completely. These data indicate that piperine possesses a blood pressure-lowering effect mediated possibly through CCB, while consistent decrease in BP was restricted by associated vasoconstrictor effect. Additionally, species selectivity exists in the CCB effect of piperine.

Topics: Alkaloids; Animals; Antihypertensive Agents; Aorta, Thoracic; Benzodioxoles; Blood Pressure; Cattle; Coronary Circulation; Coronary Vessels; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Myocardial Contraction; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rabbits; Rats; Rats, Sprague-Dawley; Vasodilation

The therapeutic potential of the chelator tiferron (sodium-4,5-dihydroxy-1,3-benzene disulphonate; 300 mg kg(-1), i.p.) and adjuvants, i.e. alpha-tocopherol (25 mg kg(-1), p.o.), propolis (a honey-bee hive product; 200 mg kg(-1), p.o.) and piperine (10 mg kg(-1), p.o.) were evaluated individually and in combination against beryllium induced biochemical alterations and oxidative stress consequences. Female albino rats were exposed to beryllium nitrate (1 mg kg(-1), i.p.) daily for 28 days followed by treatment with the above mentioned therapeutic agents for 5 consecutive days. Administration of beryllium altered blood biochemical variables with significant depletion in hemoglobin, blood sugar, total serum protein, albumin and significant enhancement in the release of serum transaminases. A significantly increased lipid peroxidation and a decreased level of glutathione after beryllium exposure indicated oxidative stress in the liver and kidney. Beryllium exposure decreased total protein and glycogen contents, whereas triglycerides and cholesterol increased significantly in liver and kidney. Individual administration of all the four compounds showed significant therapeutic potential in reverse of some of the biochemical parameters mentioned above. Furthermore, the combination of tiferron with alpha-tocopherol, propolis or piperine, respectively, could reverse all the variables significantly more towards the control. None of the test compounds showed any significant change in choleretic activity (bile flow and bile solids), indicating that these compounds had no adverse effects at these dose levels. It was concluded that all the combinations of tiferron and adjuvants played a beneficial role in reducing beryllium induced systemic toxicity at relatively lower doses and the combination of tiferron and propolis showed a more pronounced therapeutic potential.

Topics: Alanine Transaminase; Alkaloids; alpha-Tocopherol; Animals; Antioxidants; Aspartate Aminotransferases; Benzenesulfonates; Benzodioxoles; Beryllium; Blood Glucose; Blood Proteins; Chelating Agents; Cholagogues and Choleretics; Cholesterol; Female; Glutathione; Glycogen; Hemoglobins; Nitrates; Piperidines; Polyunsaturated Alkamides; Propolis; Rats; Rats, Sprague-Dawley; Serum Albumin; Thiobarbituric Acid Reactive Substances; Triglycerides

It has been reported that piplartine and piperine, alkaloid/amide compounds from Piper species, show antitumor activities. In the present paper, the effects of the combination of 5-fluorouracil (5-FU) with piplartine or piperine was determined using in vitro and in vivo experimental models. Hematological and biochemical analyses, as well as histopathological and morphological analyses of the tumor and the organs, including liver, spleen and kidney, were performed in order to evaluate the toxicological aspects associated with different treatments. The incubation of tumor cell lines with 5-FU in the presence of piplartine or piperine produced an increase in growth inhibition, as observed by lower IC50 values for 5-FU. These effects were also observed in vivo, where the combination with piplartine but not piperine with 5-FU led to a higher tumor growth inhibition. The results indicated that either piplartine- or 5-FU-treated animals showed a low inhibition rate when they were used individually at low doses of 28.67% and 47.71%, respectively, but when they were combined at the same dose, the inhibition rate increased significantly to 68.04%. The histopathological analysis showed that the livers and the kidneys of treated animals were only slightly and reversibly affected. Neither the enzymatic activity of transaminases nor the urea levels were significantly modified when compared with the control group. Hematological analysis showed leukopenia after 5-FU treatment, which was reversed by the combined use of piplartine and piperine. These findings indicate that piplartine may enhance the therapeutic effectiveness of chemotherapeutic drugs, and moreover, this combination could improve immunocompetence hampered by 5-FU.

Topics: Alanine Transaminase; Alkaloids; Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Benzodioxoles; Cell Proliferation; Dose-Response Relationship, Drug; Female; Fluorouracil; HL-60 Cells; Humans; Inhibitory Concentration 50; Kidney; Leukopenia; Liver; Mice; Piperidines; Piperidones; Polyunsaturated Alkamides; Sarcoma 180; Urea

In a previous work, we have investigated the effects of piperine and several of its chemical derivatives on the proliferation of the protozoan parasite Trypanosoma cruzi. It was observed that natural piperine is more active against intracellular amastigotes than axenically grown epimastigotes with IC50 values of 4.91 and 7.36 microM, respectively. Despite its superior trypanocidal activity against the intracellular amastigotes, here, we show that piperine did not enhance microbiocidal characteristics of murine peritoneal macrophages (Mø) based on nitric oxide production. As shown by light and electron microscopy analysis, epimastigotes treated with sublethal concentrations of piperine presented a reversible cell cycle arrestment and become round shaped, with swelling of the mitochondrion matrix and intense intracellular vacuolization with structures displaying complex membrane invaginations. Similar to the effects of exposing epimastigotes to the antitumor and microtubule stabilizer taxol, multiplication of cell organelles such as the flagellum, kinetoplast, and nucleus occurred, but division into daughter cells was impaired. Unlike the effects caused by the anti-microtubular vinca alkaloids vincristine and vinblastine, which also induce cytokinesis arrestment in T. cruzi epimastigotes, piperine did not induce the formation of giant multinucleated cells. The data reinforce the selectivity of the mechanisms of action of piperine against T. cruzi.

Topics: Alkaloids; Animals; Benzodioxoles; Cells, Cultured; Cytokinesis; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Microscopy, Electron; Nitric Oxide; Parasitic Sensitivity Tests; Piperidines; Polyunsaturated Alkamides; Trypanocidal Agents; Trypanosoma cruzi

We herein describe the synthesis and characterization of nine new 1,3,4-thiadiazolium-2-phenylamine chlorides derived from natural piperine. We evaluate their toxic effects against the different evolutive forms of Trypanosoma cruzi, and the host cell (murine macrophages). The results obtained show that mesoionic hydrochloride MI possesses the best activity profile. Compound MI may be a prototype for use in the development of a new chemotherapeutic agent with high efficiency, which may be employed in the treatment of Chagas' disease.

Topics: Alkaloids; Animals; Benzodioxoles; Chagas Disease; Macrophages; Mice; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi

The methanolic extract from the fruit of Piper chaba (Piperaceae) was found to have a hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. From the ethyl acetate-soluble fraction, a new amide constituent named piperchabamide E together with twenty known amide constituents (e.g., piperine, piperchabamides A-D, and piperanine) and two aromatic constituents were isolated as the hepatoprotective constituents. With regard to structure-activity relationships, the amide moiety and the 1,9-decadiene structure between the benzene ring and amide moiety were suggested to be important for strong inhibition of D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes. Furthermore, a principal amide constituent, piperine, dose-dependently inhibited increase in serum GPT and GOT levels at doses of 2.5-10 mg/kg (p.o.) in D-GalN/LPS-treated mice, and this inhibitory effect was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.

Topics: Alanine Transaminase; Alkaloids; Amides; Animals; Aspartate Aminotransferases; Benzodioxoles; Cell Death; Chromatography, High Pressure Liquid; Fruit; Galactosamine; Hepatocytes; Lipopolysaccharides; Liver; Liver Diseases; Male; Mice; Mice, Mutant Strains; Molecular Structure; Piperaceae; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

Evaluation of novel synthetic analogues of piperine as inhibitors of multidrug efflux pump NorA of Staphylococcus aureus.. A library of piperine-derived compounds was evaluated for their potential to inhibit ethidium bromide efflux in NorA-overexpressing S. aureus SA 1199B. The active compounds were then individually combined with ciprofloxacin to study the potentiation of ciprofloxacin's activity.. Based on the efflux inhibition assay, a library of 200 compounds was screened. Three piperine analogues, namely SK-20, SK-56 and SK-29, were found to be the most potent inhibitors of the NorA efflux pump. These inhibitors acted in a synergistic manner with ciprofloxacin, by substantially increasing its activity against both NorA-overexpressing and wild-type S. aureus isolates. These analogues were 2- to 4-fold more potent than piperine at a significantly lower minimal effective concentration. Furthermore, these inhibitors also significantly suppressed the in vitro emergence of ciprofloxacin-resistant S. aureus.. A newly identified class of compounds derived from a natural amide, piperine, is more potent than the parent molecule in potentiating the activity of ciprofloxacin through the inhibition of the NorA efflux pump. These molecules may prove useful in augmenting the antibacterial activities of fluoroquinolones in a clinical setting.

Topics: Alkaloids; Anti-Bacterial Agents; Bacterial Proteins; Benzodioxoles; Ciprofloxacin; Drug Resistance, Bacterial; Drug Synergism; Ethidium; Microbial Sensitivity Tests; Microbial Viability; Molecular Structure; Multidrug Resistance-Associated Proteins; Mutation; Piperidines; Polyunsaturated Alkamides; Staphylococcus aureus

Pepper plants accumulate pungent bioactive alkaloids called piperamides. To facilitate studies in this area, high-performance liquid chromatography (HPLC) and liquid chromatography/mass spectrometry methods were developed and used to measure the following piperamides in 10 commercial whole (peppercorns) and in 10 ground, black, white, green, and red peppers: piperanine, piperdardine, piperine, piperlonguminine, and piperettine. Structural identification of individual compounds in extracts was performed by associating the HPLC peak of each compound with the corresponding mass spectrum. The piperanine content of the peppers (in mg/g piperine equivalents) ranged from 0.3 for the ground white pepper to 1.4 in black peppercorns. The corresponding range for piperdardine was from 0.0 for seven samples to 1.8 in black peppercorns; for four isomeric piperines, from 0.7 for red to 129 in green peppercorns; for piperlonguminine, from 0.0 in red peppercorns to 1.0 in black peppercorns; and for piperyline, from 0.9 in ground black pepper to 5.9 for red peppercorn. Four well-separated stereoisomeric forms of piperettine with the same molecular weight were present in 19 peppers. The sums of the piperamides ranged from 6.6 for red to 153 for green peppercorns. In contrast to large differences in absolute concentrations among the peppers, the ratios of piperines to total piperamide were quite narrow, ranging from 0.76 for black to 0.90 for white peppercorns, with an average value of 0.84 +/- 0.04 ( n = 19). Thus, on average, the total piperamide content of the peppers consists of 84% piperines and 16% other piperamides. These results demonstrate the utility of the described extraction and analytical methods used to determine the wide-ranging individual and total piperamide contents of widely consumed peppers.

Topics: Alkaloids; Amides; Benzodioxoles; Chromatography, High Pressure Liquid; Dioxolanes; Mass Spectrometry; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Recent studies have proposed curcumin as a potential partner for artemisinin in artemisinin combination therapies to treat malaria infections. The efficacy of curcumin alone and in combination with artemisinin was evaluated on a clone of Plasmodium chabaudi selected for artemisinin resistance in vivo. The addition of piperine as an enhancer of curcumin activity was also tested. Results indicated that curcumin, both alone and in combination with piperine had only a modest antimalarial effect and was not able to reverse the artemisinin-resistant phenotype or significantly affect growth of the tested clone when used in combination with artemisinin. This is in contrast with previous in vivo work and calls for further experimental evaluation of the antimalarial potential of curcumin.

Topics: Administration, Oral; Alkaloids; Animals; Anti-Infective Agents; Artemisinins; Benzodioxoles; Biological Availability; Curcumin; Drug Resistance; Drug Therapy, Combination; Malaria; Male; Mice; Parasitemia; Piperidines; Plasmodium chabaudi; Polyunsaturated Alkamides

A simple, rapid and efficient method has been developed for the isolation of piperine from the fruits of Piper nigrum. The method involves extraction of the fruit powder with glacial acetic acid, from which piperine is partitioned into chloroform and subsequently crystallized. The identity of the compound was confirmed by its melting point, comparison of UV, IR, and mass spectral data with those from a reference standard, and co-chromatography with the reference standard using thin-layer chromatography (TLC). The purity of the compound was ascertained by TLC, by recording UV absorption spectra at the start, middle, and end positions of the spot on the plate, and by differential scanning calorimetry (DSC).

Topics: Alkaloids; Benzodioxoles; Calorimetry, Differential Scanning; Chromatography, Thin Layer; Fruit; Piper nigrum; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Reference Standards; Spectrum Analysis; Transition Temperature

Piperine, a major component of black pepper, is used as spice and nutrient enhancer. The purpose of the present study was to evaluate the effects of acute and prolonged piperine exposure on cellular P-gp expression and function in vitro and in vivo. Piperine at concentrations ranging from 10 to 100 microM, determined by MTT assay to be non-cytotoxic, was observed to inhibit P-gp mediated efflux transport of [(3)H]-digoxin across L-MDR1 and Caco-2 cell monolayers. The acute inhibitory effect was dependent on piperine concentration, with abolishment of [(3)H]-digoxin polarized transport attained at 50 microM of piperine. In contrast, prolonged (48 and 72 h) co-incubation of Caco-2 cell monolayers with piperine (50 and 100 microM) increased P-gp activity through an up-regulation of cellular P-gp protein and MDR1 mRNA levels. The up-regulated protein was functionally active, as demonstrated by a higher degree of [(3)H]-digoxin efflux across the cell monolayers, but the induction was readily reversed by the removal of the spice from the culture medium. Peroral administration of piperine at the dose of 112 microg/kg body weight/day to male Wistar rats for 14 consecutive days also led to increased intestinal P-gp levels. However, there was a concomitant reduction in the rodent liver P-gp although the kidney P-gp level was unaffected. Our data suggest that caution should be exercised when piperine is to be co-administered with drugs that are P-gp substrates, particularly for patients whose diet relies heavily on pepper.

Topics: Alkaloids; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Transport; Caco-2 Cells; Cell Proliferation; Digoxin; Humans; LLC-PK1 Cells; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Swine

Curcuminoid extract and piperine are being evaluated for beneficial effects in Alzheimer's disease, among other intractable disorders. Consequently, we studied the potential for herb-drug interactions involving cytochrome P450 (P450), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes. The curcuminoid extract inhibited SULT > CYP2C19 > CYP2B6 > UGT > CYP2C9 > CYP3A activities with IC(50) values ranging from 0.99 +/- 0.04 to 25.3 +/- 1.3 microM, whereas CYP2D6, CYP1A2, and CYP2E1 activities were less affected (IC(50) values > 60 microM). Inhibition of CYP3A activity by curcuminoid extract was consistent with competitive inhibition (K(i) = 11.0 +/- 1.3 microM), whereas inhibition of both CYP2C9 and CYP2C19 activities were consistent with mixed competitive-noncompetitive inhibition (10.6 +/- 1.1 and 7.8 +/- 0.9 microM, respectively). Piperine was a relatively selective noncompetitive inhibitor of CYP3A (IC(50) 5.5 +/- 0.7 microM, K(i) = 5.4 +/- 0.3 microM) with less effect on other enzymes evaluated (IC(50) > 29 microM). Curcuminoid extract and piperine inhibited recombinant CYP3A4 much more potently (by >5-fold) than CYP3A5. Pure synthetic curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) were also evaluated for their effects on CYP3A, CYP2C9, UGT, and SULT activities. All three curcuminoids had similar effects on CYP3A, UGT, and SULT activity, but demethoxycurcumin (IC(50) = 8.8 +/- 1.2 microM) was more active against CYP2C9 than either curcumin or bisdemethoxycurcumin (IC(50) > 50 microM). Based on these data and expected tissue concentrations of inhibitors, we predict that a p.o. administered curcuminoid/piperine combination is most likely to inhibit CYP3A, CYP2C9, UGT, and SULT metabolism within the intestinal mucosa.

Topics: Acetaminophen; Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Curcumin; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Glucuronosyltransferase; Humans; Liver; Piperidines; Polyunsaturated Alkamides; Recombinant Proteins; Spectrometry, Fluorescence; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; Sulfotransferases

Piperine, a natural product containing a conjugated diene, was reacted with polymer-supported acyl- and arylnitroso dienophiles. The reactions with arylnitroso dienophiles were also carried out in solution. The oxazine rings formed by the corresponding hetero-Diels-Alder reactions were further transformed and novel acyclic as well as heterocyclic derivatives including pyrroles and quinoxalinones were prepared.

Topics: Alkaloids; Benzodioxoles; Biological Products; Nitroso Compounds; Piperidines; Polyunsaturated Alkamides

Transient receptor potential ion channel of the vanilloid type 1 (TRPV1)-dependent pathway, consisting of capsaicin-sensitive tachykininergic primary afferent and myenteric nitrergic neurons, has been suggested to mediate the inhibitory effect of capsaicin on vagally mediated striated muscle contractions in the rat esophagus. In a recent study, similar but also different effects of capsaicin and piperine on TRPV1 were demonstrated. Therefore, this study aimed to compare the effects of these two drugs on vagally induced contractions in the mouse esophagus. Capsaicin and piperine inhibited vagally induced contractions of a thoracic esophageal segment in a concentration-dependent manner. Ruthenium red (10 microM; a non-selective blocker of transient receptor potential cation channels) and SB-366791 (10 microM; a novel selective antagonist of TRPV1) blocked the inhibitory effect of capsaicin but not that of piperine. Piperine inhibited the vagally mediated contractions in esophagi of adult mice neonatally injected with capsaicin, while capsaicin failed to do so. Desensitization of TRPV1 in the mouse esophagus by in vitro pretreatment with capsaicin failed to affect the inhibitory effect of piperine, whereas the piperine effect was cross-desensitized by capsaicin pretreatment in rat and hamster esophagi. Additionally, a tachykinin NK(1) receptor antagonist, L-732,138 (1 microM), as well as a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME 200 microM), blocked the inhibitory effect of capsaicin but not that of piperine. Taken together, the results suggest that piperine inhibits the vagally mediated striated muscle contraction in the mouse esophagus through its action on a TRPV1-dependent pathway as well as a TRPV1-independent site.

Topics: Alkaloids; Anilides; Animals; Benzodioxoles; Capsaicin; Cinnamates; Cricetinae; Enzyme Inhibitors; Esophagus; Female; Male; Mesocricetus; Mice; Muscle Contraction; Muscle, Smooth; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptors, Tachykinin; Species Specificity; TRPV Cation Channels; Tryptophan; Vagus Nerve

Vanilloids like capsaicin and resiniferatoxin (RTX) have been used for more than a decade in the treatment of neurogenic detrusor overactivity. Recently, the vanilloid molecule piperine (PIP) has been shown to have similar pharmacological properties as these drugs. In this study, we looked at PIP-effects on autonomous bladder contractile activity, with particular interest for its selectivity for the transient receptor potential channel 1 (TRPV1) receptor. Additionally, we studied the role of TRPV1 in volume-induced contractile changes using selective and non-selective TRPV1 antagonists.. The acute and prolonged effects of PIP were studied on rat bladders. Each bladder was excised and placed in a heated organ bath, where intravesical pressures were measured. In acute experiments, PIP was added directly to the bathing solution. For prolonged effects, animals were pre-treated intravesically with vehicle (ethanol 5%) or PIP (10(-4) M) and sacrificed 72 hr later. The effects of selective (capsazepine (CZP)) and non-selective (ruthenium red (RR)) TRPV1 antagonists on volume-evoked contractile parameters were also studied.. Acute administration of PIP 10(-4) M significantly increased amplitude of bladder contractions (P < 0.05). These effects were significantly antagonized (P < 0.05) by the TRPV1-selective antagonist CZP (10(-5) M) and the non-selective TRP-antagonist RR (10(-5) M). Intravesical pre-treatment with PIP induced shorter contractions with more periods of non-activity (P < 0.05) compared to controls. Inhibition of TRPV1 with CZP and RR significantly reduced the volume-evoked rise in contractile amplitude in isolated bladders (P < 0.05).. We found evidence for acute and prolonged effects of PIP on bladder contractility, which seem to be mediated through TRPV1. Furthermore, we found evidence for involvement of TRPV1 in afferent signaling of mechanical stimuli.

Topics: Alkaloids; Animals; Benzodioxoles; Capsaicin; Carbachol; Cholinergic Agonists; Dose-Response Relationship, Drug; Female; Indicators and Reagents; Mechanotransduction, Cellular; Muscle Contraction; Piperidines; Polyunsaturated Alkamides; Pressure; Rats; Rats, Wistar; Ruthenium Red; Stress, Mechanical; TRPV Cation Channels; Urinary Bladder

Influence of adjuvants i.e., alpha-tocopherol (25 mg/kg, p.o.) and piperine (10 mg/kg, p.o.) on therapeutic potential of chelator tiferron (300 mg/kg, i.p.) was evaluated to encounter toxicogenic events of beryllium exposure. Albino rats were exposed to beryllium nitrate (1 mg/kg, i.p.) daily for 28 days followed by treatment of aforesaid therapeutic agents for 5 consecutive days. Results were considered to be significant at p < or =0.01 and p < or =0.05. Exposure to beryllium increased its concentration in liver, kidney and serum causing significant alterations in the activity of CYP-450 2E1 system, microsomal lipid peroxidation and protein; alkaline phosphtase, lactate dehydrogenase, gamma-glutamyl transpeptidase, bilirubin, creatinine and urea in serum; activity of acid phosphatase, alkaline phosphatase, adenosine triphosphatase, glucose-6-phosphatase and succinic dehydrogenase in liver and kidney. Beryllium exposure also induced severe alterations in histopathology and ultramorphology of liver and kidney proving its toxic consequences at cellular level. Tiferron along with adjuvants dramatically reversed alterations of all variables more towards control rather than individual treatment. Study concluded that tiferron in combination with alpha-tocopherol and piperine respectively was beneficial in diluting beryllium induced systemic toxicity; however, combination of tiferron and piperine presented more pronounced therapeutic potential.

Topics: Adjuvants, Pharmaceutic; Alkaloids; alpha-Tocopherol; Animals; Benzodioxoles; Beryllium; Chelating Agents; Drug Therapy, Combination; Female; Hepatorenal Syndrome; Kidney; Liver; Piperidines; Polyunsaturated Alkamides; Rats

In this study, we investigated the antidepressant-like effect of piperine in mice exposed to chronic mild stress (CMS) procedure. Repeated administration of piperine for 14 days at the doses of 2.5, 5 and 10 mg/kg reversed the CMS-induced changes in sucrose consumption, plasma corticosterone level and open field activity. Furthermore, the decreased proliferation of hippocampal progenitor cells was ameliorated and the level of brain-derived neurotrophic factor (BDNF) in hippocampus of CMS stressed mice was up-regulated by piperine treatment in the same time course. In addition, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactic dehydrogenase (LDH) assays showed that piperine (6.25-25 microM) or fluoxetine (FLU, 1 microM) dose-dependently protected primary cultured hippocampal neurons from the lesion induced by 10 microM corticosterone (CORT). Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the messenger ribonucleic acid (mRNA) level of BDNF in cultured neurons. Treatment with piperine (6.25-25 microM) for 72 h reversed the CORT-induced reduction of BDNF mRNA expression in cultured hippocampal neurons. In summary, up-regulation of the progenitor cell proliferation of hippocampus and cytoprotective activity might be mechanisms involved in the antidepressant-like effect of piperine, which may be closely related to the elevation of hippocampal BDNF level.

Topics: Alkaloids; Animals; Antidepressive Agents; Benzodioxoles; Brain-Derived Neurotrophic Factor; Cell Proliferation; Cell Survival; Cells, Cultured; Chronic Disease; Corticosterone; Depression; Hippocampus; Immunohistochemistry; L-Lactate Dehydrogenase; Male; Mice; Neurons; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells; Stress, Psychological; Tetrazolium Salts; Thiazoles; Weight Gain

Allyl isothiocyanate is well known to be a principal pungent constituent of horseradish and an agonist for transient receptor potential (TRP) A1. Ally isothiocyanate markedly inhibited the formation of gastric lesions induced by ethanol (1.5 ml/rat, p.o.), 0.6 M HCl (1.5 ml/rat, p.o.), 1% ammonia (1.5 ml/rat, p.o.), and aspirin (150 mg/kg, p.o.) (ED(50)=1.6, 2.2, 1.7, ca. 6.5 mg/kg, p.o.). It also significantly inhibited the formation of gastric lesions induced by indomethacin (20 mg/kg, p.o.), though the inhibition was ca. 60% at a high dose (40 mg/kg, p.o.). Furthermore, several synthetic isothiocyanate compounds also significantly inhibited ethanol and indomethacin-induced gastric lesions. Whereas, TRPV1 agonists, capsaicin and piperine, inhibited gastric lesions induced by ethanol, 1% ammonia, and aspirin, but had less of an effect on 0.6 M HCl-induced gastric lesions. With regard to mode of action, the protective effects of ally isothiocyanate on ethanol-induced gastric lesions were attenuated by pretreatment with indomethacin, but not with N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME), or ruthenium red. Pretreatment with indomethacin reduced the protective effects of piperine, and L-NAME reduced the effects of capsaicin and omeprazole. Furthermore, ruthenium red reduced the effects of capsaicin, piperine, and omeprazole. These findings suggest that endogenous prostaglandins play an important role in the protective effect of allyl isothiocyanate in ethanol-induced gastric lesions different from capsaicin, piperine, and omeprazole.

Topics: Alkaloids; Ammonia; Animals; Armoracia; Aspirin; Benzodioxoles; Capsaicin; Dose-Response Relationship, Drug; Ethanol; Food Preservatives; Gastric Mucosa; Hydrochloric Acid; Indomethacin; Isothiocyanates; Male; NG-Nitroarginine Methyl Ester; Omeprazole; Piperidines; Polyunsaturated Alkamides; Prostaglandins; Rats; Rats, Sprague-Dawley; Ruthenium Red; Structure-Activity Relationship

Sequential presentation of 2 irritants may produce cross-sensitization or cross-adaptation effects upon introduction of the second irritant. In Experiment 1, subjects were given either 34 min of stimulation with zingerone, capsaicin, or piperine or one of those irritants for 23 min followed by blanks for 23 min. In Experiment 2, subjects received one irritant for 23-min irritants, followed immediately by another for 23 min (piperine --> zingerone, piperine --> capsaicin, zingerone --> piperine, or zingerone --> capsaicin). Cross-sensitization was observed for the piperine --> zingerone, zingerone --> piperine, and piperine --> capsaicin groups; cross-adaptation was observed for the zingerone --> capsaicin group. Cross-adaptation and cross-sensitization were predicted by adding the independent time courses of the respective irritants, starting the second at the offset of the first. These responses were also predicted by a mathematical model of central processing of primary afferent responses.

