stilbenes and epigallocatechin-gallate

Cancer is defined as the abnormal cell growth that can cause life-threatening malignancies with high financial costs for patients as well as the health care system. Natural polyphenols have long been used for the prevention and treatment of several disorders due to their antioxidant, anti-inflammatory, cytotoxic, antineoplastic, and immunomodulatory effects discussed in the literature; thus, these phytochemicals are potentially able to act as chemopreventive and chemotherapeutic agents in different types of cancer. One of the problems regarding the use of polyphenolic compounds is their low bioavailability. Different types of formulations have been designed for the improvement of bioavailability of these compounds, nanonization being one of the most notable approaches among them. This study aimed to review current data on the nanoformulations of natural polyphenols as chemopreventive and chemotherapeutic agents and to discuss their molecular anticancer mechanisms of action. Nanoformulations of natural polyphenols as bioactive agents, including resveratrol, curcumin, quercetin, epigallocatechin-3-gallate, chrysin, baicalein, luteolin, honokiol, silibinin, and coumarin derivatives, in a dose-dependent manner, result in better efficacy for the prevention and treatment of cancer. The impact of nanoformulation methods for these natural agents on tumor cells has gained wider attention due to improvement in targeted therapy and bioavailability, as well as enhancement of stability. Today, several nanoformulations are designed for delivery of polyphenolic compounds, including nanosuspensions, solid lipid nanoparticles, liposomes, gold nanoparticles, and polymeric nanoparticles, which have resulted in better antineoplastic activity, higher intracellular concentration of polyphenols, slow and sustained release of the drugs, and improvement of proapoptotic activity against tumor cells. To conclude, natural polyphenols demonstrate remarkable anticancer potential in pharmacotherapy; however, the obstacles in terms of their bioavailability in and toxicity to normal cells, as well as targeted drug delivery to malignant cells, can be overcome using nanoformulation-based technologies, which optimize the bioefficacy of these natural drugs.

Topics: Antineoplastic Agents; Antioxidants; Biological Availability; Catechin; Curcumin; Drug Delivery Systems; Humans; Nanocomposites; Nanoparticles; Neoplasms; Polyphenols; Quercetin; Resveratrol; Stilbenes

Non-alcoholic fatty liver disease (NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols (

Topics: Animals; Anthocyanins; Antioxidants; Carotenoids; Catechin; Coumestrol; Curcumin; Energy Metabolism; Fatty Liver; Glucosinolates; Humans; Imidoesters; Isothiocyanates; Lipogenesis; Mitochondria; Non-alcoholic Fatty Liver Disease; Nutritional Sciences; Oxidative Stress; Oximes; Polyphenols; Quercetin; Resveratrol; Stilbenes; Sulfoxides; Xanthophylls

In the recent years, polyphenols have gained significant attention in scientific community owing to their potential anticancer effects against a wide range of human malignancies. Epidemiological, clinical and preclinical studies have supported that daily intake of polyphenol-rich dietary fruits have a strong co-relationship in the prevention of different types of cancer. In addition to direct antioxidant mechanisms, they also regulate several therapeutically important oncogenic signaling and transcription factors. However, after the discovery of microRNA (miRNA), numerous studies have identified that polyphenols, including epigallocatechin-3-gallate, genistein, resveratrol and curcumin exert their anticancer effects by regulating different miRNAs which are implicated in all the stages of cancer. MiRNAs are short, non-coding endogenous RNA, which silence the gene functions by targeting messenger RNA (mRNA) through degradation or translation repression. However, cancer associated miRNAs has emerged only in recent years to support its applications in cancer therapy. Preclinical experiments have suggested that deregulation of single miRNA is sufficient for neoplastic transformation of cells. Indeed, the widespread deregulation of several miRNA profiles of tumor and healthy tissue samples revealed the involvement of many types of miRNA in the development of numerous cancers. Hence, targeting the miRNAs using polyphenols will be a novel and promising strategy in anticancer chemotherapy. Herein, we have critically reviewed the potential applications of polyphenols on various human miRNAs, especially which are involved in oncogenic and tumor suppressor pathways.

Topics: Catechin; Curcumin; Gene Expression Regulation, Neoplastic; Genistein; Humans; MicroRNAs; Neoplasms; Polyphenols; Resveratrol; Signal Transduction; Stilbenes

Fibrillar aggregates of human islet amyloid polypeptide, hIAPP, a pathological feature seen in some diabetes patients, are a likely causative agent for pancreatic beta-cell toxicity, leading to a transition from a state of insulin resistance to type II diabetes through the loss of insulin producing beta-cells by hIAPP induced toxicity. Because of the probable link between hIAPP and the development of type II diabetes, there has been strong interest in developing reagents to study the aggregation of hIAPP and possible therapeutics to block its toxic effects. Natural products are a class of compounds with interesting pharmacological properties against amyloids which have made them interesting targets to study hIAPP. Specifically, the ability of polyphenolic natural products, EGCG, curcumin, and resveratrol, to modulate the aggregation of hIAPP is discussed. Furthermore, we have outlined possible mechanistic discoveries of the interaction of these small molecules with the peptide and how they may mitigate toxicity associated with peptide aggregation. These abundantly found agents have been long used to combat diseases for many years and may serve as useful templates toward developing therapeutics against hIAPP aggregation and toxicity.

Topics: Catechin; Curcumin; Diabetes Mellitus, Type 2; Humans; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Resveratrol; Stilbenes

Epidemiological and laboratory data support the protective effects of bioactive nutrients in our diets for various diseases. Along with various factors, such as genetic history, alcohol, smoking, exercise, and dietary choices play a vital role in affecting an individual's immune responses toward a transforming cell, by either preventing or accelerating a neoplastic transformation. Ample evidence suggests that dietary nutrients control the inflammatory and protumorigenic responses in immune cells. Immunoprevention is usually associated with the modulation of immune responses that help in resolving the inflammation, thus improving clinical outcome. Various metabolic pathway-related nutrients, including glutamine, arginine, vitamins, minerals, and long-chain fatty acids, are important components of immunonutrient mixes. Epidemiological studies related to these substances have reported different results, with no or minimal effects. However, several studies suggest that these nutrients may have immune-modulating effects that may lower cancer risk. Preclinical studies submit that most of these components may provide beneficial effects. The present review discusses the available data, the immune-modulating functions of these nutrients, and how these substances could be used to study immune modulation in a neoplastic environment. Further research will help to determine whether the mechanistic signaling pathways in immune cells altered by nutrients can be exploited for cancer prevention and treatment.

Topics: Animals; Arginine; Catechin; Cell Line, Tumor; Diet; Disease Models, Animal; Fatty Acids, Unsaturated; Glutamine; Humans; Isothiocyanates; Lignans; Meta-Analysis as Topic; Micronutrients; Neoplasms; Observational Studies as Topic; Phytochemicals; Polyphenols; Randomized Controlled Trials as Topic; Stilbenes

Chemoprevention of human cancer by dietary products is a practical approach of cancer control, especially when chemoprevention is involved during the early stages of the carcinogenesis process. Research over the last few decades has clearly demonstrated the efficacy of dietary products for chemoprevention in cell culture and preclinical animal model systems. However, these in vitro and in vivo effects have not been able to be translated to bedside for clinical use. Among many reasons, inefficient systemic delivery and bioavailability of promising chemopreventive agents are considered to significantly contribute to such a disconnection. Since its advent in the field of cancer, nanotechnology has provided researchers with expertise to explore new avenues for diagnosis, prevention, and therapy of the disease. In a similar trait, we introduced a novel concept in which nanotechnology was utilized for enhancing the outcome of chemoprevention (Cancer Res. 2009; 69:1712-1716). This idea, which we termed as 'nanochemoprevention', was exploited by several laboratories and has now become an advancing field in chemoprevention research. This review summarizes some of these applications of nanotechnology in medicine, particularly focused on controlled and sustained release of bioactive compounds with emphasis on current and future utilization of nanochemoprevention for prevention and therapy of cancer.

Topics: Animals; Anticarcinogenic Agents; Biological Products; Catechin; Cell Line, Tumor; Chemoprevention; Curcumin; Disease Models, Animal; Humans; Nanoparticles; Nanotechnology; Neoplasms; Resveratrol; Stilbenes

Diet has been linked to an overwhelming proportion of cancers. Current chemotherapy and targeted therapies are limited by toxicity and the development of resistance against these treatments results in cancer recurrence or progression. In vitro evidence indicates that a number of dietary-derived agents have activity against a highly tumorigenic, chemoradiotherapy resistant population of cells within a tumour. This population is associated with cancer recurrence and is therefore clinically significant. Targeting this subpopulation, termed cancer stem-like cells with dietary-derived agents provides a potentially low toxicity strategy to enhance current treatment regimens. In addition, dietary-derived compounds also provide a novel approach to cancer prevention strategies. This review focusses on selected diet-derived agents that have been shown to specifically target cancer stem-like cells using in vivo models, or in clinical trials. Furthermore, the potential limitations of these studies are discussed, and areas of research that need to be addressed to allow successful translation of dietary-derived agents to the clinical arena are highlighted.

Topics: Animals; Anticarcinogenic Agents; Catechin; Cell Line, Tumor; Curcumin; Diet; Disease Models, Animal; Flavonoids; Humans; Isothiocyanates; Neoplasms; Neoplastic Stem Cells; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes; Sulfoxides; Vitamin A

Hepatocellular carcinoma (HCC) is an aggressive and life-threatening disease often diagnosed at intermediate or advanced stages, which substantially limits therapeutic approaches to its successful treatment. This indicates that the prevention of HCC may be the most promising strategy in reducing its incidence and mortality. Emerging evidence indicates that numerous nutrients and nonnutrient dietary bioactive components can reduce the occurrence and/or delay the development of HCC through modifications of deregulated epigenetic mechanisms. This review examines the existing knowledge on the epigenetic mechanism-based studies in in vitro and in vivo models of HCC on the chemopreventive potential of epigenetic food components, including dietary methyl-group donors, epigallocatechin-3-gallate, sodium butyrate, resveratrol, curcumin, and sulforaphane, on liver carcinogenesis. Future direction and potential challenges in the effective use of bioactive food constituents in the prevention of HCC are highlighted and discussed.

Topics: Animals; Butyric Acid; Carcinoma, Hepatocellular; Catechin; Cell Line, Tumor; Curcumin; Disease Models, Animal; DNA Methylation; Epigenesis, Genetic; Food; Humans; Isothiocyanates; Phytochemicals; Resveratrol; Stilbenes; Sulfoxides

The formation of blood capillaries to sustain development and growth of new tissues is referred to as angiogenesis. Angiogenesis is pivotal in both carcinogenesis and metastasis since capillaries are the sole source of supplying nutrients and oxygen to the proliferating tumor cells; therefore, this dependency of tumor growth on angiogenesis challenges researchers to halt tumor growth by targeting angiogenesis with the help of either synthetic or natural inhibitors. Many synthetic inhibitors of angiogenesis have not only come into force but also resulted in some severe adverse effects. Natural compounds may effectively fit into this condition and possibly decrease the time of treatment. In the recent past, literature is replete with evidences advocating the usefulness of natural compounds that target multiple biochemical pathways. The additional advantage of natural compounds is that their active principles interact with one another and work synergistically to give more meaningful and reliable effects than individual principle. Hence, if we are somehow able to combine more than two natural compounds, then it may be possible to enhance their potential by many folds, which shall prove to be very effective in combating tumor angiogenesis. This review shall discuss the concept of angiogenesis, molecular pathways, and angiogenic inhibitors and their specific targets and potential of natural compounds to greatly enhance the current knowledge of angiogenesis-inhibiting factors.

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Artemisinins; Catechin; Cell Proliferation; Curcumin; Humans; Neoplasms; Neovascularization, Pathologic; Plant Extracts; Resveratrol; Stilbenes; Triterpenes

Polyphenols, found abundantly in plants, display many anticarcinogenic properties including their inhibitory effects on cancer cell proliferation, tumor growth, angiogenesis, metastasis, and inflammation as well as inducing apoptosis. In addition, they can modulate immune system response and protect normal cells against free radicals damage. Most investigations on anticancer mechanisms of polyphenols were conducted with individual compounds. However, several studies, including ours, have indicated that anti-cancer efficacy and scope of action can be further enhanced by combining them synergistically with chemically similar or different compounds. While most studies investigated the anti-cancer effects of combinations of two or three compounds, we used more comprehensive mixtures of specific polyphenols and mixtures of polyphenols with vitamins, amino acids and other micronutrients. The mixture containing quercetin, curcumin, green tea, cruciferex, and resveratrol (PB) demonstrated significant inhibition of the growth of Fanconi anemia head and neck squamous cell carcinoma and dose-dependent inhibition of cell proliferation, matrix metalloproteinase (MMP)-2 and -9 secretion, cell migration and invasion through Matrigel. PB was found effective in inhibition of fibrosarcoma HT-1080 and melanoma A2058 cell proliferation, MMP-2 and -9 expression, invasion through Matrigel and inducing apoptosis, important parameters for cancer prevention. A combination of polyphenols (quercetin and green tea extract) with vitamin C, amino acids and other micronutrients (EPQ) demonstrated significant suppression of ovarian cancer ES-2 xenograft tumor growth and suppression of ovarian tumor growth and lung metastasis from IP injection of ovarian cancer A-2780 cells. The EPQ mixture without quercetin (NM) also has shown potent anticancer activity in vivo and in vitro in a few dozen cancer cell lines by inhibiting tumor growth and metastasis, MMP-2 and -9 secretion, invasion, angiogenesis, and cell growth as well as induction of apoptosis. The presence of vitamin C, amino acids and other micronutrients could enhance inhibitory effect of epigallocatechin gallate (EGCG) on secretion of MMPs. In addition, enrichment of NM with quercetin (EPQ mix) enhanced anticancer activity of NM in vivo. In conclusion, polyphenols, especially in combination with other polyphenols or micronutrients, have been shown to be effective against multiple targets in cancer development and progression, and s

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Biological Availability; Catechin; Cell Line, Tumor; Cell Proliferation; Curcumin; Disease Models, Animal; Humans; Micronutrients; Neoplasms; Plant Extracts; Polyphenols; Quercetin; Resveratrol; Stilbenes; Tea

Tocotrienol (T3), unsaturated vitamin E, is gaining a lot of attention owing to its potent anticancer effect, since its efficacy is much greater than that of tocopherol (Toc). Various factors are known to be involved in such antitumor action, including cell cycle arrest, apoptosis induction, antiangiogenesis, anti-metastasis, nuclear factor-κB suppression, and telomerase inhibition. Owing to a difference in the affinity of T3 and Toc for the α-tocopherol transfer protein, the bioavailability of orally ingested T3 is lower than that of Toc. Furthermore, cellular uptake of T3 is interrupted by coadministration of α-Toc in vitro and in vivo. Based on this, several studies are in progress to screen for molecules that can synergize with T3 in order to augment its potency. Combinations of T3 with chemotherapeutic drugs (e.g., statins, celecoxib, and gefitinib) or dietary components (e.g., polyphenols, sesamin, and ferulic acid) exhibit synergistic actions on cancer cell growth and signaling pathways. In this review, we summarize the current status of synergistic effects of T3 and an array of agents on cancer cells, and discuss their molecular mechanisms of action. These combination strategies would encourage further investigation and application in cancer prevention and therapy.

Topics: Antineoplastic Agents; Catechin; Coumaric Acids; Dietary Supplements; Dioxoles; Drug Synergism; Drug Therapy, Combination; Humans; Lignans; Neoplasms; Resveratrol; Stilbenes; Tocotrienols

Cancer remains a major health problem worldwide. Among many other factors, two regulatory defects that are present in most cancer cells are constitutive activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway and the induction of indoleamine 2, 3-dioxygenase (IDO), an enzyme that catalyzes tryptophan degradation, through JAK/STAT signaling. Cytokine signaling activates STAT proteins in regulating cell proliferation, differentiation, and survival through modulation of target genes. Many phytochemicals can inhibit both JAK/STAT signaling and IDO expression in antigen-presenting cells by targeting different pathways. Some of the promising phytochemicals that are discussed in this review include resveratrol, cucurbitacin, curcumin, (-)-epigallocatechin gallate, and others. It is now evident that phytochemicals play key roles in inhibition of tumor proliferation and development and provide novel means for therapeutic targeting of cancer.

Topics: Animals; Catechin; Cell Proliferation; Cucurbitacins; Curcumin; Disease Models, Animal; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Janus Kinases; Neoplasms; Phytochemicals; Resveratrol; Signal Transduction; STAT Transcription Factors; Stilbenes

Anti-oxidant compounds that are found in over-the-counter (OTC) supplements and foods are gaining interest as treatments for multiple sclerosis (MS). They are widely used by patients, sometimes without a clear evidence base.. We conducted a systematic review of animal and clinical research to determine the evidence for the benefits of OTC anti-oxidants in MS.. Using predefined criteria, we searched key databases. Two authors scrutinized all studies against inclusion/exclusion criteria, assessed study risk-of-bias and extracted results.. Of the 3507 titles, 145 met criteria and included compounds, α(alpha)-lipoic acid (ALA), anti-oxidant vitamins, Ginkgo biloba, quercetin, resveratrol and epigallocatechin-3-gallate (ECGC). The strongest evidence to support OTC anti-oxidants was for compounds EGCG and ALA in animal models; both consistently showed anti-inflammatory/anti-oxidant effects and reduced neurological impairment. Only vitamin E, Ginkgo biloba and ALA were examined for efficacy in pilot clinical trials with either conflicting evidence or evidence of no benefit.. OTC anti-oxidants EGCG and ALA show the most consistent benefit, however only in preclinical studies. There is no evidence that they alter MS relapses or progression. Future work should focus on testing more of these therapies for clinical efficacy before recommending them to MS patients.

Topics: Animals; Antioxidants; Catechin; Ginkgo biloba; Humans; Multiple Sclerosis; Nonprescription Drugs; Quercetin; Resveratrol; Stilbenes; Thioctic Acid

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

The prevalence of obesity has steadily increased over the past three decades both in the United States and worldwide. Recent studies have shown the role of dietary polyphenols in the prevention of obesity and obesity-related chronic diseases. Here, we evaluated the impact of commonly consumed polyphenols, including green tea catechins, especially epigallocatechin gallates, resveratrol and curcumin, on obesity and obesity-related inflammation. Cellular studies demonstrated that these dietary polyphenols reduce viability of adipocytes and proliferation of preadipocytes, suppress adipocyte differentiation and triglyceride accumulation, stimulate lipolysis and fatty acid β-oxidation, and reduce inflammation. Concomitantly, the polyphenols modulate signaling pathways including the adenosine-monophosphate-activated protein kinase, peroxisome proliferator activated receptor γ, CCAAT/enhancer binding protein α, peroxisome proliferator activator receptor gamma activator 1-alpha, sirtuin 1, sterol regulatory element binding protein-1c, uncoupling proteins 1 and 2, and nuclear factor-κB that regulate adipogenesis, antioxidant and anti-inflammatory responses. Animal studies strongly suggest that commonly consumed polyphenols described in this review have a pronounced effect on obesity as shown by lower body weight, fat mass and triglycerides through enhancing energy expenditure and fat utilization, and modulating glucose hemostasis. Limited human studies have been conducted in this area and are inconsistent about the antiobesity impact of dietary polyphenols probably due to the various study designs and lengths, variation among subjects (age, gender, ethnicity), chemical forms of the dietary polyphenols used and confounding factors such as other weight-reducing agents. Future randomized controlled trials are warranted to reconcile the discrepancies between preclinical efficacies and inconclusive clinic outcomes of these polyphenols.