Topics: Administration, Oral; Alkaloids; Benzodioxoles; Capsaicin; Guaiacol; Humans; Irritants; Piperidines; Polyunsaturated Alkamides

Piperine, the bioactive alkaloid compound of the spice black pepper (Piper nigrum) exhibits a wide range of beneficial physiological and pharmacological activities. Being essentially water-insoluble, piperine is presumed to be assisted by serum albumin for its transport in blood. In this study, the binding of piperine to serum albumin was examined by employing steady state and time resolved fluorescence techniques. Binding constant for the interaction of piperine with human serum albumin, which was invariant with temperature in the range of 17-47 degrees C, was found to be 0.5 x 10(5)M(-1), having stoichiometry of 1:1. At 27 degrees C, the van't Hoff enthalpy DeltaH degrees was zero; DeltaS degrees and DeltaG degrees were found to be 21.4 cal mol(-1) K(-1) and -6.42 kcal mol(-1). The binding constant increased with the increase of ionic strength from 0.1 to 1.0M of sodium chloride. The decrease of Stern-Volmer constant with increase of temperature suggested that the fluorescence quenching is static. Piperine fluorescence showed a blue shift upon binding to serum albumin, which reverted with the addition of ligands -triiodobenzoic acid and hemin. The distance between piperine and tryptophan after binding was found to be 2.79 nm by Förster type resonance energy transfer calculations. The steady state and time resolved fluorescence measurements suggest the binding of piperine to the subdomain IB of serum albumin. These observations are significant in understanding the transport of piperine in blood under physiological conditions.

Topics: Alkaloids; Animals; Benzodioxoles; Binding, Competitive; Cattle; Energy Transfer; Fluorescence; Humans; Kinetics; Ligands; Osmolar Concentration; Piperidines; Polyunsaturated Alkamides; Protein Binding; Serum Albumin; Spectrometry, Fluorescence; Temperature; Time Factors

An alkaloid constituent 1-[5-(1,3-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]piperidine, trivial name piperine was isolated from Ludwigia hyssopifolia Linn. (Family-Onagraceae). The ethylacetate extract of the plant and the isolated compound piperine were studied for antitumor and in vitro antibacterial activity. Ethylacetate extract showed 73.05 and 84.14% inhibition of Agrobacterium tumefaciens-induced crown gall tumor formation in potato disc. Piperine exhibited antitumor activity with IC50 value of 13.50 microg/disc. Both ethylacetate extract and piperine showed mild to moderate antibacterial activity against selected Gram-positive and Gram-negative bacteria.

Topics: Acetates; Agrobacterium tumefaciens; Alkaloids; Anti-Bacterial Agents; Antineoplastic Agents, Phytogenic; Benzodioxoles; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Onagraceae; Piperidines; Plant Extracts; Plant Tumors; Polyunsaturated Alkamides; Solvents

Piperine is a major component of black pepper, Piper nigrum Linn, used widely in traditional medicine. In this study, we examined whether piperine could protect House Ear Institute-Organ of Corti 1 (HEI-OC1) cells against cisplatin-induced apoptosis through the induction of heme oxygenase (HO)-1 expression. Piperine (10-100 microM) induced the expression of HO-1 in dose- and time-dependent manners. Piperine also induced antioxidant response element-luciferase and translocated nuclear factor-E2-related factor-2 (Nrf2) to nucleus. Piperine activated the c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase and p38 mitogen-activated protein kinase (MAPK) pathways, and the JNK pathway played an important role in piperine-induced HO-1 expression. Piperine protected the cells against cisplatin-induced apoptosis. The protective effect of piperine was abrogated by zinc protoporphyrin IX, an HO inhibitor, and antisense oligodeoxynucleotides against HO-1 gene. These results demonstrate that the expression of HO-1 by piperine is mediated by both JNK pathway and Nrf2, and the expression inhibits cisplatin-induced apoptosis in HEI-OC1 cells.

Topics: Alkaloids; Animals; Antineoplastic Agents; Apoptosis; Benzodioxoles; Cell Nucleus; Cells, Cultured; Cisplatin; Dose-Response Relationship, Drug; Hair Cells, Auditory, Outer; Heme Oxygenase-1; JNK Mitogen-Activated Protein Kinases; Mice; NF-E2-Related Factor 2; Organ of Corti; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Transfection

The effects of four alkaloids on the biosynthesis of ochratoxin A (OTA), ochratoxin B (OTB) and citrinin were examined on four OTA-producing aspergilli: Aspergillus auricomus, A. sclerotiorum and two isolates of A. alliaceus. Piperine and piperlongumine, natural alkaloids of Piper longum, significantly inhibited OTA production at 0.001% (w/v) for all aspergilli examined. Piperine and piperlongumine affected the polyketide synthesis step of OTA production and inhibited production of citrinin. Curcumin, a constituent of tumeric, completely inhibited mycelial growth of A. alliaceus isolate 791 at 0.1% (w/v) and decreased OTA production by approximately 70% at 0.01% (w/v). Sesamin, a constituent of sesame oil, inhibited OTA and OTB production by 60 and 45%, respectively, at 0.1% (w/v), showing its effect was on chloroperoxidase and polyketide synthase activity. The potential advantage of these natural products to reduce ochratoxin contamination of agricultural commodities is discussed.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Antioxidants; Aspergillus; Benzodioxoles; Carcinogens; Citrinin; Culture Media; Curcuma; Curcumin; Dioxolanes; Dioxoles; Food Contamination; Lignans; Mycelium; Mycotoxins; Ochratoxins; Piper; Piperidines; Polyunsaturated Alkamides; Sesame Oil

A comparative evaluation of the absorbability of three structurally similar and physiologically active spice principles in an in vitro system consisting of everted rat intestinal sacs was made. When everted sacs of rat intestines were incubated with 50-1000 microg of curcumin in 10 ml incubation medium, absorption of the spice principle was maximum at 100 microg concentration. The amount of absorbed curcumin present in the serosal fluid was negligible. This and the comparatively lower recovery of the original compound suggested that curcumin to some extent undergoes a modification during absorption. For similar concentrations of added piperine, about 44-63% of piperine disappeared from the mucosal side. Absorption of piperine which was maximum at 800 microg per 10 ml was about 63%. The absolute amounts of piperine absorbed in this in vitro system exceeded the amounts of curcumin. The absorbed piperine could be traced in both the serosal fluid and in the intestinal tissue, indicating that piperine did not undergo any metabolic change during the process of absorption. 7-12% of the absorbed piperine was found in the serosal fluid. When everted sacs of rat intestines were incubated with 10-500 microg of capsaicin, a maximum of 82-88% absorption could be seen in the lower concentrations, and the amount of absorbed capsaicin did not proportionately increase at higher concentrations. A relatively higher percentage of the absorbed capsaicin could be seen in the serosal fluid as compared to curcumin or piperine. When these spice active principles were associated with mixed micelles, their in vitro intestinal absorption was relatively higher. Curcumin absorption in everted intestinal sac increased from 48.7% to 56.1% when the same was present in micelles. In the case of capsaicin and piperine, increase in absorption was 27.8-44.4% and 43.4-57.4%, respectively, when they were present in micelles as compared to its native form.

Topics: Alkaloids; Animals; Benzodioxoles; Capsaicin; Curcumin; In Vitro Techniques; Intestinal Absorption; Intestinal Mucosa; Male; Micelles; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Spices

Piper longum L. has been used as a crude drug for the treatment of disorders of poor peripheral blood circulation in Asia. However, the detailed mechanism of its action has not been clarified as yet. In the present study, we examined the effects of several extracts of Piper longum L. on rabbit platelet function. Thromboxane A(2) receptor agonist U46619 caused rabbit platelet aggregation, which was potently inhibited by the ethanol or butanol extract of Piper longum L. The ethanol extract inhibited U46619-induced platelet aggregation in a concentration-dependent manner, but only weakly inhibited that induced by thrombin. The maximum response to U46619 was reduced by 100% ethanol extract concentration dependently, suggesting that the inhibitory mode of U46619-induced platelet aggregation by the ethanol extract was non-competitive. The extract also inhibited U46619-induced phosphoinositide hydrolysis with a similar concentration dependency to the platelet aggregation. Furthermore, the extract inhibited binding of [(3)H]SQ29548 to thromboxane A(2) receptor in intact platelets in a concentration-dependent manner. These results suggest that Piper longum L. contains a constituent(s) that inhibits platelet aggregation as a non-competitive thromboxane A(2) receptor antagonist.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alkaloids; Animals; Benzodioxoles; Bridged Bicyclo Compounds, Heterocyclic; Dioxolanes; Fatty Acids, Unsaturated; Hydrazines; Male; Phosphatidylinositols; Piper; Piperidines; Plant Extracts; Platelet Aggregation; Platelet Aggregation Inhibitors; Polyunsaturated Alkamides; Rabbits; Receptors, Thromboxane A2, Prostaglandin H2

The pungent compounds piperine and isomers thereof, secondary metabolites present in black and white pepper fruit, undergo light-induced isomerizations. To facilitate studies in this area, an HPLC method has been developed for analysis and isolation of the following four possible piperine-derived photoinduced isomers: piperine, isopiperine, chavicine, and isochavicine. The limits of detection (LOD) estimated from calibration plots were approximately 15-30 ng for each isomer. Reproducibilities of the analyses were excellent, and recoveries of spiked samples were as follows (average +/- SD; n = 3): chavicine, 98.4 +/- 2.1%; isopiperine, 96.2 +/- 3.2%; piperine, 104 +/- 3.8%; isochavicine, 98.9 +/- 3.0%. To determine the kinetics of these isomerizations, fluorescent light, sunlight, and UV radiation at 254 nm was used to induce cis-trans geometric isomerization as a function of light intensities and time of exposure determined with the aid of high-performance liquid chromatography (HPLC) and liquid chromatography with diode array UV detection-mass spectrometry (LC-DAD/MS). HPLC was also used to determine the distribution of the isomers in four commercial ground black pepper products used as spices in culinary practice. Isomerization increased with light intensities and time of exposure and leveled off at the so-called photostationary phases. The piperine levels of the four products were quite similar, ranging (in wt %) from 10.17 to 11.68. The amounts of the other three isomers ranged from 0.01 to 0.07 of the total for chavicine; from 0.15 to 0.23 for isopiperine; and from 0.37 to 0.42 for isochavicine. The results establish the utility of the HPLC method for simultaneous analysis of the four isomers both in pure form and in black pepper extracts. The dietary significance of the results is discussed.

Topics: Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Isomerism; Kinetics; Light; Mass Spectrometry; Piper nigrum; Piperidines; Polyunsaturated Alkamides

Piper longum Linn. and Piper nigrum Linn. are conventionally used as immuno-enhancers in Indian system of traditional medicine. The underlying mechanism remains unknown. The present study was therefore, undertaken to delineate the role of piperine (major alkaloid) in cadmium (Cd) induced immuno-compromised murine splenocytes. The various biological determinants such as oxidative stress markers (reactive oxygen species and GSH), Bcl-2 protein expression, mitochondrial membrane potential, caspase-3 activity, DNA damage, splenic B and T cell population, blastogenesis and cytokines (Interleukin-2 and gamma-Interferon) were measured to ascertain its cell protective potential. Cadmium induces apoptosis at 6 h onwards. The oxidative stress markers markedly alter prior to a decline in mitochondrial membrane potential, caspase-3 activation and DNA degradation The splenic cell population was observed to change only at 18 h and the release of two cytokines was affected at 72 h. Addition of piperine in various concentrations (1, 10 and 50 microg/ml) ameliorated the above events. The highest dose of piperine could completely abrogate the toxic manifestations of cadmium and the splenic cells behaved similar to control cells. The reported free radical scavenging property of piperine and its antioxidant potential could be responsible for the modulation of intracellular oxidative stress signals. These in turn appear to mitigate the apoptotic pathway and other cellular responses altered by cadmium. The findings strongly indicate the anti-oxidative, anti-apoptotic and chemo-protective ability of piperine in blastogenesis, cytokine release and restoration of splenic cell population and is suggestive of its therapeutic usefulness in immuno-compromised situations.

Topics: Alkaloids; Animals; Apoptosis; B-Lymphocytes; Benzodioxoles; Cadmium; Caspase 3; Cell Proliferation; Cells, Cultured; DNA Fragmentation; Glutathione; Immunologic Factors; Interferon-gamma; Interleukin-2; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Necrosis; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Spleen; T-Lymphocytes

Piperine displays antipyretic, analgesic, insecticidal and anti-inflammatory activities. It is the first amide to be isolated from Piper species. In the process of identifying non-steroidal anti-inflammatory small molecules from the natural sources, we demonstrate here that piperine inhibits adhesion of neutrophils to endothelial monolayer. The inhibition of neutrophils to endothelial monolayer by piperine is due to its ability to block the tumor necrosis factor-alpha (TNF-alpha) induced expression of cell adhesion molecules i.e. ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1) and E-selectin as analyzed by cell-ELISA and confirmed by flow cytometry. Further, we demonstrate that inhibition of ICAM-1 by piperine is reversible. As nuclear factor-kappaB (NF-kappaB) is known to control the transcriptional regulation of cell adhesion molecules hence, we measured the effect of piperine on NF-kappaB in the cytoplasm and in the nucleus of endothelial cells. We observed that pretreatment of endothelial cells with piperine blocks the nuclear translocation and activation of NF-kappaB via blocking the phosphorylation and degradation of its inhibitory protein, IkappaBalpha. Piperine blocks the phosphorylation and degradation of IkappaBalpha by attenuating TNF-alpha induced IkappaB kinase activity. These results suggest a possible mechanism of anti-inflammatory activity of piperine. Therefore, piperine or its structural analogues could be used for the development of new anti-inflammatory molecules.

Topics: Alkaloids; Anti-Inflammatory Agents; Base Sequence; Benzodioxoles; Cell Adhesion; Dose-Response Relationship, Drug; E-Selectin; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; I-kappa B Kinase; I-kappa B Proteins; Intercellular Adhesion Molecule-1; Neutrophils; NF-kappa B; NF-KappaB Inhibitor alpha; Piper; Piperidines; Polyunsaturated Alkamides; Time Factors; Vascular Cell Adhesion Molecule-1

We determined a minimum effective dose of gallic acid (3,4,5-trihydroxy benzoic acid; 50 mg/ kg, i.p.) and piperine (10 mg/kg, p.o.) through their therapeutic potential and further evaluated them individually and in combination against beryllium-induced biochemical alterations and oxidative stress consequences in female albino rats. The administration of beryllium altered blood biochemical variables by significantly depleting hemoglobin, albumin and urea, whereas it enhanced bilirubin and creatinine. The release of serum transaminase, lactate dehydrogenase and gamma-glutamyl transpeptidase was significantly greater, and was concomitant with a decrease in serum alkaline phosphatase. A significant increase in lipid peroxidation and a decrease in glutathione, superoxide dismutase and catalase in the liver and kidney was an indication of oxidative stress due to beryllium exposure. Individual administration of gallic acid and piperine moderately reversed the altered biochemical variables, whereas the combination of these was found to completely reverse the beryllium-induced biochemical alterations and oxidative stress consequences. We concluded that gallic acid exerts a synergistic effect when administered with piperine and provides a more pronounced therapeutic potential in reducing beryllium-induced hepatorenal dysfunction and oxidative stress consequences.

Topics: Alkaloids; Animals; Benzodioxoles; Beryllium; Drug Synergism; Female; Gallic Acid; Kidney; Lipid Peroxidation; Liver; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

We screened natural organic compounds, which affected the lipid accumulation and the lipid body formation in oleaginous yeast, Lipomyces starkeyi, generating large lipid bodies. We found that four natural components in spices, carvacrol, thymol, eugenol, and piperine, inhibited the lipid accumulation at concentrations of 20-50 mg/L with a slight growth inhibition. The inhibitory effects were quantitatively represented by the total lipid accumulation amount, the triacylglycerol accumulation amount, and the average lipid body size. At 50 mg/L, the effects of these compounds were not identical and exhibited 11-37% decrease in lipid amount and 15-21% decrease in lipid body size with 13-39% decrease in cell growth. The inhibitory effect of these compounds lead to 30-69% decrease in triacylglycerol accumulation without any additional accumulation of its intermediates, suggesting that they will suppress the total carbon inflow into the triacylglycerol biosynthesis.

Topics: Alkaloids; Benzodioxoles; Cymenes; Eugenol; Hypolipidemic Agents; Lipid Metabolism; Lipids; Lipomyces; Monoterpenes; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Spices; Thymol; Triglycerides

In recent years, considerable emphasis has been focused on identifying new cancer chemopreventive agents, which could be useful for the human population. Piperine is a pure, pungent alkaloid constituent of black and long peppers (Piper nigrum and Piper longum), that acts as an antioxidant and anticancer agent by its numerous macromolecules associated with them. In the present study, piperine was found to suppress benzo(a)pyrene (B(a)p) induced lung cancer in Swiss albino mice. In lung cancer bearing mice, altered levels of total protein and protein bound carbohydrate components (hexose, hexosamine and sialic acid) were observed in serum, lung and liver tissues. Dietary supplementation of piperine (50 mg/kg body weight) to B(a)p administered animals decreased the total protein and protein bound carbohydrate levels of lung cancer bearing animals in during initiation and post-initiation phases. Our data suggest that piperine may extend its chemopreventive effect through modulating the protein bound carbohydrate levels, as they are one of the indicators of tumorigenesis.

Topics: Alkaloids; Animals; Antineoplastic Agents; Antioxidants; Benzo(a)pyrene; Benzodioxoles; Glycoproteins; Liver; Lung; Lung Neoplasms; Male; Mice; Piperidines; Polyunsaturated Alkamides

Piperine, a trans-trans isomer of 1-piperoyl-piperidine, in combination with ciprofloxacin markedly reduced the MICs and mutation prevention concentration of ciprofloxacin for Staphylococcus aureus, including methicillin-resistant S. aureus. The enhanced accumulation and decreased efflux of ethidium bromide in the wild-type and mutant (CIPr-1) strains in the presence of piperine suggest its involvement in the inhibition of bacterial efflux pumps.

Topics: Alkaloids; Anti-Infective Agents; Benzodioxoles; Ciprofloxacin; Drug Resistance, Bacterial; Ethidium; Microbial Sensitivity Tests; Piperidines; Polyunsaturated Alkamides; Staphylococcus aureus

Black pepper, Piper nigrum L. (Piperaceae), has insecticidal properties and could potentially be utilized as an alternative to synthetic insecticides. Piperine extracted from P. nigrum has a biphasic effect upon cytochrome P450 monooxygenase activity with an initial suppression followed by induction. In this study, an ethyl acetate extract of P. nigrum seeds was tested for insecticidal activity toward adult Musca domestica and Drosophila melanogaster. The effect of this same P. nigrum extract upon differential gene expression in D. melanogaster was investigated using cDNA microarray analysis of 7380 genes. Treatment of D. melanogaster with P. nigrum extract led to a greater than 2-fold upregulation of transcription of the cytochrome P450 phase I metabolism genes Cyp 6a8, Cyp 9b2, and Cyp 12d1 as well as the glutathione-S-transferase phase II metabolism gene Gst-S1. These data suggests a complex effect of P. nigrum upon toxin metabolism.

Topics: Alkaloids; Animals; Benzodioxoles; Blotting, Northern; Cytochrome P-450 Enzyme Inhibitors; DNA, Complementary; Drosophila melanogaster; Enzyme Inhibitors; Gene Expression Profiling; Gene Expression Regulation; Insecticides; Oligonucleotide Array Sequence Analysis; Piper nigrum; Piperidines; Polyunsaturated Alkamides

The effect of alkaloid piperine against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)) in differentiated PC12 cells was assessed. Piperine treatment revealed a differential effect on the cytotoxicity of MPP(+) and had its maximum inhibitory effect at 1 microM. The addition of piperine (0.5-10 microM) significantly reduced the MPP(+)-induced nuclear damage, mitochondrial membrane permeability changes, formation of reactive oxygen species and depletion of GSH. In contrast, piperine at 50-100 microM showed cytotoxicity and exhibited an additive effect against the MPP(+) toxicity. The results indicate that piperine had a differential effect on the cytotoxicity of MPP(+) depending on concentration. Piperine at low concentrations may reduce the MPP(+)-induced viability loss in PC12 cells by suppressing the changes in the mitochondrial membrane permeability, leading to the release of cytochrome c and subsequent activation of caspase-3. The effects may be ascribed to its inhibitory action on the formation of reactive oxygen species and depletion of GSH.

Topics: 1-Methyl-4-phenylpyridinium; Alkaloids; Animals; Benzodioxoles; Caspase 3; Caspases; Cell Death; Cell Membrane Permeability; Cytochromes c; DNA Fragmentation; Glutathione; Lipid Peroxidation; Malondialdehyde; Membrane Potentials; Mitochondria; Mitochondrial Membranes; PC12 Cells; Piperidines; Polyunsaturated Alkamides; Rats; Reactive Oxygen Species; Thiobarbituric Acid Reactive Substances

Piplartine {5,6-dihydro-1-[1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl]-2(1H)pyridinone} and piperine {1-5-(1,3)-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]piperidine} are alkaloid amides isolated from Piper. Both have been reported to show cytotoxic activity towards several tumor cell lines. In the present study, the in vivo antitumor activity of these compounds was evaluated in 60 female Swiss mice (N = 10 per group) transplanted with Sarcoma 180. Histopathological and morphological analyses of the tumor and the organs, including liver, spleen, and kidney, were performed in order to evaluate the toxicological aspects of the treatment with these amides. Administration of piplartine or piperine (50 or 100 mg kg(-1) day(-1) intraperitoneally for 7 days starting 1 day after inoculation) inhibited solid tumor development in mice transplanted with Sarcoma 180 cells. The inhibition rates were 28.7 and 52.3% for piplartine and 55.1 and 56.8% for piperine, after 7 days of treatment, at the lower and higher doses, respectively. The antitumor activity of piplartine was related to inhibition of the tumor proliferation rate, as observed by reduction of Ki67 staining, a nuclear antigen associated with G1, S, G2, and M cell cycle phases, in tumors from treated animals. However, piperine did not inhibit cell proliferation as observed in Ki67 immunohistochemical analysis. Histopathological analysis of liver and kidney showed that both organs were reversibly affected by piplartine and piperine treatment, but in a different way. Piperine was more toxic to the liver, leading to ballooning degeneration of hepatocytes, accompanied by microvesicular steatosis in some areas, than piplartine which, in turn, was more toxic to the kidney, leading to discrete hydropic changes of the proximal tubular and glomerular epithelium and tubular hemorrhage in treated animals.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Benzodioxoles; Cell Proliferation; Disease Models, Animal; Female; Kidney; Liver; Mice; Neoplasm Transplantation; Piper; Piperidines; Piperidones; Plant Extracts; Plant Roots; Polyunsaturated Alkamides; Sarcoma 180; Spleen

Piperine, the active principle of Piper longum, Piper nigrum and Zingiber officinalis, has been reported to enhance the oral bioavailability of phenytoin in human volunteers. The objective of this study was to explore the effect of a single dose of piperine in patients with uncontrolled epilepsy on the steady-state pharmacokinetics of phenytoin. Two groups of 10 patients each receiving either a 150 mg or 200 mg twice daily dose of phenytoin were selected. Twelve hours after the night dose, venous blood samples were collected at 0, 0.5, 1, 2, 4, 6, 9, 12 h after administration of phenytoin. On the next study day, piperine 20 mg was administered along with phenytoin and samples were collected similarly. The mean plasma drug concentrations at different time points and the pharmacokinetic parameters before and after piperine administration were compared by Student's t-test. Piperine increased significantly the mean plasma concentration of phenytoin at most of the time points in both dose groups. There was a significant increase in AUC((0-12h)) (p < 0.01), C(max) (p < 0.001) and K(a) (p < 0.05) whereas the changes in K(el) and t(max) were not significant. The results showed that piperine enhanced the bioavailability of phenytoin significantly, possibly by increasing the absorption.

Topics: Adult; Alkaloids; Anticonvulsants; Area Under Curve; Benzodioxoles; Biological Availability; Dose-Response Relationship, Drug; Drug Interactions; Epilepsy; Female; Humans; Male; Middle Aged; Phenytoin; Piper; Piperidines; Polyunsaturated Alkamides

Piperine, a main component of Piper longum Linn. and Piper nigrum Linn., is a plant alkaloid with a long history of medicinal use in Indian medicine. It is known to exhibit a variety of biological activities which include anti-pyretic, anti-inflammatory, anti-depressant, hepatoprotective and antitumor. Its immunomodulatory role has so far been limited to humoral response. The influence of piperine on murine thymocytes, immunocompromised by cadmium has been reported by us in this investigation. The various biochemical parameters such as oxidative stress markers (ROS and GSH), Bcl-2 protein expression, mitochondrial membrane potential, caspase-3 activity, DNA damage, blastogenesis and T lymphocyte phenotypes were determined. Cadmium (25 microM) induced apoptosis earliest at 6 h. Alterations in ROS and GSH preceded mitochondrial membrane depolarization and caspase-3 activation followed by apoptosis. The phenotypic changes occurred at 18 h and blastogenesis at 72 h. Various conc. of piperine (1, 10 and 50 microg/ml) when added along with Cd (25 microM) from 1.5 to 72 h, caused a dose and time dependent amelioration in all the cellular events mentioned above. Modulation of oxidative stress has earlier been reported to reduce Cd induced apoptosis in murine lymphocytes. Inhibition of the ROS production and replenishment of GSH by piperine, may in part be responsible for the suppression of downstream cascade of events, i.e. apoptosis, blastogenesis and T lymphocyte phenotyping. The study clearly demonstrated the anti-oxidative, anti-apoptotic, and restorative ability against cell proliferative mitogenic response and phenotypic alterations by piperine, suggesting its therapeutic usefulness in immunocompromised conditions.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Cadmium Chloride; Caspase 3; Caspase Inhibitors; Caspases; CD4-CD8 Ratio; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Flow Cytometry; Glutathione; Immunophenotyping; Intracellular Fluid; Membrane Potentials; Mice; Mice, Inbred BALB C; Mitochondrial Membranes; Molecular Structure; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Thymus Gland

During the course of neuronal development or regeneration, the axonal growth cone protein growth-associated protein 43 (GAP-43) is expressed in a great majority of differentiating neurons, suggesting that the regulation of this gene is tied to important differentiation signals common to many neurons. In order to discover non-peptide molecules capable of mimicking the effects of NGF, we developed a reporter gene assay system based on measurement of light production in PC12 cells stably transfected with the luciferase reporter gene, the expression of which depends on the transcriptional activation of GAP-43. High throughput screening of the proprietary compound collection using this system revealed (E,E)-1-[5-(3,4-dihydroxyphenyl)-1-oxo-2,4-pentadienyl]piperidine (HU0622), a piperine derivative, to be an activator of GAP-43 transcription. HU0622 strongly induced neurite outgrowth and extension in PC12 and sensory neuronal cultures of chick dorsal root ganglia. The compound induced sustained extracellular signal-regulated kinase (ERK) activation that is crucial for neurite outgrowth activity without activating NGF receptor, TrkA. Furthermore, HU0622 as well as NGF promoted PC12 survival under serum-free conditions and activated Akt/protein kinase B downstream from phosphatidylinositol 3-kinase (PI3K). HU0622 also promoted survival of rat dorsal root ganglion neurons deprived of NGF. HU0622, a small non-peptidyl molecule, may be a novel promising lead compound for the stimulation of nerve regeneration.

Topics: Alkaloids; Animals; Benzodioxoles; Cell Survival; Cells, Cultured; Chick Embryo; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Activation; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Ganglia, Spinal; GAP-43 Protein; Immunohistochemistry; Luciferases; Nerve Growth Factors; Neurites; Neurons; Piperidines; Polyunsaturated Alkamides; Rats; Transfection; Tubulin

To study the effect of piperine, an alkaloid, on thyroid hormones and apolipoproteins in high-fat-diet (HFD) and antithyroid drug-induced hyperlipidemic rats.. Male Wistar rats were first divided into two groups, control diet and high-fat diet (HFD) and then subdivided into four subgroups of ten animals each. The animals were treated with the following regimens for 10 weeks: 1% carboxymethyl cellulose; 10 mg carbimazole (CM)/kg body weight; 10 mg CM + 40 mg piperine/kg body weight, and 10 mg CM + 2 mg atorvastatin /ATV//kg body weight. Lipid profiles, hormone levels, and apolipoprotein levels were studied in all groups.. HFD and/or CM administration significantly elevated the plasma levels of total cholesterol, VLDL, LDL, triglycerides, free fatty acids, and phospholipids, but significantly reduced the HDL levels. Moreover, CM administration significantly reduced apo A-I levels and T3, T4 and testosterone levels while significantly elevating plasma apo B, thyroid stimulating hormone (TSH) and insulin levels. The simultaneous administration of piperine and HFD significantly reduced plasma lipids and lipoproteins levels, except for HDL, which was significantly elevated. Piperine supplementation also improved the plasma levels of apo A-I, T3, T4, testosterone, and I and significantly reduced apo B, TSH, and insulin to near normal levels.. The data presented here provide evidence that piperine possesses thyrogenic activity, thus modulating apolipoprotein levels and insulin resistance in HFD-fed rats, opening a new view in the management of dyslipidemia by dietary supplementation with nutrients.

Topics: Alkaloids; Animals; Apolipoproteins; Benzodioxoles; Dietary Fats; Hormones; Hyperlipidemias; Hypolipidemic Agents; Insulin; Lipids; Male; Piper; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Testosterone; Thyroid Hormones

The effect of dietary supplementation of spice-active principles, curcumin (0.2%), capsaicin (0.015%), and piperine (0.02%) on the activities of the liver drug-metabolizing enzyme system was examined. All the 3 dietary spice principles significantly stimulated the activity of aryl hydroxylase. A synergistic action of dietary curcumin and capsaicin with respect to stimulating the activity of aryl hydroxylase was also evidenced when fed in combination. The activity of N-demethylase essentially remained unaffected by dietary curcumin, capsaicin, or their combination, but was significantly lowered as a result of piperine feeding. Uridine dinucleotide phosphate (UDP)-glucuronyl transferase activity was decreased by dietary piperine and the combination of curcumin and capsaicin. NADPH-cytochrome c reductase activity was significantly decreased by dietary piperine. The levels of hepatic microsomal cytochrome P450 and cytochrome b5 were not influenced by any of the dietary spice-active principles. These spice-active principles were also examined for their possible in vitro influence on the components of the hepatic drug-metabolizing enzyme system in rat liver microsomal preparation. Piperine significantly decreased the activity of liver microsomal aryl hydroxylase activity when included in the assay medium at 1 x 10(-6) mol/L, 1 x 10(-5) mol/L, and 1x 10(-4) mol/L level. Lowered activity of N-demethylase was observed in presence of capsaicin or piperine at 1 x 10(-6) mol/L in the assay medium. Hepatic microsomal glucuronyl transferase activity was significantly decreased in vitro by addition of capsaicin or piperine. Capsaicin and piperine brought about significant decrease in liver microsomal cytochrome P450 when included at 1 x 10(-6) mol/L and 1 x 10(-5) mol/L, the effect being much higher in the case of piperine. The results suggested that whereas the 3 spice principles have considerable similarity in structure, piperine is exceptional in its influence on the liver drug-metabolizing enzyme system. The study also indicated that a combination of curcumin and capsaicin does not produce any significant additive effect on the liver drug-metabolizing enzyme system.

Topics: Alkaloids; Animals; Aryl Hydrocarbon Hydroxylases; Benzodioxoles; Capsaicin; Carrier Proteins; Curcumin; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Synergism; Enzyme Activation; Enzyme Inhibitors; Glucuronosyltransferase; Heme-Binding Proteins; Hemeproteins; In Vitro Techniques; Liver; Male; Microsomes, Liver; NADPH-Ferrihemoprotein Reductase; Oxidoreductases, N-Demethylating; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

1. We have characterised the effects of piperine, a pungent alkaloid found in black pepper, on the human vanilloid receptor TRPV1 using whole-cell patch-clamp electrophysiology. 2. Piperine produced a clear agonist activity at the human TRPV1 receptor yielding rapidly activating whole-cell currents that were antagonised by the competitive TRPV1 antagonist capsazepine and the non-competitive TRPV1 blocker ruthenium red. 3. The current-voltage relationship of piperine-activated currents showed pronounced outward rectification (25+/-4-fold between -70 and +70 mV) and a reversal potential of 0.0+/-0.4 mV, which was indistinguishable from that of the prototypical TRPV1 agonist capsaicin. 4. Although piperine was a less potent agonist (EC50=37.9+/-1.9 microM) than capsaicin (EC50=0.29+/-0.05 microM), it demonstrated a much greater efficacy (approximately two-fold) at TRPV1. 5. This difference in efficacy did not appear to be related to the proton-mediated regulation of the receptor since a similar degree of potentiation was observed for responses evoked by piperine (230+/-20%, n=11) or capsaicin (284+/-32%, n=8) upon acidification to pH 6.5. 6. The effects of piperine upon receptor desensitisation were also unable to explain this effect since piperine resulted in more pronounced macroscopic desensitisation (t(1/2)=9.9+/-0.7 s) than capsaicin (t(1/2)>20 s) and also caused greater tachyphylaxis in response to repetitive agonist applications. 7. Overall, our data suggest that the effects of piperine at human TRPV1 are similar to those of capsaicin except for its propensity to induce greater receptor desensitisation and, rather remarkably, exhibit a greater efficacy than capsaicin itself. These results may provide insight into the TRPV1-mediated effects of piperine on gastrointestinal function.

Topics: Alkaloids; Benzodioxoles; Capsaicin; Cell Line; Humans; Hydrogen-Ion Concentration; Patch-Clamp Techniques; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Receptors, Drug; Ruthenium Red; Structure-Activity Relationship

[structure: see text] Fifteen novel dimeric amide alkaloids possessing a cyclohexene ring, nigramides A-O (1-15), as well as four novel dimeric amide alkaloids possessing a cyclobutane ring, nigramides P-S (17-20), have been isolated from the roots of Piper nigrum. Their structures were elucidated on the basis of their spectroscopic data. The biosynthestic hypothesis of nigramides A-O (1-15) was proposed by an intermolecular Diels-Alder reaction from the corresponding monomeric amides. On the basis of this biosynthetic hypothesis, the first study of the thermal and Lewis acid mediated Diels-Alder reactions of piperine in different organic solvents and under solventless conditions is also described.

Topics: Alkaloids; Amides; Benzodioxoles; Catalysis; Crystallography, X-Ray; Cyclization; Cyclohexanes; Dimerization; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Conformation; Molecular Structure; Piper nigrum; Piperidines; Plant Roots; Polyunsaturated Alkamides; Solvents; Temperature

In recent years, considerable emphasis has been focused on identifying new chemopreventive agents, which could be useful for the human population. Piperine is a pure, pungent alkaloid constituent of black and long peppers (piper nigrum and piper longum), which is a most common spice used throughout the world. In the present study, we examined the protective role of piperine during experimental lung carcinogenesis with reference to its effect on DNA damage and detoxification enzyme system. The activities of detoxifying enzymes such as glutathione transferase (GST), quinone reductase (QR) and UDP-glucuronosyl transferase (UDP-GT) were found to be decreased while the hydrogen peroxide level was increased in the lung cancer bearing animals. Supplementation of piperine (50 mg/kg bwt) enhanced the detoxification enzymes and reduced DNA damage as determined by single cell electrophoresis. Furthermore, the DNA-Protein cross links which was found to be high in lung cancer bearing animals was also modulated upon supplementation with piperine. Our present results explain the understanding of unique association between anti-peroxidative effect of piperine and ultimately the capability of piperine to prevent cancer.

Topics: Administration, Oral; Alkaloids; Animals; Benzo(a)pyrene; Benzodioxoles; DNA; DNA Damage; Down-Regulation; Glucuronosyltransferase; Glutathione Transferase; Hydrogen Peroxide; Lung Neoplasms; Male; Mice; NAD(P)H Dehydrogenase (Quinone); Piperidines; Polyunsaturated Alkamides

A method for extraction and high performance liquid chromatography-mass spectrometer (HPLC-MS) analysis of the medicinally important genus Piper (Piperaceae) was developed. This allows for a rapid and accurate measure of unsaturated amides, or piperamides, in black pepper, Piper nigrum L., and in wild species from Central America. Reflux extraction provided the highest recovery of piperine (>80%) from leaf and peppercorn material. HPLC analysis using a binary gradient of acetonitrile and water separated the major amide peaks between 5 and 12 min. Atmospheric pressure chemical ionization (APCI)-MS improved the detection limit to 0.2 ng, 10-fold below the 2 ng limit of the HPLC-diode array detector (DAD) based on linear standard curves between 0.1 and 250 microg/mL (R2 = 0.999). The HPLC-MS method identified pellitorine, piperylin, 4,5-dihydropiperlonguminine, piperlonguminine, 4,5-dihydropiperine, piperine, and pipercide. The biological activity of six Costa Rican Piper species assessed by mosquito larval bioassays correlated well with piperamide content.

Topics: Aedes; Alkaloids; Amides; Animals; Benzodioxoles; Chromatography, High Pressure Liquid; Insecticides; Larva; Mass Spectrometry; Piperaceae; Piperidines; Plant Extracts; Polyunsaturated Alkamides

Piperine is a major component of black (Piper nigrum Linn) and long pepper (Piper longum Linn) used widely in various systems of traditional medicine. We have evaluated the effect of piperine on mitochondrial tricarboxylic acid cycle and phase I and glutathione-metabolizing enzymes in Benzo(a)pyrene induced experimental lung carcinogenesis in swiss albino mice. Lung cancer bearing mice showed a significant decrease in the activities of mitochondrial enzymes-isocitrate dehydrogenase (ICDH), -ketoglutarate dehydrogenase (KDH), succinate dehydrogenase (SDH), malate dehydrogenase (MDH) and significantly increased NADPH-Cytochorome reductase (NADPH-C reductase), cytochrome P450 (cyt-p450) and cytochrome b5(cyt-b5). The activities of glutathione-metabolizing enzymes glutathione peroxidase(GPx), glutathione reductase (GR) and glucose-6-phospho dehydrogenase(G6PDH) were significantly lowered in lung-cancer bearing mice when compared with control mice. Piperine supplementation to tumour-induced animals significantly lowered the phase-I enzymes (NADPH-C reductase, cyt-p450 and cyt-b5)) and there was a rise in glutathione-metabolizing enzymes (GPx, GR and G6PDH), which indicated an antitumour and anti-cancer effect. Comparison of normal control mice and mice administered piperine only as drug control showed no significant variations in enzyme activities. Piprine administration to benzo(a)pyrene induced animals significantly increased the activities of mitochondrial enzymes, thereby suggesting its role in mitochondrial energy production.

Topics: Alkaloids; Animals; Anticarcinogenic Agents; Benzo(a)pyrene; Benzodioxoles; Citric Acid Cycle; Cytochrome P-450 Enzyme Inhibitors; Enzymes; Glutathione; Liver; Lung Neoplasms; Male; Mice; Mitochondria; Piperidines; Polyunsaturated Alkamides

A significant suppression (33.9-66.5%) in the micronuclei formation induced by benzo(a)pyrene and cyclophosphamide was reduced following oral administration of piperine at doses of 25, 50 and 75 mg/kg in mice.

Topics: Alkaloids; Animals; Antimutagenic Agents; Benzo(a)pyrene; Benzodioxoles; Cyclophosphamide; Dose-Response Relationship, Drug; Male; Mice; Micronuclei, Chromosome-Defective; Piperidines; Polyunsaturated Alkamides

[reaction: see text] An intermolecular cobalt-phosphine-catalyzed Diels-Alder reaction of piperine is described. The dimerization of piperine in the presence of cobalt-phosphine complexes gave much better yields than that in the presence of only cobalt, which, combined with the result under the purely thermal conditions, indicates that addition of phosphine ligands changes the inhibition of cobalt to the reaction into promotion. For elucidation of the distinction, different cobalt-catalyzed mechanisms were proposed for the Diels-Alder dimerization of piperine.

Topics: Alkaloids; Benzodioxoles; Catalysis; Cobalt; Cyclization; Dimerization; Molecular Structure; Phosphines; Piper nigrum; Piperidines; Plant Roots; Polyunsaturated Alkamides

A bioassay-guided isolation of the ethanol extract from the fruits of Piper longum yielded a known piperidine alkaloid, piperine, as a monoamine oxidase (MAO) inhibitor. Piperine showed an inhibitory effect against MAO-A (IC50 value: 20.9 microM) and MAO-B (IC50 value: 7.0 microM). Kinetic analyses by a Lineweaver-Burk plot clearly indicated that piperine competitively inhibited MAO-A and MAO-B with Ki values of 19.0+/-0.9 microM and 3.19+/-0.5 microM, respectively. The inhibition by piperine was found to be reversible by dialysis of the incubation mixture. In addition, the immobility times in the tail suspension test were significantly reduced by piperine, similar to that of the reference antidepressant fluoxetine, without accompanying changes in ambulation when assessed in an open-field. These results suggest that piperine possesses potent antidepressant-like properties that are mediated in part through the inhibition of MAO activity, and therefore represent a promising pharmacotherapeutic candidate as an antidepressant agent.

Topics: Alkaloids; Animals; Antidepressive Agents; Benzodioxoles; Male; Mice; Mice, Inbred ICR; Monoamine Oxidase Inhibitors; Motor Activity; Piper; Piperidines; Polyunsaturated Alkamides

Studies with animals that are deficient in the vanilloid (capsaicin) receptor TRPV1 have confirmed the pivotal role that TRPV1 has in the development of post-inflammatory hyperalgesia, and enhanced TRPV1 expression has been described in various human disorders. Natural products have provided several lead structures for the development of vanilloid ligands. A recent study shows that piperine, the irritant principle in black pepper, is more efficient than capsaicin in the desensitization of human TRPV1, which suggests that this pharmacological aspect of vanilloids can be dissociated from its potency. This finding raises the intriguing possibility that piperine can be used as a chemical template for the design of improved TRPV1 agonists.

Topics: Alkaloids; Benzodioxoles; Humans; Medicine, Traditional; Pest Control; Piperidines; Polyunsaturated Alkamides; Receptors, Drug; Spices

To study the chemical constituents from herb of Rhodobryum roseum.. The compounds were isolated by column chromatography, and identified by IR, NMR data.. 8 compounds were isolated and identified. They are piperine (1), caffeic acid methyl ester (2), uracil glucoside (3), ursolic acid (4), 5alpha, 8alpha-epidioxy-methylcholesta-6, 22-dien-3beta-ol (5), 5alpha, 8alpha-epidioxy-methylcholesta-6,9(11), 22-trien-3beta-ol (6), beta-sitosterol (7), daucosterol (8).. 7 compounds (1-6,8) were isolated from this plant for the first time.

Topics: Alkaloids; Benzodioxoles; Bryophyta; Caffeic Acids; Piperidines; Plants, Medicinal; Polyunsaturated Alkamides; Sitosterols; Triterpenes; Ursolic Acid

To study the effect of piperine on the epididymal antioxidant system of adult male rats.. Adult male rats were orally administered piperine at doses of 1 mg/kg, 10 mg/kg and 100 mg/kg body weight each day for 30 consecutive days. Twenty-four hours after the last treatment, the rats were weighed and killed with ether and the epididymis was dissected from the bodies. Sperm collected from the cauda region of the epididymis was used for the assessment of its count, motility and viability. Caput, corpus and cauda regions of the epididymis were separated and homogenized separately to obtain 10 % homogenates. The supernatants were used for the assays of sialic acid, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, lipid peroxidation and hydrogen peroxide generation.. Body weight of the piperine-treated rats remained unchanged. The weights of the caput, corpus and cauda regions of the epididymis significantly decreased at dose of 100 mg/kg. Epididymal sperm count and motility decreased at 10 mg/kg and 100 mg/kg, and sperm viability decreased significantly at 100 mg/kg. Sialic acid levels in the epididymis decreased significantly at 100 mg/kg while significant decrease in the cauda region alone was observed at 10 mg/kg. A significant decline in the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, along with an increase in hydrogen peroxide generation and lipid peroxidation were observed at 10 mg/kg and 100 mg/kg.. Piperine caused a decrease in the activity of antioxidant enzymes and sialic acid levels in the epididymis and thereby increased reactive oxygen species levels that could damage the epididymal environment and sperm function.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Body Weight; Catalase; Epididymis; Glutathione Peroxidase; Glutathione Reductase; Hydrogen Peroxide; Lipid Peroxidation; Male; Medicine, Ayurvedic; N-Acetylneuraminic Acid; Organ Size; Piper; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Sperm Count; Sperm Motility; Superoxide Dismutase

We report here the isolation and characterization of two active principles, ethyl 3',4',5'-trimethoxycinnamate (1) and piperine (2), from the combined hexane and chloroform extracts of Piper longum. Using primary human umbilical vein endothelial cells, we evaluated the activities of compound 1 on TNF-alpha-induced expression of cell adhesion molecules, viz., ICAM-1, VCAM-1, and E-selectin, which play key roles in controlling various inflammatory diseases. Both compounds 1 and 2 inhibited the TNF-alpha-induced expression of ICAM-1 in a dose- and time-dependent manner; however, the activity of ethyl 3',4',5'-trimethoxycinnamate (1) was approximately 1.3 times higher than that of piperine (2). As ethyl 3',4',5'-trimethoxycinnamate (1) has been isolated for the first time from a natural source, Piper longum, and it exhibited higher activity, we carried out further studies on it. To correlate its cell adhesion molecule inhibitory activity with its functional consequences, we showed that it significantly blocked the adhesion of neutrophils to endothelium in a time- and concentration-dependent manner. Importantly, the inhibitory effect of cinnamate 1 was found to be reversible. To elucidate its structure-function-activity relationship, we synthesized nine different analogues of ethyl 3',4',5'-trimethoxycinnamate, i.e., compounds 3-11, and compared the ICAM-1 inhibitory activity of compound 1 with those of its synthetic analogues as well as the corresponding acids 12-15. The structure-activity studies indicate that the chain length of the alcohol moiety, substituents in the aromatic ring, and alpha, beta-double bond of the cinnamic acid ester have significant effects on the inhibition of TNF-alpha-induced expression of ICAM-1 on endothelial cells. These findings have implications in developing compounds with a better therapeutic index against various inflammatory diseases.

Topics: Alkaloids; Benzodioxoles; Cell Adhesion; Cell Adhesion Molecules; Cells, Cultured; Cinnamates; E-Selectin; Endothelium, Vascular; Flow Cytometry; Gene Expression Regulation; Humans; Intercellular Adhesion Molecule-1; Piper; Piperidines; Polyunsaturated Alkamides; Structure-Activity Relationship; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

The pepper alkaloid piperine is a nontoxic, natural dietary compound with a broad range of physiological activity. The present work is the first demonstration of its interaction with a mammalian protein. Circular dichroism (CD) spectroscopy was used to reveal and analyze the binding of piperine to a lipocalin protein. Induced CD spectra measured in pH 7.7 phosphate buffer at 37 degrees C demonstrated reversible, non-covalent association of piperine with bovine beta-lactoglobulin (BLG), the major whey protein in milk. The binding parameters (K(a) approximately 8 x 10(4) M(-1), n = 0.8) determined from the CD titration data showed no significant differences between the piperine binding properties of the two main genetic variants of BLG (A and B). The vanishing extrinsic CD signal obtained upon acidification of the piperine-BLG sample solution (Tanford transition) suggested that the ligand binds in the central hydrophobic cavity of the beta-barrel. The cavity binding concept was further supported by a CD displacement experiment using palmitic acid, the well-known hydrophobic ligand of BLG. Molecular docking calculations showed that piperine can be efficiently accommodated within the calyx of BLG. Additional molecular modeling calculations indicated that the beta-barrel of human tear lipocalin, human serum retinol binding protein, and human neutrophil gelatinase associated lipocalin might also accommodate a piperine molecule.

Topics: Alkaloids; Animals; Benzodioxoles; Cattle; Circular Dichroism; Hydrogen-Ion Concentration; Lactoglobulins; Models, Molecular; Piperidines; Polyunsaturated Alkamides; Protein Binding; Regression Analysis; Spectrophotometry, Ultraviolet; X-Ray Diffraction

It was recently shown that in some subjects capsaicin can evoke bitterness as well as burning and stinging, particularly in the circumvallate (CV) region of the tongue. Because perception of bitterness from capsaicin is characterized by large individual differences, the main goal of the present study was to learn whether people who taste capsaicin as bitter also report bitterness from structurally similar sensory irritants that are known to stimulate capsaicin-sensitive neurons. The irritancy and taste of capsaicin and two of its most commonly studied congeners, piperine and zingerone, were measured in individuals who had been screened for visibility of, and reliable access to, the CV papillae. Approximately half of these individuals reported tasting bitterness from all three irritants when the stimuli were swabbed directly onto the CV papillae. Concentrations that produced similar levels of burning sensation across subjects also produced similar (though lower) levels of bitter taste. These results are consistent with the hypothesis that capsaicin and its congeners stimulate bitterness via a common sensory receptor that is distributed differentially among individuals. Additionally, bitter tasters rated gustatory qualities (but not burning and stinging) slightly but significantly higher than did bitter non-tasters, which suggests that perception of capsaicin bitterness is associated with a higher overall taste responsiveness (but not chemesthetic responsiveness) in the CV region.

Topics: Adolescent; Adult; Alkaloids; Benzodioxoles; Capsaicin; Female; Guaiacol; Humans; Male; Middle Aged; Perception; Piperidines; Polyunsaturated Alkamides; Receptors, Cell Surface; Taste; Taste Buds

Chemoprevention has emerged as a very effective preventive measure against carcinogenesis. Many bioactive compounds present in edible as well in herbal plants have revealed their cancer chemopreventive potential. In the present study, our goal was to investigate the impact of piperine, a principle ingredient of pepper, on alterations of mitochondrial antioxidant system and lipid peroxidation in Benzo(a)pyrene (B(a)P) induced experimental lung carcinogenesis. Oral supplementation of piperine (50 mg/kg body weight) effectively suppressed lung carcinogenesis in B(a)p induced mice as revealed by the decrease in the extent of mitochondrial lipid peroxidation and concomitant increase in the activities of enzymatic antioxidants (superoxide dismutase, catalase and glutathione peroxidase) and non enzymatic antioxidant (reduced glutathione, vitamin E and vitamin C) levels when compared to lung carcinogenesis bearing animals. Our data suggests that piperine may extent its chemopreventive effect by modulating lipid peroxidation and augmenting antioxidant defense system.

Topics: Alkaloids; Animals; Antineoplastic Agents; Antioxidants; Benzo(a)pyrene; Benzodioxoles; Disease Models, Animal; Lipid Peroxidation; Lung Neoplasms; Male; Mice; Mitochondria; Phytotherapy; Piperidines; Plants, Medicinal; Polyunsaturated Alkamides

Alcoholic extract of the fruits of the plant Piper longum and its component piperine was studied for their immunomodulatory and antitumor activity. Alcoholic extract of the fruits was 100% toxic at a concentration of 500 microg/ml to Dalton's lymphoma ascites (DLA) cells and 250 microg/ml to Ehrlich ascites carcinoma (EAC) cells. Piperine was found to be cytotoxic towards DLA and EAC cells at a concentration of 250 microg/ml. Alcoholic extract and piperine was also found to produce cytotoxicity towards L929 cells in culture at a concentration of 100 and 50 microg/ml, respectively. Administration of alcoholic extract of Piper longum (10 mg/dose/animal) as well as piperine (1.14 mg/dose/animal) could inhibit the solid tumor development in mice induced with DLA cells and increase the life span of mice bearing Ehrlich ascites carcinoma tumor to 37.3 and 58.8%, respectively. Administration of Piper longum extract and piperine increased the total WBC count to 142.8 and 138.9%, respectively, in Balb/c mice. The number of plaque forming cells also enhanced significantly by the administration of the extract (100.3%) and piperine (71.4%) on 5th day after immunization. Bone marrow cellularity and alpha-esterase positive cells were also increased by the administration of Piper longum extract and piperine.

Topics: Adjuvants, Immunologic; Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Benzodioxoles; Carcinoma, Ehrlich Tumor; Mice; Mice, Inbred BALB C; Piper; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Sheep; Xenograft Model Antitumor Assays

The immunotoxicological effects of piperine were investigated in Swiss male mice, gavaged at a dose of 1.12, 2.25 or 4.5 mg/kg body weight for five consecutive days. All the dose levels had no overt toxic effect and the liver gained weight normally. Treatment at highest dose, however, resulted in significant decrease in the weight of spleen, thymus and mesenteric lymph nodes, but not of peripheral lymph nodes. All the dose levels suppressed the cellular population of lymphoid organs, except for the spleen, where the doses of 1.12 and 2.25 caused an increase. Haematologically, doses of 2.25 and 4.5 mg/kg caused a significant reduction in total leucocyte counts and differential leucocyte counts showed an increase in the percentage of neutrophils. The higher doses of 2.25 and 4.5 mg/kg suppressed the mitogenic response of B-lymphocyte to lipopolysaccharide. The number of primary antibody (IgM) forming cells in the spleen and the level of primary antibody in serum, was decreased. The doses of 1.12 and 2.25 mg/kg suppressed the mitogenic response of T-lymphocytes to phytohaemagglutinin and the nitroblue tetrazolium (NBT) dye reducing activity of peritoneal exudate cells (PECs). Since the lowest dose of 1.12 mg of piperine per kg body weight had no immunotoxic effect, it may be considered as immunologically safe "no observed adverse effect level (NOAEL)" dose.