Topics: Adipocytes; Animals; Catechin; Cell Differentiation; Curcumin; Diet; Humans; Obesity; Plant Extracts; Polyphenols; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes; Tea

Nanotechnology is an innovative approach that has potential applications in nutraceutical research. Phytochemicals have promising potential for maintaining and promoting health, as well as preventing and potentially treating some diseases. However, the generally low solubility, stability, bioavailability and target specificity, together with the side effects seen when used at high levels, have limited their application. Indeed, nanoparticles can increase solubility and stability of phytochemicals, enhance their absorption, protect them from premature degradation in the body and prolong their circulation time. Moreover, these nanoparticles exhibit high differential uptake efficiency in the target cells (or tissue) over normal cells (or tissue) through preventing them from prematurely interacting with the biological environment, enhanced permeation and retention effect in disease tissues and improving their cellular uptake, resulting in decreased toxicity, In this review, we outline the commonly used biocompatible and biodegradable nanoparticles including liposomes, emulsions, solid lipid nanoparticles, nanostructured lipid carriers, micelles and poly(lactic-co-glycolic acid) nanoparticles. We then summarize studies that have used these nanoparticles as carriers for epigallocatechin gallate, quercetin, resveratrol and curcumin administration to enhance their aqueous solubility, stability, bioavailability, target specificity and bioactivities.

Topics: Biological Availability; Catechin; Curcumin; Emulsions; Lactic Acid; Liposomes; Micelles; Nanoparticles; Nanotechnology; Phytochemicals; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Quercetin; Resveratrol; Solubility; Stilbenes

Melanoma is one of the deadliest forms of skin cancer, having a high metastatic potential and afflicting all age groups. The need for successful preventative measures is particularly urgent as metastatic melanoma is largely incurable. The beneficial role of nutrition and other natural compounds in the prevention and treatment of melanoma has been clearly demonstrated in the past, and is an exciting source for potential therapies in the future.. We sought to review updates in the current literature regarding new developments in the relationship between nutrition and melanoma risk and treatment.. Articles in the public domain regarding the impact of diet, grape seed proanthocyanidins, selenium, vitamin D, vitamin E, epigallocatechin-3-gallate, resveratrol, rosmarinic acid, lycopene, and fig latex on melanoma were included.. Grape seed proanthocyanidins, epigallocatechin-3-gallate, resveratrol, rosmarinic acid, lycopene, and fig latex have demonstrated clear anticancer effects toward melanoma. The roles of selenium, vitamin D, and vitamin E, however, have been more controversial.. None.. The role of natural compounds in the future of melanoma prevention and treatment is promising and one that is worthy of further exploration.

Topics: Antioxidants; Carotenoids; Catechin; Diet; Grape Seed Extract; Humans; Lycopene; Melanoma; Nutrition Policy; Proanthocyanidins; Resveratrol; Selenium; Skin Neoplasms; Stilbenes; Vitamin D; Vitamin E

It is becoming progressively more understandable that different phytochemicals isolated from edible plants interfere with specific stages of carcinogenesis. Cancer cells have evolved hallmark mechanisms to escape from death. Concordant with this approach, there is a disruption of spatiotemproal behaviour of signaling cascades in cancer cells, which can escape from apoptosis because of downregulation of tumor suppressor genes and over- expression of oncogenes. Genomic instability, intra-tumor heterogeneity, cellular plasticity and metastasizing potential of cancer cells all are related to molecular alterations. Data obtained through in vitro studies has convincingly revealed that curcumin, EGCG, resveratrol and quercetin are promising anticancer agents. Their efficacy has been tested in tumor xenografted mice and considerable experimental findings have stimulated researchers to further improve the bioavailability of these nutraceuticals. We partition this review into different sections with emphasis on how bioavailability of curcumin, EGCG, resveratrol and quercetin has improved using different nanotechnology approaches.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Antioxidants; Apoptosis; Catechin; Cell Proliferation; Cell Transformation, Neoplastic; Curcumin; Drug Carriers; Humans; Lactic Acid; Mice; Nanoparticles; Neoplasms; Phytochemicals; Polyglycolic Acid; Polyhydroxyethyl Methacrylate; Polylactic Acid-Polyglycolic Acid Copolymer; Quercetin; Resveratrol; Silicon Dioxide; Stilbenes; Xenograft Model Antitumor Assays

Many diseases have been described to be associated with inflammatory processes. The currently available anti-inflammatory drug therapy is often not successful or causes intolerable side effects. Thus, new anti-inflammatory substances are still urgently needed. Plants were the first source of remedies in the history of mankind. Since their chemical characterization in the 19th century, herbal bioactive compounds have fueled drug development. Also, nowadays, new plant-derived agents continuously enrich our drug arsenal (e.g., vincristine, galantamine, and artemisinin). The number of new, pharmacologically active herbal ingredients, in particular that of anti-inflammatory compounds, rises continuously. The major obstacle in this field is the translation of preclinical knowledge into evidence-based clinical progress. Human trials of good quality are often missing or, when available, are frequently not suitable to really prove a therapeutical value. This minireview will summarize the current situation of 6 very prominent plant-derived anti-inflammatory compounds: curcumin, colchicine, resveratrol, capsaicin, epigallocatechin-3-gallate (EGCG), and quercetin. We will highlight their clinical potential and/or pinpoint an overestimation. Moreover, we will sum up the planned trials in order to provide insights into the inflammatory disorders that are hypothesized to be beneficially influenced by the compound.

Topics: Animals; Anti-Inflammatory Agents; Capsaicin; Catechin; Colchicine; Curcumin; Humans; Imidazoles; Inflammation; Niacin; Resveratrol; Stilbenes

MicroRNAs (miRNAs) are short noncoding RNA which regulate gene expression by messenger RNA (mRNA) degradation or translation repression. The plethora of published reports in recent years demonstrated that they play fundamental roles in many biological processes, such as carcinogenesis, angiogenesis, programmed cell death, cell proliferation, invasion, migration, and differentiation by acting as tumour suppressor or oncogene, and aberrations in their expressions have been linked to onset and progression of various cancers. Furthermore, each miRNA is capable of regulating the expression of many genes, allowing them to simultaneously regulate multiple cellular signalling pathways. Hence, miRNAs have the potential to be used as biomarkers for cancer diagnosis and prognosis as well as therapeutic targets. Recent studies have shown that natural agents such as curcumin, resveratrol, genistein, epigallocatechin-3-gallate, indole-3-carbinol, and 3,3'-diindolylmethane exert their antiproliferative and/or proapoptotic effects through the regulation of one or more miRNAs. Therefore, this review will look at the regulation of miRNAs by natural agents as a means to potentially enhance the efficacy of conventional chemotherapy through combinatorial therapies. It is hoped that this would provide new strategies in cancer therapies to improve overall response and survival outcome in cancer patients.

Topics: Antineoplastic Agents; Biological Products; Biomarkers, Tumor; Catechin; Curcumin; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms; Resveratrol; RNA Stability; Stilbenes

Nutraceuticals with anti-neoplastic potential are suitable candidates for extending the range of therapeutic options for several types of cancers. One of these malignancies is oral cancer of the squamous cell carcinoma type, for which current treatment approaches have not succeeded in improving long-term clinical outcome. We recently reviewed the beneficial effects of curcumin for the treatment of oral cancer. In the current review, we focused on the beneficial effects of other two nutraceuticals, green tea extracts [especially (-)-epigallocatechin-3-gallate (EGCG)] and resveratrol, in the treatment of oral cancer. In vivo and in vitro studies as well as clinical trials were reviewed, focusing on the beneficial effect of each of these plant-derived dietary agents, either alone or in combination with various pharmacological agents. We also presented the anti-cancer effects against cancer cells and against components of the tumor microenvironment. It emerged that the poor bioavailability of these nutraceuticals poses an obstacle to their exerting adequate anti-cancer potential. Ground-breaking studies employing new nanotechnology-based therapeutic approaches were presented.

Topics: Animals; Catechin; Dietary Supplements; Humans; Mice; Mouth Neoplasms; Plant Extracts; Resveratrol; Stilbenes; Tea

MicroRNAs (miRNAs) are small single-strand non-coding endogenous RNAs that regulate gene expression by multiple mechanisms. Recent evidence suggests that miRNAs are critically involved in the pathogenesis, evolution, and progression of cancer. The miRNAs are also crucial for the regulation of cancer stem cells (CSCs). In addition, miRNAs are known to control the processes of Epithelial-to-Mesenchymal Transition (EMT) of cancer cells. This evidence suggests that miRNAs could serve as targets in cancer treatment, and as such manipulating miRNAs could be useful for the killing CSCs or reversal of EMT phenotype of cancer cells. Hence, targeting miRNAs, which are deregulated in cancer, could be a promising strategy for cancer therapy. Recently, the regulation of miRNAs by natural, nontoxic chemopreventive agents including curcumin, resveratrol, isoflavones, (-)-epigallocatechin-3-gallate (EGCG), lycopene, 3,3'- diindolylmethane (DIM), and indole-3-carbinol (I3C) has been described. Therefore, natural agents could inhibit cancer progression, increase drug sensitivity, reverse EMT, and prevent metastasis though modulation of miRNAs, which will provide a newer therapeutic approach for cancer treatment especially when combined with conventional therapeutics.

Topics: Animals; Antineoplastic Agents; Carotenoids; Catechin; Curcumin; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Lycopene; MicroRNAs; Molecular Targeted Therapy; Neoplasms; Neoplastic Stem Cells; Resveratrol; Stilbenes

The pronounced effects of the epigenetic diet (ED) and caloric restriction (CR) have on epigenetic gene regulation have been documented in many pre-clinical and clinical studies. Understanding epigenetics is of high importance because of the concept that external factors such as nutrition and diet may possess the ability to alter gene expression without modifying the DNA sequence. The ED introduces bioactive medicinal chemistry compounds such as sulforaphane (SFN), curcumin (CCM), epigallocatechin gallate (EGCG) and resveratrol (RSV) that are thought to aid in extending the human lifespan. CR, although similar to ED in the target of longevity, mildly reduces the total daily calorie intake while concurrently providing all beneficial nutrients. Both CR and ED may act as epigenetic modifiers to slow the aging process through histone modification, DNA methylation, and by modulating microRNA expression. CR and ED have been proposed as two important mechanisms that modulate and potentially slow the progression of age-related diseases such as cardiovascular disease (CVD), cancer, obesity, Alzheimer's and osteoporosis to name a few. While many investigators have examined CR and ED as separate entities, this review will primarily focus on both as they relate to age-related diseases, their epigenetic effects and their medicinal chemistry.

Topics: Aging; Anticarcinogenic Agents; Caloric Restriction; Catechin; Chemistry, Pharmaceutical; Curcumin; Epigenesis, Genetic; Humans; Isothiocyanates; Resveratrol; Stilbenes; Sulfoxides

Numerous studies have demonstrated the importance of naturally occurring dietary polyphenols in promoting cardiovascular health and emphasized the significant role these compounds play in limiting the effects of cellular aging. Polyphenols such as resveratrol, epigallocatechin gallate (EGCG), and curcumin have been acknowledged for having beneficial effects on cardiovascular health, while some have also been shown to be protective in aging. This review highlights the literature surrounding this topic on the prominently studied and documented polyphenols as pertaining to cardiovascular health and aging.

Topics: Aging; Animals; Cardiovascular System; Catechin; Curcumin; Diet; Disease Models, Animal; Fruit; Heart Diseases; Humans; Olive Oil; Plant Oils; Polyphenols; Quercetin; Randomized Controlled Trials as Topic; Reactive Oxygen Species; Resveratrol; Stilbenes

From a nutritional point of view, several factors are involved in ensuring optimal bone health. The most documented of these are calcium and vitamin D. However, it is now well acknowledged that some phytochemicals, also known as phytonutrients, which are plant-based compounds that are present in our daily diet, can positively regulate a number of physiological functions in mammalian systems involved in chronic diseases such as osteoporosis. Indeed, emerging data in animal models of postmenopausal osteoporosis has shown that exposure to some of these naturally plant-derived compounds (e.g. flavonoids) positively influences bone metabolism through preserved bone mineral density. In vitro experiments with bone cells have reported cellular and molecular mechanisms of phytonutrients involved in bone metabolism. Indeed, phytonutrients and especially polyphenols can act on both osteoblasts and osteoclasts to modulate bone metabolism, a balance between both cell type activities being required for bone health maintenance. To date, most studies investigating the effects of polyphenols on osteoblast cells have reported involvement of complex networks of anabolic signalling pathways such as BMPs or estrogen receptor mediated pathways. This review will report on the interaction between phytochemicals and bone metabolism in cell or animal models with a particular focus on the molecular mechanisms involved in the bone anabolic response.

Topics: Bone and Bones; Bone Density; Carotenoids; Catechin; Flavonoids; Humans; Lignans; Osteoporosis; Plants; Polyphenols; Signal Transduction; Stilbenes

Alzheimer's disease (AD) is a severe chronic neurodegenerative disorder of the brain characterised by progressive impairment in memory and cognition. In the past years an intense research has aimed at dissecting the molecular events of AD. However, there is not an exhaustive knowledge about AD pathogenesis and a limited number of therapeutic options are available to treat this neurodegenerative disease. Consequently, considering the heterogeneity of AD, therapeutic agents acting on multiple levels of the pathology are needed. Recent findings suggest that phytochemicals compounds with neuroprotective features may be an important resources in the discovery of drug candidates against AD. In this paper we will describe some polyphenols and we will discuss their potential role as neuroprotective agents. Specifically, curcumin, catechins, and resveratrol beyond their antioxidant activity are also involved in antiamyloidogenic and anti-inflammatory mechanisms. We will focus on specific molecular targets of these selected phytochemical compounds highlighting the correlations between their neuroprotective functions and their potential therapeutic value in AD.

Topics: Alzheimer Disease; Catechin; Curcumin; Humans; Neuroprotective Agents; NF-E2-Related Factor 2; Polyphenols; Resveratrol; Stilbenes

Prostate cancer is is the most common solid neoplasm and it is now recognized as one of the most important medical problems facing the male population. Due to its long latency and its identifiable preneoplastic lesions, prostate cancer is an ideal target tumor for chemoprevention. Different compounds are available and certainly polyphenols represent those with efficacy against prostate cancer. This review take a look at activity and properties of major polyphenolic substances, such as epigallocatechin-3-gallate, curcumin, resveratrol and the flavonoids quercetin and genistein. Although the current studies are limited, mechanisms of action of polyphenols added with the lack of side effects show a a start for future strategies in prostate chemoprevention.

Topics: Antioxidants; Catechin; Curcumin; Flavonoids; Genistein; Humans; Male; Polyphenols; Prostatic Neoplasms; Quercetin; Resveratrol; Stilbenes

Osteoarthritis is a condition caused in part by injury, loss of cartilage structure and function, and an imbalance in inflammatory and anti-inflammatory pathways. It primarily affects the articular cartilage and subchondral bone of synovial joints and results in joint failure, leading to pain upon weight bearing including walking and standing. There is no cure for osteoarthritis, as it is very difficult to restore the cartilage once it is destroyed. The goals of treatment are to relieve pain, maintain or improve joint mobility, increase the strength of the joints and minimize the disabling effects of the disease. Recent studies have shown an association between dietary polyphenols and the prevention of osteoarthritis-related musculoskeletal inflammation. This review discusses the effects of commonly consumed polyphenols, including curcumin, epigallocatechin gallate and green tea extract, resveratrol, nobiletin and citrus fruits, pomegranate, as well as genistein and soy protein, on osteoarthritis with an emphasis on molecular antiosteoarthritic mechanisms.

Topics: Cartilage, Articular; Catechin; Citrus; Curcumin; Flavones; Genistein; Humans; Lythraceae; Osteoarthritis; Plant Extracts; Polyphenols; Resveratrol; Stilbenes

Polyphenolic compounds derived mainly from plant products have demonstrated neuroprotective properties in a number of experimental settings. Such protective effects have often been ascribed to antioxidant capacity, but specific augmentation of other cellular defences and direct interactions with neurotoxic proteins have also been demonstrated. With an emphasis on neurodegenerative conditions, such as Alzheimer's disease, we highlight recent findings on the neuroprotection ascribed to bioactive polyphenols capable of directly interfering with the Alzheimer's disease hallmark toxic β-amyloid protein (Aβ), thereby inhibiting fibril and aggregate formation. This includes compounds such as the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) and the phytoalexin resveratrol. Targeted studies on the biomolecular interactions between dietary polyphenolics and Aβ have not only improved our understanding of the pathogenic role of β-amyloid, but also offer fundamentally novel treatment options for Alzheimer's disease and potentially other amyloidoses.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Catechin; Cell Line; Curcumin; Diet; Humans; Models, Molecular; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Plants; Polyphenols; Resveratrol; Stilbenes; Tea

Cancer is one of the leading causes of death in the United States and around the world. Most modern drug-targeted therapies, besides being enormously expensive, are associated with serious side effects and morbidity. Still, the search continues for an ideal treatment that has minimal side effects and is cost-effective. Indeed, the design and development of chemopreventive agents that act on specific and/or multiple molecular and cellular targets is gaining support as a rational approach to prevent and treat cancer. We present evidence on numerous dietary agents identified from fruits and vegetables that act on multiple signal transduction and apoptotic cascades in various tumor cells and animal models. Some of the most interesting and well documented are turmeric (curcumin), resveratrol, silymarin, EGCG, and genistein. This review will provide an insight on the cellular and molecular mechanism(s) by which dietary agents modulate multiple signaling and apoptotic pathways in tumor cells and elucidate the role of these agents in both prevention and treatment of cancer.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Catechin; Clinical Trials as Topic; Curcuma; Curcumin; Diet; Disease Models, Animal; Fruit; Genistein; Humans; Neoplasms; Resveratrol; Signal Transduction; Silymarin; Stilbenes; United States; Vegetables

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

Microglial cells play a dual role in the central nervous system as they have both neurotoxic and neuroprotective effects. Uncontrolled and excessive activation of microglia often contributes to inflammation-mediated neurodegeneration. Recently, much attention has been paid to therapeutic strategies aimed at inhibiting neurotoxic microglial activation. Pharmacological inhibitors of microglial activation are emerging as a result of such endeavors. In this review, natural products-based inhibitors of microglial activation will be reviewed. Potential neuroprotective activity of these compounds will also be discussed. Future works should focus on the discovery of novel drug targets that specifically mediate microglial neurotoxicity rather than neuroprotection. Development of new drugs based on these targets may require a better understanding of microglial biology and neuroinflammation at the molecular, cellular, and systems levels.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Benzyl Alcohols; Biological Products; Biphenyl Compounds; Catechin; Catechols; Curcumin; Encephalitis; Fatty Alcohols; Ginsenosides; Glucosides; Microglia; Molecular Structure; Nerve Degeneration; Neuroprotective Agents; Phenyl Ethers; Plant Extracts; Resveratrol; Stilbenes

Greater understanding about the pathogenesis of metabolic syndrome and potential causes suggests that plant polyphenols might be useful as a treatment. Dietary excess energy can be stored in adipocytes, leading to the release of proinflammatory cytokines and adipose-related hormones that cause vascular injury. Plant polyphenols, organic compounds found in numerous plant species and their fruits, are being actively studied as potential treatments for components of the metabolic syndrome. Individual polyphenols that have been examined include resveratrol, quercetin, epigallocathechin-3-gallate, and curcumin. Resveratrol lowers weight, blood pressure, glucose, and insulin resistance in rodents, and a human trial is currently underway. Quercetin decreases lipid and glucose levels in obese rats, and in a human investigation of subjects with the metabolic syndrome has lowered blood pressure without significant alteration of lipids. Epigallocathechin-3-gallate-induced weight loss has attenuated glucose levels and insulin resistance in rodents and improved hemoglobin A(1c) and lipid in human studies. Plant extracts also can be used. Grape seed and chokeberry extracts have decreased blood pressure and lipid levels in small human trials. Other human investigations have shown the beneficial effects of cocoa, coffee, carob, and Momordica charantia. Thus far, most studies have involved a small number of subjects and have been of short duration. Future studies should be designed to account for a disease process in which the pathogenic factors may take place for years before disease manifestations take place, the possibly limited bioavailability of polyphenols, and the potential need to provide combinations or modifications of polyphenols.