Topics: Alkaloids; Animals; Antibody Formation; B-Lymphocytes; Benzodioxoles; Blood Cell Count; Hemolytic Plaque Technique; Hypersensitivity, Delayed; Immunity, Cellular; Immunoglobulin M; Lipopolysaccharides; Lymph Nodes; Male; Mice; Monocytes; Nitroblue Tetrazolium; Phagocytosis; Phytohemagglutinins; Piperidines; Polyunsaturated Alkamides; Sheep; Spleen; T-Lymphocytes; Thymus Gland

A wide range of piperine analogues has been synthesised in order to undertake a structure-activity study of their ability to stimulate melanocyte proliferation. Results demonstrate that an aromatic ring containing at least one ether function and a carbonyl group containing side chain is essential for this activity. A number of highly active piperine analogues have been identified, for instance 1-(3,4-methylenedioxyphenyl)-penta-2E,4E-dienoic acid methyl ester (5a), 1-E,E-piperinoyl-isobutylamine (4f) and 1-(3,4-methylenedioxyphenyl)-pentanoic acid cyclohexyl amide (20). A selection of analogues has also been evaluated for their effect on melanocyte morphology and melanogenesis. The piperine analogues altered cell morphology by increasing dendrite formation leading to bi-, tri- and quadripolar cells. These same analogues were found to increase total melanin in cell cultures, although melanin content per cell was not significantly altered from control in the presence of these compounds.

Topics: Alkaloids; Animals; Benzodioxoles; Cell Differentiation; Cell Division; Cells, Cultured; Dose-Response Relationship, Drug; Melanocytes; Mice; Mice, Inbred C57BL; Piperidines; Polyunsaturated Alkamides

Present studies are aimed to find out the utility of oil-in-water emulsions also known as lipid nanospheres (LN) or fat emulsions for delivering piperine for the treatment of visceral leishmaniasis. Lipid nanosphere formulations of piperine were prepared using soybean oil, egg lecithin, cholesterol, stearylamine and phosphatidylethanolamine distearylmethoxypolyethyleneglycol (DSPE-PEG) by homogenization followed by ultrasonication of oil and aqueous phases. Antileishmanial activity of all the formulations was assessed in BALB/c mice infected with Leishmania donovani AG83 for 60 days. A single dose (5 mg/kg) of piperine, or lipid nanospheres of piperine (LN-P), or lipid nanosphere of piperine with stearylamine (LN-P-SA) or pegylated lipid nanospheres of piperine (LN-P-PEG) was injected intravenously. Mice were sacrificed after 15 days of treatment with piperine or formulations and Leishman Donovan Unit (LDU) is counted. Toxicity of formulations and pure piperine was assessed in normal mice. The size distribution of formulations ranged from 200 to 885 nm. Piperine reduced the parasite burden in liver and spleen by 38% and 31% after 15 days post infection respectively. LN-P reduced the parasite burden in liver and spleen by 63% and 52% after 15 days post infection, respectively. LN-P-PEG reduced the parasite burden in liver and spleen by 78% and 75% after 15 days post infection, respectively. LN-P-SA reduced the parasite burden in liver and spleen by 90% and 85% after 15 days post infection, respectively. LN-P, LN-P-PEG, LN-P-SA treated mice did not show any significant changes in the serum levels of SGOT, ALP, creatinine and urea compared to normal mice. Stable and sterile formulations of lipid nanospheres of piperine were developed. A single dose of 5 mg/kg of lipid nanospheres of piperine could significantly reduce the liver and splenic parasite burden.

Topics: Algorithms; Alkaloids; Animals; Antiprotozoal Agents; Benzodioxoles; Chemical Phenomena; Chemistry, Pharmaceutical; Chemistry, Physical; Emulsions; Leishmania donovani; Leishmaniasis, Visceral; Liposomes; Liver; Mice; Mice, Inbred BALB C; Microspheres; Oils; Particle Size; Piperidines; Polyunsaturated Alkamides; Solutions; Spleen; Sterilization; Water

We describe herein an evaluation of trypanocidal effects of the natural alkaloid piperine and twelve synthetic derivatives against epimastigote and amastigote forms of the protozoan parasite Trypanosoma cruzi, the causative agent of the incurable human disease, Chagas' disease. The results obtained point to piperine as a suitable template for the development of new drugs with trypanocidal activity.

Topics: Alkaloids; Animals; Benzodioxoles; Cells, Cultured; Chagas Disease; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Humans; Inhibitory Concentration 50; Parasitic Sensitivity Tests; Piperidines; Polyunsaturated Alkamides; Trypanocidal Agents; Trypanosoma cruzi

The current study was designed to evaluate the effects of oral supplementation of the piperine on lung tumour initiation by orally applied benzo(a)pyrene (B(a)p). To evaluate the effects of orally supplemented piperine on lung tumour initiation by B(a)p, its effects on ATPase enzymes were first evaluated. Lung cancer bearing mice showed an increase in erythrocyte membrane and tissues ATPase enzymes (Na(+)/K(+)-ATPases, Mg(2+)-ATPases and Ca(2+)-ATPases). Na(+) K-ATPase and Mg-ATPase enzyme activities were decreased and calcium ATPase increased (P < 0.05) in erythrocyte membrane and tissues of lung cancer bearing animals compared with control groups. The elevation of these enzyme activities in membrane and tissues were indicative of the persistent deteriorating effect of B(a)p in cancer bearing animals. These enzyme activities were reversed to near normal control values in animals treated with piperine (50 mg/kg body weight). It is apparent that the beneficial effect of piperine is primarily exerted on the during initiation phase and post-initiation stage of B(a)p induced lung carcinogenesis. Overall, these data indicative that piperine has chemopreventive effects when administered orally on lung cancer bearing animals.

Topics: Alkaloids; Animals; Anticarcinogenic Agents; Benzo(a)pyrene; Benzodioxoles; Ca(2+) Mg(2+)-ATPase; Calcium-Transporting ATPases; Carcinogens; Enzyme Inhibitors; Erythrocyte Membrane; Lipid Peroxidation; Lung Neoplasms; Male; Mice; Piperidines; Polyunsaturated Alkamides; Sodium-Potassium-Exchanging ATPase

The present study was aimed to explore the effect of black pepper (Piper nigrum L.) on tissue lipid peroxidation, enzymic and non-enzymic antioxidants in rats fed a high-fat diet. Thirty male Wistar rats (95-115 g) were divided into 5 groups. They were fed standard pellet diet, high-fat diet (20% coconut oil, 2% cholesterol and 0.125% bile salts), high-fat diet plus black pepper (0.25 g or 0.5 g/kg body weight), high-fat diet plus piperine (0.02 g/kg body weight) for a period of 10 weeks. Significantly elevated levels of thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and significantly lowered activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and reduced glutathione (GSH) in the liver, heart, kidney, intestine and aorta were observed in rats fed the high fat diet as compared to the control rats. Simultaneous supplementation with black pepper or piperine lowered TBARS and CD levels and maintained SOD, CAT, GPx, GST, and GSH levels to near those of control rats. The data indicate that supplementation with black pepper or the active principle of black pepper, piperine, can reduce high-fat diet induced oxidative stress to the cells.

Topics: Alkaloids; Animals; Antioxidants; Aorta; Benzodioxoles; Catalase; Dietary Fats; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Heart; Intestines; Kidney; Lipid Peroxidation; Liver; Male; Oxidative Stress; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

(-)-Epigallocatechin-3-gallate (EGCG), from green tea (Camellia sinensis), has demonstrated chemopreventive activity in animal models of carcinogenesis. Previously, we reported the bioavailability of EGCG in rats (1.6%) and mice (26.5%). Here, we report that cotreatment with a second dietary component, piperine (from black pepper), enhanced the bioavailability of EGCG in mice. Intragastric coadministration of 163.8 micromol/kg EGCG and 70.2 micromol/kg piperine to male CF-1 mice increased the plasma C(max) and area under the curve (AUC) by 1.3-fold compared to mice treated with EGCG only. Piperine appeared to increase EGCG bioavailability by inhibiting glucuronidation and gastrointestinal transit. Piperine (100 micromol/L) inhibited EGCG glucuronidation in mouse small intestine (by 40%) but not in hepatic microsomes. Piperine (20 micromol/L) also inhibited production of EGCG-3"-glucuronide in human HT-29 colon adenocarcinoma cells. Small intestinal EGCG levels in CF-1 mice following treatment with EGCG alone had a C(max) = 37.50 +/- 22.50 nmol/g at 60 min that then decreased to 5.14 +/- 1.65 nmol/g at 90 min; however, cotreatment with piperine resulted in a C(max) = 31.60 +/- 15.08 nmol/g at 90 min, and levels were maintained above 20 nmol/g until 180 min. This resulted in a significant increase in the small intestine EGCG AUC (4621.80 +/- 1958.72 vs. 1686.50 +/- 757.07 (nmol/g.min)). EGCG appearance in the colon and the feces of piperine-cotreated mice was slower than in mice treated with EGCG alone. The present study demonstrates the modulation of the EGCG bioavailablity by a second dietary component and illustrates a mechanism for interactions between dietary chemicals.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Area Under Curve; Benzodioxoles; Biological Availability; Catechin; Cells, Cultured; Enzyme Inhibitors; Humans; Male; Mice; Microsomes, Liver; Piperidines; Polyunsaturated Alkamides

Immune regulation, induction of various inflammatory and growth regulatory genes such as IL-1beta, IL-6, TNF-alpha and GM-CSF require activation of transcription factors such as nuclear factor-kappaB (NF-kappaB), activated transcription factor (ATF-2), c-Fos and cAMP response element-binding protein (CREB). Untreated B16F-10 cells produce very high amount of proinflammatory cytokines such as IL-1beta, IL-6, TNF-alpha and GM-CSF. Piperine treatment significantly reduced the above proinflammatory cytokines. We also found that piperine could reduce the expression of IL-1beta, IL-6, TNF-alpha, GM-CSF and IL-12p40 genes. Piperine at a concentration of 2.5, 5 and 10 microg/ml inhibited the collagen matrix invasion of B16F-10 melanoma cells in a dose-dependent manner. Piperine could inhibit the matrix metalloproteinase production which was demonstrated by zymographic analysis. We found that the nuclear translocation of p65, p50, c-Rel subunits of NF-kappaB and other transcription factors such as ATF-2, c-Fos and CREB were inhibited by the treatment of piperine.

Topics: Activating Transcription Factor 2; Alkaloids; Benzodioxoles; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Collagen; Cyclic AMP Response Element-Binding Protein; Cytokines; Enzyme-Linked Immunosorbent Assay; Gelatin; Gene Expression; Genes, fos; Humans; Matrix Metalloproteinases; Melanoma, Experimental; NF-kappa B; Piperidines; Polyunsaturated Alkamides; Reverse Transcriptase Polymerase Chain Reaction; RNA; Transcription Factors

We describe herein the structural optimization of new piperamide analogues, designed from two natural prototypes, piperine 1 and piperdardine 2, obtained from Piper tuberculatum Jacq. (Piperaceae). Molecular modeling studies using semiempirical AM1 method were made in order to establish rational modifications to optimize them by molecular simplification. The targeted compounds (10) and (11) were respectively obtained using benzaldehyde (12) and para-anisaldehyde (13) as starting materials. 1H NMR spectra showed that the target compounds were diastereoselectively obtained as the (E)-isomer, the same geometry of the natural prototypes. These new synthetic amides presented significant hypotensive effects in cardiovascular essays using in vivo methodologies. Compound 11 (N-[5-(4'-methoxyphenyl)-2(E)-pentenoyl]thiomorpholine) showed a potency 10,000 times greater than its prototype 5, evidencing an optimization of the molecular architecture for this class of hypotensive drug candidates.

Topics: Alkaloids; Amides; Animals; Antihypertensive Agents; Benzodioxoles; Blood Pressure; Male; Models, Molecular; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Effect of piperine which is an alkaloid present in plants such as Piper nigrum and Piper longum on the production of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) level was analyzed using in vitro as well as in vivo systems. The level of nitrite in the LPS stimulated Balb/C mice (95.3 microM) was reduced in the piperine treated animals (25 microM) significantly. Nitrite level in the Concanavalin-A (Con-A) treated control animals (83.1 microM) was also significantly reduced to 18.5 microM in the piperine treated mice. The drastically elevated levels of TNF-alpha in the lipopolysaccharide (LPS) stimulated animals (625.8 pg/mL) was lowered in the piperine treated animals (105.8 pg/mL). Piperine also inhibited the Con-A induced TNF-alpha production. Piperine could inhibit the nitrite production by in vitro activated macrophages (116.25 microM) to the normal level (15.67 microM) at concentration of 5 microg/mL. In vitro L929 bioassay also revealed the inhibition of TNF-alpha production by the piperine treatment.

Topics: Alkaloids; Animals; Benzodioxoles; Cell Line; Concanavalin A; Down-Regulation; Immunologic Factors; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Mice, Inbred BALB C; Nitric Oxide; Piperidines; Polyunsaturated Alkamides; Tumor Necrosis Factor-alpha

The cytoprotective effect of piperine on benzo[a]pyrene (B[a]P) induced experimental lung cancer was investigated in male Swiss albino mice. Oral administration of piperine (100 mg/kg body wt.) effectively suppressed lung cancer initiated with B[a]P as revealed by the decrease in the extent of lipid peroxidation with concomitant increase in the activities of enzymatic antioxidants (superoxide dismutase, catalase and glutathione peroxidase) and non-enzymatic antioxidant (reduced glutathione, vitamin E and vitamin C) levels when compared to lung cancer bearing animals. Our data suggest that piperine may extend its chemopreventive effect by modulating lipid peroxidation and augmenting antioxidant defense system.

Topics: Administration, Oral; Alkaloids; Animals; Antioxidants; Benzo(a)pyrene; Benzodioxoles; Cytoprotection; Lipid Peroxidation; Lung; Lung Neoplasms; Male; Mice; Phytotherapy; Piperidines; Polyunsaturated Alkamides

Potential of piperine, an active alkaloid of black and long peppers, to increase the bioavailability of drugs in humans is of great clinical significance owing to its omnipresence in food. In an attempt to further study the reported differences in its metabolism in rats and humans, a new major urinary metabolite was detected in rat urine and plasma using HPLC. The metabolite was partially purified using reverse phase column chromatography on Sephadex((R))-LH 20 and characterized as 5-(3, 4-methylenedioxy phenyl)-2E,4E-pentadienoic acid-N-(3-yl propionic acid)-amide with the help of LC/NMR/positive ESI-MS studies. Complete mass fragmentation pattern could be assigned with MS/MS studies. The metabolite has a unique structure compared to the previously reported metabolites in that it retains methylenedioxy ring and conjugated double bonds while the piperidine ring is modified to form propionic acid group. Mechanism of formation of the metabolite by oxidation and cleavage of piperidine ring is proposed. Kidney appears to be the major excretion route for piperine metabolites in rats as no metabolite could be detected in feces.

Topics: Alkaloids; Animals; Benzodioxoles; Biotransformation; Chromatography, High Pressure Liquid; Feces; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Spectrophotometry, Ultraviolet

Piperine, the main alkaloid of Piper nigrum fruits, was evaluated for its thyroid hormone and glucose regulatory efficacy in adult male Swiss albino mice. Its daily oral administration (2.50 mg/kg) for 15 days lowered the serum levels of both the thyroid hormones, thyroxin (T (4)) and triiodothyronine (T (3)) as well as glucose concentrations with a concomitant decrease in hepatic 5'D enzyme and glucose-6-phospatase (G-6-Pase) activity. However, no significant alterations were observed in animals treated with 0.25 mg/kg of piperine in any of the activities studied except an inhibition in serum T (3) concentration. The decrease in T (4), T (3) concentrations and in G-6-Pase were comparable to that of a standard antithyroid drug, Proylthiouracil (PTU). The hepatic lipid-peroxidation (LPO) and the activity of endogenous antioxidants, superoxide dismutase (SOD), and catalase (CAT) were not significantly altered in either of the doses. It appears that the action of P. nigrum on thyroid functions is mediated through its active alkaloid, piperine. We also suggest that a higher dose of piperine may inhibit thyroid function and serum glucose concentration in euthyroid individuals.

Topics: Alkaloids; Analysis of Variance; Animals; Antithyroid Agents; Benzodioxoles; Blood Glucose; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glucose-6-Phosphatase; Iodide Peroxidase; Lipid Peroxidation; Liver; Male; Mice; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Propylthiouracil; Thyroid Gland; Thyroxine; Triiodothyronine

The efficacy of extracts from two Piperaceae species, Piper nigrum L. and P. tuberculatum Jacq. were evaluated using larvae and adults of the Colorado Potato Beetle Leptinotarsa decemlineata (Say). Young larvae and neonates were the most susceptible; a 24-h LD(50) of 0.064% extract of P. tuberculatum was determined for 4-day-old larvae, while 0.05% extract of P. nigrum reduced larval survival up to 70% within one week after treatment of potato Solanum tuberosum L. (Solanaceae) plants. When an insecticide resistant strain of L. decemlineata larvae was tested with the P. tuberculatum extract, there was less than a 2-fold tolerance ratio compared to the 22-fold tolerance ratio to cypermethrin, a pyrethroid. Older larvae, pre-pupal stage and adults, were less sensitive to the P. nigrum extracts; the 24-h LD(50) was 0.5% (95% C.I. = 0.36, 0.65). However, the same concentration was equally effective under field conditions. In the greenhouse, P. nigrum at 0.5% was as effective at reducing adult L. decemlineata feeding as combinations with 2 separate botanical mixtures, garlic and lemon grass oil. Under field conditions, the residual activity of the P. nigrum extracts was less than 3 h. When adult L. decemlineata were placed on treated plants exposed to full sunlight for 0, 1.5, and 3 h, leaf damage progressively increased as the main active compound, piperine, was found to degrade by 80% after 3 h. An in vitro polysubstrate monoxygenase (PSMO) enzyme assay, using the substrate methoxyresorufin O-demethylation (MROD), determined that the principal P. nigrum active compound, piperine, is responsible for inhibition of that specific enzyme. The results suggest that Piper extracts could be used effectively as contact botanical insect control agents to protect potato plants from developing L. decemlineata larvae at concentrations less than 0.1%. There is also potential for Piper extracts to control insecticide resistant populations in conjunction with other integrated pest management (IPM) strategies used in conventional and organic agriculture.

Topics: Agriculture; Alkaloids; Amides; Animals; Benzodioxoles; Coleoptera; Dose-Response Relationship, Drug; Insecticide Resistance; Insecticides; Larva; Lethal Dose 50; Mixed Function Oxygenases; Permethrin; Pest Control, Biological; Piper; Piperidines; Plant Extracts; Plant Leaves; Polyunsaturated Alkamides; Solanum tuberosum; Sunlight; Survival Analysis; Time Factors

Dietary constituents (e.g., in grapefruit juice; NaCl) and phytochemicals (e.g., St. John's wort) are important agents modifying drug metabolism and transport and thereby contribute to interindividual variability in drug disposition. Most of these drug-food interactions are due to induction or inhibition of P-glycoprotein and/or CYP3A4. Preliminary data indicate that piperine, a major component of black pepper, inhibits drug-metabolizing enzymes in rodents and increases plasma concentrations of several drugs, including P-glycoprotein substrates (phenytoin and rifampin) in humans. However, there are no direct data whether piperine is an inhibitor of human P-glycoprotein and/or CYP3A4. We therefore investigated the influence of piperine on P-glycoprotein-mediated, polarized transport of digoxin and cyclosporine in monolayers of Caco-2 cells. Moreover, by using human liver microsomes we determined the effect of piperine on CYP3A4-mediated formation of the verapamil metabolites D-617 and norverapamil. Piperine inhibited digoxin and cyclosporine A transport in Caco-2 cells with IC(50) values of 15.5 and 74.1 microM, respectively. CYP3A4-catalyzed formation of D-617 and norverapamil was inhibited in a mixed fashion, with K(i) values of 36 +/- 8 (liver 1)/49 +/- 6 (liver 2) and 44 +/- 10 (liver 1)/77 +/- 10 microM (liver 2), respectively. In summary, we showed that piperine inhibits both the drug transporter P-glycoprotein and the major drug-metabolizing enzyme CYP3A4. Because both proteins are expressed in enterocytes and hepatocytes and contribute to a major extent to first-pass elimination of many drugs, our data indicate that dietary piperine could affect plasma concentrations of P-glycoprotein and CYP3A4 substrates in humans, in particular if these drugs are administered orally.

Topics: Alkaloids; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Biological Transport; Colonic Neoplasms; Cyclosporine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Digoxin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Kinetics; Mixed Function Oxygenases; Piperidines; Polyunsaturated Alkamides; Tumor Cells, Cultured

Piperine, a major alkaloid of Piper longum and Piper nigrum has been reported to have several pharmacological/toxicological effects. Though a number of methods for analysis of this omnipresent food component in pepper fruits are available, its analysis in body fluids has been largely neglected. A high-performance liquid chromatography method for the analysis of piperine in rat plasma is presented in this communication. Analysis was performed using a Symmetry C(18) column (250x4.6 mm) by isocratic elution with 25 mM KH(2)PO(4) (pH 4.5)-acetonitrile (35:65) and UV detection at 340 nm. The calibration plot was linear over the range studied (2-2000 ng) with correlation coefficient of 0.9984. Limit of detection and limit of quantitation were 1 ng/ml and 3 ng/ml, respectively. Good overall recovery (85.5+/-6%) was obtained with 4 ml ethyl acetate and extraction time of 3 min. Intra- and inter-assay coefficient of variation was found to be less than 7.5%. Plasma concentration-time profile of piperine in a conscious rat implanted with jugular vein cannula was obtained using this method. The method is simple, sensitive and reproducible.

Topics: Alkaloids; Animals; Benzodioxoles; Chromatography, High Pressure Liquid; Piperidines; Polyunsaturated Alkamides; Rats; Spectrophotometry, Ultraviolet

A new analytical method for the determination of piperine and its isomers in egg yolk and albumen is described here. All four isomers were separated by HPLC and detected using UV, DAD and electrochemical detection. The absolute detection limit (UV detection, S/ N=3) of a standard solution of piperine was 370 pg piperine. The correlation coefficients for the linear calibration graphs (concentration range: c=100 ng-10 micro g piperine isomer/mL) are generally better than 0.996. The piperine isomers were characterized and identified by spectroscopy (MS, (1)H-NMR, FT-IR). The method was successfully applied to the determination of piperine deposits in eggs (egg yolk and albumen) after feeding hens with piperine-spiked feed. The detection limit for piperine (24.8(+/-0.2) ng/g egg yolk and 37.9(+/-4.9) ng/g albumen) and the recoveries (70.3(+/-7.7)% (egg yolk) and 75.7(+/-1.9)% (albumen)) of piperine were determined.

Topics: Alkaloids; Animals; Benzodioxoles; Chickens; Chromatography, High Pressure Liquid; Egg Yolk; Electrochemistry; Isomerism; Magnetic Resonance Spectroscopy; Mass Spectrometry; Ovalbumin; Piperidines; Polyunsaturated Alkamides; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared

We have investigated the effect piperine on castor oil-stimulated fluid accumulation in the mouse small intestine. Piperine (2.5-20 mg/kg, i.p.) dose-dependently reduced castor oil-induced intestinal fluid accumulation. The inhibitory effect of piperine (10 mg/kg i.p.) was strongly attenuated in capsaicin (75 mg/kg in total, s.c.)-treated mice but it was not modified by the vanilloid receptor antagonist capsazepine (30 mg/kg i.p.). Pretreatment of mice with hexamethonium (1 mg/kg i.p.), naloxone (2 mg/kg i.p.), yohimbine (1 mg/kg i.p.) or the cannabinoid CB(1) receptor antagonist SR141716A (0.3 mg/kg i.p.) did not modify the inhibitory effect of piperine (10 mg/kg i.p.). These results suggest that piperine reduces castor oil-induced fluid secretion with a mechanism involving capsaicin-sensitive neurons, but not capsazepine-sensitive vanilloid receptors.

Topics: Alkaloids; Animals; Anti-Ulcer Agents; Benzodioxoles; Capsaicin; Castor Oil; Dose-Response Relationship, Drug; Drug Interactions; Injections, Intraperitoneal; Intestinal Secretions; Intestine, Small; Male; Mice; Mice, Inbred ICR; Organ Size; Piperidines; Polyunsaturated Alkamides

A novel piperine dimer, named chabamide, was isolated from stems of Piper chaba Hunter and its structure was elucidated on the basis of spectroscopic evidence. Chabamide showed antimalarial activity with an IC(50) value of 2.7 microg/ml and antituberculosis activity with the minimum inhibitory concentration (MIC) of 12.5 microg/ml.

Topics: Alkaloids; Animals; Antimalarials; Antitubercular Agents; Benzodioxoles; Dimerization; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Mycobacterium tuberculosis; Piper; Piperidines; Plant Extracts; Plant Stems; Plasmodium falciparum; Polyunsaturated Alkamides

Bioactivity guided isolation of the bark of Careya arborea afforded piperine--an alkaloid chemically known as 1-[5-(1,3-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]piperidine, which was found to possess significant central and peripheral analgesic activity. At oral doses of 10, 20 and 30 mg/kg body weight, piperine exhibited 41 (p < 0.01), 45 (p < 0.01) and 53% (p < 0.001) inhibition of acetic acid induced writhing in mice respectively. At doses of 20 and 30 mg/kg body weight, the compound also showed 31.8 (p < 0.05) and 52.4% (p < 0.01) prolongation of tail flicking time of mice 30 min after the treatments determined by the radiant heat method.

Topics: Acetic Acid; Alkaloids; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bangladesh; Behavior, Animal; Benzodioxoles; Female; Lecythidaceae; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Mice; Pain; Pain Measurement; Piperidines; Plant Epidermis; Plant Extracts; Polyunsaturated Alkamides; Reaction Time

The effect of piperine on the inhibition of lung metastasis induced by B16F-10 melanoma cells was studied in C57BL/6 mice. Simultaneous administration of the compound with tumor induction produced a significant reduction (95.2%) in tumor nodule formation. Increased lung collagen hydroxyproline (22.37 microg/mg protein) in the metastasized lungs of the control animals compared to normal animals (0.95 microg/mg protein) was significantly reduced (2.59 microg/mg protein) in the piperine-treated animals. The high amount of uronic acid (355.83 microg/100 mg tissue) in the metastasized control animals was significantly reduced (65 microg/100 mg tissue) in the animals treated with piperine. Lung hexosamine content was also significantly reduced in the piperine-treated animals (0.98 mg/100 mg lyophilized tissue) compared to the untreated tumor-bearing animals (4.2 mg/100 mg lyophilized tissue). The elevated levels of serum sialic acid and serum gamma glutamyl transpeptidase activity in the untreated control animals was significantly reduced in the animals treated with piperine. The piperine-treated animals even survived the experiment (90 days). Histopathology of the lung tissue also correlated with the lifespan of the drug-treated animals. Our results demonstrate the antimetastatic activity of piperine, an alkaloid present in plants such as Piper nigrum and Piper longum.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Cell Division; gamma-Glutamyltransferase; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; N-Acetylneuraminic Acid; Piperidines; Polyunsaturated Alkamides; Tumor Cells, Cultured

Co-administration of piperine, an alkaloid isolated from Piper nigrum L. enhanced bioavailability of beta lactam antibiotics, amoxycillin trihydrate and cefotaxime sodium significantly in rats. The improved bioavailability is reflected in various pharmacokinetic parameters viz. tmax, Cmax, t(1/2) and AUC, of these antibiotics. The increased bioavailability could be attributed to the effect of piperine on microsomal metabolising enzymes or enzymes system.

Topics: Alkaloids; Amoxicillin; Animals; Anti-Bacterial Agents; Benzodioxoles; Biological Availability; Cefadroxil; Cefotaxime; Drug Interactions; Female; Male; Mice; Piperidines; Polyunsaturated Alkamides; Rats

Piperine, the pungent principle in Piper nigrum and Piper guinensis was studied for its effect on gastric acid secretion in white albino rats. Increasing the dose from 20 mg kg(-1) weight to 142 mg kg(-1) body weight produced dose dependent increases in gastric acid secretion. When compared with control basal acid secretion, these increases were significant (P<0.05). 20 mg kg(-1) produced a 22.2% (n=7) increase, while the highest dose employed in this study (142 mg kg(-1)) produced 334.6% (n=7) increase in the gastric acid secretion. Piperine was however about 40 times less effective than histamine in increasing gastric acid secretion. The effect of piperine was significantly antagonized by cimetidine (1 mg kg(-1), n=6) but not by atropine (1 mg kg(-1), n=6). Any involvement of cholinergic receptors in the observed piperine-induced increase in gastric acid secretion is thus excluded. There is however an indication that stimulation of histamine H2 receptors by piperine is likely to be involved in the increased acidity induced by piperine.

Topics: Alkaloids; Animals; Anti-Ulcer Agents; Benzodioxoles; Dose-Response Relationship, Drug; Female; Gastric Acid; Gastric Mucosa; Histamine; Male; Models, Animal; Piperidines; Polyunsaturated Alkamides; Rats

We have evaluated the effect of the vanilloid receptor agonists resiniferatoxin (RTX), capsaicin and piperine and of the vanilloid receptor antagonist capsazepine on the resting tone in the isolated rat ileum. Capsazepine (10(-8)-3 x 10(-5) M) produced a concentration-related relaxation (8 +/-3%-49 +/-3%) of the rat ileum. By contrast RTX (up to 10(-8) M), capsaicin (up to 10(-6) M) and piperine (up to 10(-5) M) were without effect. Pre-treatment with capsaicin [either in vivo (50 mg/kg s.c.) or in vitro (10(-6) M)] did not modify the inhibitory effect of capsazepine. The L-type Ca2+ channel antagonist nifedipine (10(-6) M), but not the N-type Ca2+ channel antagonist omega-conotoxin GVIA (3 x 10(-8) M) nor the Na+ channel blocker tetrodotoxin (3 x 10(-7) M), counteracted the inhibitory effect of capsazepine. The NK1 receptor antagonist SR 140333 (10(-7) M), the NK2 receptor antagonist SR 48968 (10(-6) M), the NK3 receptor antagonist SR 142801 (10(-7) M), atropine (10(-6) M), hexamethonium (10(-4) M), phentolamine (10(-6) M) plus propranolol (10(-6) M), N(G)-nitro- L-arginine methyl ester ( L-NAME 3 x 10(-4) M), apamin (10(-7) M), methysergide (10(-6) M), the calcitonin gene-related peptide (CGRP) antagonist hCGRP 8-37 (1.5 x 10(-6) M), the VIP antagonist hGRF 1-29 (10(-5) M) did not modify the inhibitory effect of capsazepine. Capsazepine (2.5-40 mg/kg) also decreased upper gastrointestinal transit in vivo. It is concluded that the vanilloid antagonist capsazepine has a direct relaxing effect on rat intestinal smooth muscle which could involve L-type calcium channels. We found no evidence to suggest that capsazepine is antagonizing an endogenous vanilloid.

Topics: Alkaloids; Animals; Benzodioxoles; Calcium Channels, L-Type; Capsaicin; Diterpenes; Dose-Response Relationship, Drug; Gastrointestinal Transit; Ileum; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptors, Drug

Spice components and their active principles are potential antioxidants. In this study we examined the effect of phenolic and non-phenolic active principles of common spices on copper ion-induced lipid peroxidation of human low density lipoprotein (LDL) by measuring the formation of thiobarbituric acid reactive substance (TBARS) and relative electrophoretic mobility (REM) of LDL on agarose gel. Curcumin, capsaicin, quercetin, piperine, eugenol and allyl sulfide inhibited the formation of TBARS effectively through out the incubation period of 12 h and decreased the REM of LDL. Spice phenolic active principles viz. curcumin, quercetin and capsaicin at 10 microM produced 40-85% inhibition of LDL oxidation at different time intervals while non-phenolic antioxidant allyl sulfide was less potent in inhibiting oxidation of LDL. However, allyl sulfide, eugenol and ascorbic acid showed pro-oxidant activity at lower concentrations (10 microM) and antioxidant activity at higher concentrations (50 microM) only. Among the spice principles tested quercetin and curcumin showed the highest inhibitory activity while piperine showed least antioxidant activity at equimolar concentration during initiation phase of oxidation of LDL. The inhibitory effect of curcumin, quercetin and capsaicin was comparable to that of BHA, but relatively more potent than ascorbic acid. Further, the effect of curcumin, quercetin, capsaicin and BHA on initiation and propagation phases of LDL oxidation showed that curcumin significantly inhibited both initiation and propagation phases of LDL oxidation, while quercetin was found to be ineffective at propagation phase. These data suggest that the above spice active principles, which constitute about 1-4% of above spices, are effective antioxidants and offer protection against oxidation of human LDL.

Topics: Alkaloids; Allyl Compounds; Ascorbic Acid; Benzodioxoles; Butylated Hydroxyanisole; Capsaicin; Curcumin; Eugenol; Humans; In Vitro Techniques; Lipoproteins, LDL; Oxidation-Reduction; Piperidines; Polyunsaturated Alkamides; Quercetin; Spices; Sulfides

Piperine, a major alkaloid of black and long peppers has been reported to act as bioavailability enhancer of several drugs by inhibiting drug metabolising enzymes and/or by increasing oral absorption. Ketoconazole is a well established potent inhibitor of CYP 3A4 and P-glycoprotein. A simple and rapid HPLC method has been developed for the simultaneous analysis of ketoconazole and piperine in rat plasma and hepatocyte culture. Analysis was performed using a Symmetry C18 column (150x4.6 mm, 5 microm) and isocratic elution with 25 mM KH2PO4 (pH 4.5)-acetonitrile (50:50) with a flow-rate of 1 ml/min. Photodiode array detection was used to simultaneously monitor piperine at 340 nm and ketoconazole at 231 nm in a single sample. Calibration plots in spiked plasma, hepatocytes and William's medium E were linear over the range studied (10-2000 ng for both drugs). The detection limits for piperine and ketoconazole are 2 and 4 ng, respectively, and the limits of quantitation are 10 and 12 ng, respectively. Intra- and inter-assay variations were less than 8%.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Chromatography, High Pressure Liquid; Hepatocytes; Ketoconazole; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Sensitivity and Specificity; Spectrophotometry, Ultraviolet

Piperine (1-Piperoyl piperidine) is a major alkaloid of Piper nigrum Linn. and Piper longum Linn. It is shown to possess bioavailability-enhancing activity with various structurally and therapeutically diverse drugs. The mechanism of enhancing the bioavailability, is, however, not understood. We hypothesize that piperine's bioavailability-enhancing property may be attributed to increased absorption, which may be due to alteration in membrane lipid dynamics and change in the conformation of enzymes in the intestine. Results of membrane fluidity studies using an apolar fluorescent probe, pyrene (which measures the fluid properties of hydrocarbon core), showed an increase in intestinal brush border membrane (BBM) fluidity. Piperine also stimulated Leucine amino peptidase and Glycyl-glycine dipeptidase activity, due to the alteration in enzyme kinetics. This suggests that piperine could modulate the membrane dynamics due to its apolar nature by interacting with surrounding lipids and hydrophobic portions in the protein vicinity, which may decrease the tendency of membrane lipids to act as stearic constrains to enzyme proteins and thus modify enzyme conformation. Ultra structural studies with piperine showed an increase in microvilli length with a prominent increase in free ribosomes and ribosomes on the endoplasmic reticulum in enterocytes, suggesting that synthesis or turnover of cytoskeletal components or membrane proteins may be involved in the observed effect. In conclusion, it is suggested that piperine may be inducing alterations in membrane dynamics and permeation characteristics, along with induction in the synthesis of proteins associated with cytoskeletal function, resulting in an increase in the small intestine absorptive surface, thus assisting efficient permeation through the epithelial barrier.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Dipeptidases; Drug Synergism; Enzyme Inhibitors; Intestinal Mucosa; Jejunum; Leucyl Aminopeptidase; Male; Membrane Fluidity; Microvilli; Phytotherapy; Piper; Piperidines; Polyunsaturated Alkamides; Rats

1. We have studied the effect of capsaicin, piperine and anandamide, drugs which activate vanilloid receptors and capsazepine, a vanilloid receptor antagonist, on upper gastrointestinal motility in mice. 2. Piperine (0.5 - 20 mg kg(-1) i.p.) and anandamide (0.5 - 20 mg kg(-1) i.p.), dose-dependently delayed gastrointestinal motility, while capsaicin (up to 3 mg kg(-1) i.p.) was without effect. Capsazepine (15 mg kg(-1) i.p.) neither per se affected gastrointestinal motility nor did it counteract the inhibitory effect of both piperine (10 mg kg(-1)) and anandamide (10 mg kg(-1)). 3. A per se non effective dose of SR141716A (0.3 mg kg(-1) i.p.), a cannabinoid CB(1) receptor antagonist, counteracted the inhibitory effect of anandamide (10 mg kg(-1)) but not of piperine (10 mg kg(-1)). By contrast, the inhibitory effect of piperine (10 mg kg(-1)) but not of anandamide (10 mg kg(-1)) was strongly attenuated in capsaicin (75 mg kg(-1) in total, s.c.)-treated mice. 4. Pretreatment of mice with N(G)-nitro-L-arginine methyl ester (25 mg kg(-1) i.p.), yohimbine (1 mg kg(-1), i.p.), naloxone (2 mg kg(-1) i.p.), or hexamethonium (1 mg kg(-1) i.p.) did not modify the inhibitory effect of both piperine (10 mg kg(-1)) and anandamide (10 mg kg(-1)). 5. The present study indicates that the vanilloid ligands anandamide and piperine, but not capsaicin, can reduce upper gastrointestinal motility. The effect of piperine involves capsaicin-sensitive neurones, but not vanilloid receptors, while the effect of anandamide involves cannabinoid CB(1), but not vanilloid receptors.

Topics: Alkaloids; Animals; Arachidonic Acids; Benzodioxoles; Capsaicin; Dose-Response Relationship, Drug; Endocannabinoids; Gastrointestinal Transit; Hexamethonium; Male; Mice; Mice, Inbred ICR; Naloxone; NG-Nitroarginine Methyl Ester; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Drug; Rimonabant; Yohimbine

Piperine (1), an alkaloid of black and long peppers, inhibited gastric emptying (GE) of solids/liquids in rats and gastrointestinal transit (GT) in mice in a dose and time dependent manner. Compound 1 significantly inhibited GE of solids and GT at the doses extrapolated from humans (1 mg/kg and 1.3 mg/kg p.o. in rats and mice, respectively). However, at the same dose the effect was insignificant for GE of liquids. One week oral treatment of 1 mg/kg and 1.3 mg/kg in rats and mice, respectively, did not produce a significant change in activity as compared to single dose administration. GE inhibitory activity of 1 is independent of gastric acid and pepsin secretion.

Topics: Alkaloids; Animals; Benzodioxoles; Digestive System; Dose-Response Relationship, Drug; Gastric Emptying; Male; Mice; Molecular Structure; Piperidines; Plant Extracts; Plants, Medicinal; Polyunsaturated Alkamides; Rats

Peppers are common food ingredients used worldwide. They are also added in traditional antidiarrhoeal formulations of different herbs. Piperine (1) is an alkaloidal constituent of black and long peppers recently established as a bioavailability enhancer of drugs and other substances. As a part of efforts to study its effects on the gastrointestinal tract, the experiments were performed to determine the rationale, if any, for its use in traditional antidiarrhoeal formulations. Antidiarrhoeal activity of 1 against castor oil, MgSO4 and arachidonic acid was studied in mice. It significantly inhibited diarrhoea produced by these cathartics at 8 and 32 mg/kg p.o. dose. Inhibition of castor oil induced enteropooling by 1 suggests its inhibitory effect on prostaglandins. The results validate the rationale for its use in traditional antidiarrhoeal formulations.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antidiarrheals; Benzodioxoles; Cathartics; Diarrhea; Digestive System; Male; Mice; Phytotherapy; Piperidines; Plant Extracts; Polyunsaturated Alkamides

A reverse phase HPLC method to determine piperine, a pungent constituent of black pepper, in rabbit serum and various tissues of the rat was developed. A pharmacokinetic study was performed in rabbits and tissue distribution studies were carried out in rats. High reproducibility was achieved in quantitative analysis over the concentration range of 0.2-20 micrograms/ml serum. After bolus intravenous administration of piperine at a dose of 10 mg/kg, the serum concentration--time curve fitted the two-compartment open model. The tissue distribution pattern of piperine in rats also supports the two-compartment open model.

Topics: Alkaloids; Animals; Area Under Curve; Benzodioxoles; Calibration; Chromatography, High Pressure Liquid; Half-Life; Injections, Intravenous; Male; Piperidines; Polyunsaturated Alkamides; Rabbits; Rats; Reproducibility of Results; Tissue Distribution

Three spices, chili, black pepper, and turmeric, were tested for the effect of their aqueous extracts on the sensitivity of three bacteria, Escherichia coli, Bacillus megaterium, and Bacillus pumilusspores, to gamma-radiation. It was found that the extracts of the three spices offered protection to these organisms against inactivation by gamma-radiation. These spice extracts were also tested for their protection of naked plasmid DNA. Radiation-induced degradation of plasmid pUC18 DNA was reduced in the presence of the spice extracts. The maximum protection was offered by the chili extract followed by that of black pepper and turmeric. The two known antioxidants, curcumin and piperine from turmeric and black pepper, respectively, were shown to protect the plasmid DNA from the degradation by gamma-radiation. Experiments with the plasmid pUC18 DNA indicated that the spice extracts probably protected microorganisms by protecting their DNA. These studies indicated the importance of spices among ingredients in food as dose-modifying factors during radiation processing.

Topics: Alkaloids; Antioxidants; Bacillus; Bacillus megaterium; Benzodioxoles; Curcuma; Curcumin; Dose-Response Relationship, Radiation; Escherichia coli; Gamma Rays; Piperidines; Plant Extracts; Plasmids; Polyunsaturated Alkamides; Radiation Tolerance; Spices

Piperine is an inhibitor of various hepatic and other enzymes involved in the biotransformation of drugs. Preliminary pharmacokinetic studies conducted by us suggested the increased bioavailability of nimesulide co-administered with piperine. The present study was, thus, conducted to evaluate the antinociceptive, anti-inflammatory and toxicity profile of a new nimesulide-piperine combination administered orally as compared with nimesulide alone. Antinociceptive efficacy was tested using an acetic acid writhing test and tail flick latency test (TFL). The ED50 value of a nimesulide-piperine combination in writhing test was calculated to be significantly lower (1.5 mg kg(-1)) as compared to (11.2 mg kg(-1)) of nimesulide alone. The antinociceptive effect was lesser in the tail flick latency test as compared to what was observed in the writhing test indicating the peripheral action of the Non-Steriodal Anti-Inflammatory Drug (NSAID). In carrageenan-induced inflammatory tests, the nimesulide-piperine combination was found to be dose-to-dose superior than nimesulide alone. Acute toxicity studies on mice revealed a reduction in lethal dose (LD50) of the combination (980 mg kg(-1)) as compared to nimesulide (1500 mg kg(-1)) alone. Results from the present study suggest a better therapeutic index for the nimesulide-piperine combination indicating that this combination would further reduce the frequency of adverse effects associated with nimesulide alone.

Topics: Administration, Oral; Alkaloids; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Drug Combinations; Drug Interactions; Female; Inflammation; Lethal Dose 50; Male; Mice; Nociceptors; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Sulfonamides

Piperine (CAS 94-62-2) is a constituent of various spices which are used as common food additives all over the world. The reproductive toxicity of piperine was studied in Swiss albino mice. Relevant short-term tests were employed to assess the effect on estrous cycle, mating behaviour, toxicity to male germ cells, fertilization, implantation and growth of pups. Piperine (10 and 20 mg/kg b.w.) increased the period of the diestrous phase which seemed to result in decreased mating performance and fertility. Post-partum litter growth was not affected by the piperine treatment. Sperm shape abnormalities were not induced by piperine at doses up to 75 mg/kg b.w. Considerable anti-implantation activity was recorded after five days post-mating oral treatment with piperine. The sex ratio and post-implantation loss were unaffected after treatment with piperine. Intrauterine injection of piperine caused the total absence of implants in either of the uterine horns (16.66%) or one of the horns (33%) of treated females. No histopathological changes were detected in the ovary and the uterus at the cellular level. Prostaglandin E1-induced acute inflammation of rat paw was significantly reduced after piperine treatment. Our results show that piperine interferes with several crucial reproductive events in a mammalian model.

Topics: Alkaloids; Animals; Benzodioxoles; Embryo Implantation; Female; Fetal Death; Food Additives; Male; Mice; Piperidines; Polyunsaturated Alkamides; Rats; Spermatozoa; Teratogens; Uterus

Inhibitors of drug metabolism have important implications in pharmaco-toxicology and agriculture. We have reported earlier that piperine, a major alkaloid of black and long peppers inhibits both constitutive and inducible cytochrome P450 (CYP)-dependent drug metabolising enzymes. In the present study, an attempt has been made to prepare several novel synthetic analogues so as to relate various modifications in the parent molecule to the inhibition of CYP activities. Two types of mono-oxygenase reactions arylhydrocarbon hydroxylase (AHH) and 7-methoxycoumarin-O-demethylase (MOCD) have been studied. Inhibition studies were investigated in rat microsomal fraction prepared from untreated, 3MC- and PB- treated rat liver in vitro. Modifications were introduced into the piperine molecule: (i) in the phenyl nucleus, (ii) in the side chain and (iii) in the basic moiety. Thus, 38 compounds have been subjected to such studies, and simultaneously an attempt has also been made to arrive at the structure-activity relationship of synthetic analogues. In general, most of the inhibitory potential of the parent molecule is lost with modification in either of the three components of piperine. Saturation of the side chain resulted in significantly enhanced inhibition of CYP while modifications in the phenyl and basic moieties in few analogues offered maximal selectivity in inhibiting either constitutive or inducible CYP activities. Thus few novel analogues as CYP inactivators have been synthesized which may have important consequences in pharmacokinetics and bioavailability of drugs.

Topics: Alkaloids; Animals; Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Induction; Enzyme Inhibitors; Kinetics; Male; Microsomes, Liver; Piperidines; Polyunsaturated Alkamides; Rats; Spectrum Analysis; Structure-Activity Relationship; Tumor Cells, Cultured

Oxygen radical injury and lipid peroxidation have been suggested as major causes of atherosclerosis, cancer, liver disease and the aging process. Piperine, having an antiinflammatory effect, has been demonstrated in in vitro experiments to protect against oxidative damage by inhibiting or quenching free radicals and reactive oxygen species and hydroxyl radicals. The effect on lipid peroxidation was also examined and IC50 values were calculated. Piperine was found to act as a hydroxyl radical scavenger at low concentrations, but at higher concentrations, it activated the fenton reaction resulting in increased generation of hydroxyl radicals. Whereas it acts as a powerful superoxide scavenger and IC50 is 1.82 mM, a 52% inhibition of lipid peroxidation was observed at a dose of 1400 microM with an IC50 of 1.23 mM. The results depict that piperine possesses direct antioxidant activity against various free radicals. This study also opens newer views on the potential efficacy of piperine in protecting tissues from peroxidative damage.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Free Radical Scavengers; Hydroxyl Radical; In Vitro Techniques; Iron; Lipid Peroxidation; Liver; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Subcellular Fractions; Superoxides

Using diabetes mellitus as a model of oxidative damage, this study investigated whether subacute treatment (10 mg/kg/day, intraperitoneally for 14 days) with the compound piperine would protect against diabetes-induced oxidative stress in 30-day streptozotocin-induced diabetic Sprague-Dawley rats. Liver, kidney, brain, and heart were assayed for degree of lipid peroxidation, reduced and oxidized glutathione (GSH and GSSG, respectively) content, and activities of the free-radical detoxifying enzymes catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase. Piperine treatment of normal rats enhanced hepatic GSSG concentration by 100% and decreased renal GSH concentration by 35% and renal glutathione reductase activity by 25% when compared to normal controls. All tissues from diabetic animals exhibited disturbances in antioxidant defense when compared with normal controls. Treatment with piperine reversed the diabetic effects on GSSG concentration in brain, on renal glutathione peroxidase and superoxide dismutase activities, and on cardiac glutathione reductase activity and lipid peroxidation. Piperine treatment did not reverse the effects of diabetes on hepatic GSH concentrations, lipid peroxidation, or glutathione peroxidase or catalase activities; on renal superoxide dismutase activity; or on cardiac glutathione peroxidase or catalase activities. These data indicate that subacute treatment with piperine for 14 days is only partially effective as an antioxidant therapy in diabetes.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Brain; Diabetes Mellitus, Experimental; Enzyme Inhibitors; Glutathione; Glutathione Disulfide; Glutathione Reductase; Glutathione Transferase; Heart; Kidney; Lipid Peroxidation; Liver; Male; Myocardium; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Reference Values; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

To study the effects of piperine (Pip) on several experimental gastric ulcers in rats and mice.. The gastric mucosa damage was induced by stress, indometacin, HCl, and pyloric ligation in rats or mice. The number of gastric ulcers, the volume and acidity of gastric juices, and pepsin A activity were detected.. Pip 25, 50, 100 mg/kg ig protected animals from gastric ulceration in a dose-dependent manner. The inhibitory rates were 16.9%, 36.0%, and 48.3% in stress ulcers; 4.4%, 51.1%, and 64.4% in indometacin ulcers; 19.2%, 41.5%, and 59.6% in HCl ulcers; 4.8%, 11.9%, and 26.2% in pyloric ligation ulcers, respectively; Pip inhibited the volume of gastric juice, gastric acidity, and pepsin A activity.. Pip has the protective effects against gastric ulceration.

Topics: Alkaloids; Animals; Anti-Ulcer Agents; Benzodioxoles; Dose-Response Relationship, Drug; Female; Gastric Acid; Gastric Juice; Gastric Mucosa; Male; Mice; Piperidines; Polyunsaturated Alkamides; Rats; Stomach Ulcer; Tyrosine

Effects of piperine at two oral doses (5 and 10 mg/kg body weight for 30 days) on the lipid composition and some lipogenic enzymes of the rat testis were studied. Piperine treatment depleted the total lipid content which was mainly due to the diminution of the total phospholipid concentration. All the classes of phospholipids were decreased markedly following high dose piperine treatment. In contrast, a marked increase in total cholesterol and cholesterol ester was evident with a concomitant fall in free cholesterol. A similar trend was found for the total glyceride glycerol and its fractions. Total glyceride glycerol and triacyl glycerol showed a significant increase at the expense of diacyl glycerol in rats treated with the high dose of piperine. Lipogenic enzymes, malate dehydrogenase (MDH), malic enzyme (ME) and isocitrate dehydrogenase (ICDH) were inhibited by the high dose and only MDH and ME activities were inhibited by the low dose treatment.

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Body Weight; Cholesterol; Cholesterol Esters; Glycerides; Isocitrate Dehydrogenase; Lipid Metabolism; Malate Dehydrogenase; Male; Molecular Structure; Organ Size; Phospholipids; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Spices; Testis

Piperine was administered to mature male albino rats at doses of 5 and 10 mg/kg body weight, p.o., respectively, for 30 days. Only a 10 mg dose of piperine treatment caused a significant reduction in the weights of testis and accessory sex organs. Histological studies revealed that piperine at a 5 mg dose caused partial degeneration of germ cell types, whereas at a 10 mg dose, it caused severe damage to the seminiferous tubule, decrease in seminiferous tubular and Leydig cell nuclear diameter and desquamation of spermatocytes and spermatids. Correlated to the structural changes, a fall in caput and cauda epididymal sperm concentrations was also evident. A 10 mg dose of piperine also caused a marked increase in serum gonadotropins and a decrease in intratesticular testosterone concentration, despite normal serum testosterone titres.

Topics: Abortifacient Agents, Steroidal; Alkaloids; Animals; Benzodioxoles; Body Weight; Cell Nucleus; Dose-Response Relationship, Drug; Enzymes; Gonadotropins; Leydig Cells; Male; Organ Size; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Seminiferous Tubules; Sertoli Cells; Spermatozoa; Testis; Testosterone

Using a bipolar rating scale, human subjects rated the intensity of irritation sensation evoked by repeated application of piperine (75 p.p.m.) or nicotine (0.12%) to one side of the dorsal surface of the tongue. The intensity of irritation elicited by repeated application of piperine significantly increased, while irritation elicited by repeated nicotine significantly decreased. We additionally tested if nicotine or piperine desensitized the tongue. After either piperine or nicotine was repeatedly applied to one side of the tongue, a 5 or 10 min rest period ensued, followed by re-application of piperine or nicotine to both sides of the tongue. Subjects were asked to choose which side of the tongue gave rise to a stronger irritation in a two-alternative forced choice (2-AFC) paradigm. In addition, they gave separate ratings of the intensity of irritation on the two sides of the tongue. When piperine was applied bilaterally after unilateral pretreatment with piperine and a 10 min rest period, subjects consistently chose the non-pretreated side to yield stronger irritation and assigned significantly higher ratings to that side, indicative of piperine self-desensitization. A similar self-desensitization effect was found when bilateral application of nicotine followed unilateral treatment with nicotine and a 5 min rest period. Unilateral treatment with piperine also reduced nicotine-evoked irritation on the pretreated side (cross-desensitization), but treatment with nicotine did not affect piperine-evoked irritation. This asymmetrical cross-desensitization pattern is similar to that observed between capsaicin and nicotine and constitutes an additional similarity between piperine and capsaicin.