Topics: Animals; Antioxidants; Catechin; Curcumin; Flavonoids; Humans; Metabolic Syndrome; Phenols; Plant Extracts; Polyphenols; Quercetin; Resveratrol; Stilbenes

Colorectal cancer (CRC) is the second most fatal and the third most diagnosed type of cancer worldwide. Despite having multifactorial causes, most CRC cases are mainly determined by dietary factors. In recent years, a large number of studies have attributed a protective effect to polyphenols and foods containing these compounds (fruits and vegetables) against CRC. Indeed, polyphenols have been reported to interfere with cancer initiation, promotion, and progression, acting as chemopreventive agents. The aim of this review is to summarize the main chemopreventive properties of some polyphenols (quercetin, rutin, myricetin, chrysin, epigallocatechin-3-gallate, epicatechin, catechin, resveratrol, and xanthohumol) against CRC, observed in cell culture models. From the data reviewed in this article, it can be concluded that these compounds inhibit cell growth, by inducing cell cycle arrest and/or apoptosis; inhibit proliferation, angiogenesis, and/or metastasis; and exhibit anti-inflammatory and/or antioxidant effects. In turn, these effects involve multiple molecular and biochemical mechanisms of action, which are still not completely characterized. Thus, caution is mandatory when attempting to extrapolate the observations obtained in CRC cell line studies to humans.

Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Antioxidants; Apoptosis; Catechin; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Diet; Flavonoids; Fruit; Humans; Phenols; Polyphenols; Propiophenones; Quercetin; Resveratrol; Rutin; Stilbenes; Vegetables

A number of bioactive dietary components are of particular interest in the field of epigenetics. Many of these compounds display anticancer properties and may play a role in cancer prevention. Numerous studies suggest that a number of nutritional compounds have epigenetic targets in cancer cells. Importantly, emerging evidence strongly suggests that consumption of dietary agents can alter normal epigenetic states as well as reverse abnormal gene activation or silencing. Epigenetic modifications induced by bioactive dietary compounds are thought to be beneficial. Substantial evidence is mounting proclaiming that commonly consumed bioactive dietary factors act to modify the epigenome and may be incorporated into an 'epigenetic diet'. Bioactive nutritional components of an epigenetic diet may be incorporated into one's regular dietary regimen and used therapeutically for medicinal or chemopreventive purposes. This article will primarily focus on dietary factors that have been demonstrated to influence the epigenome and that may be used in conjunction with other cancer prevention and chemotherapeutic therapies.

Topics: Anticarcinogenic Agents; Catechin; Curcumin; Diet; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Epigenesis, Genetic; Epigenomics; Genistein; Histones; Humans; Isothiocyanates; MicroRNAs; Neoplasms; Polyphenols; Resveratrol; Stilbenes; Tea

Accumulating data clearly indicate that induction of apoptosis is an important event for chemoprevention of cancer by naturally occurring dietary agents. In mammalian cells, apoptosis has been divided into two major pathways: the extrinsic pathway, activated by pro-apoptotic receptor signals at the cellular surface; and the intrinsic pathway, which involves the disruption of mitochondrial membrane integrity. This process is strictly controlled in response to integrity of pro-death signaling and plays critical roles in development, maintenance of homeostasis, and host defense in multicellular organisms. For chemoprevention studies, prostate cancer (PCa) represents an ideal disease due to its long latency, its high incidence, tumor marker availability, and identifiable preneoplastic lesions and risk groups. In this article, we highlight the studies of various apoptosis-inducing dietary compounds for prevention of PCa in vitro in cell culture, in preclinical studies in animals, and in human clinical trials.

Topics: Adenocarcinoma; Aged; Animals; Apoptosis; Carotenoids; Catechin; Clinical Trials as Topic; Curcumin; Drug Screening Assays, Antitumor; Flavonoids; Flavonols; Genistein; Humans; Lycopene; Lythraceae; Male; Mice; Mice, Nude; Mice, Transgenic; Middle Aged; Neoplasm Proteins; Pentacyclic Triterpenes; Phytotherapy; Plant Extracts; Prostatic Neoplasms; Resveratrol; Stilbenes; Tumor Cells, Cultured

Alzheimer's disease (AD) is an age-related neurodegenerative disease increasingly recognized as one of the most important medical problems affecting the elderly. Although a number of drugs, including several cholinesterase inhibitors and an NMDA receptor antagonist, have been approved for use, they have been shown to produce diverse side effects and yield relatively modest benefits. To overcome these limitations of current therapeutics for AD, extensive research and development are underway to identify drugs that are effective and free of undesirable side effects. Certain naturally occurring dietary polyphenolic phytochemicals have received considerable recent attention as alternative candidates for AD therapy. In particular, curcumin, resveratrol, and green tea catechins have been suggested to have the potential to prevent AD because of their anti-amyloidogenic, anti-oxidative, and anti-inflammatory properties. These polyphenolic phytochemicals also activate adaptive cellular stress responses, called 'neurohormesis', and suppress disease processes. In this commentary, we describe the amyloid-beta-induced pathogenesis of AD, and summarize the intracellular and molecular targets of selected dietary phytochemicals that might slow the progression of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Catechin; Cognition Disorders; Curcumin; Dietary Supplements; Humans; Oxidative Stress; Phytotherapy; Plant Extracts; Resveratrol; Stilbenes

Head and neck squamous cell carcinoma (HNSCC) is one of the most fatal cancers worldwide. Despite advances in the management of HNSCC, the overall survival for patients has not improved significantly due to advanced stages at diagnosis, high recurrence rate after surgical removal, and second primary tumor development, which underscore the importance of novel strategies for cancer prevention. Cancer chemoprevention, the use of natural or synthetic compounds to prevent, arrest, or reverse the process of carcinogenesis at its earliest stages, aims to reverse premalignancies and prevent second primary tumors. Genomics and proteomics information including initial mutation, cancer promotion, progression, and susceptibility has brought molecularly targeted therapies for drug development. The development of preventive approaches using specific natural or synthetic compounds, or both, requires a depth of understanding of the cross-talk between cancer signaling pathways and networks to retain or enhance chemopreventive activity while reducing known toxic effects. Many natural dietary compounds have been identified with multiple molecular targets, effective in the prevention and treatment of cancer. This review describes recent advances in the understanding of the complex signaling networks driving cancer progression and of molecularly targeted natural compounds under preclinical and clinical investigation.

Topics: Animals; Anticarcinogenic Agents; Carcinoma, Squamous Cell; Catechin; Curcumin; Cyclooxygenase 2 Inhibitors; ErbB Receptors; Head and Neck Neoplasms; Humans; NF-kappa B; Resveratrol; Stilbenes; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53

A voluminous literature suggests that an increase in consumption of fruit and vegetables is a relatively easy and practical strategy to reduce significantly the incidence of cancer. The beneficial effect is mostly associated with the presence of phytochemicals in the diet. This review focuses on a group of them, namely isothiocyanate, curcumin, genistein, epigallocatechin gallate, lycopene and resveratrol, largely studied as chemopreventive agents and with potential clinical applications. Cellular and animal studies suggest that these molecules induce apoptosis and arrest cell growth by pleiotropic mechanisms. The anticancer efficacy of these compounds may result from their use in monotherapy or in association with chemotherapeutic drugs. This latter approach may represent a new pharmacological strategy against several types of cancers. However, despite the promising results from experimental studies, only a limited number of clinical trials are ongoing to assess the therapeutic efficacy of these molecules. Nevertheless, the preliminary results are promising and raise solid foundations for future investigations.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Carotenoids; Catechin; Curcumin; Genistein; Humans; Isothiocyanates; Lycopene; Neoplasms; Resveratrol; Stilbenes

Hepatocellular carcinoma (HCC) is the fifth commonest malignancy worldwide and the incidence is rising. Surgery, including transplantation resection, is currently the most effective treatment for HCC; however, recurrence rates are high and long-term survival is poor. Identifying novel chemopreventive and chemotherapeutic agents and targeting them to patients at high risk of developing HCC or following curative treatment may go some way towards improving prognosis. This review examines current knowledge regarding the chemopreventive and chemotherapeutic potential of phytochemicals in heptocarcinogenesis. Both in-vitro and animal studies demonstrate that several phytochemicals, including curcumin, resveratrol, green tea catechins, oltipraz and silibinin, possess promising chemopreventive and chemotherapeutic properties. Despite this, very few clinical trials have been performed. Problems regarding validation of biomarkers, agent delivery, side effects and patient selection are barriers that need to be overcome to determine the potential of such agents in clinical practice.

Topics: Animals; Antineoplastic Agents, Phytogenic; Brassicaceae; Caffeine; Capsaicin; Carcinoma, Hepatocellular; Catechin; Chemoprevention; Curcumin; Flavonoids; Humans; Liver Neoplasms; Phenols; Plant Extracts; Polyphenols; Resveratrol; Stilbenes

Various studies have reported on the neuroprotective effects of polyphenols, widely present in food, beverages, and natural products. For example, we have shown that resveratrol, a polyphenol enriched in red wine and other foods such as peanuts, protects hippocampal cells against beta-amyloid (Abeta)-induced toxicity, a key protein involved in the neuropathology of Alzheimer disease. This effect involves, at least in part, the capacity of resveratrol to activate the phosphorylation of delta isoform of protein kinase C (PKC-delta). The neuroprotective action of resveratrol is shared by piceatannol, a stilbene derivative, as well as by tea-derived catechin gallate esters. The thioflavin T assay indicated that all these polyphenols inhibited the formation of Abeta fibrils, suggesting that this action likely also contributes to their neuroprotective effects. Binding and autoradiographic studies revealed that the effects of polyphenols might involve specific binding sites that are particularly enriched in the choroid plexus in the rat brain. Interestingly, the choroid plexus secretes transthyretin, a protein that has been shown to modulate Abeta aggregation and that may be critical to the maintenance of normal learning capacities in aging. Taken together, these data suggest that polyphenols target multiple enzymes/proteins, leading to their neuroprotective actions, possibly through action via specific plasma membrane binding sites.

Topics: Amyloid beta-Peptides; Autoradiography; Catechin; Cell Membrane; Flavonoids; Neuroprotective Agents; Phenols; Polyphenols; Prealbumin; Protein Kinase C-delta; Resveratrol; Stilbenes; Structure-Activity Relationship; Tea

Cancer cells are known to have alterations in multiple cellular signaling pathways and because of the complexities in the communication between multiple signaling networks, the treatment and the cure for most human malignancies is still an open question. Perhaps, this is the reason why specific inhibitors that target only one pathway have been typically failed in cancer treatment. However, the in vitro and in vivo studies have demonstrated that some natural products such as isoflavones, indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), curcumin, (-)-epigallocatechin-3-gallate (EGCG), resveratrol, lycopene, etc, have inhibitory effects on human and animal cancers through targeting multiple cellular signaling pathways and thus these "natural agents" could be classified as multi-targeted agents. This is also consistent with the epidemiological studies showing that the consumption of fruits, soybean and vegetables is associated with reduced risk of several types of cancers. By regulating multiple important cellular signaling pathways including NF-kappaB, Akt, MAPK, Wnt, Notch, p53, AR, ER, etc, these natural products are known to activate cell death signals and induce apoptosis in pre-cancerous or cancer cells without affecting normal cells. Therefore, non-toxic "natural agents" harvested from the bounties of nature could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies.

Topics: Antineoplastic Agents; Carotenoids; Catechin; Curcumin; Humans; Indoles; Isoflavones; Lycopene; Neoplasms; Resveratrol; Signal Transduction; Stilbenes

A regulated low level of nitric oxide (NO) production in the body is essential for maintaining homeostasis (neuroprotection, vasorelaxation, etc.), though certain pathophysiological conditions associated with inflammation involve de novo synthesis of inducible NO synthase (iNOS) in immune cells, including macrophages. A large body of evidence indicates that many inflammatory diseases, such as colitis and gastritis, as well as many types of cancer, occur through sustained and elevated activation of this particular enzyme. The biochemical process of iNOS protein expression is tightly regulated and complex, in which the endotoxin lipopolysaccharide selectively binds to toll-like receptor 4 and thereby activates its adaptor protein MyD88, which in turn targets downstream proteins such as IRAK and TRAF6. This leads to functional activation of key protein kinases, including IkB kinases and mitogen-activated protein kinases (MAPKs), such as p38 MAPK, JNK1/2, and ERK1/2, all of which are involved in activating key transcription factors, including nuclear factor-kappaB and activator protein-1. In addition, the production of proinflammatory cytokines such as interferon-gamma and interleukin-12 potentiates iNOS induction in autocrine fashions. Meanwhile, an LPS-stimulated p38 MAPK pathway plays a pivotal role in the stabilization of iNOS mRNA, which has the AU-rich element in its 3'-untranslated region, for rapid NO production. Thus, suppression and/or inhibition of the above-mentioned signaling molecules may have a great potential for the prevention and treatment of inflammation-associated carcinogenesis. In fact, there have been numerous reports of phytochemicals found capable of targeting NO production by unique mechanisms, including polyphenols, terpenoids, and others. This review article briefly highlights the molecular mechanisms underlying endotoxin-induced iNOS expression in macrophages, and also focuses on promising natural agents that may be useful for anti-inflammation and anticarcinogenesis strategies.

Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Antioxidants; Benzyl Alcohols; Catechin; Chemoprevention; Coumarins; Curcumin; Flavones; Mice; Nitric Oxide Synthase Type II; Rats; Resveratrol; Sesquiterpenes; Stilbenes

The development of cancer is associated with disorders in the regulation of the cell cycle. The purpose of this review is to briefly summarize the known sequence of events that regulate cell cycle progression with an emphasis on the checkpoints and the mechanisms cell employ to insure DNA stability in the face of genotoxic stress. Key transitions in the cell cycle are regulated by the activities of various protein kinase complexes composed of cyclin and cyclin-dependent kinases (CDK) molecules. The cyclins are CDK binding partners which are required for kinase activity and their protein levels are intimately linked to the cell cycle stage. CDK activity can be regulated by other mechanisms, such as phosphorylation events, that may contribute to deregulation of cell cycle and the development of cancer. While fruits and vegetables are recommended for prevention of cancer, their active ingredients and mechanisms of action are less well understood. Here, we briefly present evidence that dietary agents identified from fruits and vegetables can act to modulate the effects of deregulated cell cycle checkpoints, and that this may contribute to the prevention of cancer. The agents include apigenin (celery, parsley), curcumin (turmeric), (-)-epigallocatechin-3-gallate (green tea), resveratrol (red grape, peanuts and berries), genistein (soybean), and silymarin (milk thistle). The teachings of Hippocrates are still true "let food be thy medicine and medicine be thy food".

Topics: Animals; Anticarcinogenic Agents; Apigenin; Catechin; Cell Cycle; Cell Proliferation; Curcumin; Cyclin-Dependent Kinases; Diet; Genistein; Humans; Neoplasms; Resveratrol; Silymarin; Stilbenes; Tea

There is growing interest in the ability of phytochemicals to prevent chronic diseases, such as cancer and heart disease. However, some of these agents have poor bioavailability and many of the in-depth studies into their mechanisms of action have been carried out in vitro using doses which are unachievable in humans. In order to optimize the design of chemopreventive treatment, it is important to determine which of the many reported mechanisms of action are clinically relevant. In this review we consider the physiologically achievable doses for a few of the best studied agents (indole-3-carbinol, diindolylmethane, curcumin, epigallocatechin-3-gallate and resveratrol) and summarize the data derived from studies using these low concentrations in cell culture. We then cite examples of in vitro effects which have been observed in vivo. Finally, the ability of agent combinations to act synergistically or antagonistically is considered. We conclude that each of the compounds shows an encouraging range of activities in vitro at concentrations which are likely to be physiologically relevant. There are also many examples of in vivo studies which validate in vitro observations. An important consideration is that combinations of agents can result in significant activity at concentrations where any single agent is inactive. Thus, for each of the compounds reviewed here, in vitro studies have provided useful insights into their mechanisms of action in humans. However, data are lacking on the full range of activities at low doses in vitro and the benefits or otherwise of combinations in vivo.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Catechin; Curcumin; Humans; Indoles; Neoplasms; Resveratrol; Stilbenes

Oxidative stress imposed by reactive oxygen species (ROS) plays a crucial role in the pathophysiology associated with neoplasia, atherosclerosis, and neurodegenerative diseases. The ROS-induced development of cancer involves malignant transformation due to altered gene expression through epigenetic mechanisms as well as DNA mutations. Considerable attention has been focused on identifying naturally occurring antioxidative phenolic phytochemicals that are able to decrease ROS levels, but the efficacies of antioxidant therapies have been equivocal at best. Several studies have shown that some antioxidants exhibit prooxidant activity under certain conditions and potential carcinogenicity under others, and that dietary supplementation with large amounts of a single antioxidant may be deleterious to human health. This article reviews the intracellular signaling pathways that respond to oxidative stress and how they are modulated by naturally occurring polyphenols. The possible toxicity and carcinogenicity of polyphenols is also discussed.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Carcinogens; Catechin; Cell Communication; Cyclooxygenase Inhibitors; Diet; Flavonoids; Gap Junctions; Genistein; Humans; Matrix Metalloproteinases; Neoplasms; Oxidative Stress; Phenols; Polyphenols; Prostaglandin-Endoperoxide Synthases; Quercetin; Reactive Oxygen Species; Resveratrol; Signal Transduction; Stilbenes

A major challenge in cancer therapy is tumor drug resistance. To overcome it, it is essential to understand the mechanisms and identify the molecules involved, so that they can be specifically targeted in combination therapies. The proteasome is such a validated target: it plays a key role in cancer cell proliferation, inhibition of chemotherapy-induced apoptosis and drug resistance development. Bortezomib (Velcade, PS-341) was the first proteasome inhibitor to receive regulatory approval from the US Food and Drug Administration for the treatment of multiple myeloma. Clinical combination trials have demonstrated a chemo-sensitizing effect of bortezomib on conventional agents in hematological malignancies and some solid tumors such as androgen-independent prostate and ovarian cancer. Although generally well-tolerated, bortezomib still generates toxicity which underscores the need for less toxic proteasome inhibitors. Several naturally occurring products, such as green tea polyphenols and the antibiotic lactacystin, have been shown to be potent proteasome inhibitors. Significantly, green tea polyphenols, as well as several flavonoids such as genistein, curcumin and resveratrol, have also been shown to have chemo-sensitizing properties in prostate, breast, hepatic, and lung tumors. Further studies on natural proteasome inhibitors as chemo-sensitizers could lead to identification of more potent and less toxic compounds that could be used in combination therapies for drug-resistant tumors.

Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Catechin; Clinical Trials as Topic; Curcumin; Drug Resistance, Neoplasm; Drug Therapy, Combination; Genistein; Humans; Neoplasms; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Radiation-Sensitizing Agents; Resveratrol; Stilbenes; Structure-Activity Relationship; Ubiquitin

Epidemiologic studies in human populations and experimental studies in rodents provide evidence that green tea and its constituents can inhibit both the development and growth of tumors at a variety of tissue sites. In addition, EGCG, a major biologically active component of green tea, inhibits growth and induces apoptosis in a variety of cancer cell lines. The purpose of this paper is to review evidence that these effects are mediated, at least in part, through inhibition of the activity of specific receptor tyrosine kinases (RTKs) and related downstream pathways of signal transduction. We also review evidence indicating that the antitumor effects of the related polyphenolic phytochemicals resveratrol, genistein, curcumin, and capsaicin are exerted via similar mechanisms. Some of these agents (EGCG, genistein, and curcumin) appear to directly target specific RTKs, and all of these compounds cause inhibition of the activity of the transcription factors AP-1 and NF-kappaB, thus inhibiting cell proliferation and enhancing apoptosis. Critical areas of future investigation include: (1) identification of the direct molecular target(s) of EGCG and related polyphenolic compounds in cells; (2) the in vivo metabolism and bioavailability of these compounds; (3) the ancillary effects of these compounds on tumor-stromal interactions; (4) the development of synergistic combinations with other antitumor agents to enhance efficacy in cancer prevention and therapy, and also minimize potential toxicities.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Capsaicin; Catechin; Curcumin; Genistein; Humans; Molecular Structure; Protein Kinases; Resveratrol; Signal Transduction; Stilbenes; Tea; Transcription Factors

Early investigations of gene regulation revealed that nutrients could modulate gene expression, an example being the discovery of metal-regulated gene transcription ( 11, 19, 44). Only more recently have we focused on the ability of non-nutritional botanicals or functional food components to affect gene expression at the transcriptional level. Significant findings include the discovery that hyperforin is an active ingredient of the herbal remedy St. John's wort, and activates gene transcription of cytochrome p450-3A4, causing significant botanical-drug interactions. Recently, the lipid-regulating peroxisome proliferator-activated receptors have been studied as receptors activated by soy isoflavones, perhaps explaining the lipid-lowering effect of soy intake. Epigallocatechin gallate has been shown to be an inhibitor of the protealytic activity of the proteasome; this inhibition has a significant implication for cell proliferation and the stability of transcription factors in the nucleus. Very recently, the effects of botanicals have been studied as activators of sirtuins, important deacetylation enzymes that have been shown to enhance lifespan in a variety of organisms. Sirtuins have been implicated in the lifespan-enhancing effect of caloric restriction. Originally presumed to act mainly on compaction or accessibility of DNA, recent evidence shows important activity of sirtuins as controllers of transcriptional coactivator availability. This review focuses on novel mechanisms by which botanical products regulate cell function via gene transcription. Investigating these newly appreciated mechanisms will assist with the characterization and clarification of specific effects of botanicals on gene expression.

Topics: Animals; Bridged Bicyclo Compounds; Catechin; Gene Expression Regulation; Glycine max; Humans; Isoflavones; Peroxisome Proliferator-Activated Receptors; Phloroglucinol; Plants; Pregnane X Receptor; Proteasome Endopeptidase Complex; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Resveratrol; Sirtuins; Stilbenes; Terpenes; Transcription, Genetic; Ubiquitin

Recently, considerable attention has been focused on identifying naturally occurring chemopreventive substances capable of inhibiting, retarding, or reversing the multi-stage carcinogenesis. A wide array of phenolic substances, particularly those present in dietary and medicinal plants, have been reported to possess substantial anticarcinogenic and antimutagenic activities. The majority of these naturally occurring phenolics retain antioxidative and anti-inflammatory properties which appear to contribute to their chemopreventive or chemoprotective activity. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a pungent ingredient of hot chili pepper, protects against experimentally-induced mutagenesis and tumorigenesis. It also induces apoptosis in various immortalized or malignant cell lines. Plants of ginger family (Zingiberaceae) have been frequently and widely used as spices and also, in traditional oriental medicine. Curcumin, a yellow ingredient from turmeric (Curcuma longa L., Zingiberaceae), has been extensively investigated for its cancer chemopreventive potential. Yakuchinone A [1-(4'-hydroxy-3'-methoxyphenyl)-7-phenyl-3-heptanone] and yakuchinone B [1-(4'-hydroxy-3'-methoxyphenyl)-7-phenylhept-1-en-3-one] present in Alpinia oxyphylla Miquel (Zingiberaceae) have inhibitory effects on phorbol ester-induced inflammation and skin carcinogenesis in mice, and oxidative stress in vitro. These diarylheptanoids suppress phorbol ester-induced activation of ornithine decarboxylase and production of tumor necrosis factor-alpha or interleukin-1alpha and their mRNA expression. They also nullified the phorbol ester-stimulated induction of activator protein 1 (AP-1) in cultured human promyelocytic leukemia (HL-60) cells. In addition, both yakuchinone A and B induced apoptotic death in HL-60 cells. Ginger (Zingiber officinale Roscoe, Zingiberaceae) contains such pungent ingredients as [6]-gingerol and [6]-paradol, which also have anti-tumor promotional and antiproliferative effects. Resveratrol (3, 5,4'-trihydroxy-trans-stilbene), a phytoalexin found in grapes and other dietary and medicinal plants, and (-)-epigallocatechin gallate, a major antioxidative green tea polyphenol, exert striking inhibitory effects on diverse cellular events associated with multi-stage carcinogenesis. In addition, these compounds have ability to suppress proliferation of human cancer cells via induction of apoptosis.

Topics: Animals; Capsaicin; Catechin; Catechols; Curcumin; Diet; Fatty Alcohols; Humans; Mice; Neoplasms; Neoplasms, Experimental; Phenols; Plants, Edible; Plants, Medicinal; Resveratrol; Stilbenes

The intestinal microbiota may have a profound impact on host metabolism. As evidence suggests that polyphenols affect substrate utilization, the present study aimed to investigate the effects of polyphenol supplementation on intestinal microbiota composition in humans. Furthermore, we examined whether (changes in) gut microbiota composition may determine the metabolic response to polyphenol supplementation.. Fecal abundance of Bacteroidetes was higher in men as compared with women, whereas other assessed bacterial taxa were comparable. EGCG+RES supplementation significantly decreased Bacteroidetes and tended to reduce Faecalibacterium prausnitzii in men (P=0.05 and P=0.10, respectively) but not in women (P=0.15 and P=0.77, respectively). Strikingly, baseline Bacteroidetes abundance was predictive for the EGCG+RES-induced increase in fat oxidation in men but not in women. Other bacterial genera and species were not affected by EGCG+RES supplementation.. We demonstrated that 12-week EGCG+RES supplementation affected the gut microbiota composition in men but not in women. Baseline microbiota composition determined the increase in fat oxidation after EGCG+RES supplementation in men.

Topics: Absorptiometry, Photon; Adult; Bacteroidetes; Catechin; Double-Blind Method; Energy Metabolism; Faecalibacterium prausnitzii; Feces; Female; Gastrointestinal Microbiome; Humans; Male; Muscle, Skeletal; Overweight; Polyphenols; Resveratrol; Stilbenes; Treatment Outcome

The obese insulin-resistant state is characterized by impairments in lipid metabolism. We previously showed that 3-d supplementation of combined epigallocatechin-3-gallate and resveratrol (EGCG+RES) increased energy expenditure and improved the capacity to switch from fat toward carbohydrate oxidation with a high-fat mixed meal (HFMM) test in men.. The present study aimed to investigate the longer-term effect of EGCG+RES supplementation on metabolic profile, mitochondrial capacity, fat oxidation, lipolysis, and tissue-specific insulin sensitivity.. In this randomized double-blind study, 38 overweight and obese subjects [18 men; aged 38 ± 2 y; body mass index (kg/m(2)): 29.7 ± 0.5] received either EGCG+RES (282 and 80 mg/d, respectively) or placebo for 12 wk. Before and after the intervention, oxidative capacity and gene expression were assessed in skeletal muscle. Fasting and postprandial (HFMM) lipid metabolism was assessed by using indirect calorimetry, blood sampling, and microdialysis. Tissue-specific insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp with [6,6-(2)H2]-glucose infusion.. EGCG+RES supplementation did not affect the fasting plasma metabolic profile. Although whole-body fat mass was not affected, visceral adipose tissue mass tended to decrease after the intervention compared with placebo (P-time × treatment = 0.09). EGCG+RES supplementation significantly increased oxidative capacity in permeabilized muscle fibers (P-time × treatment < 0.05, P-EGCG+RES < 0.05). Moreover, EGCG+RES reduced fasting (P-time × treatment = 0.03) and postprandial respiratory quotient (P-time × treatment = 0.01) compared with placebo. Fasting and postprandial fat oxidation was not significantly affected by EGCG+RES (P-EGCG+RES = 0.46 and 0.38, respectively) but declined after placebo (P-placebo = 0.05 and 0.03, respectively). Energy expenditure was not altered (P-time × treatment = 0.96). Furthermore, EGCG+RES supplementation attenuated the increase in plasma triacylglycerol concentrations during the HFMM test that was observed after placebo (P-time × treatment = 0.04, P-placebo = 0.01). Finally, EGCG+RES had no effect on insulin-stimulated glucose disposal, suppression of endogenous glucose production, or lipolysis.. Twelve weeks of EGCG+RES supplementation increased mitochondrial capacity and stimulated fat oxidation compared with placebo, but this did not translate into increased tissue-specific insulin sensitivity in overweight and obese subjects. This trial was registered at clinicaltrials.gov as NCT02381145.

Topics: Adult; Blood Glucose; Catechin; Dietary Supplements; Double-Blind Method; Energy Metabolism; Fasting; Female; Humans; Insulin; Insulin Resistance; Intra-Abdominal Fat; Lipid Metabolism; Male; Mitochondria; Muscles; Obesity; Plant Extracts; Postprandial Period; Resveratrol; Stilbenes

Impaired regulation of lipid oxidation (metabolic inflexibility) is associated with obesity and type 2 diabetes mellitus. Recent evidence has indicated that dietary polyphenols may modulate mitochondrial function, substrate metabolism and energy expenditure in humans. The present study investigated the effects of short-term supplementation of two combinations of polyphenols on energy expenditure (EE) and substrate metabolism in overweight subjects.. Eighteen healthy overweight volunteers (9 women, 9 men; age 35±2.5 years; body mass index 28.9±0.4 kg m(-2)) participated in a randomized, double-blind cross-over trial. Combinations of epigallocatechin-gallate (E, 282 mg day(-1))+resveratrol (R, 200 mg day(-1)) and E+R+80 mg day(-1) soy isoflavones (S) or placebo capsules (PLA) were supplemented twice daily for a period of 3 days. On day 3, circulating metabolite concentrations, EE and substrate oxidation (using indirect calorimetry) were measured during fasting and postprandial conditions for 6 h (high-fat-mixed meal (2.6 MJ, 61.2 E% fat)).. Short-term supplementation of E+R increased resting EE (E+R vs PLA: 5.45±0.24 vs 5.23±0.25 kJ min(-1), P=0.039), whereas both E+R (699±18 kJ 120 min(-1) vs 676±20 kJ 120 min(-1), P=0.028) and E+R+S (704±18 kJ 120 min(-1) vs 676±20 kJ 120 min(-1), P=0.014) increased 2-4 h-postprandial EE compared with PLA. Metabolic flexibility, calculated as the postprandial increase to the highest respiratory quotient achieved, tended to be improved by E+R compared with PLA and E+R+S only in men (E+R vs PLA: 0.11±0.02 vs 0.06±0.02, P=0.059; E+R+S: 0.03±0.02, P=0.009). E+R+S significantly increased fasting plasma free fatty acid (P=0.064) and glycerol (P=0.021) concentrations compared with PLA.. We demonstrated for the first time that combined E+R supplementation for 3 days significantly increased fasting and postprandial EE, which was accompanied by improved metabolic flexibility in men but not in women. Addition of soy isoflavones partially reversed these effects possibly due to their higher lipolytic potential. The present findings may imply that long-term supplementation of these dosages of epigallocatechin-gallate combined with resveratrol may improve metabolic health and body weight regulation.

Topics: Adult; Antioxidants; Body Mass Index; Catechin; Dietary Supplements; Double-Blind Method; Drug Therapy, Combination; Energy Metabolism; Female; Humans; Lipid Metabolism; Male; Middle Aged; Overweight; Oxidation-Reduction; Polyphenols; Postprandial Period; Resveratrol; Stilbenes; Treatment Outcome

This study investigated the influence of carrier oils on the

Topics: Animals; Biological Availability; Caco-2 Cells; Catechin; Corn Oil; Delayed-Action Preparations; Emulsions; Excipients; Gonads; Humans; Mice; Micelles; Oils; Pectinidae; Proteins; Stilbenes

The co-encapsulation of multiple bioactive components in a carrier may produce synergistic effects and improve health benefits. In this study, the interactions of β-lactoglobulin (β-LG) with epigallocatechin-3-gallate (EGCG) and/or piceatannol (PIC)/oxyresveratrol (OXY) were investigated by multispectroscopic techniques, isothermal titration calorimetry, and molecular docking. The static quenching mechanism of β-LG by EGCG, PIC and OXY was confirmed by fluorescence spectroscopy and UV-vis absorption difference spectroscopy. The binding sites of these three polyphenols in β-LG were identified by site marking fluorescence experiments and molecular docking. The thermodynamic parameters of the β-LG + EGCG/PIC/OXY binary complex and β-LG + EGCG + PIC/OXY ternary complex were obtained from fluorescence data and used to analyze the main driving force for complex formation. The exothermic binding process was further confirmed by isothermal titration calorimetry. The α-helical content, particle size and morphology of free and ligand-bound β-LG were determined by circular dichroism spectroscopy, dynamic light scattering and transmission electron microscopy, respectively. The effect of EGCG, PIC and OXY on the conformation of β-LG was studied by Fourier transform infrared spectroscopy. In addition, the maximum synergistic antioxidant activity between EGCG and PIC/OXY was obtained by response surface analysis. The effects of β-LG in the binary and ternary systems on the antioxidant activity, stability, solubility and cytotoxicity of the polyphenols were also studied. Finally, the different cytotoxicities of the complexes and nanoparticles of the binary and ternary systems were compared. The results of this study are expected to provide a theoretical basis for the development of β-LG-based carriers co-encapsulating a variety of bioactive components.

Topics: Antioxidants; Catechin; In Vitro Techniques; Lactoglobulins; Molecular Docking Simulation; Plant Extracts; Protein Binding; Spectrometry, Fluorescence; Stilbenes

The anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid cancer with a high mortality rate. Since nutraceuticals may exert beneficial effects on tumor biology, here, effects of four of these compounds [resveratrol, genistein, curcumin and epigallocatechin-3-gallate (EGCG)] on ATC cell lines were investigated.. Two ATC-derived cell lines were used: SW1736 and 8505C. Cell viability and in vitro aggressiveness was tested by MTT and soft agar assays. Apoptosis was investigated by Western Blot, using an anti-cleaved-PARP antibody. mRNA and miRNA levels were quantified by real-time PCR.. All tested nutraceuticals caused in both cell lines decrease of cell viability and increase of apoptosis. In contrast, only curcumin reduced in vitro aggressiveness in both SW1736 and 8505C cell lines, while genistein and EGCG determined a reduction of colony formation only in 8505C cells. Effects on genes related to the thyroid-differentiated phenotype were also tested: resveratrol and genistein administration determined the increment of almost all tested mRNAs in both cell lines. Instead curcumin and EGCG treatments had opposite effects in the two cell lines, causing the increment of almost all the mRNAs in 8505C cells and their reduction in SW1736. Finally, effects of nutraceuticals on levels of several miRNAs, known as important in thyroid cancer progression (hsa-miR-221, hsa-miR-222, hsa-miR-21, hsa-miR-146b, hsa-miR-204), were tested. Curcumin induced a strong and significant reduction of all miR analyzed, except for has-miR-204, in both cell lines.. Altogether, our results clearly indicate the anti-cancer proprieties of curcumin, suggesting the promising use of this nutraceutical in ATC treatment. Resveratrol, genistein and EGCG have heterogeneous effects on molecular features of ATC cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Catechin; Cell Differentiation; Cell Growth Processes; Cell Line, Tumor; Curcumin; Dietary Supplements; Genistein; Humans; MicroRNAs; Resveratrol; Stilbenes; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

Frozen-thawed boar semen suffer a fertility decrease that negatively affects its widespread use. In recent years supplementing frozen-thawed boar sperm with different antioxidants gave interesting and promising results; the aim of the present work was to study the effect of supplementing boar sperm thawing medium for 1 h with combination of epigallocatechin-3-gallate (EGCG, 50 μM) and Resveratrol (R, 2 mM), on boar sperm motility (assessed by CASA), viability, acrosome integrity, mitochondrial function, lipid peroxidation and DNA integrity (assessed by flow cytometry), protein tyrosine phosphorylation (assessed by immunofluorescence) and on in vitro fertilization (IVF). Our results demonstrate that sperm motility is negatively affected by R (alone or associated with EGCG, p < 0.05) in comparison to control and EGCG groups both at 1 h and 4 h; this effect is evident both in average motility parameters and in single cells kinematics, studied by cluster analysis, that showed the presence of a specific cell population with simil-hyperactivated features in R group (p < 0.01). Viability, acrosome integrity, mitochondrial functionality and lipid peroxidation are not influenced by the addition of the antioxidants; finally, DNA integrity is negatively influenced by R (both alone or associated with EGCG) both at 1 h and 4 h incubation (p < 0.05). Finally, tyrosine phosphorylated protein immunolocalization, used as capacitation parameter, is not affected by the different treatments. Penetration rate is strongly enhanced by R, both alone or associated with EGCG (p < 0.05); EGCG increases penetration rate as well but to a lower extent. Our findings demonstrate that the combination of R and EGCG could positively affect frozen-thawed boar sperm fertility in vitro; the effect is evident also in R groups, thus demonstrating that this antioxidant is predominant, and no synergic effect is present. Some insights are needed to understand if, in particular R (that showed the strongest effect) could be profitably used for artificial insemination in vivo, given the detrimental effect of this molecule on both sperm motility and DNA integrity.