Topics: Adult; Alkaloids; Benzodioxoles; Female; Humans; Irritants; Male; Nicotine; Piperidines; Polyunsaturated Alkamides; Psychophysics; Tongue

During a herbal screening programme to find potential repigmenting agents for the treatment of vitiligo, Piper nigrum L. fruit (black pepper) extract was found to possess growth-stimulatory activity towards cultured melanocytes. Its aqueous extract at 0.1 mg/ml was observed to cause nearly 300% stimulation of the growth of a cultured mouse melanocyte line, melan-a, in 8 days (p < 0.01). Piperine (1-piperoylpiperidine), the main alkaloid from Piper nigrum fruit, also significantly stimulated melan-a cell growth. Both Piper nigrum extract and piperine induced morphological alterations in melan-a cells, with more and longer dendrites observed. The augmentation of growth by piperine was effectively inhibited by RO-31-8220, a selective protein kinase C (PKC) inhibitor, suggesting that PKC signalling is involved in its activity. This is the first full report on such an activity of black pepper and piperine.

Topics: Alkaloids; Animals; Benzodioxoles; Cell Division; Cell Line; Fruit; Melanins; Melanocytes; Mice; Mitogens; Piperidines; Plant Extracts; Plants, Medicinal; Polyunsaturated Alkamides

The leishmanicidal property of piperine intercalated in liposomes and in mannose-coated liposomes was tested in experimental visceral leishmaniasis in hamsters. Mannose-coated liposomal piperine eliminated intracellular amastigotes of Leishmania donovani in splenic macrophages much more efficiently than did the liposomal piperine or free piperine. At a dose equivalent to 6 mg/kg body wt every 4th day for a total of 4 doses in 12 days, the mannose-coated liposomal piperine was found to reduce spleen parasite load to the extent of 90% in comparison to that achieved by liposomal piperine (77%) or free piperine (29%). Histological examination of spleen and liver function tests showed that the toxicity of piperine was reduced when mannosylated liposomal piperine was administered.

Topics: Alkaloids; Animals; Antiprotozoal Agents; Benzodioxoles; Cricetinae; Drug Carriers; Leishmaniasis, Visceral; Liposomes; Liver Function Tests; Macrophages; Mannose; Mesocricetus; Piperidines; Polyunsaturated Alkamides; Spleen

In the present work we report the development of a new radioimmunoassay method for measuring the substance P content liberated from isolated rat tracheae in response to electrical or chemical (capsaicin, resiniferatoxin, piperine) stimulation. The amount of substance P released by electrical stimulation has been found to be dependent on the number of pulses and chemically elicited substance P release also proved to be dose-dependent. Our findings reinforce previous data that resiniferatoxin is approximately 100 times more potent than capsaicin and the potency ratio between piperine and capsaicin is 1/50.

Topics: Alkaloids; Animals; Benzodioxoles; Calibration; Capsaicin; Diterpenes; Electric Stimulation; Enzyme Inhibitors; Female; Neurons, Afferent; Piperidines; Polyunsaturated Alkamides; Radioimmunoassay; Rats; Rats, Wistar; Stimulation, Chemical; Substance P; Trachea

Piperine (1-Piperoyl piperidine) is the major alkaloid of black and long peppers used widely in various systems of traditional medicine. The present study investigates the toxicity of piperine via free-radical generation by determining the degree of lipid peroxidation and cellular thiol status in the rat intestine. Lipid peroxidation content, measured as thiobarbituric reactive substances (TBARS), was increased with piperine treatment although conjugate diene levels were not altered. A significant increase in glutathione levels was observed, whereas protein thiols and glutathione reductase activity were not altered. The study suggests that increased TBARS levels may not be a relevant index of cytotoxicity, since thiol redox was not altered, but increased synthesis transport of intracellular GSH pool may play an important role in cell hemostasis and requires further study.

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Epithelial Cells; Free Radicals; Intestinal Mucosa; Lipid Peroxidation; Male; Piperidines; Polyunsaturated Alkamides; Rats; Sulfhydryl Compounds; Thiobarbituric Acid Reactive Substances

We compared neurotoxicity of piperine and low K+ on cultured cerebellar granule neurons. As considered from lactate dehydrogenase release and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide reduction, both piperine and shifting from high K+ (25 mM) to low K+ (5.4 mM) were cytotoxic to cerebellar granule neurons. Protein synthesis inhibitors, cycloheximide and anisomycin, and an endonuclease inhibitor, aurintricarboxylic acid, were protective against low K+-induced neuronal death whereas they were ineffective against that induced by piperine. D-alpha-tocopherol, trolox, and a spin trap 3,3,5,5-tetramethyl-1-pyrroline-1-oxide were protective against piperine neurotoxicity whereas they had no effect on that induced by low K+. These results suggest that piperine and low K+ may exert neurotoxic effects on cerebellar granule neurons through different mechanisms. Death of cerebellar granule neurons induced by piperine may be mediated by non-apoptotic mechanisms and may involve membrane lipid peroxidation and/or free radical generation.

Topics: Alkaloids; Animals; Anisomycin; Aurintricarboxylic Acid; Benzodioxoles; Cell Death; Cells, Cultured; Cerebellum; Chromans; Cyclic N-Oxides; Cycloheximide; Free Radical Scavengers; Kinetics; L-Lactate Dehydrogenase; Neurons; Piperidines; Polyunsaturated Alkamides; Potassium; Protein Synthesis Inhibitors; Rats; Rats, Wistar; Spin Labels; Vitamin E

Piperine, [1-[5-[1,3-benzodioxol-5-yl]-1-oxo-2,4, pentadienyl] piperidine], is a pungent alkaloid present in Piper nigrum Linn, and P. longum Linn. It is shown to enhance the bioavailability of various structurally and therapeutically diverse drugs. A concise mechanism responsible for its bioavailability enhancing action is poorly understood. This study is an effort to understand the absorption dynamics of piperine in intestine on oral absorption. It encompasses intestinal everted sacs as an experimental model. Cycloheximide treatment and exclusion of Na+ salts from incubating medium were the variables used. Absorption half life, absorption rate, absorption clearance and apparent permeability co-efficient were computed from the data. Experiments to denote physico-chemical characteristics of this moiety exhibited that it is a weak base, highly lipophilic in nature with partial solubility in aqueous media. It exhibited passive diffusion constituting non-saturable absorption kinetics. Transport of piperine was not resisted by UWL and was proposed to be absorbed through transcellular pathway. It displayed short absorption clearance and high apparent permeability co-efficient. Data thus obtained suggested that piperine is absorbed very fast across the intestinal barrier. It may act as an apolar molecule and form apolar complex with drugs and solutes. It may modulate membrane dynamics due to its easy partitioning thus helping in efficient permeability across the barriers.

Topics: Absorption; Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biological Availability; In Vitro Techniques; Intestinal Absorption; Jejunum; Permeability; Piperidines; Polyunsaturated Alkamides; Rats; Spices

To investigate the role of trigeminal subnucleus caudalis in neural mechanisms of irritation, we recorded single-unit responses to application of a variety of irritant chemicals to the tongue or ocular mucosa in thiopental-anesthetized rats. Recordings were made from wide dynamic range (WDR) and nociceptive-specific units in superficial layers of the dorsomedial caudalis (0-3 mm caudal to obex) responsive to mechanical stimulation and noxious heating of the ipsilateral tongue ("tongue" units) and from WDR units in ventrolateral caudalis (0-2 caudal to obex) responsive to mechanical and noxious thermal stimulation of cornea-conjunctiva and frequently also surrounding skin ("cornea-conjunctival" units). The following chemicals were delivered topically (0.1 ml) onto the dorsal anterior tongue or instilled into the ipsilateral eye: capsaicin (0.001-1% = 3.3 x 10(-2) to 3.3 x 10(-5) M), ethanol (15-80%), histamine (0.01-10% = 9 x 10(-1) to 9 x 10(-4) M), mustard oil (allyl-isothiocyanate, 4-100% = 4 x 10(-1) to 10 M), NaCl (0.5-5 M), nicotine (0.01-10% = 6 x 10(-1) to 6 x 10(-4) M), acidified phosphate buffer (pH 1-6), piperine (0.01-1% = 3.5 x 10(-2) to 3.5 x 10(-4) M), serotonin (5-HT; 0.3-3% = 1.4 x 10(-1) to 1.4 x 10(-2) M), and carbonated water. The dose-response relationship and possible tachyphylaxis were tested for each chemical. Of 32 tongue units, 31 responded to one or more, and frequently all, chemicals tested. The population responded to 75.3% of the various chemicals tested (

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Capsaicin; Conjunctiva; Cornea; Dose-Response Relationship, Drug; Electrophysiology; Ethanol; Ganglionic Stimulants; Histamine; Irritants; Male; Mouth Mucosa; Mustard Plant; Neurons; Nicotine; Piperidines; Plant Extracts; Plant Oils; Polyunsaturated Alkamides; Rats; Rats, Wistar; Reaction Time; Serotonin; Sodium Chloride; Solvents; Stimulation, Chemical; Tachyphylaxis; Tongue; Trigeminal Nuclei

Reactive oxygen species (ROS) and reactive metabolic intermediates generated from various chemical carcinogens are known to play an important role in cell damage and in the initiation and progression of carcinogenesis. Many radical scavengers, interestingly naturally occuring antioxidants have been found to be effective in inhibiting the induction of carcinogenesis by a wide variety of chemical carcinogens. Studies have also indicated that various spice principles form an important group as antioxidants. In the present study our goal was to investigate whether piperine an pungent principle of black and long peppers was able to inhibit or reduce the oxidative changes induced by chemical carcinogens in rat intestinal model. Carcinogenesis was initiated in intestinal lumen of male rats with 7,12,dimethyl benzanthracene, dimethyl amino-methyl azobenzene and 3-methyl cholenthrene. Oxidative alterations were assessed by determining thiobarbituric reactive substances, mainly malonaldehyde (as a measure of lipid peroxidation), thiol status and expression of gamma-GT and Na+-K+-ATPase activity in intestinal mucosa. Data indicated that carcinogens treatment induced GSH depletion with substantial increase in thiobarbituric reactive substances and enzyme activities. Piperine treatment with carcinogens resulted in inhibition of thiobarbituric reactive substances. It mediated a significant increase in the GSH levels and restoration in gamma-GT and Na+-K+-ATPase activity. The studies thus indicate a protective role of piperine against the oxidative alterations by carcinogens. It may be suggested that piperine modulates the oxidative changes by inhibiting lipid peroxidation and mediating enhanced synthesis or transport of GSH thereby replenishing thiol redox.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Alkaloids; Animals; Benzodioxoles; Carcinogens; Enzyme Inhibitors; gamma-Glutamyltransferase; Intestinal Mucosa; Male; Malondialdehyde; Methylcholanthrene; Oxidative Stress; p-Dimethylaminoazobenzene; Piperidines; Polyunsaturated Alkamides; Rats; Sodium-Potassium-Exchanging ATPase; Sulfhydryl Compounds; Thiobarbituric Acid Reactive Substances

The aim of this study was to investigate the perception of chemosensory irritation in the oropharyngeal region during the ingestion of irritants. In two experiments subjects sipped and swallowed small samples of an ascending concentration series of capsaicin or piperine and rated the intensity of sensations or irritation perceived at four locations: the anterior tongue, the posterior tongue, the roof of the mouth and the throat. Both experiments revealed that the responsiveness to irritation from capsaicin was significantly higher in the throat than at either the front or back of the tongue. There was no difference between irritation ratings for the throat and the roof of the mouth. Compared with capsaicin, the responsiveness to piperine was more uniform along the rostro-caudal axis; for example, irritation ratings for the throat were similar to those for the anterior tongue. These results support previous findings which indicated that the oral mucosae were not uniformly sensitive to chemical irritants, and suggest further that the throat, which is innervated by both the glossopharyngeal and vagus nerves, plays an important role in the perception of chemesthetic stimuli during ingestion.

Topics: Adult; Alkaloids; Benzodioxoles; Capsaicin; Chemoreceptor Cells; Female; Glossopharyngeal Nerve; Humans; Irritants; Male; Mouth; Perception; Pharynx; Piperidines; Polyunsaturated Alkamides; Tongue; Trigeminal Nerve

Both trigeminal and spinal ganglion neurons show a strong potentiation of responses to the irritant capsaicin in an acidic environment. The present study revealed that there is also a strong interaction between protons and piperine, another vanilloid irritant. We studied the mechanism of the interaction between protons and piperine. Whole-cell patch clamp recordings were performed on cultured adult rat trigeminal ganglion (TG) neurons voltage-clamped near their resting membrane potential (-60 mV). Piperine (10 microM) caused a sustained net inward current associated with either an increase or decrease in membrane conductance. When protons and piperine were co-applied, the membrane currents evoked in piperine-sensitive TG neurons far exceeded the algebraic sum of the responses to the two stimuli applied in isolation. Capsazepine blocked the response of TG neurons to piperine at both physiological and acidic pH. In the presence of capsazepine, responses to the mixture of piperine and protons resembled the response to the low pH stimulus applied alone. Capsazepine had no effect on the sustained proton-induced current. These findings suggest that protons enhance the piperine current by altering the vanilloid receptor/channel complex or increasing the length constant of the space clamp.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Binding, Competitive; Capsaicin; Female; Hydrogen-Ion Concentration; Male; Membrane Potentials; Neurons; Patch-Clamp Techniques; Piperidines; Polyunsaturated Alkamides; Protons; Rats; Rats, Sprague-Dawley; Trigeminal Ganglion

The effect of piperine on the fertilization of eggs with sperm was investigated in female hamsters. They were intragastrically treated with piperine at doses of 50 and 100 mg/kg BW from day 1 through day 4 of the oestrous cycle. During piperine treatment, these females were superovulated and artificially inseminated (AI) with spermatozoa from untreated male hamsters at 12 h after hCG injection. The fertilization and growth of embryos were examined at various times after AI. In control hamsters, the percent fertilization increased with time, from 27.4 +/- 3.3% at 9 h after AI to 75.3 +/- 9.6 at 24 h after AI. Administration of piperine to the superovulated animals markedly enhanced the percent fertilization at 9 h after AI. It was increased to 85.4 +/- 4.1 and 82.8 +/- 4.8% by piperine at doses of 50 and 100 mg/kg BW, respectively. However, examination of the embryos retrieved 48 h after AI revealed no differences in the stage of embryonic development among different groups of animals. The possibility that this effect was due to the direct action of vanillic acid, a major piperine metabolite, was tested in vitro. Direct exposure of spermatozoa to vanillic acid at doses 25-100 mg% did not significantly affect their motility, percent acrosome reaction or fertilizing ability. This suggests that the enhancement of fertilization by piperine treatment was not related to the secretion of vanillic acid into the oviduct.

Topics: Alkaloids; Animals; Benzodioxoles; Cricetinae; Embryonic and Fetal Development; Female; Insemination, Artificial; Male; Mesocricetus; Piperidines; Polyunsaturated Alkamides; Sperm Capacitation; Sperm-Ovum Interactions; Superovulation; Vanillic Acid

The present study investigated the selective cytotoxicity of piperine on cultured brain cells by using lactate dehydrogenase release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium reduction, and protein content assay. Exposure to piperine induced marked injuries on cultured hippocampal neurons whereas it induced only a marginal toxicity on cultured astrocytes. The mechanism of cytotoxicity in hippocampal neurons was studied by pharmacological methods. The membrane-permeable free radical scavengers, D-alpha-tocopherol and trolox, protected neurons from piperine toxicity whereas membrane-impermeable agents, superoxide dismutase and catalase, were ineffective. A lipoxygenase inhibitor, nordihydroguaiaretic acid, but not a cyclo-oxygenase inhibitor, indomethacin, attenuated piperine toxicity. We provide the first evidence that piperine induces selective neurotoxicity in vitro. Although the exact mechanism is still unclear, pharmacological evidence indicates the possible involvement of lipid peroxidation and the generation of free radicals, at least partly, through an arachidonate-lipoxygenase pathway.

Topics: Alkaloids; Animals; Astrocytes; Benzodioxoles; Cell Survival; Cells, Cultured; Free Radicals; Hippocampus; Lipid Peroxidation; Neurons; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

We have investigated the potential of piperine for inhibiting the activity of cytochrome P4502B1 and protecting against aflatoxin B1 (AFB1) in V79MZr2B1 (r2B1) cells, i.e. V79 Chinese hamster cells engineered for the expression of rat CYP4502B1. The cells were found to contain high activities of 7-methoxycoumarin demethylase (MOCD). Piperine inhibited MOCD in preparations of r2B1 cells with an IC50 of approximately 10 microM. The cells in culture dealkylated 7-methoxycoumarin (MOC) to 7-OH-coumarin linearly, at least for 12 h, where piperine produced concentration-dependent inhibition with IC50 < 30 microM. The time required for maximal inhibition was approximately 8 h with both 30 and 60 microM concentrations of piperine used. AFB1 at 0.1-20 microM caused a concentration dependent decrease in the amount of DNA and an increase in the formation of micronuclei (MN). The mycotoxin at 10 microM reduced DNA by approximately 30% and increased MN appearance by 20-fold against the background level of 7 MN per 500 nuclei. Piperine at 60 microM completely counteracted cytotoxicity and formation of MN by 10 microM AFB1 and reduced the toxic effects of 20 microM AFB1 by > 50%. The results suggest that: (i) Piperine is a potent inhibitor of rat CYP4502B1 activity; (ii) AFB1 is activated by r2B1 cells to cytotoxic and genotoxic metabolites; and (iii) piperine counteracts CYP4502B1 mediated toxicity of AFB1 in the cells and might, therefore, offer a potent chemopreventive effect against procarcinogens activated by CYP4502B1.

Topics: Aflatoxin B1; Alkaloids; Animals; Anticarcinogenic Agents; Antimutagenic Agents; Benzodioxoles; Carcinogens; Cricetinae; Cricetulus; Cytochrome P-450 CYP2B1; Dealkylation; DNA; Enzyme Inhibitors; Micronucleus Tests; Mutagens; Piperidines; Polyunsaturated Alkamides; Protein Synthesis Inhibitors; Rats; Tumor Cells, Cultured

Modulation of benzo(a)pyrene (BP) metabolism and regulation of CYP1A1 gene expression by piperine in 5L cells in culture was studied. Treatment of cultures with 60 microM piperine for different time periods inhibited metabolism of BP by 50% within 4-8 h. Piperine uptake in 5L cells attained saturation plateau at 8 h and this related with the maximal impairment of BP metabolism. Exposure of cell cultures to piperine for 24 h indicated activation of CYP1A1 gene transcription. There was a 10-fold increase in CYP1A1mRNA and an approximately 7-fold increase in arylhydrocarbon hydroxylase (AHH) activity, while treatment with benzanthacene (BA) increased CYP1A1mRNA by 86- and AHH by 56-fold. Combined treatment with BA plus piperine further increased CYP1A1mRNA contents by about 25%. The BA-inducible AHH activity, however, registered a decrease of about 45%. Piperine neither destroyed CYP1A1-protein nor affected the total cellular protein contents. Exposure of cultures to 0.01 to 3.0 microM trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene for 24 h reduced maximum cellular growth by about 50%. Piperine at 60 microM offered full protection against the diol cytotoxicity. The results, suggest that piperine mediated inhibition of the AHH activity and consequent suppression of the procarcinogen activation is the result of direct interaction of piperine with CYP1A1-protein and not because of down regulation of the CYP1A1 gene expression.

Topics: Alkaloids; Animals; Aryl Hydrocarbon Hydroxylases; Benzo(a)pyrene; Benzodioxoles; Biological Transport; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dihydroxydihydrobenzopyrenes; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Liver Neoplasms, Experimental; Piperidines; Polyunsaturated Alkamides; Rats; RNA, Messenger; Tumor Cells, Cultured

The fruits of Piper longum used in traditional remedies against intestinal distress have been tested for their efficacy against experimental caecal amoebiasis of rats. The ethanolic extract, hexane fraction, n-butanol soluble fraction exerted in vitro amoebicidal action at 1000 micrograms/mL and the chloroform fraction at 500 micrograms/mL. The ethanolic extract and piperine, a pure compound, from this plant material cured 90% and 40% of rats with caecal amoebiasis, respectively.

Topics: Alkaloids; Amebiasis; Animals; Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Entamoeba; Enzyme Inhibitors; Fruit; Humans; Medicine, Traditional; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Rats; Therapeutic Equivalency

In traditional Chinese medicine, a mixture of radish and pepper is used to treat epilepsy. The presumptive effectiveness of this prescription might be due to the anticonvulsant actions of the principal component of pepper, the alkaloid piperine (CAS 94-62-2). The effects of piperine on convulsions induced in mice by agonists at different excitatory amino acid receptor subtypes were studied. Piperine was shown to significantly block convulsions induced by intracerebroventricular injection of threshold doses of kainate, but to have no or only slight effects on convulsions induced by L-glutamate, N-methyl-D-aspartate or guanidinosuccinate. Piperine suspensions, injected intraperitoneally, 1 h before injection of the threshold intracerebroventricular dose of kainate for the induction of clonic convulsions (1 nmol), blocked these convulsions with an ED50 (and 95% confidence interval) of 46 (25-86) mg/kg. Although piperine did block convulsions, induced by kainate, the compound does not appear to act as a kainate receptor antagonist. Whole-cell currents induced by the application of kainate to spinal cord cells in primary dissociated cultures were not affected by co-application of piperine.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Excitatory Amino Acid Agonists; Female; Injections, Intraventricular; Kainic Acid; Male; Mice; Patch-Clamp Techniques; Piperidines; Polyunsaturated Alkamides; Seizures; Spinal Cord

1. Capsaicin, piperine, and zingerone are natural pungent-tasting compounds found in chili pepper, black pepper, and ginger, respectively. These structurally related compounds evoke many of the same physiological responses, but at comparable concentrations capsaicin produces complete tachyphylaxis, piperine produces partial tachyphylaxis, and zingerone can either induce or not induce tachyphylaxis. Whole cell patch-clamp studies were performed on rat trigeminal ganglion cells to determine the similarities and differences between these three pungent compounds. 2. Capsaicin (1 microM) activated a variety of inward currents having peak times ranging from 2 to 46 s that desensitized to various extents ranging from 0 to 100%. The inward currents activated by zingerone (30 mM) had peak times of approximately 2 s and all currents exhibited marked desensitization. The inward currents activated by piperine (100 microM) had peak times of approximately 25 s and all exhibited a small desensitization. 3. Piperine- and zingerone-induced currents were found only in cells that could be activated by capsaicin. 4. Capsazepine (10 microM), an established antagonist of capsaicin-induced currents, inhibited the currents evoked by piperine and zingerone, suggesting that all three compounds activate vanilloid receptors. 5. Dose-response relationships for capsaicin, piperine, and zingerone obtained at a holding potential of -60 mV had threshold and apparent dissociation constants of 0.1 and 0.68 microM, 3 and 35 microM, and 1 and 15 mM, respectively. These values were consistent with those previously obtained in behavioral studies. 6. After seven 30-s applications of 1 microM capsaicin or 100 microM piperine (in a buffer with 2 mM Ca2+), each interspersed with 2-min, 50-s washes, the peak currents were inhibited by approximately 60 and 40%, respectively. In contrast, 30 mM zingerone failed to evoke a current after six applications. After complete tachyphylaxis produced by 30 mM zingerone, 1 microM capsaicin failed to evoke a current, suggesting that these two compounds cross desensitize. 7. The similar physiological responses produced by these three compounds can be rationalized by their binding to receptors and activating currents that can all be inhibited by capsazepine. Their different physiological responses evoked by these compounds can be rationalized, in part, by their very different activation and desensitization kinetics, and perhaps by the existence of different subtyp

Topics: Alkaloids; Animals; Benzodioxoles; Biotransformation; Calcium; Capsaicin; Cells, Cultured; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Guaiacol; Ion Channels; Neurons; Patch-Clamp Techniques; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptors, Drug; Structure-Activity Relationship; Tachyphylaxis; Trigeminal Ganglion

Piperine (CAS 94-62-2) is a constituent of various spices and is used as a common food additive all over the world. The genotoxic potential of piperine was assessed using four different test systems, namely, Ames test using Salmonella typhimurium, micronucleus test, sperm shape abnormality test and dominant lethal test using Swiss albino mice. In the Ames test, six different doses of piperine, in the range of 0.005-10 mumol/plate, did not induce his+ revertants, with or without metabolic activation, indicating its nonmutagenic nature. In the bone narrow micronucleus test using two doses in the range of therapeutic usage (10 and 20 mg/kg body weight), piperine itself was non-mutagenic. Like in somatic cells, piperine (10 and 50 mg/kg body weight) failed to induce mutations in male germ cells of mouse as assessed by using the sperm shape abnormality and dominant lethal tests. Piperine thus appears to be a non-genotoxic chemical.

Topics: Alkaloids; Animals; Benzodioxoles; Bone Marrow; Bone Marrow Cells; Genes, Lethal; Germ Cells; Histidine; Male; Mice; Micronucleus Tests; Mutagenicity Tests; Mutagens; Piperidines; Polyunsaturated Alkamides; Salmonella typhimurium; Spermatozoa

A quantitative method has been developed for the determination of piperylpiperidine in Wuwei Qingzhuo powder by reversed phase HPLC. The average recovery is 102.0% (RSD = 0.46%) and lowest detection concentration 0.03 microgram/ml. The linear range of piperylpiperidine is 1.875-30 micrograms/ml, r = 0.9999.

Topics: Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Drug Combinations; Drugs, Chinese Herbal; Piperidines; Polyunsaturated Alkamides; Powders

The effect of piperine on CCl4-induced hepatotoxicity was investigated in rats. Piperine pretreatment potentiated the hepatotoxicity of CCl4 in a dose-dependent manner. The maximum potentiation occurred when piperine at a dose of 100 mg/kg BW was intragastrically administered 4 h prior to an intraperitoneal injection of CCl4, at which time the activities of plasma glutamic pyruvic transaminase (PGPT) and plasma glutamic oxaloacetic transaminase (PGOT) were elevated by 70-80%. Concurrent with the rise in PGPT and PGOT activities, the accumulation of hepatic triglyceride increased whereas the plasma level of triglyceride decreased. Piperine pretreatment also potentiated CCl4-induced lipid peroxidation in the liver. The extent of potentiation correlated well with the rise of hepatic enzyme activity in plasma. In the in vitro system in which the tissue was preincubated with piperine and CCl4 was added into the incubation medium, piperine also exhibited a concentration dependent potentiation on CCl4-induced lipid peroxidation and on the activity of NADPH-cytochrome c-reductase. The results indicated that piperine potentiated CCl4-induced hepatotoxicity by interacting with liver cells and increased the activity of NADPH-cytochrome c reductase. The increase in activity of this enzyme accelerated biotransformation of CCl4, thereby increasing lipid peroxidation and enhancing hepatotoxicity.