Topics: Animals; Catechin; Fertilization in Vitro; Male; Resveratrol; Semen Analysis; Spermatozoa; Stilbenes; Swine

Previous studies of the neuroprotective activity of polyphenols have used ununiform culture systems, making it difficult to compare their neuroprotective potency. We have established a new and simple method for preparing differentiated PC12 cells by removing the toxic coating step. Cells were induced to differentiate with the nerve growth factor (NGF) in a serum-free medium, without a medium change, but with a one-time overlay supplementation of NGF. The optimal inoculation density of the cells was 6⁻12 × 10³ cells/cm², and the presence of serum inhibited the differentiation. Neuroprotective activity could be quantified by the specific index (SI) value, that is, the ratio of the 50% cytotoxic concentration to the 50% effective concentration. Alkaline extract from the leaves of

Topics: Amyloid beta-Peptides; Animals; Catechin; Cell Culture Techniques; Cell Differentiation; Culture Media, Serum-Free; Curcumin; Hormesis; Nerve Growth Factor; Neurons; Neuroprotective Agents; PC12 Cells; Plant Extracts; Plant Leaves; Polyphenols; Rats; Resveratrol; Sasa; Stilbenes; Taxoids

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) have been studied as potential carriers for both dermal and transdermal drug delivery. SLN contain lipid droplets that are fully crystallized and have a highly-ordered crystalline structure. NLC are modified SLN in which the lipid phase contains both solid and liquid lipids at room temperature. SLN and NLC are thought to combine the advantages of polymeric particles, liposomes and emulsions. Therefore they provide high encapsulation percentages, better protection for incorporated actives and allow for control of desired release profile. In this work, Resveratrol, Vitamin E (VE), and Epigallocatechin Gallate (EGCG) all potent antioxidants known to provide protection to the skin, were formulated into lipid nanoparticles. Several different formulations were successfully developed and demonstrated high uniformity and stability. Both resveratrol and VE lipid nanoparticles provided effective protection of actives against UV induced degradation. However, lipid nanoparticles did not show protection from UV degradation for EGCG in this work. An active release study exhibited a sustained release of resveratrol over 70% after 24h. Skin penetration studies showed that lipid nanoparticles directionally improved the penetration of resveratrol through the stratum corneum. Our findings suggest that lipid nanoparticles are promising viable carriers for the delivery of resveratrol and VE to provide longlasting antioxidant benefits to the skin.

Topics: Catechin; Drug Evaluation, Preclinical; Female; Humans; Lipid Metabolism; Lipids; Middle Aged; Nanoparticles; Organ Culture Techniques; Resveratrol; Skin; Skin Care; Stilbenes; Vitamin E

The biphenyl neolignan honokiol is a neuroprotectant which has been proposed as a treatment for central nervous system disorders such as Alzheimer's disease (AD). The death of cholinergic neurons in AD is attributed to multiple factors, including accumulation and fibrillation of amyloid beta peptide (Aβ) within the brain; metal ion toxicity; and oxidative stress. In this study, we used a transgenic Caenorhabditis elegans model expressing full length Aβ

Topics: Amyloid beta-Peptides; Animals; Biphenyl Compounds; Caenorhabditis elegans; Catechin; Chelating Agents; Cholinesterase Inhibitors; Drug Stability; Free Radical Scavengers; Humans; Iron; Lignans; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; Paralysis; Peptide Fragments; Picrates; Protein Aggregation, Pathological; Protein Multimerization; Resveratrol; Stilbenes

Although some naturally occurring polyphenols have been found to inhibit amyloid β (Aβ) fibril formation and reduce neuron cell toxicity in vitro, their exact inhibitory mechanism is unknown. In this work, discontinuous molecular dynamics combined with the PRIME20 force field and a newly built inhibitor model are performed to examine the effect of vanillin, resveratrol, curcumin, and epigallocatechin-3-gallate (EGCG) on the aggregation of Aβ(17-36) peptides. Four sets of peptide/inhibitor simulations are performed in which inhibitors (1) bind to Aβ(17-36) monomer (2) interfere with Aβ(17-36) oligomerization (3) disrupt a pre-formed Aβ(17-36) protofilament, and (4) prevent the growth of Aβ(17-36) protofilament. The single-ring compound, vanillin, slightly slows down but cannot inhibit the formation of a U-shaped Aβ(17-36) protofilament. The multiple-ring compounds, EGCG, resveratrol, and curcumin, redirect Aβ(17-36) from a fibrillar aggregate to an unstructured oligomer. The three aromatic groups of the EGCG molecule are in a stereo (nonplanar) configuration, helping it contact the N-terminal, middle, and C-terminal regions of the peptide. Resveratrol and curcumin bind only to the hydrophobic residues near peptide termini. The rank order of inhibitory effectiveness of Aβ(17-36) aggregation is as follows: EGCG > resveratrol > curcumin > vanillin, consistent with experimental findings on inhibiting full-length Aβ fibrillation. Furthermore, we learn that the inhibition effect of EGCG is specific to the peptide sequence, while those of resveratrol and curcumin are non-specific in that they stem from strong interference with hydrophobic side-chain association, regardless of the residues' location and peptide sequence. Our studies provide molecular-level insights into how polyphenols inhibit Aβ fibril formation, knowledge that could be useful for designing amyloid inhibitors.

Topics: Amyloid beta-Peptides; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Benzaldehydes; Catechin; Curcumin; Hydrophobic and Hydrophilic Interactions; Molecular Dynamics Simulation; Protein Aggregates; Resveratrol; Stilbenes

The activity of acetylcholinesterase (AChE) from human erythrocytes was tested in the presence of the phenolic compounds resveratrol and epigallocatechin-3-gallate (EGCG). Even though the stilbene barely changed this enzymatic activity, EGCG did inhibit AChE. Importantly, it preferentially acted on the membrane-bound enzyme rather than on its soluble form. Actually, it was shown that this flavonoid may bind to the red blood cell membrane surface, which may improve the interaction between EGCG and AChE. Therefore, caution should be taken when screening AChE inhibitors. In fact, testing compounds with the soluble form of the enzyme may underestimate the activity of some of these potential inhibitors, hence it would be advisable not to use them as a sole model system for screening. Moreover, erythrocyte AChE is proposed as a good model for these enzymatic assays. © 2016 BioFactors, 43(1):73-81, 2017.

Topics: Acetylcholinesterase; Catechin; Cholinesterase Inhibitors; Drug Evaluation, Preclinical; Erythrocyte Membrane; Humans; Inhibitory Concentration 50; Resveratrol; Stilbenes

Alzheimer's disease (AD) is the leading cause of dementia, and as its prevalence increases, so does its detrimental impact on society. The currently available therapies have limited efficacy, leaving AD patients on an irrevocably fatal path of this disease.. The purpose of this study was to test efficacy of a novel combinatorial treatment approach to alleviate AD-like pathology.. We selected four naturally occurring compounds and used them in different combinations to test their effect on AD-like pathology. Employing a well-established cell culture AD model system, we evaluated levels of several diverse biomarkers associated with a number of cellular pathways associated with AD. The readouts included: amyloid-β peptides, anti-inflammatory and anti-apoptotic proteins, oxidative enzymes, and reactive oxygen species.. Using this approach, we demonstrated that the compounds delivered in combination had higher efficacy than individual treatments. Specifically, we observed significant reduction in levels of the amyloid-β peptides, as well as pro-inflammatory proteins and reactive oxygen species. Similarly, delivery of compounds in combination resulted in an increased expression of anti-apoptotic proteins and anti-oxidative enzymes. Collectively, these modifications in AD pathology biomarkers reflect a promising therapeutic and preventive strategy to combat this disease.. The above findings support a novel therapeutic approach to address a currently unmet medical need, which would benefit not only AD patients and their caregivers, but also society as a whole.

Topics: Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Antipsychotic Agents; Catechin; Cell Line, Tumor; Cytokines; Drug Combinations; Gene Expression Regulation, Neoplastic; Humans; Melatonin; Mice; Mutation; Neuroblastoma; Peptide Fragments; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Resveratrol; Stilbenes; Transfection

Natural bioactive compounds are considered an excellent alternative strategy for developing effective, safe, and cost-effective antiobesity agents. The aim of this study was to investigate if combinations of soy bean genistein (G), green tea epigallocatechin-3-gallate (E), and/or grape resveratrol (R) at low dosages synergistically inhibit preadipocyte differentiation both in 3T3-L1 cells and human primary preadipocytes (HPAs). Our results show that combinations of G, E, and/or R additively inhibited preadipocyte differentiation (39-56% of control) both in 3T3-L1 cells at 30 μM and HPAs at 15 μM, while the individual compounds have no antiadipogenic effect at the selected concentrations. We also observed similar patterns that combinations of G, E, and/or R additively reduced protein expressions of peroxisome proliferator-activated receptor gamma (PPAR-γ) and CCAAT binding proteins alpha (C/EBP-α), the two key preadipocyte differentiation regulators, both in differentiated 3T3-L1 cells and HPAs. Moreover, combined G, E, and/or R attenuated protein expressions of fatty acid binding protein 4 and perilipin, two PPAR-γ/C/EBP-α downstream molecules in fat drop development in a very similar pattern, in inhibiting differentiation in preadipocytes. This combined antiadipogenic effect of G + E + R is additive, not synergistic according to our results and the Median-Effect Principle. In addition, we found that a lower concentration (15 μM) of G, E, and/or R is required in HPAs than the concentration (30 μM) needed in 3T3-L1 cells, to exert the combined antiadipogenic effect. These data suggest that combinations of G, E, and/or R intake or soy bean, green tea, and/or grape simultaneous consumption may prevent obesity in human being.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Catechin; CCAAT-Enhancer-Binding Protein-alpha; Fats; Genistein; Humans; Mice; PPAR gamma; Resveratrol; Stilbenes

Thawing is one of the most delicate process after semen cryopreservation as spermatozoa pass from a dormant metabolic stage to a sudden awakening in cellular metabolism. The rapid oxygen utilization leads to an overproduction of reactive oxygen species that can damage sperm cells, thus causing a significant decrease of fertilizing potential of frozen-thawed spermatozoa. Resveratrol (Res) is a natural grape-derived phytoalexin and Epigallocatechin-3-gallate (EGCG) is the major polyphenol in green tea (Camellia sinensis); both molecules are known to possess high levels of antioxidant activity. The objective of the present study was to assess the effect of different concentrations of Res (0.5, 1 or 2 mM; Experiment 1) or EGCG (25, 50 or 100 μM; Experiment 2) supplementation to thawing boar semen extender on sperm quality parameters (viability and acrosome integrity) and in vitro fertilization (IVF). Semen after thawing and dilution with three volumes of Beltsville Thawing Solution (BTS), was immediately divided in control group without antioxidants addition (CTR) and either Res or EGCG groups. Sperm viability and acrosome integrity were evaluated in CTR, Res or EGCG groups after 1 h of incubation at 37 °C. The addition of different doses of Res or EGCG to thawing extender for 1 h did not induce any effect on boar sperm viability and acrosome integrity. However, both Res and EGCG treated samples exhibited a significantly higher penetration rate compared with CTR when used for IVF. In particular the treatment with all the EGCG concentrations increased the penetration rate (P < 0.01) while only Res 2 mM induced a significant increase of this parameter (P < 0.01). In addition, EGCG 25 and 50 μM supplementation significantly increased total fertilization efficiency as compared to control (EGCG 25 μM: 40.3 ± 8.2 vs 26.8 ± 9.5, P < 0.05; EGCG 50 μM: 40.4 ± 7.8 vs 26.8 ± 9.5, P < 0.01). The same effect was observed with Res 2 mM (51.0 ± 7.6 vs 29.6 ± 11.3, P < 0.01). In conclusion, our results indicate that the addition of different doses of the two antioxidants to thawed spermatozoa for one hour, even if does not exert any effect on sperm viability and acrosome integrity, efficiently improves in vitro penetration rate. Moreover, both molecules (EGCG 25 and 50 μM and Res 2 mM) significantly increases the total efficiency of fertilization.

Topics: Acrosome; Animals; Antioxidants; Catechin; Cryopreservation; Dose-Response Relationship, Drug; Female; Fertilization in Vitro; Male; Resveratrol; Semen Preservation; Sperm Motility; Sperm-Ovum Interactions; Spermatozoa; Stilbenes; Sus scrofa

The main scope of the present study was to analyze the membrane interaction of members of different classes of polyphenols, i.e. resveratrol, naringenin, epigallocatechin gallate and enterodiol, in model systems of different compositions and phase states. In addition, the possible association between membrane affinity and membrane protection against both lipid oxidation and bilayer-disruptive compounds was studied. Gibbs monolayer experiments indicated that even though polyphenols showed poor surface activity, it readily interacted with lipid films. Actually, a preferential interaction with expanded monolayers was observed, while condensed and cholesterol-containing monolayers decreased the affinity of these phenolic compounds. On the other hand, fluorescence anisotropy studies showed that polyphenols were able to modulate membrane order degree, but again this effect was dependent on the cholesterol concentration and membrane phase state. In fact, cholesterol induced a surface rather than deep into the hydrophobic core localization of phenolic compounds in the membranes. In general, the polyphenolic molecules tested had a better antioxidant activity when they were allowed to get inserted into the bilayers, i.e. in cholesterol-free membranes. On the other hand, a membrane-protective effect against bilayer permeabilizing activity of lysozyme, particularly in the presence of cholesterol, could be assessed. It can be hypothesized that phenolic compounds may protect membrane integrity by loosely covering the surface of lipid vesicles, once cholesterol push them off from the membrane hydrophobic core. However, this cholesterol-driven distribution may lead to a reduced antioxidant activity of linoleic acid double bonds.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Antioxidants; Catechin; Cholesterol; Dimyristoylphosphatidylcholine; Flavanones; Fluorescence Polarization; Hydrophobic and Hydrophilic Interactions; Lignans; Linoleic Acid; Lipid Bilayers; Lipid Peroxidation; Liposomes; Muramidase; Reactive Oxygen Species; Resveratrol; Stilbenes; Surface Properties

Inflammation is an important therapeutic target. Due to their potency, steroidal drugs dominate the current treatment of inflammatory disorders. However, steroidal drugs can also exert a broad range of side effects and appear not always effective. This calls for the development of alternative drugs with a different mechanism of action, which are likely to be found in the field of natural products (NPs). For many NPs strong anti-inflammatory effects have been described, but usually investigating a single compound in a single assay. In this study, eight promising NPs were selected and tested against the strong anti-inflammatory drug prednisolone. For this head-to-head comparison, in vitro assays were used which represent different pathways of the inflammatory response: TNF-α and IL-6 expression by macrophages, IL-8 expression by colon epithelial cells, ROS production in polymorphonuclear leukocytes and platelet activation in whole blood. Performance profiles were established which allowed us to identify curcumin, berberine chloride and epigallocatechin gallate as potential alternatives for prednisolone or other glucocorticoids in inflammation.

Topics: Acetophenones; Animals; Anti-Inflammatory Agents; Berberine; Biological Products; Blood Platelets; Caco-2 Cells; Catechin; Cell Line; Curcumin; Humans; Interleukin-6; Interleukin-8; Macrophages; Mice; Neutrophils; Platelet Activation; Pravastatin; Prednisolone; Primary Cell Culture; Reactive Oxygen Species; Stilbenes; Tumor Necrosis Factor-alpha

The process of amyloid formation by the normally soluble hormone islet amyloid polypeptide (IAPP) contributes to β-cell death in type 2 diabetes and in islet transplants. There are no clinically approved inhibitors of islet amyloidosis, and the mode of action of existing inhibitors is not well-understood. Resveratrol, a natural polyphenol, has been reported to inhibit amyloid formation by IAPP and by the Alzheimer's disease Aβ peptide. The mechanism of action of this compound is not known, nor is its mode of interaction with IAPP. In this study, we use a series of IAPP variants to examine possible interactions between resveratrol and IAPP. Fluorescence assays, transmission electron microscopy, and mass spectrometry demonstrate that resveratrol is much less effective as an inhibitor of IAPP amyloid formation than the polyphenol (-)-epigallocatechin 3-gallate (EGCG) and, unlike EGCG, does not significantly disaggregate preformed IAPP amyloid fibrils. Resveratrol is also shown to interfere with thioflavin-T assays. His-18 mutants, a truncation mutant, mutants of each of the aromatic residues, and mutants of Arg-11 of IAPP were examined. Mutation of His to Gln or Leu weakens the ability of resveratrol to inhibit amyloid formation by IAPP, as do mutations of Arg-11, Phe-15, or Tyr-37 to Leu, and truncation to form the variant Ac 8-37-IAPP, which removes the first seven residues to eliminate Lys-1 and the N-terminal amino group. In contrast, replacement of Phe-23 with Leu has a smaller effect. The data highlight Phe-15, His-18, and Tyr-37 as being important for IAPP-resveratrol interactions and are consistent with a potential role of the N-terminus and Arg-11 in polypeptide-resveratrol interactions.

Topics: Amino Acid Sequence; Amino Acids, Aromatic; Amyloid; Arginine; Benzothiazoles; Catechin; DNA Mutational Analysis; Histidine; Humans; Islet Amyloid Polypeptide; Molecular Sequence Data; Mutant Proteins; Resveratrol; Spectrometry, Mass, Electrospray Ionization; Stilbenes; Structure-Activity Relationship; Thiazoles

Ubiquitin activating enzyme E1-like (UBE1L) is the activating enzyme for ISG15ylation (ISG15, interferon stimulated gene 15). UBE1L is thought to be a candidate tumor suppressor gene and has positive activity against stress responses such as viral infections. Both type I interferon and retinoic acid are known to induce UBE1L expression. However, the molecular mechanism of UBE1L regulation is unclear. Here, the effect of several chemopreventive polyphenols on UBE1L expression in human bronchial epithelial cells (Beas-2B) was investigated. Lower concentrations of curcumin, (-)-epigallocatechin-3-gallate (EGCG) and resveratrol upregulated UBE1L, while high concentrations of curcumin, EGCG and resveratrol downregulated UBE1L levels. Interestingly, curcumin, EGCG and resveratrol diminished intracellular reactive oxygen species (ROS) at lower concentrations but generated ROS at higher concentrations. The antioxidant N-acetylcysteine (NAC) increased UBE1L protein levels, while pro-oxidants such as hydrogen peroxide and tert-butyl hydroperoxide (tBHP) decreased UBE1L protein levels, indicating that the intracellular redox status is associated with UBE1L expression. Kinase inhibitors were used to examine the contribution of mitogen-activated protein kinase (MAPK) activity to the polyphenol-regulated UBE1L. Only the inhibition of c-Jun N-terminal kinase (JNK) significantly reduced UBE1L expression. Knockdown of nuclear factor erythroid-2 related factor-2 (Nrf2) caused a concomitant decrease in UBE1L protein levels. It is concluded from the above mentioned results that JNK/Nrf2 signal pathway is involved in the regulation of UBE1L via intracellular ROS status when cells came in contact with polyphenols.

Topics: Antineoplastic Agents; Bronchi; Catechin; Cell Line; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Epithelial Cells; Gene Expression Regulation; Humans; Polyphenols; Reactive Oxygen Species; Resveratrol; Signal Transduction; Stilbenes; tert-Butylhydroperoxide; Ubiquitin-Activating Enzymes

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

Anticancer polyphenolic nutraceuticals from fruits, vegetables, and spices are generally recognized as antioxidants, but can be prooxidants in the presence of copper ions. We earlier proposed a mechanism for such activity of polyphenols and now we provide data in multiple cancer cell lines in support of our hypothesis.. Through multiple assays, we show that polyphenols luteolin, apigenin, epigallocatechin-3-gallate, and resveratrol are able to inhibit cell proliferation and induce apoptosis in different cancer cell lines. Such cell death is prevented to a significant extent by cuprous chelator neocuproine and reactive oxygen species scavengers. We also show that normal breast epithelial cells, cultured in a medium supplemented with copper, become sensitized to polyphenol-induced growth inhibition.. Since the concentration of copper is significantly elevated in cancer cells, our results strengthen the idea that an important anticancer mechanism of plant polyphenols is mediated through intracellular copper mobilization and reactive oxygen species generation leading to cancer cell death. Moreover, this prooxidant chemopreventive mechanism appears to be a mechanism common to several polyphenols with diverse chemical structures and explains the preferential cytotoxicity of these compounds toward cancer cells.

Topics: Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Apigenin; Apoptosis; Catechin; Cell Death; Cell Line, Tumor; Cell Proliferation; Chelating Agents; Copper; Drug Screening Assays, Antitumor; Humans; Luteolin; Phenanthrolines; Polyphenols; Reactive Oxygen Species; Resveratrol; Stilbenes

Modulation of miR-33 and miR-122 has been proposed to be a promising strategy to treat dyslipidemia and insulin resistance associated with obesity and metabolic syndrome. Interestingly, specific polyphenols reduce the levels of these mi(cro)RNAs. The aim of this study was to elucidate the effect of polyphenols of different chemical structure on miR-33a and miR-122 expression and to determine whether direct binding of the polyphenol to the mature microRNAs (miRNAs) is a plausible mechanism of modulation. The effect of two grape proanthocyanidin extracts, their fractions and pure polyphenol compounds on miRNA expression was evaluated using hepatic cell lines. Results demonstrated that the effect on miRNA expression depended on the polyphenol chemical structure. Moreover, miR-33a was repressed independently of its host-gene SREBP2. Therefore, the ability of resveratrol and epigallocatechin gallate to bind miR-33a and miR-122 was measured using (1)H NMR spectroscopy. Both compounds bound miR-33a and miR-122 and differently. Interestingly, the nature of the binding of these compounds to the miRNAs was consistent with their effects on cell miRNA levels. Therefore, the specific and direct binding of polyphenols to miRNAs emerges as a new posttranscriptional mechanism by which polyphenols could modulate metabolism.

Topics: Animals; ATP Binding Cassette Transporter 1; Catechin; Cell Line, Tumor; Fatty Acid Synthases; Flavonoids; Humans; Liver; MicroRNAs; Plant Extracts; Polyphenols; Rats; Resveratrol; Sterol Regulatory Element Binding Protein 2; Stilbenes; Vitis

Gold nanoparticles (GNPs) are likely to provide an attractive platform for combining a variety of biophysicochemical properties into a unified nanodevice with great therapeutic potential. In this study we investigated the capabilities of three different natural polyphenols, epigallocatechin-3-gallate (EGCG), resveratrol (RSV), and fisetin (FS), to allow synergistic chemical reduction of gold salts to GNPs and stabilization in a single-step green process. Moreover, antioxidant properties of the nanosystems, as well as preliminary antiproliferative activity and apoptotic process investigation of model EGCG-GNPs on stable clones of neuroblastoma SH-SY5Y cells expressing CFP-DEVD-YFP reporter, were examined.. The GNPs were characterized by physicochemical techniques, polyphenol content, and in vitro stability. The antioxidant activity of the GNPs was also determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) cation (ABTS) radical-scavenging assays. Stable clones of neuronal SH-SY5Y-CFP-DEVD-YFP were generated and characterized, and cell viability after treatment with EGCG-GNPs was assessed after 72 hours through a 3(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Activation of the apoptotic pathways was also investigated by Western blot analysis.. With a diameter in the size range of 10-25 nm, the obtained nanoparticles (NPs) were found to contain 2.71%, 3.23%, and 5.47% of EGCG, RSV, and FS, respectively. Nanoprototypes exhibited remarkable in vitro stability in various media, suggesting that NP surface coating with phytochemicals prevents aggregation in different simulated physiological conditions. The scavenging activities for DPPH and ABTS were highly correlated with EGCG, RSV, and FS content. Moreover, high correlation coefficients between the ABTS and DPPH values were found for the prepared nanosystems. EGCG-GNPs induce a dose-dependent reduction on SH-SY5Y-CFP-DEVD-YFP cell viability that is likely to involve the activation of the apoptotic pathways, similarly to free EGCG, as suggested by the processing of the CFP-DEVD-YFP reporter.. These results prompted us to propose the ecofriendly synthesized EGCG-, RSV-, and FS-based nanogold conjugates as suitable carriers for bioactive polyphenols to be used for the treatment of disorders associated with oxidative stress, including neurodegenerative disorders, cardiovascular disease, and cancer.

Topics: Antioxidants; Apoptosis; Catechin; Cell Line, Tumor; Cell Proliferation; Drug Stability; Flavonoids; Flavonols; Gold; Green Chemistry Technology; Humans; Metal Nanoparticles; Polyphenols; Resveratrol; Stilbenes

Nutrient depletion, which is one of the physiological triggers of autophagy, results in the depletion of intracellular acetyl coenzyme A (AcCoA) coupled to the deacetylation of cellular proteins. We surmise that there are 3 possibilities to mimic these effects, namely (i) the depletion of cytosolic AcCoA by interfering with its biosynthesis, (ii) the inhibition of acetyltransferases, which are enzymes that transfer acetyl groups from AcCoA to other molecules, mostly leucine residues in cellular proteins, or (iii) the stimulation of deacetylases, which catalyze the removal of acetyl groups from leucine residues. There are several examples of rather nontoxic natural compounds that act as AcCoA depleting agents (e.g., hydroxycitrate), acetyltransferase inhibitors (e.g., anacardic acid, curcumin, epigallocatechin-3-gallate, garcinol, spermidine) or deacetylase activators (e.g., nicotinamide, resveratrol), and that are highly efficient inducers of autophagy in vitro and in vivo, in rodents. Another common characteristic of these agents is their capacity to reduce aging-associated diseases and to confer protective responses against ischemia-induced organ damage. Hence, we classify them as "caloric restriction mimetics" (CRM). Here, we speculate that CRM may mediate their broad health-improving effects by triggering the same molecular pathways that usually are elicited by long-term caloric restriction or short-term starvation and that imply the induction of autophagy as an obligatory event conferring organismal, organ- or cytoprotection.

Topics: Acetyl Coenzyme A; Anacardic Acids; Animals; Autophagy; Caloric Restriction; Catalysis; Catechin; Curcumin; Food Deprivation; Humans; Leucine; Mice; Models, Animal; Niacinamide; Plant Extracts; Resveratrol; Spermidine; Starvation; Stilbenes; Terpenes

Epigallocatechin-3-gallate (EGCG), a catechin gallate ester, is the major component of green tea and has been demonstrated to inhibit tumor growth as well as inhibit smooth muscle cell migration. We evaluated the effect of the phytochemicals resveratrol, allicin, sulforaphane (SFN), and EGCG on intimal hyperplasia in the carotid artery injury model.. Intimal hyperplasia was induced in carotid arteries of adult Sprague-Dawley rats with a wire injury. Experimental animals received intraperitoneal injections of one of the four phytochemicals daily beginning 1 day prior to surgery and continued for up to 4 weeks. Control animals were administered saline. Carotid specimens were harvested at 2 weeks and subjected to quantitative image analysis. In addition, EGCG specimens were analyzed for cell proliferation, immunohistochemistry, and Western blot analysis.. Quantitative image analysis showed significant phytochemical suppression of intimal hyperplasia at 2 and 4 weeks postoperatively with EGCG (62% decrease in intimal area). Significant decreases were also noted at 2 weeks for SFN (56%) and resveratrol (44%), whereas the decrease with allicin (24%) was not significant. Quantification of intimal hyperplasia by intima:media ratio showed similar results. Cell proliferation assay of specimens demonstrated suppression by EGCG. Immunohistochemical staining of EGCG-treated specimens showed extracellular signal-regulated kinase (ERK) suppression but not of the c-jun N-terminal kinase or p38 pathways. Western blot analysis confirmed reduced ERK activation in arteries treated with EGCG.. Intraperitoneal injection of the phytochemicals EGCG, SFN, resveratrol, and allicin have suppressive effects on the development of intimal hyperplasia in the carotid artery injury model, with maximal effect due to EGCG. The mechanism of EGCG action may be due to inhibition of ERK activation. EGCG may affect a common pathway underlying either neoplastic cellular growth or vascular smooth muscle cellular proliferation.

Topics: Animals; Cardiovascular Agents; Carotid Artery Injuries; Carotid Artery, Common; Carotid Intima-Media Thickness; Catechin; Cell Proliferation; Disease Models, Animal; Disulfides; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Hyperplasia; Injections, Intraperitoneal; Isothiocyanates; Male; Neointima; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Sulfinic Acids; Sulfoxides; Time Factors

The aim of this study was to determine the protective effect of quercetin, epigallocatechingallate, resveratrol, and rutin against the disruption of epithelial integrity induced by indomethacin in Caco-2 cell monolayers. Indomethacin decreased the transepithelial electrical resistance and increased the permeability of the monolayers to fluorescein-dextran. These alterations were abolished by all the tested polyphenols but rutin, with quercetin being the most efficient. The protective effect of quercetin was associated with its capacity to inhibit the redistribution of ZO-1 protein induced in the tight junction by indomethacin or rotenone, a mitochondrial complex-I inhibitor, and to prevent the decrease of ZO-1 and occludin expression induced by indomethacin. The fact that the antioxidant polyphenols assayed in this study differ in their protective capacity against the epithelial damage induced by indomethacin suggests that this damage is due to the ability of this agent to induce not only oxidative stress but also mitochondrial dysfunction.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Caco-2 Cells; Catechin; Enterocytes; Functional Food; Gene Expression Regulation; Humans; Indomethacin; Occludin; Permeability; Polyphenols; Protein Transport; Quercetin; Resveratrol; Stilbenes; Tight Junctions; Zonula Occludens-1 Protein

Much evidence indicates that various naturally occurring compounds have an anti-cancer effect, but the detailed mechanisms are not well understood. In this study, we selected anti-cancer phytochemicals such as epigallocatechin-3-gallate (EGCG), resveratrol (RES) and α-mangostin (α-M), all of which are well-characterized chemopreventive agents. We sought to elucidate the mechanism of their anti-cancer effects and the synergistic effects obtained by combined treatment with the anti-cancer drug 5-fluorouracil (5-FU) in three human colon cancer cell lines. The numbers of viable cells were consistently decreased by the treatment with EGCG, RES or α-M at more than 10 μM in all three cell lines tested. All compounds mainly induced apoptosis and suppressed the PI3K/Akt signaling pathway. Additionally, α-M, which had the greatest PI3K/Akt-suppressing activity, also suppressed MAP kinase (MAPK)/Erk1/2 signaling. Importantly, the combination treatment with RES and 5-FU induced a remarkably synergistic enhancement of growth inhibition and apoptosis through the additional suppression of the MAPK/Erk1/2 signaling pathway in colon cancer DLD-1 cells. Interestingly, RES increased the intracellular expression level of miR-34a, which down-regulated the target gene E2F3 and its downstream Sirt1, resulting in growth inhibition. These findings indicate that these compounds functioned as chemosensitizers when combined with anti-cancer drugs through the modulation of apoptotic and growth-related signaling pathways. Also, RES exerted its anti-cancer activity in part through a newly defined mechanism, i.e., the miR-34a/E2F3/Sirt1 cascade.

Topics: Antineoplastic Agents; Apoptosis; Catechin; Cell Line, Tumor; Colonic Neoplasms; Drug Resistance, Neoplasm; Humans; MicroRNAs; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphatidylinositol 3-Kinases; Resveratrol; Signal Transduction; Stilbenes; Xanthones

Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by extracellular deposits of amyloid beta (Aβ) protein and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. Various studies suggest that the tau tangle pathology, which lies downstream to Aβ pathology, is essential to produce AD-associated clinical phenotype and thus treatments targeting tau pathology may prevent or delay disease progression effectively. In this context, our present study examined three polyphenol compounds (curcumin, EGCG and resveratrol) for their possible activity against two endogenous proteins (BAG2 and LAMP1) that are shown to play a vital role in clearing tau tangles from neurons. Human epidemiological and animal data suggest potential positive effects of these polyphenols against AD. Here, primary rat cortical neurons treated with these polyphenols significantly up-regulated BAG2 levels at different concentrations, while only EGCG upregulated LAMP1 levels, although at higher concentrations. Importantly, curcumin doubled BAG2 levels at low micromolar concentrations that are clinically relevant. In addition, curcumin also downregulated levels of phosphorylated tau, which may be potentially attributed to the curcumin-induced upregulation in BAG2 levels in the neurons. The present results demonstrate novel activity of polyphenol curcumin in up-regulating an anti-tau cochaperone BAG2 and thus, suggest probable benefit of curcumin against AD-associated tauopathy.

Topics: Animals; Catechin; Cerebral Cortex; Curcumin; Lysosomal Membrane Proteins; Molecular Chaperones; Neurons; Primary Cell Culture; Rats; Resveratrol; Stilbenes; tau Proteins; Up-Regulation

Can resveratrol and epigallocatechin-3-gallate (EGCG) inhibit the growth and survival of endometriotic-like lesions in vivo in a BALB/c model of endometriosis, and in vitro in primary cultures of human endometrial epithelial cells (EECs)?. Resveratrol and EGCG exerted a potent inhibitory effect on the development of endometriosis in a BALB/c murine model and on the survival of EECs.. Endometriosis is a common condition associated with infertility and pelvic pain in women of reproductive age. Resveratrol and EGCG are two polyphenols with anticarcinogenic and antioxidant properties that have been proposed as natural therapies to treat endometriosis.. Fifty-six 2-month-old female BALB/c mice underwent surgical induction of endometriosis. Treatments with resveratrol or EGCG started 15 days post-surgery and continued for 4 weeks. Human biopsies were taken with a metal Novak curette from the posterior uterine wall from 16 patients with untreated endometriosis and 15 controls who underwent diagnostic laparoscopy for infertility.. After the treatments, animals were sacrificed and lesions were counted, measured, excised and fixed. Immunohistochemistry for proliferating cell nuclear antigen and CD34 was performed for cell proliferation and vascularization assessment in the lesions. The terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) technique was performed for apoptosis evaluation. Peritoneal fluid was collected to analyze vascular endothelial growth factor levels. Human EECs were purified from proliferative-phase endometrial biopsies and cultured. The effect of both polyphenols on cell proliferation was determined by a colorimetric assay using the CellTiter 96®AQueous One Solution Cell Proliferation Assay kit and on apoptosis by the TUNEL technique, using an In Situ Cell Death Detection Kit with Fluorescein.. In the mouse model, both treatments significantly reduced the mean number (P < 0.05 versus control) and the volume of established lesions (P < 0.05 versus control). Treatments consistently statistically significantly diminished cell proliferation (resveratrol P < 0.01 and EGCG P < 0.05, versus control), reduced vascular density (resveratrol P < 0.01 and EGCG P < 0.001, versus control) and increased apoptosis within the lesions (resveratrol P < 0.01 and EGCG P < 0.05, versus control). Both compounds induced reduction in human EEC proliferation (P < 0.05 versus basal) and increased apoptosis (P < 0.05 versus basal) in primary cultures.. In vitro studies were only carried out in epithelial cells from human eutopic endometrium.. The present findings are promising and will assist the development of novel natural treatments for endometriosis.. This study was supported by ANPCYT (PICT 6384 BID 1201 OC-AR) and CONICET (PIP 5471), Argentina. None of the authors has any conflict of interest to declare.

Topics: Angiogenesis Inhibitors; Animals; Antioxidants; Apoptosis; Catechin; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Endometriosis; Endometrium; Female; Humans; Injections, Intraperitoneal; Intestinal Diseases; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Random Allocation; Resveratrol; Stilbenes

Soluble oligomers of the amyloid-β (Aβ) peptide cause neurotoxicity, synaptic dysfunction, and memory impairments that underlie Alzheimer disease (AD). The cellular prion protein (PrP(C)) was recently identified as a high affinity neuronal receptor for Aβ oligomers. We report that fibrillar Aβ oligomers recognized by the OC antibody, which have been shown to correlate with the onset and severity of AD, bind preferentially to cells and neurons expressing PrP(C). The binding of Aβ oligomers to cell surface PrP(C), as well as their downstream activation of Fyn kinase, was dependent on the integrity of cholesterol-rich lipid rafts. In SH-SY5Y cells, fluorescence microscopy and co-localization with subcellular markers revealed that the Aβ oligomers co-internalized with PrP(C), accumulated in endosomes, and subsequently trafficked to lysosomes. The cell surface binding, internalization, and downstream toxicity of Aβ oligomers was dependent on the transmembrane low density lipoprotein receptor-related protein-1 (LRP1). The binding of Aβ oligomers to cell surface PrP(C) impaired its ability to inhibit the activity of the β-secretase BACE1, which cleaves the amyloid precursor protein to produce Aβ. The green tea polyphenol (-)-epigallocatechin gallate and the red wine extract resveratrol both remodeled the fibrillar conformation of Aβ oligomers. The resulting nonfibrillar oligomers displayed significantly reduced binding to PrP(C)-expressing cells and were no longer cytotoxic. These data indicate that soluble, fibrillar Aβ oligomers bind to PrP(C) in a conformation-dependent manner and require the integrity of lipid rafts and the transmembrane LRP1 for their cytotoxicity, thus revealing potential targets to alleviate the neurotoxic properties of Aβ oligomers in AD.