Topics: Alanine Transaminase; Alkaloids; Analysis of Variance; Animals; Aspartate Aminotransferases; Benzodioxoles; Carbon Tetrachloride; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Injections, Intraperitoneal; Lipid Peroxidation; Liver; Male; Microsomes, Liver; NADPH-Ferrihemoprotein Reductase; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Topics: Adenosine; Affinity Labels; Alkaloids; Animals; Antimalarials; Benzodioxoles; Benzoquinones; Biological Transport; Ciona intestinalis; Crithidia; Dilazep; Erythrocytes; Furosemide; HeLa Cells; Humans; Malaria, Falciparum; Phlorhizin; Piperidines; Plasmodium falciparum; Polyunsaturated Alkamides; Stereoisomerism; Thioinosine; Trichomonas vaginalis

1. Treatment of rat with piperine (PIP) (1.4 mmol/kg, 3 days ip injections) resulted in an approximate two-fold increase in total liver microsomal P450 content relative to that in uninduced animals. 2. 4-Nitrophenol and aniline hyroxylase activities in the hepatic microsomes prepared from rat treated with PIP decreased by 30 and 28% respectively as compared with control. Immunoblot analyses also revealed decreased P4502E1 levels in hepatic microsomes from PIP-treated animals. 3. In contrast with P4502E1 suppression, hepatic 2B1 and 2B2 levels were significantly increased in PIP-induced animals, as evidence by both metabolic activity and immunoblot analysis of the liver microsomal fractions. The rate of hexobarbital hydroxylase activity in microsomes from PIP-treated animals was markedly elevated and was inhibited by approximately 62% in the presence of monoclonal anti-P4502B IgG. Immunoblot analyses demonstrated that P4502B1 and 2B2 levels in hepatic microsomes from PIP-treated animals were comparable with those from phenobarbital-treated animals. 4. 7-Ethoxycoumarin deethylase activity was elevated approximately two-fold in PIP-induced animals and was 17% of that derived from 3-methylcholanthrene-induced animals. 7-ethoxycoumarin deethylase activity in PIP-induced hepatic microsomes was inhibited 63% in the presence of monoclonal anti-P4501A antibody. Immunoblot analysis confirmed the increase in P4501A levels by PIP, which was 15% of that in hepatic microsomes from 3-methylcholanthrene-induced animals. 5. PIP treatment failed to affect microsomal epoxide hydrolase (mEH) and glutathione S-transferases (GST) expression, as indicated by immunoblot analyses using polyclonal antibodies toward mEH and GST subunits Ya, Yb1, Yb2 and Yc. 6. These results demonstrate that PIP treatment suppressed P4502E1 expression and enhanced 2B and 1A expression, whereas this agent failed to affect hepatic mEH and GST expression.

Topics: 7-Alkoxycoumarin O-Dealkylase; Alkaloids; Aniline Hydroxylase; Animals; Aryl Hydrocarbon Hydroxylases; Benzodioxoles; Cytochrome P-450 CYP2E1; Cytochrome P-450 Enzyme System; Epoxide Hydrolases; Glutathione Transferase; Isoniazid; Male; Microsomes, Liver; Mixed Function Oxygenases; Oxidoreductases, N-Demethylating; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Steroid Hydroxylases

We studied the effect of piperine on the cytotoxicity and genotoxicity of aflatoxin B1 (AFB1) in rat hepatoma cells H4IIEC3/G-(H4IIE) using cellular growth and formation of micronuclei as endpoints. Piperine was earlier shown to inhibit cytochrome P-450-dependent aryl hydrocarbon hydroxylase and 7-methoxycoumarin demethylase activities in preparations of these cells with 1/2 maximum inhibition at 30-50 microM (Singh J. and Reen R.K., Current Science, 66, 365-369, 1994). The results of the present study showed that AFB1 inhibited the growth of H4IIE cells with an ED50 of 15 nM. Piperine markedly reduced the toxicity of the mycotoxin. Thus at 100 microM piperine largely restored the rate of growth of the cells. Likewise, piperine reduced the AFB1-induced formation of micronuclei in a concentration-dependent manner. Piperine itself was not toxic to the cells up to a concentration of almost 100 microM. The results suggest, that piperine is capable of counteracting AFB1 toxicity by suppressing cytochromes P-450 mediated bioactivation of the mycotoxin.

Topics: Aflatoxin B1; Alkaloids; Animals; Benzodioxoles; Cell Death; Liver Neoplasms, Experimental; Micronucleus Tests; Piperidines; Polyunsaturated Alkamides; Rats; Tumor Cells, Cultured

The presence of piperine in a serum-free medium for 72 h markedly inhibited the neurite extension of cultured hippocampal and septal neurons under both high and low density cell culture conditions (initial cell density was 10(5) cells/cm2 and 2.5-5 x 10(3) cells/cm2, respectively). The average length of neurites decreased over a concentration range of piperine (12.5-100 microM), and the distribution of neurite population shifted towards the shorter neurite lengths whereas an increase in the soma size was observed only with high piperine concentrations (75 and 100 microM, in a high density cell culture). This indicates that the piperine effect was relatively selective to the neurite extension. The neurite extension in low density cell cultures was considerably more susceptible to piperine than that in high density cell cultures (hippocampus: EC50 = 39 versus 113 microM, septum: EC50 = 48 versus 101 microM, in the low and high density cell cultures, respectively). This difference may be due to a lack of neurotrophic supports from non-neuronal cells under the low density cell culture condition. These findings suggest that piperine, in addition to its cytotoxic effect on the neuronal survival, suppresses the neurite extension in developing neurons.

Topics: Alkaloids; Animals; Benzodioxoles; Cells, Cultured; Culture Media, Serum-Free; Hippocampus; Microtubule-Associated Proteins; Neurites; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Septum Pellucidum

The present study reveals that piperine, a pungent alkaloid present in various Piper species, is cytotoxic to cultured brain neurons. Exposure to piperine (12.5-100 microM) for 72 h caused a concentration-dependent reduction in the survival of primary cultured neurons from various regions of the embryonic rat brain under high density cell culture conditions. There were relative regional differences in the susceptibility to cytotoxic effects of piperine in which septum and hippocampus showed higher vulnerability among the eight regions. The primary cultures of septal and hippocampal neurons under low density cell culture condition were performed to evaluate the contribution of non-neuronal cells. The concentration-response profiles in both high and low density cell culture conditions were comparable (septum: EC50 = 43 and 27 microM, hippocampus: EC50 = 50 and 44 microM, under high and low density cell culture conditions, respectively) suggesting a minor role of non-neuronal cells on cytotoxicity of piperine to developing neurons.

Topics: Alkaloids; Animals; Benzodioxoles; Brain; Cell Survival; Cells, Cultured; Culture Media; Hippocampus; Neurons; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

The naturally occurring capsaicin-like molecules, resiniferatoxin (RTX, Euphorbia spp.) and piperine (Piper nigrum), each stimulated oxygen uptake (VO2) in association with increased vascular resistance in a concentration-dependent manner when infused into the perfused rat hindlimb. 5 microM glyceryl trinitrate (GTN, a nitrovasodilator) significantly blocked the oxygen and pressure responses to both RTX and piperine, indicating a close relationship between changes in VO2 and the vasoconstriction. Concentrations greater than those required for maximal VO2 resulted in an inhibition of VO2, although perfusion pressure continued to increase. Time course studies showed that both RTX and piperine at high doses resulted in a tri-phasic response. An initial phase of transient VO2 stimulation was followed by a second phase of inhibition. A third phase involving an often larger but transient stimulation of VO2 followed removal of the agents and continued after the pressure returned to basal. The actions of RTX and piperine were similar to those of other active capsaicin-like molecules tested previously in this system, including capsaicinoids (Capsicum spp.), gingerols (Zingiber officinale), and shogoals (Zingiber officinale). RTX was the most potent, and piperine the least potent of this series. Although receptor involvement has yet to be unequivocally established, the data are consistent with the presence of a functional capsaicin-like (vanilloid) receptor in the vasculature of the rat hindlimb that mediates vasoconstriction and oxygen uptake. These findings may have implications for the future development of thermogenic agents.

Topics: Alkaloids; Animals; Benzodioxoles; Capsaicin; Diterpenes; Hindlimb; Male; Nitroglycerin; Oxygen Consumption; Perfusion; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Taste responses of bullfrogs to various pungent compounds and taste substances were electrophysiologically recorded from glossopharyngeal nerves. The threshold concentrations were approximately 10(-7) M for piperine, approximately 10(-6) M for capsaicin and approximately 10(-4) M for allyl isothiocyanate. At any concentration examined, piperine was more potent than capsaicin. Both piperine and capsaicin elicited desensitizing responses, but the taste receptors recovered from the desensitization within 10 min after washing with deionized water. Cross-adaptation experiments revealed that capsaicin only partially desensitizes receptors for piperine, L-leucine, HCl or quinine. Perfusion of the lingual artery with a solution containing no added Ca decreased the responses to capsaicin. Such a solution has been shown to suppress the taste nerve responses by blocking synaptic transmissions between taste cells and taste nerves [8]. These results suggest that the gustatory effects of capsaicin are different from its pharmacological effects on sensory neurons. It is likely that capsaicin and other pungent compounds, when they act as seasonings, stimulate taste cells rather than the free nerve endings of the sensory neurons.

Topics: Adaptation, Physiological; Alkaloids; Animals; Benzodioxoles; Capsaicin; Chemoreceptor Cells; Electrophysiology; Glossopharyngeal Nerve; In Vitro Techniques; Isothiocyanates; Neurons, Afferent; Piperidines; Polyunsaturated Alkamides; Rana catesbeiana; Regional Blood Flow; Sensory Thresholds; Stimulation, Chemical; Taste; Tongue

Piperine, a major component of black pepper and long peppers, has been reported previously to have an effect on the activation and deactivation of some exogenous substances. In the present study, piperine was found to promote DNA damage and cytotoxicity induced by benzo[a]pyrene (B[a]P) in cultured V-79 lung fibroblast cells. The V-79 cells were treated with a non-toxic dose of piperine (1-20 microM) plus 10 microM B[a]P, or pretreated with piperine for 30 min or 2 hr prior to the administration of 10 microM B[a]P. B[a]P cytotoxicity was potentiated significantly by piperine under each experimental condition. The relative plating efficiency (RPE) was 71% when V-79 cells were exposed to 10 microM B[a]P alone. When the culture was exposed to B[a]P plus piperine or pretreated with piperine for 30 min prior to the administration of B[a]P, the RPE values were 63 and 44% (P < 0.001), respectively. Pretreatment with piperine for 2 hr had no significant effect (P > 0.05). Furthermore, the lowest activities (P < 0.05) of glutathione S-transferase (GST) and uridine diphosphate glucuronyl transferase (UDP-GTase) of piperine-treated V-79 cells occurred 30 min to 1 hr after the piperine pretreatment. Pretreatment of V-79 cells with piperine also caused an increase in the covalent binding of B[a]P-diol-epoxide to DNA, 2.3 times greater than that of the V-79 cells without piperine treatment. These results suggest that the promotion by piperine of B[a]P-induced cytotoxicity in V-79 lung fibroblast cells is due to mechanisms that decrease the activities of GST and UDP-GTase and increase the formation of a B[a]P-DNA adduct.

Topics: Alkaloids; Benzo(a)pyrene; Benzodioxoles; Cell Death; Cell Line; DNA; DNA Damage; Drug Synergism; Fibroblasts; Glucuronosyltransferase; Glutathione Transferase; Kinetics; Lung; Piperidines; Polyunsaturated Alkamides

The influence of piperine on the enzymes and bioenergetic functions in isolated rat liver mitochondria and hepatocytes was studied. Piperine at lower concentrations (< 50 microM) did not affect the RCR and ADP:O ratios, state 4 and 3 respirations supported by site-specific substrates, viz. glutamate+malate, succinate, and ascorbate+TMPD. The site-specific effects became significantly apparent only at higher concentrations. Only the state 3 respiration supported by NAD-linked substrates was impaired equipotently in mitochondria and permeabilized hepatocytes; the effect appeared to be localized at energy-coupling site 1. In hypotonic treated mitochondria, respiration supported by three kinds of substrates was not affected. Among the respiratory chain-linked enzymes, the activity of NADH-dehydrogenase registered a significant decrease of about 25, 42, and 53% at 100, 150, and 180 microM piperine, respectively. The activity of Mg(++)-ATPase, however, was stimulated at concentrations above 150 microM. Among the matrix enzymes, only malate and succinate dehydrogenases were studied. Malate dehydrogenase only showed a strong concentration-related inhibition in both the forward and backward directions. Enzyme kinetics indicated noncompetitive inhibition with a very low Ki of 10 microM. The presence of unsaturated double bonds in the side chain of piperine appeared essential for producing this strong inhibition. The studies suggested that piperine produces concentration related site-specific effects on mitochondrial bioenergetics and enzymes of energy metabolism.

Topics: Alkaloids; Animals; Benzodioxoles; Electron Transport; Energy Metabolism; In Vitro Techniques; Liver; Male; Mitochondria, Liver; Oxidation-Reduction; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Substrate Specificity

Piperine, an active alkaloidal constituent of the extract obtained from Piper longum and Piper nigrum, was evaluated for its antihepatotoxic potential in order to validate its use in traditional therapeutic formulations. This plant principle exerted a significant protection against tert-butyl hydroperoxide and carbon tetrachloride hepatotoxicity by reducing both in vitro and in vivo lipid peroxidation, enzymatic leakage of GPT and AP, and by preventing the depletion of GSH and total thiols in the intoxicated mice. Silymarin, a known hepatoprotective drug was tested simultaneously for comparison. Piperine showed a lower hepatoprotective potency than silymarin.

Topics: Alkaloids; Animals; Benzodioxoles; Liver; Male; Mice; Piperidines; Polyunsaturated Alkamides; Silymarin; Vegetables

Topics: Alkaloids; Animals; Antiprotozoal Agents; Benzodioxoles; Leishmania donovani; Piperidines; Polyunsaturated Alkamides

The effects of piperine, a major ingredient of black pepper, on UDP-glucose dehydrogenase (UDP-GDH) and glucuronidation potentials of rat and guinea pig liver and intestine were studied. Piperine caused a concentration-related strong inhibition of UDP-GDH (50% at 10 microM) reversibly and equipotently, in both tissues. Partially purified rat liver UDP-GDH was used to obtain the kinetic values at pH optima of 9.4 and 8.6. At pH 9.4: KmUDP-glucose = 15 microM, Vmax = 5.2 nmol NADH/min/mg protein, Ki = 6 microM. With NAD, a Ki of 16 microM was obtained. At pH 8.6: Km = 35 microM, Vmax = 7.5 nmol, Ki = 15 microM. In all of these cases, piperine caused non-competitive inhibition. Data from structure-activity comparisons of piperine analogs indicated that the presence of conjugated double bonds in the side chain of the molecule is a factor in piperine inhibition. However, the UDP-glucuronic acid (UDPGA) contents were decreased less effectively by piperine in isolated rat hepatocytes compared with enterocytes of guinea pig small intestine. Piperine at 50 microM caused a marginal decrease of UDPGA in hepatocytes when the rate of glucuronidation of 3-hydroxybenzo[a]pyrene (3-OH-BP) decreased by about 40%. The decrease obtained at 10 microM piperine in intestinal cells was comparable to that obtained at 50-100 microM in hepatocytes. UDP-glucuronosyltransferase (UGT) activities towards 3-OH-BP (UGT1A1) and 4-OH-biphenyl (UGT2B1) were also determined. Piperine did not affect the rate of glucuronidation of 4-OH-biphenyl in rat liver, whereas that of 3-OH-BP was impaired significantly. In guinea pig small intestine, both these activities were inhibited significantly requiring less than 25 microM piperine to produce a more than 50% inhibition of UGT(s). The results suggested that (i) piperine is a potent inhibitor of UDP-GDH, (ii) inhibition is offered exclusively by the conjugated double bonds of the molecule, and (iii) piperine exerts stronger effects on intestinal glucuronidation than in rat liver.

Topics: Alkaloids; Animals; Benzodioxoles; Cells, Cultured; Glucuronidase; Guinea Pigs; Intestine, Small; Kinetics; Liver; Male; Microsomes, Liver; Piperidines; Polyunsaturated Alkamides; Rats; Structure-Activity Relationship; Uridine Diphosphate Glucose Dehydrogenase

Carrageenin induced rat paw oedema shows a direct co-relationship with liver lipid peroxidation and not with kidney or brain. Pretreatment with piperine or oxyphenylbutazone reduced the liver lipid peroxidation, acid phosphatase and oedema induced by carrageenin. However, no such co-relationship was observed with treatment of these anti-inflammatory agents in control animals. It is, therefore, suggested that the inhibition of these liver enzymes is non specific in nature.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Carrageenan; Inflammation; Lipid Peroxidation; Piperidines; Polyunsaturated Alkamides; Rats

The effect of piperine (1-[5-(1,3-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]piperidin e), (from Piper nigrum) on the absorptive function of the intestine was studied. In vitro experiments showed that piperine (25-100 microM) significantly stimulated gamma-glutamyl transpeptidase (gamma-GT, EC 2.3.2.2.) activity, enhanced the uptake of radiolabelled L-leucine, L-isoleucine and L-valine, and increased lipid peroxidation in freshly isolated epithelial cells of rat jejunum. The kinetic behaviour of gamma-GT towards substrate and acceptor altered in the presence of piperine. In the presence of benzyl alcohol, an enhanced gamma-GT activity due to piperine was maintained. These results suggested that piperine may interact with the lipid environment to produce effects which lead to increased permeability of the intestinal cells.

Topics: Alkaloids; Amino Acids; Animals; Benzodioxoles; Benzyl Alcohol; Benzyl Alcohols; Cell Membrane Permeability; Enzyme Activation; Epithelium; gamma-Glutamyltransferase; Intestines; Jejunum; Kinetics; Lipid Peroxidation; Piperidines; Polyethylene Glycols; Polyunsaturated Alkamides; Rats

In mice, injection of safrole, tannic acid or methylcholanthrene (MCA) during the preweaning period induced tumors in different organs. Safrole and tannic acid (constituents of black pepper) were weak carcinogens when compared with MCA which was used as a carcinogenic control substance. Force feeding of d-limonene (one of the pepper terpenoids) for a long time to the mice which were injected with any of the above 3 substances reduced their carcinogenic activity, while force feeding of piperine (one of black pepper alkaloids) was ineffective.

Topics: Alkaloids; Animals; Benzodioxoles; Carcinogenicity Tests; Carcinogens; Condiments; Cyclohexenes; Female; Hydrolyzable Tannins; Limonene; Male; Mice; Piperidines; Polyunsaturated Alkamides; Safrole; Terpenes

Piperine is the main pungent principle of pepper, a spice consumed by people all over the world. It is the trans-trans isomer of 1-piperoylpiperidine and contains the methylene dioxy moiety. It is known to give unidentified mutagenic products on reaction with nitrite. The nitrosation reaction of piperine is of concern as endogenous nitrosation could take place in the human stomach from ingested precursors, piperine and nitrite. Nitrites can be ingested directly by consuming cured foods or indirectly as nitrates, which could be converted to nitrites under appropriate conditions. We have nitrosated piperine using aqueous nitrous acid and have isolated and identified some N-nitroso and C-nitro compounds. Their isolation, characterization and potential mutagenicity has been discussed.

Topics: Alkaloids; Benzodioxoles; Mass Spectrometry; Mutagens; Nitrosation; Nitrous Acid; Piperidines; Polyunsaturated Alkamides

Piperine is known to modify the biotransformation of drugs. The effect of piperine on the metabolic activation and distribution of [3H]-aflatoxin B1 (AFB1) in rats has been described. Piperine markedly inhibited liver microsome-catalysed [3H]AFB1 binding to calf thymus DNA in vitro, in a dose dependent manner. Rats pretreated with piperine accumulated considerable [3H]AFB1 radioactivity in plasma and in the tissues examined as compared to the controls. However, piperine had no influence on hepatic [3H]AFB1-DNA binding in vivo, which could possibly be due to the null effect of piperine on liver cytosolic glutathione (GSH) 5-transferase activity. Piperine-treated rat liver microsomes demonstrated a tendency to enhance [3H]AFB1 binding to calf thymus DNA in vivo. The effect of piperine on AFB1 metabolism thus closely resembles the mode of action of SKF 525-A on biotransformation of foreign compounds.

Topics: Aflatoxin B1; Alkaloids; Animals; Benzodioxoles; Biological Availability; Biotransformation; Male; Microsomes, Liver; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Tissue Distribution; Tritium

The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline has been examined in a crossover study. Six subjects in each group received a single oral dose of propranolol 40 mg or theophylline (150 mg) alone or in combination with piperine 20 mg daily for 7 days. An earlier tmax and a higher Cmax and AUC were observed in the subjects who received piperine and propranolol. It produced a higher Cmax, longer elimination half-life and a higher AUC with theophylline. In clinical practice, the enhanced systemic availability of oral propranolol and theophylline could be exploited to achieve better therapeutic control and improved patient compliance.

Topics: Administration, Oral; Adolescent; Adult; Alkaloids; Benzodioxoles; Biological Availability; Drug Therapy, Combination; Humans; Middle Aged; Piperidines; Polyunsaturated Alkamides; Propranolol; Theophylline

The effect of piperine on the fertilizing ability of hamster sperm was investigated in vitro. Sperm were incubated in a capacitation medium for 3 h prior to co-incubation with hamster eggs in a fertilization medium for another 3 h. Addition of 0.18-1.05 mM piperine to the capacitation medium reduced both the percentage of eggs fertilized and the degree of polyspermia in a dose-dependent manner. When piperine was added to the fertilization medium alone, a significant reduction in fertilization was observed only at high doses (0.70-1.05 mM). The presence of piperine in the capacitation medium inhibited the acrosome reaction in a dose-dependent manner but had no effect on sperm motility, whether this was measured quantitatively or qualitatively. Piperine also inhibited the influx of calcium into sperm during capacitation. It is suggested that such an inhibition might be a major cause of a reduction of the acrosome reaction and the subsequent impairment of fertilizing ability of sperm.

Topics: Acrosome; Alkaloids; Animals; Benzodioxoles; Calcium; Cricetinae; Epididymis; Female; Fertilization in Vitro; Male; Mesocricetus; Piperidines; Polyunsaturated Alkamides; Sperm Capacitation; Sperm Motility; Spermatozoa

An i.p. administration of rats with piperine (100 mg/kg) and piperonyl butoxide (400 mg/kg) produced a significant decrease in hepatic cytochrome P-450, and activities of benzphetamine N-demethylase, aminopyrine N-demethylase and aniline hydroxylase 1 hr after the treatment. Twenty-four hr later, these parameters along with cytochrome b5 and NADPH-cytochrome c reductase remained depressed only in piperine-treated rats. In contrast, piperonyl butoxide caused a significant induction of these parameters with the exception of cytochrome b5 and aminopyrine N-demethylase, which were up by 36 and 33% over their respective controls but not significantly. These results point up that effect of piperine on hepatic mixed-function oxidases is monophasic while that of piperonyl butoxide is biphasic.

Topics: Alkaloids; Animals; Benzodioxoles; Cytochrome P-450 Enzyme System; Liver; Male; Mixed Function Oxygenases; Piperidines; Piperonyl Butoxide; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains

In vitro and in vivo modulation of drug metabolizing enzymes by piperine was investigated in microsomes of rats and guinea pigs. In vitro piperine caused concentration related inhibition (50% at 100 microM) of arylhydrocarbon hydroxylase (AHH) and 7-ethoxycourmarin deethylase (7ECDE) activities, which were comparable in control and 3-methylcholanthrene (3MC) treated rats. In guinea pig microsomes however, piperine caused strong inhibition at lower concentrations (35% at 10 microM) and relatively much lesser inhibition with further increase in piperine concentrations. A Dixon plot of the kinetic data of both AHH and 7ECDE indicated noncompetitive inhibition with a Ki of approx. 100 microM. In vivo, piperine given at a dose of 25 mg/kg body wt to rats caused a maximal inhibition at 1 hr of both the enzymes, while only AHH returned to normal value within 4 hr. Similarly, upon daily treatment of piperine (15 mg/kg body wt) to rats for 7 days, 7ECDE was consistently inhibited, while AHH showed faster recovery. Piperine thus appeared to cause differential inhibition of two forms of cytochrome P450 and thus would accordingly affect the steady-state level of those drugs metabolized by these pulmonary forms of cytochromes P450.

Topics: Alkaloids; Animals; Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Guinea Pigs; Lung; Male; Piperidines; Polyunsaturated Alkamides; Rats

Piperine, a major pungent constituent of black and red peppers, was administered to rats intragastrically and intraperitoneally to study whether it alters the activities of hepatic mixed-function oxidases (MFO) and serum enzymes as specific markers of hepatotoxicity. An intragastric dose of 100 mg/kg of piperine to adult, male Sprague-Dawley rats caused an increase in hepatic microsomal cytochrome P-450 and cytochrome b5, NADPH-cytochrome c reductase, benzphetamine N-demethylase, aminopyrine N-demethylase and aniline hydroxylase 24 h following treatment. On the other hand, a 10 mg/kg dose given i.p. exhibited no effect on the activities of the aforementioned parameters of the hepatic drug-metabolizing enzyme system. However, when the intragastric and intraperitoneal doses were increased to 800 mg/kg and 100 mg/kg, respectively, the black pepper alkaloid produced a significant decrease in the levels of cytochrome P-450, benzphetamine N-demethylase, aminopyrine N-demethylase and aniline hydroxylase 24 h after treatment. None of the treatments significantly elevated the activities of serum sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and isocitrate dehydrogenase (ICD), suggesting that piperine is not a hepatotoxic agent.

Topics: Alkaloids; Animals; Benzodioxoles; Injections, Intraperitoneal; Liver; Male; Microsomes, Liver; Mixed Function Oxygenases; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Stomach

Human red cells infected in vitro with Plasmodium falciparum showed a significant increase in the rate of both ouabain-sensitive and ouabain-insensitive 86Rb+ influx. The increase in ouabain-insensitive 86Rb+ influx was due, in part, to increased transport via a bumetanide-sensitive system and, in part to transport via a pathway that was absent (or at least inactive) in uninfected cells. The parasite-induced pathway was inhibited by piperine and had a dose response very similar to that of the Gardos channel of uninfected cells but was less sensitive than the Gardos channel to inhibition by quinine.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Transport; Bumetanide; Dose-Response Relationship, Drug; Erythrocytes; Humans; In Vitro Techniques; Malaria; Ouabain; Piperidines; Polyunsaturated Alkamides; Potassium; Quinine; Rubidium Radioisotopes

1. The effects of some naturally occurring pungent substances, piperine, mustard oil, eugenol and curcumin, were compared to those of capsaicin in the rat isolated urinary bladder. 2. All test compounds dose-dependently contracted the rat bladder and produced desensitization toward capsaicin (1 mumol/l). Development of cross-tachyphylaxis among the natural pungent substances on one hand and capsaicin on the other, suggested a common site of action on visceral primary afferents. 3. Contractile responses to piperine, mustard oil and eugenol were partially tetrodotoxin and ruthenium red-sensitive, suggesting that activation of sensory terminals by these agents takes place indirectly, as well as by a direct action on sensory receptors. 4. The presence of the secondary acrylamide linkage (present in the backbone of capsaicin, but not in that of test compounds) does not appear to be essential to produce desensitization of sensory nerve terminals.