Topics: Amyloid beta-Peptides; Animals; Caspase 3; Catechin; Cell Line, Tumor; Cell Membrane; Hippocampus; Humans; Low Density Lipoprotein Receptor-Related Protein-1; Membrane Microdomains; Microscopy, Fluorescence; Neurons; Prions; Protein Binding; Proto-Oncogene Proteins c-fyn; Rats; Rats, Wistar; Resveratrol; RNA Interference; Stilbenes; Tea

Endometrial cancer, in developed countries, is the most common malignancy of the female genital tract. Surgery and radiotherapy are successful in many patients but systemic and recurrent diseases have no consistently effective treatments, and for high grade advanced disease the prognosis is poor. The study investigated characteristics of adrenomedullin in endometrial cancer to assist in identifying targets for developing treatments.. Endometrial samples of women with and without cancer, and the Ishikawa cell line were used to investigate adrenomedullin mRNA regulation, peptide expression, adrenomedullin secretion and effects of adrenomedullin on VEGF secretion.. Expression of adrenomedullin mRNA was upregulated compared to that in healthy post-menopausal endometria. Adrenomedullin secretion was increased by cobalt chloride in this study. Secretion was reduced by the naturally-occurring compounds, (-)-epigallocatechin gallate (EGCG) and 3,4',5-trihydroxystilbene (resveratrol), which we have previously demonstrated to also suppress VEGF secretion in endometrial tumour tissue. We noted, for the first time, that adrenomedullin enhanced VEGF secretion from tumour cells.. Increased adrenomedullin expression may result in amplifying both tumorigenic and angiogenic activities. A substantial impact on growth of tumours may result in vivo as a consequence of the synergism between adrenomedullin and VEGF. Adrenomedullin, which has altered cellular characteristics in tumour compared to healthy tissue, offers an understudied target with potential to modify endometrial cancer behaviour, complementing other treatments.

Topics: Adenocarcinoma; Adrenomedullin; Biomarkers, Tumor; Case-Control Studies; Catechin; Cell Line, Tumor; Cobalt; Endometrial Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Grading; Resveratrol; RNA, Messenger; Stilbenes; Up-Regulation; Vascular Endothelial Growth Factor A

The beneficial effects of dietary polyphenols on health are due not only to their antioxidant properties but also to their antibacterial, anti-inflammatory and/or anti-tumoral activities. It has recently been proposed that protection of mitochondrial function (which is altered in several diseases such as Alzheimer, Parkinson, obesity and diabetes) by these compounds, may be important in explaining the beneficial effects of polyphenols on health. The aim of this study was to evaluate the protective effects of dietary polyphenols quercetin, rutin, resveratrol and epigallocatechin gallate against the alterations of mitochondrial function induced by indomethacin (INDO) in intestinal epithelial Caco-2 cells, and to address the mechanism involved in such damaging effect by INDO, which generates oxidative stress. INDO concentration dependently decreases cellular ATP levels and mitochondrial membrane potential in Caco-2 cells after 20min of incubation. INDO also inhibits the activity of mitochondrial complex I and causes accumulation of NADH; leading to overproduction of mitochondrial O(2)()(-), since it is prevented by pyruvate. Quercetin (0.01mg/ml), resveratrol (0.1mg/ml) and rutin (1mg/ml) protected Caco-2 cells against INDO-induced mitochondrial dysfunction, while no protection was observed with epigallocatechin gallate. Quercetin was the most efficient in protecting against mitochondrial dysfunction; this could be due to its ability to enter cells and accumulate in mitochondria. Additionally its structural similarity with rotenone could favor its binding to the ubiquinone site of complex I, protecting it from inhibitors such as INDO or rotenone. These findings suggest a possible new protective role for dietary polyphenols for mitochondria, complementary of their antioxidant property. This new role might expand the preventive and/or therapeutic use of PPs in conditions involving mitochondrial dysfunction and associated with increased oxidative stress at the cellular or tissue levels.

Topics: Adenosine Triphosphate; Caco-2 Cells; Catechin; Drug Interactions; Electron Transport Complex I; Gastrointestinal Diseases; Humans; Indomethacin; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Diseases; Quercetin; Resveratrol; Rutin; Stilbenes; Superoxides

Cancer chemoprevention with low-dose combinations of bioactive phytochemicals instead of single agents has been suggested to induce less toxicity and improve efficacy. In this study, we selected four plant food-based phytochemicals, viz. chlorogenic acid (CLA), pelargonidin (PEL), resveratrol (RES) and epigallocatechin gallate (EGCG) to evaluate the in vitro chemoprevention of genotoxic damage in HL-60 cells. These agents were tested either individually or as a combination at two concentrations (with a 10-fold difference) against the genotoxins mitomycin C (MMC), diepoxybutane (DEB) and patulin (PAT). Our preliminary ferric reducing antioxidant power (FRAP) assay demonstrated additive effects when PEL, CLA, RES and EGCG were combined. Results of the cytokinesis-block micronucleus test showed significant protection against genotoxic damage induced by PAT, DEB and MMC when CLA, PEL, RES and EGCG were tested individually. This protective effect of the phytochemicals was not concentration-related. Both low- and high-concentration combinations of CLA, PEL, RES and EGCG showed significant reducing effects on the frequencies of micronuclei induced by PAT, DEB and MMC. However, the micronucleus test did not provide indications of additive or synergistic effects with this combination of phytochemicals. In conclusion, the chemo-preventive effects of PEL, CLA, RES and EGCG against genotoxic damage induced by MMC, DEB and PAT are indicative of a 'saturation effect' when higher concentrations and combinations of these phytochemicals are used.

Topics: Anthocyanins; Antimutagenic Agents; Antioxidants; Catechin; Chlorogenic Acid; Diet; DNA Damage; HL-60 Cells; Humans; Micronucleus Tests; Mitomycin; Phytotherapy; Plants; Reactive Oxygen Species; Resveratrol; Stilbenes

It has been previously shown that the naturally occurring antioxidant (-)-epigallocatechin-3-gallate (EGCG), found in green tea, and pterostilbene, a stilbenoid derived from blueberries, inhibit pancreatic cancer in vitro when used individually. We hypothesized that the combination of EGCG and pterostilbene would reveal additive effects in vitro.. Using the pancreatic cancer cell lines MIA PaCa-2 and PANC-1, efficacy and synergism were evaluated for cell proliferation and viability (3-(4,5-dimethyltiazol-2-y1)-2,5-diphenltetrazolium bromide assays, cell cycle analysis) and mitochondrial apoptosis (mitochondrial depolarization, cytochrome C release, caspase-3/7 activity, cell death detection using enzyme-linked immunosorbent assay).. Cell proliferation assays revealed significant additive antiproliferative effects with pterostilbene and EGCG in both cell lines at the later, 72-h, point (P < 0.05). MIA underwent S-phase arrest with the combination (10-12% increase); however, cell cycle arrest was not observed in PANC. The combination induced mitochondrial depolarization and upregulated cytochrome C (P < 0.05) in MIA, but these effects were not observed in PANC. EGCG increased caspase-3/7 in MIA; however, the combination did not significantly increase the activity in either cell line (P < 0.05). Apoptosis was only observed in PANC (P < 0.05). The reduction in proliferation in MIA in the 3-(4,5-dimethyltiazol-2-y1)-2,5-diphenltetrazolium bromide assays with the combination indicated that cell death occurs, possibly through another mechanism.. Our results are encouraging regarding the future use of EGCG and pterostilbene to improve traditional pancreatic cancer therapies. In conclusion, EGCG and pterostilbene have additive, antiproliferative effects in vitro and alter the apoptotic mechanisms in both cell lines by modulation at different points in the mechanism.

Topics: Anticarcinogenic Agents; Carcinoma; Caspases; Catechin; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cytochromes c; DNA Fragmentation; Drug Evaluation, Preclinical; Humans; Pancreatic Neoplasms; Stilbenes

Currently, there is no effective treatment for neurological complications of infection with the human immunodeficiency virus that persists despite the use of combination antiretroviral therapy. A medium throughput assay was developed for screening neuroprotective compounds using primary mixed neuronal cells and mitochondrial toxin 3-nitropropionic acid. Using this assay, a library of 2,000 compounds was screened. Out of 256 compounds that showed variable degrees of neuroprotection, nine were related to epicatechin, a monomeric flavonoid found in cocoa and green tea leaves that readily crosses the blood-brain barrier. Hence, catechin, epicatechin, and the related compound, epigallocatechin gallate (EGCG) were further screened for their neuroprotective properties against HIV proteins Tat and gp120, and compared to those of resveratrol. Epicatechin and EGCG targets the brain-derived neurotrophic factor (BDNF) and its precursor proBDNF signaling pathways, normalizing both Tat-mediated increases in proapoptotic proBDNF and concomitant Tat-mediated decreases in the mature BDNF protein in hippocampal neurons. Epicatechin and epigallocatechin gallate were more potent than catechin or resveratrol as neuroprotectants. Due to its simpler structure and more efficient blood-brain barrier penetration properties, epicatechin might be the best therapeutic candidate for neurodegenerative diseases including HIV-associated neurocognitive disorders where oxidative stress is an important pathophysiological mechanism.

Topics: Animals; Anti-HIV Agents; Brain-Derived Neurotrophic Factor; Catechin; Embryo, Mammalian; Gene Expression Regulation; High-Throughput Screening Assays; Hippocampus; HIV Envelope Protein gp120; Humans; Mitochondria; Neurons; Neuroprotective Agents; Nitro Compounds; Oxidative Stress; Primary Cell Culture; Propionates; Protein Precursors; Rats; Resveratrol; Signal Transduction; Stereoisomerism; Stilbenes; tat Gene Products, Human Immunodeficiency Virus

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid β (Aβ) peptides and the failure of mechanisms to clear toxic aggregates. The Aβ42 peptide is considered to be a causative factor that underlies the pathophysiology of AD, in part due to its propensity for misfolding and aggregation; the small oligomers that result represent toxic species. Thus agents that prevent Aβ42 misfolding/aggregation or, alternatively improve Aβ42 oligomer clearance, may have significant therapeutic value. We have developed the basis for a drug screening system based on transgenic plant cells that express Aβ42 fusion proteins to serve as the reliable indicators of the general conformational status of Aβ42. Within cells of transgenic tobacco and Nicotiana benthamiana, misfolding of Aβ42 causes the misfolding of a GFP fusion partner, and consequently there is a loss of fluorescence associated with the native GFP protein. In a similar fusion consisting of Aβ42 linked to hygromycin phosphotransferase II (Hpt II), a hygromycin-resistance marker, misfolding of Aβ42 leads to a misfolded Hpt II, and consequently the transgenic cells are unable to grow on media containing hygromycin. Importantly, substitution of the 'aggregation-prone' Aβ42 with a missense mutant of Aβ42 (F19S/L34F) that is not prone to misfolding/aggregation, 'rescues' both fusion partners. Several 'positive control' chemicals that represent inhibitors of Aβ42 aggregation, including curcumin, epigallocatechin-3-gallate (EGCG), and resveratrol show efficacy in preventing the Aβ42-fusion proteins from misfolding/aggregating in the transgenic plant cells. We discuss the potential of the two fusion protein systems to serve as the basis for an inexpensive, selective, and efficient screening system in which a plant cell can fluoresce or survive only in the presence of drug candidates that are able to prevent Aβ42 misfolding/aggregation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Catechin; Cell Engineering; Curcumin; Drug Evaluation, Preclinical; Gene Expression; Genes, Reporter; Green Fluorescent Proteins; Humans; Microscopy, Fluorescence; Models, Biological; Mutation; Nicotiana; Peptide Fragments; Phosphotransferases (Alcohol Group Acceptor); Plant Cells; Protein Binding; Protein Conformation; Protein Folding; Recombinant Fusion Proteins; Resveratrol; Stilbenes

A variety of polyphenol antioxidant compounds derived from natural products have demonstrated neuroprotective activity against neuronal cell death. The objective of this study was to investigate the effect of resveratrol (RESV) and bioflavonoids in attenuating hydrogen peroxide (H(2)O(2))-induced oxidative stress in neuronal cells. H2O2 levels were increased by the addition of L-3,4-dihydroxyphenylalanine (L-DOPA) to cultured dopaminergic SKNSH cells. H(2)O(2) was monitored by peroxyfluor-1, a selective H(2)O(2) optical probe. To examine the neuroprotective effects of RESV and bioflavonoids against L-DOPA, we cotreated RESV, quercetin, or (-) epigallocatechin gallate with L-DOPA and monitored for H(2)O(2) levels. The combination of RESV and L-DOPA was 50% more effective at reducing H(2)O(2) levels than the combination of quercetin or epigallocatechin gallate with L-DOPA. However, the combination of each antioxidant with L-DOPA was effective at preserving cell viability.

Topics: Antioxidants; Catechin; Cell Line, Tumor; Cell Survival; Drug Evaluation, Preclinical; Drug Interactions; Fibroblasts; Fluoresceins; Humans; Hydrogen Peroxide; Levodopa; Monoamine Oxidase; Nerve Tissue Proteins; Neuroblastoma; Neurons; Neuroprotective Agents; Oxidative Stress; Quercetin; Resveratrol; Stilbenes; Tyrosine; Tyrosine 3-Monooxygenase

The abnormalities associated with cancer cachexia include anorexia, weight loss, muscle loss and atrophy, anaemia and alterations in carbohydrate, lipid and protein metabolism. The aim of the present investigation was to examine the anti-wasting effects of some nutraceuticals such as genistein, resveratrol, epigallocatechin gallate and diallyl sulphide (DAS).. The in vitro effects of these nutraceuticals on proteolysis were examined in muscle cell cultures submitted to hyperthermia. The in vivo effects of DAS were also tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma).. Although all the nutraceuticals tested inhibited muscle proteolysis, the most promising effects were related with DAS. In vivo administration of DAS only leads to a small improvement in tibialis muscle and heart weights; however, administration of DAS to healthy animals increased all muscle weights, this being associated with a decreased gene expression of proteolytic systems components.. It may be suggested that DAS could be used to improve muscle mass during healthy conditions.

Topics: Allyl Compounds; Animals; Anorexia; Cachexia; Catechin; Cells, Cultured; Dietary Supplements; Genistein; Male; Muscle, Skeletal; Muscular Atrophy; Neoplasms; Rats; Rats, Wistar; Resveratrol; Stilbenes; Sulfides; Weight Loss

Our aim was to investigate the effect of several dietary polyphenols on uptake of (14)C-butyrate ((14)C-BT) by Caco-2 cells and try to correlate this effect with the modulation of the anticarcinogenic effect of BT in these cells. Acutely, uptake of (14)C-BT (10 μM) was decreased by resveratrol, quercetin, myricetin, and chrysin, and increased by xanthohumol, catechin, and epicatechin; and uptake of (14)C-BT (20 mM) was reduced by resveratrol, quercetin, myricetin, chrysin, EGCG, and epicatechin. Resveratrol acts as a competitive inhibitor of (14)C-BT uptake. Chronically, quercetin and EGCG increased uptake of (14)C-BT (10 μM), whereas myricetin, rutin, chrysin, and xanthohumol decreased it. Moreover, catechin (1 μM), quercetin, myricetin, rutin, EGCG, and chrysin increased uptake of (14)C-BT (20 mM), whereas catechin (0.1 μM) decreased it. EGCG, myricetin, and catechin decreased MCT1 mRNA expression, while chrysin increased it; quercetin, rutin, and xanthohumol had no effect. BT (5 mM; 48 h) markedly decreased cellular viability and proliferation and increased cell differentiation and apoptosis. In general, combination of polyphenolic compounds with BT did not significantly modify these changes. In conclusion, changes in uptake of BT induced by polyphenols do not correlate with changes on the effect of BT upon cell viability, cell proliferation, differentiation, and apoptosis.

Topics: Analysis of Variance; Anticarcinogenic Agents; Apoptosis; Butyrates; Caco-2 Cells; Catechin; Cell Differentiation; Cell Proliferation; Cell Survival; Flavonoids; Humans; Phenols; Polyphenols; Propiophenones; Quercetin; Regression Analysis; Resveratrol; Rutin; Stilbenes

Epigallocatechin-gallate (EGCG) and resveratrol (RSVL) are two of the most promising natural medicines. We verified their capacity to ameliorate cisplatin (CP)-induced disruption of renal glomerular filtration rate (GFR) in rats, and sought the mediatory involvement of lipid peroxidation (malondialdehyde [MDA]-level) and inflammatory cytokine (TNF-α) therein. CP (10 mg kg⁻¹), a single i.p. dose, disrupted GFR (11-fold-rise in proteinuria, 2-5-fold rise in serum creatinine/urea levels) after 7 days, and killed all animals after 10 days. Kidney-homogenates from CP-treated rats displayed higher MDA and TNF-α, but lower reduced-glutathione (GSH) levels. Rats treated with EGCG (50 mg kg⁻¹, but not 25 mg kg⁻¹) had no fatalities and showed significantly-recovered GFR; while their kidney-homogenates had markedly reduced MDA, TNF-α and enhanced GSH levels at 7 days. Conversely, RSVL or quercetin (25, 50 mg kg⁻¹) neither improved GFR nor reduced (MDA)/TNF-α levels after 7 days. Resuming treatment with 50 mg kg⁻¹ for 10 days rescued only 25% of animals (p > 0.05). Correlation studies showed a significant association between creatinine level, and each of MDA (r = 0.91), GSH (r = -0.87), and TNF-α (0.91). The study showed for the first time that EGCG, unlike RSVL, can protect against CP-induced nephrotoxicity. At the molecular level, CP triggers a high level of oxidative stress and systemic inflammation, events that were all abrogated with EGCG; better than RSVL or quercetin.

Topics: Animals; Camellia sinensis; Catechin; Cisplatin; Cross-Linking Reagents; Cytokines; Dose-Response Relationship, Drug; Gene Expression Regulation; Kidney Diseases; Lipid Peroxidation; Oxidative Stress; Rats; Resveratrol; Stilbenes; Vitis

Polyphenols can oxidize in culture medium and produce artifacts in cell culture studies. However, the extent and mechanism of the oxidation of resveratrol, a polyphenol abundant in red wine, is unclear. We investigated the oxidation of resveratrol in vitro and the effects of various components of the culture medium on the degradation of resveratrol and the production of H(2)O(2). We found that 96% of resveratrol at a concentration of 200 microM was degraded in Base Modified Eagle Medium after 24 h of incubation at 37 degrees C, producing about 90 microM of H(2)O(2). Including sodium bicarbonate in the medium markedly stimulated resveratrol degradation and H(2)O(2) production. In sum, we found that bicarbonate ions played a crucial role in the oxidative degradation of resveratrol in vitro, and that the degradation of resveratrol can be avoided by withdrawing sodium bicarbonate from the medium. A mechanism for the oxidation of resveratrol is proposed.