Topics: Alkaloids; Animals; Benzodioxoles; Capsaicin; Curcumin; Eugenol; In Vitro Techniques; Isothiocyanates; Male; Muscle Contraction; Mustard Plant; Nerve Endings; Neurons, Afferent; Piperidines; Plant Extracts; Plant Oils; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Ruthenium Red; Tetrodotoxin; Thiocyanates

Piperine (1 microM), a congener of capsaicin, produced an initial contraction blocked the capsaicin-sensitive contractile response to mesenteric nerve stimulation and inhibited the twitch response induced by field stimulation in the isolated guinea-pig ileum. These three effects of piperine (1 microM) were rapidly desensitized and significantly antagonized by ruthenium red (0.5-1 microM), an inorganic dye known to antagonize the effects of capsaicin. The contractile effect of piperine was abolished by application of tetrodotoxin plus desensitization with substance P or by extrinsic denervation. The inhibitory effect of piperine (1 microM) on the twitch response was antagonized by desensitization with calcitonin gene-related peptide (CGRP). Moreover, cross-tachyphylaxis between piperine and capsaicin was observed, suggesting that a similar mechanism may be involved in the effects of these agents. The contractile effects induced by piperine (10 microM) and the subsequent inhibitory effects on the twitch response were not desensitized and largely persisted after extrinsic denervation. The contractile effects of piperine (10 microM) were not strongly inhibited by tetrodotoxin plus desensitization with substance P. It was concluded that the lower concentration of piperine caused contraction and inhibited the twitch responses by releasing substance P and CGRP, respectively, from sensory nerves, and blocked the response to mesenteric nerve stimulation by a mechanism similar to that of capsaicin. At higher concentrations, piperine had non-specific direct actions on the smooth muscle.

Topics: Alkaloids; Animals; Anticonvulsants; Atropine; Benzodioxoles; Calcitonin Gene-Related Peptide; Capsaicin; Electric Stimulation; Female; Guinea Pigs; Ileum; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Nerve Endings; Neurons, Afferent; Piperidines; Polyunsaturated Alkamides; Ruthenium Red; Substance P; Tachyphylaxis; Tetrodotoxin

Piperine (1-peperoyl piperidine) was isolated from Piper nigrum Linn for the evaluation of anti-inflammatory activity in rats. Different acute and chronic experimental models like carrageenin-induced rat paw edema, cotton pellet granuloma, and croton oil-induced granuloma pouch, were employed. Simultaneously, biochemical estimations were made to elucidate the underlying mechanism of the action. Piperine acted significantly on early acute changes in inflammatory processes and chronic granulative changes. It also acted partially through stimulation of pituitary adrenal axis. Exudative changes in both acute and chronic models, however, were insignificant.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Disease Models, Animal; Drug Evaluation, Preclinical; Granuloma; Inflammation; Male; Piperidines; Pituitary-Adrenal System; Polyunsaturated Alkamides; Rats

Topics: Alkaloids; Animals; Anti-Ulcer Agents; Benzodioxoles; Capsaicin; Diterpenes; Ethanol; Female; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Stomach Ulcer

Piperine (1-peperoyl piperidine), a major alkaloid isolated from Piper nigrum Linn, potentiated pentobarbitone sleeping time in dose dependant manner, with peak effect at 30 min. Blood and brain pentobarbitone levels were higher in piperine treated animals. Piperine treatment in rats, treated chronically with phenobarbitone, significantly potentiated pentobarbitone sleeping time, as compared to the controls. There was no alteration in barbital sodium sleeping time. It is possible that, piperine inhibits liver microsomal enzyme system and thereby potentiates the pentobarbitone sleeping time.

Topics: Alkaloids; Animals; Benzodioxoles; Drug Synergism; Hypnotics and Sedatives; Male; Microsomes, Liver; Pentobarbital; Piperidines; Polyunsaturated Alkamides; Rats; Sleep

Piperine as well as capsaicin showed positive chronotropic and inotropic effects in the isolated spontaneously beating right atria and electrically driven left atria of rats, respectively. The responses to piperine were not affected by the presence of the antagonists to norepinephrine, acetylcholine, histamine and serotonin. However, once the tissue was pretreated with piperine or capsaicin, the response to subsequent application of piperine was reduced significantly. Both positive chronotropic and inotropic effects of capsaicin were also attenuated after the tissue was treated with piperine or capsaicin. Thus, not only a tachyphylaxis to either piperine or capsaicin itself but also a cross-tachyphylaxis between piperine and capsaicin developed. Nonadrenergic noncholinergic calcitonin gene-related peptide (CGRP)-like immunoreactive nerves were distributed in the muscle layers of both atria. CGRP-like immunoreactivity was depleted considerably by treatment of the tissue with piperine or capsaicin. When endogenous CGRP was depleted, although the positive chronotropic and inotropic effects of piperine and capsaicin were abolished, the effects of CGRP and isoproterenol were not affected. These results indicate that both piperine and capsaicin cause positive chronotropic and inotropic responses by releasing CGRP from nonadrenergic noncholinergic nerves, and that the development of cross-tachyphylaxis between piperine and capsaicin is due to the depletion of endogenous CGRP.

Topics: Alkaloids; Animals; Benzodioxoles; Calcitonin Gene-Related Peptide; Capsaicin; Dose-Response Relationship, Drug; Heart Rate; In Vitro Techniques; Isoproterenol; Male; Myocardial Contraction; Neuropeptides; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Stimulation, Chemical; Tachyphylaxis

The in vitro effects of piperine on three bioenergetic reactions namely, oxidative phosphorylation, ATPase activity and calcium transport by isolated rat liver mitochondria have been investigated. Piperine was found to inhibit state 3 and DNP-stimulated respiration by mitochondria respiring with glutamate plus malate or succinate as substrates. The I50 values of piperine on oxidative phosphorylation in the presence of glutamate plus malate and succinate were 22 and 12 micrograms/mg mitochondrial protein respectively. With HTM preparations, the oxidation of added NADH and succinate was depressed by piperine while ascorbate plus TMPD oxidation was slightly affected. Piperine did not inhibit the mitochondrial ATPase activity induced by DNP, but by itself exerted stimulating activity on this enzyme. Piperine was also found to diminish calcium uptake and to facilitate the release of accumulated calcium by the mitochondria incubated with succinate or ATP. These results suggest that piperine inhibits mitochondrial oxidative phosphorylation at the level of respiratory chain, and the inhibitory site(s) is in the segment(s) ahead of cytochrome C. The mechanism of the piperine-induced ATPase activity is not known; but the effect of piperine on calcium transport is likely to be consequential to the effects of this compound on the mitochondrial respiratory chain and ATPase activity.

Topics: 2,4-Dinitrophenol; Adenosine Triphosphatases; Alkaloids; Animals; Benzodioxoles; Biological Transport; Calcium; Dinitrophenols; Energy Metabolism; In Vitro Techniques; Male; Mitochondria, Liver; Oxygen Consumption; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains

Piperine, a major pungent agent of black peppers, induced both positive chronotropic and inotropic responses in the isolated atria of rats. These responses were not blocked by various antagonists but exhibited rapid tachyphylaxis. After exposure to piperine in vitro, endogenous calcitonin gene-related peptide (CGRP) was profoundly depleted from intracardiac nerves. These results suggest that piperine releases endogenous CGRP from intracardiac non-adrenergic non-cholinergic nerves and that released CGRP exerts positive chronotropic and inotropic effects.

Topics: Alkaloids; Animals; Benzodioxoles; Calcitonin Gene-Related Peptide; Heart Atria; In Vitro Techniques; Male; Myocardial Contraction; Neuropeptides; Peripheral Nerves; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains

Topics: Adolescent; Adult; Alkaloids; Benzodioxoles; Capsaicin; Female; Humans; Male; Mouth; Piperidines; Polyunsaturated Alkamides; Sensation; Time Factors; Tongue

We recently reported that capsaicin, a pungent principle of hot red pepper, evokes catecholamine secretion from the rat adrenal medulla. In this study, the effects of some pungent principles of spices on adrenal catecholamine secretion were investigated as compared with that of capsaicin. An increase in catecholamine, especially epinephrine, secretion was observed not only on capsaicin infusion but also on piperine (a pungent principle of pepper) and zingerone (ginger) infusion. Even on infusion of the same amount (650 nmol/kg, i.v.), the order of potency as to catecholamine secretion was capsaicin much greater than piperine greater than or equal to zingerone. While, sulfur-containing and volatile pungent principles, allylisothiocyanate (mustard, etc.) and diallyldisulfide (garlic, etc.), did not even cause slight catecholamine secretion. Furthermore, these adrenergic secretagogues were readily transported via the gut into the body. These results indicate that some pungent principles of dietary spices can induce a warming action via adrenal catecholamine secretion.

Topics: Adrenal Medulla; Alkaloids; Animals; Benzodioxoles; Capsaicin; Catecholamines; Condiments; Epinephrine; Guaiacol; Intestinal Absorption; Kinetics; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains

The influence of black pepper (Piper nigrum L.) and its active principle, piperine on the secretion and composition of bile was investigated in the rat. They were administered by gavage (black pepper at 250 or 500 mg and piperine at 12.5 or 25 mg/kg body wt.) or fed in the diet for 4 weeks (black pepper at 0.2 and 0.4%, piperine at 0.01 and 0.02%). The lower dose by gavage of black pepper caused an increase in bile solids while with other treatments bile secretion or dry matter in bile was not changed. Dietary feeding of black pepper caused an increase in bile flow with a concomitant decrease in bile solids -- a hydrocholagoguic effect. Cholesterol and bile acid output were not affected by black pepper or piperine at either level irrespective of the mode of administration; in contrast, the secretion of uronic acids in bile was enhanced by both levels of pepper as also of piperine indicating possible excretion of some of the components of black pepper or of piperine as glucuronides.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Bile; Cholesterol; Condiments; Diet; Male; Phospholipids; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Uronic Acids

Topics: Adult; Alkaloids; Anticonvulsants; Benzodioxoles; Drug Interactions; Humans; Male; Phenytoin; Piperidines; Polyunsaturated Alkamides

The irritative flavor compounds, capsaicin and piperine, were presented in sequence to the oral cavity of human subjects and rated for perceived intensity of irritation. Marked increases in perceived irritation were reported when the second-presented irritant differed from the first, as compared with control conditions in which the same irritant was repeated. This cross-enhancement is explained most simply by recruitment of additional receptors or fiber types, and implies a greater degree of specificity (narrowness of tuning) of trigeminal receptors than previously suggested by desensitization studies.

Topics: Alkaloids; Benzodioxoles; Capsaicin; Drug Administration Schedule; Drug Synergism; Humans; Irritants; Mouth; Piperidines; Polyunsaturated Alkamides

Pretreatment of adult male albino rats with piperine did not induce cytochrome P-450 whereas safrole did cause such induction. Piperine and safrole interacted with different forms of cytochrome P-450 as indicated by their in vivo effect on drug metabolising enzymes and mixed function oxidases and electrophoretic patterns. Incubation of piperine or safrole with dithionite- or NADPH-reduced microsomes from untreated rats resulted in a modified type II difference spectrum with an absorption maximum at 427 nm and a trough at 408 nm.

Topics: Alkaloids; Animals; Benzodioxoles; Cytochrome P-450 Enzyme System; Electrophoresis, Polyacrylamide Gel; Male; Microsomes, Liver; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Safrole

After oral administration of piperine (170 mg/kg) to rats, the metabolites in bile and urine were examined by thin-layer chromatography, high-performance liquid chromatography and combined gas chromatography-mass spectrometry. Four metabolites of piperine, viz. piperonylic acid, piperonyl alcohol, piperonal and vanillic acid were identified in the free form in 0-96 h urine whereas only piperic acid was detected in 0-6 h bile. Based on these results, a pathway for the biotransformation of piperine in rats is proposed.

Topics: Alkaloids; Animals; Benzodioxoles; Bile; Biotransformation; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Safrole

Piperine (1-peperoyl piperidine), a major component of the Piper species was reported recently by us to inhibit the activities of rat hepatic monooxygenases and UDP-glucuronyltransferase. This study explores further the basis of inhibition of glucuronidation. The effect of piperine on the rate of glucuronidation of 3-hydroxybenzo(a) pyrene and UDP-glucuronic acid content in the intact isolated epithelial cells of the guinea-pig small intestine was studied. The cells offered a fairly good system to study the modulation of glucuronidation activity. Glucuronidation of 3-hydroxybenzo(a) pyrene was dependent on the time of incubation, cellular protein and substrate concentration. From the kinetics of glucuronidation of 3-hydroxybenzo(a)pyrene in the isolated cell preparation the Vmax of 0.5 nmol of BP-3-glucuronide formed per min/mg of protein and Km of 25 microM were observed. The endogeneous concentration of UDP-glucuronic acid observed was 1.6 to 2.3 nmol/mg of cellular protein. Piperine caused a concentration-related decrease in UDP-glucuronic acid content and the rate of glucuronidation in the cells. It required much lower concentrations of piperine than D-galactosamine to diminish the endogeneous level of UDP-glucuronic acid. Rate of glucuronidation of 3-hydroxybenzo (a) pyrene was dependent on the endogeneous level of UDP-glucuronic acid. At 50 microM piperine, the rate of glucuronidation was reduced to about 50% of the basal rate. Piperine caused noncompetitive inhibition of hepatic microsomal UDP-glucuronyltransferase with Ki of 70 microM. The studies demonstrate that piperine modifies the rate of glucuronidation by lowering the endogeneous UDP-glucuronic acid content and also by inhibiting the transferase activity.

Topics: Alkaloids; Animals; Benzodioxoles; Benzopyrenes; Cell Survival; Epithelium; Galactosamine; Glucuronates; Glucuronosyltransferase; Guinea Pigs; In Vitro Techniques; Intestine, Small; Kinetics; Male; Piperidines; Polyunsaturated Alkamides; Uridine Diphosphate Glucuronic Acid; Uridine Diphosphate Sugars

Upon administration of piperine, the major bite factor of black pepper, to male albino rats at a dose of 30 mg (170 mg/kg) by gavage or 15 mg (85 mg/kg) intraperitoneally, about 97% was absorbed irrespective of the mode of dosing. Three per cent of the administered dose was excreted as piperine in the feces. Piperine was not detectable in urine. When everted sacs of rat intestines were incubated with 200-1000 micrograms of piperine, about 47-64% of the added piperine disappeared from the mucosal side. Only piperine was present in the serosal fluid and also the intestinal tissue, indicating that piperine did not undergo any metabolic change during absorption. Examination of the passage of piperine through the gut indicated that the highest concentration in the stomach and small intestine was attained at about 6 h. Only traces (less than 0.15%) of piperine were detected in serum, kidney and spleen from 30 min to 24 h. About 1-2.5% of the intraperitoneally administered piperine was detected in the liver during 0.5-6 h after administration as contrasted with 0.1-0.25% of the orally administered dose. The increased excretion of conjugated uronic acids, conjugated sulphates and phenols indicated that scission of the methylenedioxy group of piperine, glucuronidation and sulphation appear to be the major steps in the disposition of piperine in the rat.

Topics: Administration, Oral; Alkaloids; Animals; Benzodioxoles; Biotransformation; In Vitro Techniques; Injections, Intraperitoneal; Intestinal Absorption; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Tissue Distribution

Topics: Adult; Alkaloids; Benzodioxoles; Capsaicin; Citrates; Citric Acid; Humans; Piperidines; Polyunsaturated Alkamides; Quinine; Sodium Chloride; Sucrose; Taste; Water

Piperine, a major active component of black and long peppers, has been reported to enhance drug bioavailability. The present studies were aimed at understanding the interaction of piperine with enzymatic drug biotransforming reactions in hepatic tissue in vitro and in vivo. Piperine inhibited arylhydrocarbon hydroxylation, ethylmorphine-N-demethylation, 7-ethoxycoumarin-O-deethylation and 3-hydroxy-benzo(a)pyrene glucuronidation in rat postmitochondrial supernatant in vitro in a dose-dependent manner. Piperine inhibition of these reactions in postmitochondrial supernatant from 3-methylcholanthrene- and phenobarbital-treated rats was similar to the controls. Inhibition by piperine of arylhydrocarbon hydroxylase (AHH) from 3-methylcholanthrene-treated rats was comparable to that observed with 7,8-benzoflavone. Piperine caused noncompetitive inhibition of hepatic microsomal AHH from the untreated and 3-methylcholanthrene-treated rats with a Ki of 30 microM which was close to the apparent Km of AHH observed in the controls. Similarly, the kinetics of inhibition of ethylmorphine-N-demethylase from control rat liver microsomes exhibited noncompetitive inhibition with an apparent Km of 0.8 mM and Ki of 35 microM. These studies demonstrated that piperine is a nonspecific inhibitor of drug metabolism which shows little discrimination between different cytochrome P-450 forms. Oral administration of piperine in rats strongly inhibited the hepatic AHH and UDP-glucuronyltransferase activities. The maximal inhibition of AHH observed within 1 hr restored to normal value in 6 hr. Pretreatment with piperine prolonged hexobarbital sleeping time and zoxazolamine paralysis time in mice at half the dose of SKF-525A. These results demonstrate that piperine is a potent inhibitor of drug metabolism.

Topics: Alkaloids; Animals; Aryl Hydrocarbon Hydroxylases; Benzodioxoles; Biological Availability; Dose-Response Relationship, Drug; Ethylmorphine-N-Demethylase; Glucuronosyltransferase; Hexobarbital; Kinetics; Male; Mice; Microsomes, Liver; Paralysis; Pharmaceutical Preparations; Piperidines; Polyunsaturated Alkamides; Proadifen; Rats; Sleep; Zoxazolamine

Topics: Alkaloids; Animals; Benzodioxoles; Body Fluids; Chromatography, Thin Layer; Densitometry; Lipids; Male; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Spectrophotometry, Ultraviolet

Topics: Alkaloids; Animals; Benzodioxoles; Chiroptera; Electric Stimulation; Guinea Pigs; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Piperidines; Polyunsaturated Alkamides

Topics: Adult; Alkaloids; Benzodioxoles; Biological Availability; Female; Humans; Male; Middle Aged; Piperidines; Polyunsaturated Alkamides; Rifampin; Tuberculosis, Pulmonary

Convulsions of E1 mice were completely suppressed by 60 mg/kg of piperine injected intraperitoneally. The ED50 was 21.1 mg/kg. The brain 5-HT, dopamine and norepinephrine levels were estimated 1 hour after the intraperitoneal injection of piperine. The 5-HT level was significantly higher in the cerebral cortex of piperine treated mice than in control mice. This increase may be related directly to the mechanism of inhibition of convulsions by piperine. On the other hand, lower levels of 5-HT were observed in the hippocampus, midbrain and cerebellum. The dopamine level in the piperine treated mice was markedly higher only in the hypothalamus, while the norepinephrine levels were lower in every part of the brain.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Brain Chemistry; Catecholamines; Dopamine; Mice; Norepinephrine; Piperidines; Polyunsaturated Alkamides; Seizures; Serotonin

Topics: Alkaloids; Benzodioxoles; Carbohydrates; Cobalt Radioisotopes; Condiments; Food Irradiation; Food Microbiology; Piperidines; Polyunsaturated Alkamides

Aspergillus parasiticus Speare NRRL 2999 growth and aflatoxin production in black and white pepper and the penetration of the fungus in black pepper corn over various incubation periods were studied. Also, the effects of piperine and pepper oil on growth and aflatoxin production were studied. Under laboratory conditions, black and white pepper supported aflatoxin production (62.5 and 44 ppb (ng/g), respectively) over 30 days of incubation. Fungal growth measured in terms of chitin was considerably less in white pepper than in black pepper. A histological study of black pepper corn showed the fungus penetrating up to the inner mesocarp and establishing itself in the middle mesocarp. Piperine and pepper oil were found to inhibit fungal growth and toxin production in a dose-dependent manner. Thus, both black and white pepper could be considered as poor substrates for fungal growth and aflatoxin production.

Topics: Aflatoxin B1; Aflatoxins; Alkaloids; Aspergillus; Benzodioxoles; Carcinogens; Condiments; Piperidines; Polyunsaturated Alkamides

Oral irritation was induced by rinses with capsicum oleoresin and with piperine, constituents of red and black pepper, respectively. The perceived intensities of two concentrations of each of four tastants representing the four classical taste qualities were evaluated after rinsing with these irritants. Comparing taste intensity after rinses with capsicum and after control rinses with emulsifying agents or water, there were significant decrements in taste intensity of citric acid and quinine, and on one concentration of sucrose, but no effect on salt. The effects of piperine were more broad, with significant decrements in perceived intensity relative to emulsion controls for all substances.

Topics: Adult; Alkaloids; Benzodioxoles; Capsicum; Eating; Female; Humans; Irritants; Male; Piperidines; Plants, Medicinal; Polyunsaturated Alkamides; Taste; Taste Buds; Taste Threshold; Trigeminal Nerve

The intrathecal administration of capsaicin, a homovanillylamide derivative, has been demonstrated to cause analgesia in response to thermal stimuli. This analgesia has been correlated with a profound depletion of spinal substance P, a putative primary afferent transmitter. We studied the effects of capsaicin, a series of capsaicin analogues, piperine and kainic acid on the immunohistochemical staining of substance P, cholecystokinin, somatostatin, methionine-enkephalin and serotonin. Capsaicin and an analogue 1-nonenoyl-vanillylamide significantly elevated the tail flick latency and when the spinal cords of the rats were analyzed immunohistochemically, a profound depletion of substance P and cholecystokinin was observed. The spinal somatostatin-immunoreactivity of these rats was slightly reduced. Piperine also depleted substance P and reduced somatostatin staining but did not alter the staining intensity or density of cholecystokinin, methionine-enkephalin or serotonin. Kainate-depleted methionine-enkephalin but did not alter any other neuropeptides studied or serotonin. These results may indicate a link between capsaicin-induced analgesia and the concomitant depletion of cholecystokinin and substance P.

Topics: Alkaloids; Animals; Benzodioxoles; Capsaicin; Cholecystokinin; Enkephalin, Methionine; Fatty Acids, Unsaturated; Ganglia, Spinal; Kainic Acid; Male; Microscopy, Fluorescence; Nociceptors; Peptides; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Inbred Strains; Sensory Thresholds; Serotonin; Somatostatin; Substance P

Contraction of the isolated tracheal strip to capsaicin was prevented by chronic denervation of the tissue. Tetrodotoxin, hyoscine and hexamethonium caused no inhibition of the response, suggesting that tetrodotoxin-resistant terminal portions of non-cholinergic nerves were activated in this way. There was a strong correlation between the pain-producing and tracheoconstrictor effects of piperine, pungent and non-pungent capsaicin congeners. Common site of action was evidenced by crossed tachyphylaxis. It is concluded that the capsaicin-sensitive sensory nerve endings have a dual sensory-efferent function. Excitation-secretion coupling in this system could operate without an axon reflex.

Topics: Alkaloids; Animals; Benzodioxoles; Capsaicin; Denervation; Dose-Response Relationship, Drug; Drug Interactions; Guinea Pigs; Muscle, Smooth; Neuromuscular Junction; Pain; Piperidines; Polyunsaturated Alkamides; Tetrodotoxin; Trachea

Piperine is acutely toxic to mice, rats and hamsters. The LD50 values for a single i.v., i.p., s.c., i.g. and i.m. administration of piperine to adult male mice were 15.1, 43, 200, 330 and 400 mg/kg body wt, respectively. The i.p. LD50 value was increased to 60 mg/kg body wt in adult female and 132 mg/kg body wt in weanling male mice. In adult female rats, the i.p. LD50 value was 33.5 mg/kg body wt whereas the i.g. LD50 value was increased to 514 mg/kg body wt. Most animals given a lethal dose died of respiratory paralysis within 3-17 min. In subacute toxicity studies, the rats died within 1-3 days after treatment. Histopathologic changes included severe hemorrhagic necrosis and edema in gastrointestinal tract, urinary bladder and adrenal glands. Death of these animals may be attributable to multiple dysfunctions in their organs.

Topics: Adrenal Gland Diseases; Alkaloids; Animals; Benzodioxoles; Cricetinae; Female; Gastrointestinal Diseases; Intestine, Small; Lethal Dose 50; Male; Mesocricetus; Mice; Piperidines; Polyunsaturated Alkamides; Rats; Stomach; Time Factors; Urinary Bladder Diseases

Topics: Alkaloids; Benzodioxoles; Chromatography, High Pressure Liquid; Condiments; Piperidines; Polyunsaturated Alkamides

The antifertility activity of piperine was investigated in pregnant mice when given by various routes of administration and at different periods of gestation. Piperine effectively inhibited implantation, produced abortion and delayed labor when it was given from day 2 through 5, day 8 through 12 and day 15 until labor, respectively. At the same dose level which interrupts pregnancy, piperine did not affect the estrous cycle. Neither uterotropic, antiestrogenic nor antiprogestational property was observed. Additionally, piperine also inhibited uterine contraction both in vivo and in vitro. These results suggested that the antifertility activity of piperine did not operate through any hormonal actions or uterotonic activity.

Topics: Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Abortion, Spontaneous; Alkaloids; Animals; Benzodioxoles; Chemical Phenomena; Chemistry; Depression, Chemical; Embryo Implantation; Embryo Implantation, Delayed; Female; Fetal Death; In Vitro Techniques; Litter Size; Mice; Mice, Inbred Strains; Piperidines; Polyunsaturated Alkamides; Pregnancy; Pregnancy, Prolonged; Uterine Contraction

Experiments were conducted to evaluate the scientific basis of the use of the trikatu group of acrids (long pepper, black pepper and ginger) in the large number of prescriptions in Ayurveda. [3H] vasicine and [3H] sparteine were taken as test drugs. Piper longum (long pepper) increased the blood levels of vasicine by nearly 233%. Under the influence of piperine, the active principle of Piper species, sparteine blood levels increased more than 100%. The results suggest that these acrids have the capacity to increase the bioavailability of certain drugs. It appears that the trikatu group of drugs increase bioavailability either by promoting rapid absorption from the gastrointestinal tract, or by protecting the drug from being metabolised/oxidised in its first passage through the liver after being absorbed, or by a combination of these two mechanisms.

Topics: Abortifacient Agents; Alkaloids; Animals; Benzodioxoles; Biological Availability; Drug Synergism; Female; India; Medicine, Ayurvedic; Pharmaceutical Preparations; Phytotherapy; Piperidines; Plant Extracts; Plants, Medicinal; Polyunsaturated Alkamides; Quinazolines; Rats; Sparteine

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Dioxolanes; Mice; Piperidines; Polyunsaturated Alkamides; Rats; Seizures

Topics: Alkaloids; Benzodioxoles; Chemistry Techniques, Analytical; Condiments; Nitrates; Nitric Acid; Piperidines; Polyunsaturated Alkamides; Research

Topics: Alkaloids; Benzodioxoles; Humans; Irritants; Piperidines; Polyunsaturated Alkamides