Topics: Bicarbonates; Butanols; Catalase; Catechin; Culture Media; HEPES; Hydrogen-Ion Concentration; Nitrogen; Oxidation-Reduction; Phosphates; Pyruvic Acid; Resveratrol; Sodium Bicarbonate; Stilbenes; Tromethamine; Water

Herbal medicine has long been used in traditional medicinal systems. The authors carried out a first-line screening of four herbal chemicals with reported antioxidative properties and capabilities to suppress endothelial cell growth and migration. These herbal chemicals were isoliquiritigenin (ISL) from licorice, epigallocatechin gallate (EGCG) from green tea, resveratrol (Rst) from grapes, and gambogic acid (GA) from the resin of Garcinia hanburyi.. Cytotoxicity was studied by MTT cell viability/proliferation assay on human retinal pigment epithelial cells (ARPE19). Effects on vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation and migration were investigated by a scratch-wound model using human umbilical vein endothelial cells (HUVECs). The effects on VEGF signaling in HUVECs were analyzed by Western blotting.. At sub-cytotoxic levels, ISL (10 μM), EGCG (50 μM), and Rst (10 μM) suppressed HUVEC proliferation and migration under VEGF (20 ng/mL) stimulation in our scratch-wound model. HUVEC migration was reduced more by ISL and EGCG than bevacizumab, a humanized monoclonal antibody against VEGF. The efficiency of Rst was similar to that of bevacizumab. GA, however, was toxic to cells even at nanomolar concentrations. Western blot analysis showed that these chemicals affected focal adhesion kinase activation and expression of pigment epithelial growth factor.. ISL, EGCG, and Rst are highly effective and efficient in suppressing endothelial cell proliferation and migration, with low cytotoxicity on ARPE19 and HUVEC lines. They are potentially useful for further investigation to develop antiangiogenic therapies by virtue of their small molecular sizes for easy penetration through tissue cells and their low effective dosages.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Blotting, Western; Catechin; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Chalcones; Drug Evaluation, Preclinical; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Eye Proteins; Focal Adhesion Protein-Tyrosine Kinases; Humans; Nerve Growth Factors; Plant Preparations; Resveratrol; Retinal Pigment Epithelium; Serpins; Stilbenes; Umbilical Veins; Vascular Endothelial Growth Factor A; Xanthones

AMP-activated protein kinase (AMPK) has been reported to stimulate differentiation and proliferation of osteoblasts, but the role of AMPK in the physiology of osteoclasts has not been investigated.. Osteoclasts were differentiated from mouse BMMϕs. TRAP-positive multinucleated cells were considered to be osteoclasts using TRAP staining, and resorption area was determined by incubation of cells on dentine discs. Signaling pathways were investigated using Western blotting and RT-PCR.. RANKL induced phosphorylation/activation of AMPK-α in BMMϕs and stimulated formation of TRAP-positive multinucleated cells. Pharmacological inhibition of AMPK with compound C and siRNA-mediated knockdown of AMPK-α1, the predominant α-subunit isoform in BMMϕs, increased RANKL-induced formation of TRAP-positive multinucleated cells and bone resorption via activation of the downstream signaling elements p38, JNK, NF-κB, Akt, CREB, c-Fos, and NFATc1. STO-609, an inhibitor of CaMKK, completely blocked the RANKL-induced activation of AMPK-α, but KN-93, an inhibitor of CaMK, did not. siRNA-mediated TAK1 knockdown also blocked RANKL-induced activation of AMPK-α. The AMPK activators metformin, (-)-epigallocatechin-3-gallate, berberine, resveratrol, and α-lipoic acid dose-dependently suppressed formation of TRAP-positive multinucleated cells and bone resorption.. AMPK negatively regulates RANKL, possibly by acting through CaMKK and TAK1. Thus, the development of AMPK activators may be a useful strategy for inhibiting the resorption of bone that is stimulated under RANKL-activated conditions.

Topics: Adenylate Kinase; Animals; Apoptosis; Blotting, Western; Bone Resorption; Catechin; Cell Differentiation; Cell Survival; Cells, Cultured; Macrophage Colony-Stimulating Factor; MAP Kinase Kinase Kinases; Metformin; Mice; Mice, Inbred ICR; Osteoclasts; Osteogenesis; Pyrazoles; Pyrimidines; RANK Ligand; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Stilbenes

To investigate potential inhibitory effects of three polyphenolic agents, epigallocatechin gallate (EGCG; from green tea), resveratrol (from red wine), and curcumin (from turmeric), on the proliferation of human retinal pigment epithelial (RPE) cells and to elucidate unwanted effects.. ARPE19 cells and primary human RPE cells were cultured in the presence of various concentrations of EGCG, resveratrol, or curcumin, and compared with controls. The number of viable cells was determined after 24, 48, and 72 hr by flow cytometrical enumeration. Furthermore, cell division was measured by dye dilution assay using carboxyfluorescein succinimidyl ester (CFSE), cell death by Hoechst 33258 staining, and apoptosis by staining for active caspase 3/7 and 8.. The three drugs inhibited the increase of RPE cell numbers at all time points, with resveratrol being the most efficient and curcumin being the least efficient. EGCG inhibited cell proliferation with intermediate efficiency, and showed little induction of cell death. Resveratrol almost completely suppressed cell proliferation, and induced RPE cell necrosis and caspase 3/7- and caspase 8-dependent apoptosis. Curcumin inhibited RPE cell increase exclusively by inducing caspase 3/7-dependent but caspase 8-independent cell death and necrosis.. All three polyphenols tested reduced the absolute number of cells, but had different effects on cell proliferation, apoptosis, and necrosis. Resveratrol was most potent and EGCG induced the least cell death. These polyphenols may aid treatment of proliferative vitreoretinopathy (PVR).

Topics: Antioxidants; Apoptosis; Caspases; Catechin; Cell Division; Cell Proliferation; Cell Survival; Cells, Cultured; Curcumin; Flow Cytometry; Humans; Necrosis; Resveratrol; Retinal Pigment Epithelium; Stilbenes

Transforming growth factor beta 1 (TGF-β1) is an inhibitor of muscle cell differentiation that is associated with fibrosis, poor regeneration and poor function in some diseases of muscle. When neutralizing antibodies to TGF-β1 or the angiotensin II inhibitor losartan were used to reduce TGF-β1 signaling, muscle morphology and function were restored in mouse models of Marfan Syndrome and muscular dystrophy. The goal of our studies was to identify additional agents that overcome the anti-myogenic effect of TGF-β1.. A high-content cell-based assay was developed in a 96-well plate format that detects the expression of myosin heavy chain (MHC) in C2C12 cells. The assay was used to quantify the dose-dependent responses of C2C12 cell differentiation to TGF-β1 and to the TGF-β1 Type 1 receptor kinase inhibitor, SB431542. Thirteen agents previously described as promoting C2C12 differentiation in the absence of TGF-β1 were screened in the presence of TGF-β1. Only all-trans retinoic acid and 9-cis retinoic acid allowed a maximal level of C2C12 cell differentiation in the presence of TGF-β1; the angiotensin-converting enzyme inhibitor captopril and 10 nM estrogen provided partial rescue. Vitamin D was a potent inhibitor of retinoic acid-induced myogenesis in the presence of TGF-β1. TGF-β1 inhibits myoblast differentiation through activation of Smad3; however, retinoic acid did not inhibit TGF-β1-induced activation of a Smad3-dependent reporter gene in C2C12 cells.. Retinoic acid alleviated the anti-myogenic effect of TGF-β1 by a Smad3-independent mechanism. With regard to the goal of improving muscle regeneration and function in individuals with muscle disease, the identification of retinoic acid is intriguing in that some retinoids are already approved for human therapy. However, retinoids also have well-described adverse effects. The quantitative, high-content assay will be useful to screen for less-toxic retinoids or combinations of agents that promote myoblast differentiation in the presence of TGF-β1.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Benzamides; Captopril; Catechin; Cell Differentiation; Cell Line; Cell Proliferation; Dioxoles; Dose-Response Relationship, Drug; Mice; Muscle Development; Myoblasts; Receptors, Transforming Growth Factor beta; Resveratrol; Signal Transduction; Smad3 Protein; Stilbenes; Transforming Growth Factor beta1; Tretinoin; Vitamin D; Vitamins

Our purpose was to establish whether resveratrol and (-)-epigallocatechin-3-gallate (EGCG), two compounds extracted from food, would reduce the amount of Vascular Endothelial Growth Factor (VEGF) secreted into the supernatants of cultured endometrial cancer cells.. Endometrial cancer samples were collected from 19 consenting women who were undergoing hysterectomy operations to remove tumours. Tumour cells were dispersed into single cell suspensions and cultured. Two immortalised cell lines were also studied. After incubating cells under various test and control conditions, ELISA was used to measure VEGF levels in the supernatants.. VEGF was measurable at varied concentrations in the supernatants of cultured cells, from both cell lines and primary cultures. Cobalt chloride (CoCl(2)), a hypoxia mimic, increased the measured secretion of VEGF from these cells. In contrast, treatment with either resveratrol or EGCG significantly reduced secretion of VEGF. Further, resveratrol and EGCG inhibited release from cells that were also exposed to CoCl(2).. Both resveratrol and EGCG induced significant reductions in the amount of VEGF secreted into the supernatant of cultured endometrial cancer cells. These results suggest that resveratrol and EGCG may have the potential to inhibit angiogenesis in endometrial tumours. Further investigation of these substances in endometrial cancer is warranted.

Topics: Anticarcinogenic Agents; Catechin; Endometrial Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Humans; Resveratrol; Stilbenes; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Sirtuins are nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylases that catalyze the deacetylation of proteins such as histones and p53. A sensitive and convenient fluorometric assay for evaluating the SIRT1 enzymatic activity was developed here. Specifically, the remaining NAD(+) after the deacetylation was determined by converting NAD(+) to a highly fluorescent cyclized alpha-adduct compound. By this assay, we found that nicotinamide, Cu(2+), and Zn(2+) antagonize the activity of SIRT1. Resveratrol stimulates the enzymatic activity specifically with 7-amino-4-methylcoumarin (AMC)-labeled acetylated peptide. Epigallocatechin galate (EGCG) inhibits SIRT1 activity with both AMC-labeled and unlabeled peptide. However, a combination of vitamin C with EGCG can reverse the inhibition of EGCG with the unlabeled peptide or stimulate the deacetylation of AMC-labeled peptide by SIRT1. The assay does not require any isotopic material and thus is biologically safe. It can be adapted to a 96-well microplate for high-throughput screening. Notably, the acetylated peptides with or without fluorescent labels may be used in the assay, which facilitates the substrate specificity study of SIRT1 activators or inhibitors in vitro.

Topics: Catechin; Coumarins; Fluorescent Dyes; NAD; Peptides; Resveratrol; Sirtuin 1; Spectrometry, Fluorescence; Stilbenes

The vasorelaxing properties of chocolate and wine might relate to the presence of phenolic compounds. One of the potential mechanisms involved is stimulation of endothelial nitric oxide (NO) production, as NO is a major regulator of vasodilatation. This study aimed to develop an in vitro assay using the hybrid human endothelial cell line EA.hy926 to rapidly screen phenolic compounds for their NO-stimulating potential. The assay was optimized, and a selection of 33 phenolics, namely, procyanidins, monomeric flavan-3-ols, flavonols, a flavone, a flavanone, a chalcone, a stilbene, and phenolic acids, was tested for their ability to enhance endothelial NO level. Resveratrol, a well-known enhancer of NO level, was included as a positive control. Of the 33 phenolics tested, only resveratrol (285% increase in NO level), quercetin (110% increase), epicatechingallate (ECg) (85% increase), and epigallocatechingallate (EGCg) (60% increase) were significant (P

Topics: Catechin; Cell Line; Endothelial Cells; Gene Expression; Humans; Nitric Oxide; Nitric Oxide Synthase Type III; Phenols; Quercetin; Resveratrol; Stilbenes

Polyphenolic natural products from green tea and red wine have been identified as metalloproteinase inhibitors. Members from the flavonoid and stilbene families found to possess metalloproteinase inhibitory activities include (-)-epigallocatechin gallate, (-)-epicatechin gallate and piceatannol, but their minimally active pharmacophores have not been evaluated. The present study has examined compounds that are structural components of or structurally related to (-)-epigallocatechin gallate, (-)-epicatechin gallate and piceatannol for inhibition of aggrecanases and four representative matrix metalloproteinases. Piceatannol and pyrogallol were found to inhibit all aggrecanases and matrix metalloproteinases studied, indicating a crucial reliance on multiple hydroxyl groups for (-)-epigallocatechin gallate, (-)-epicatechin gallate and piceatannol activity. Differences in K(i) values for pyrogallol as determined with two structurally distinct substrates indicated the likelihood that this compound binds in a non-competitive modality. Further analysis showed that pyrogallol acts as an exosite inhibitor, consistent with the action of (-)-epigallocatechin gallate. In contrast, piceatannol was shown to be a competitive binding inhibitor and showed no differences in apparent K(i) values as determined by distinct substrates, illustrating the benefits of using two structurally distinct substrates to assist the analysis of protease inhibitors. The compounds identified here could be utilized to develop novel metalloproteinase probes or as fragment components of more active inhibitors.

Topics: ADAM Proteins; ADAMTS4 Protein; ADAMTS5 Protein; Amino Acid Sequence; Antioxidants; Catechin; Enzyme Activation; Enzyme Inhibitors; Flavonoids; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Sequence Data; Molecular Structure; Peptides; Procollagen N-Endopeptidase; Stilbenes

Numerous dietary phytochemicals have shown anti-breast carcinogenic activities when tested in vitro; however, in most cases, the demonstrated efficacy of individual phytochemicals requires doses not readily achievable in vivo. Therefore, whether diets might exert translational promises and benefits in clinical settings and prevention of breast cancer remain unclear. Since cancer cells are endowed with complex, redundant, converging and diverging pathways spanning both the genetic and metabolic networks that are not merely replicates of those in normal cells, it is of interest to test whether a multicomponent approach involving lower, physiologically relevant doses of natural dietary agents may be developed as a chemopreventive strategy for breast cancer. Herein, we investigated, using the estrogen receptor-positive MCF-7 breast cancer cells as a model, whether the combination of epigallocatechin gallate (EGCG), resveratrol and gamma-tocotrienol at suboptimal doses elicits synergism in suppressing cell proliferation, modulating gene expression, and increasing antioxidant activity, as compared to each of the three phytochemicals added alone. The results showed that there was a approximately 33, 50 and 58% inhibition of cell proliferation by > or =50 microM EGCG, > or =25 microM resveratrol and > or =10 microM gamma-tocotrienol, respectively, added as a single agent. When a suboptimal dose (10 microM) of each phytochemical was used, a significant additive effect in suppression of cell proliferation was observed with the combination of resveratrol and gamma-tocotrienol whereas the three phytochemicals added together did not produce more pronounced inhibition of cell proliferation. A significant additive effect in reducing cyclin D1 and bcl-2 expression was found when gamma-tocotrienol was added with either EGCG or resveratrol. Functional synergism among the three phytochemicals was only observed in the induction of quinone reductase NQO1. These results suggest that diet-based protection against breast cancer may partly derive from synergy amongst dietary phytochemicals directed against specific molecular targets in responsive breast cancer cells, and provide support for the feasibility of the development of a diet-based combinatorial approach in the prevention and treatment of breast cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Catechin; Cell Line, Tumor; Cell Proliferation; Chromans; Dose-Response Relationship, Drug; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Mice; Models, Biological; Resveratrol; Stilbenes; Superoxide Dismutase; Vitamin E

The loss of survival motor neuron-1 (SMN1) is responsible for the development of the neurodegenerative disorder spinal muscular atrophy (SMA). A nearly identical copy of SMN1 is present on the same chromosomal region called SMN2. While SMN2 encodes a normal SMN protein, the majority of SMN2-derived transcripts are alternatively spliced, resulting in a truncated protein that lacks the 16 amino acids encoded by SMN exon 7. Numerous studies have shown that the SMN2-derived protein product, called SMNDelta7, is unstable and dysfunctional. Therefore, identifying molecules that stimulate full-length SMN expression from the SMN2 gene could lead to the development of effective therapies for a broad range of SMA patient populations. Polyphenol compounds have been shown to provide benefit in varied genetic disease contexts. For example, epigallocatechin galate (EGCG) was found to correct aberrant alternative mRNA splicing in familiar dysautonomia (FD). A series of polyphenols were screened and a subset was shown to increase full-length SMN expression from SMN2. Curcumin, EGCG, and resveratrol increased exon 7 inclusion of SMN2 transcripts in transient reporter assays. In SMA patient fibroblasts, these compounds stimulated the production of full-length SMN RNA and protein as well as the formation of SMN-containing nuclear gems. Collectively, these compounds elevated total SMN concentrations in SMA patient fibroblasts, potentially through the modulation of SMN2 exon 7 alternative splicing.

Topics: Alternative Splicing; Catechin; Cells, Cultured; Curcumin; Cyclic AMP Response Element-Binding Protein; Exons; Flavonoids; Humans; Models, Biological; Nerve Tissue Proteins; Phenols; Plants; Polyphenols; Resveratrol; RNA Precursors; RNA-Binding Proteins; SMN Complex Proteins; Stilbenes; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein; Up-Regulation

It is well known that ethanol damages the developing nervous system by augmenting apoptosis. Previously, this laboratory reported that ethanol augments apoptosis in fetal rhombencephalic neurons, and that the increased apoptosis is associated with reduced activity of the phosphatidylinositol 3-kinase pathway and downstream expression of pro-survival genes. Other laboratories have shown that another mechanism by which ethanol induces apoptosis in developing neurons is through the generation of reactive oxygen species (ROS) and the associated oxidative stress. The present study used an in vitro model to investigate the potential neuroprotective effects of several antioxidants against ethanol-associated apoptosis in fetal rhombencephalic neurons. The investigated antioxidants included three phenolics: (-)-epigallocatechin-3-gallate (EGCG), a flavanoid polyphenol found in green tea; curcumin, found in tumeric; and resveratrol (3,5,4'-trihydroxystilbene), a component of red wine. Additional antioxidants, including melatonin, a naturally occurring indole, and alpha-lipoic acid, a naturally occurring dithiol, were also investigated. These studies demonstrated that a 24-hour treatment of fetal rhombencephalic neurons with 75 mM ethanol caused a 3-fold increase in the percentage of apoptotic neurons. However, co-treatment of these cultures with any of the five different antioxidants prevented ethanol-associated apoptosis. Antioxidant treatment did not alter the extent of apoptosis in control neurons, i.e., those cultured in the absence of ethanol. These studies showed that several classes of antioxidants can exert neuroprotection against ethanol-associated apoptosis in fetal rhombencephalic neurons.

Topics: Antioxidants; Apoptosis; Benzimidazoles; Catechin; Cells, Cultured; Central Nervous System Depressants; Curcumin; Ethanol; Fluorescent Dyes; Melatonin; Neurons; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Resveratrol; Rhombencephalon; Signal Transduction; Stilbenes; Thioctic Acid

Based on animal models, dietary polyphenols are predicted to be promising chemopreventive agents in humans. Allspice, clove, and thyme extracts as well as defined dietary polyphenolic compounds were, therefore, tested for their ability to activate mechanisms related to phase 1 enzymes, i.e., the PXR-regulated CYP3A4 promoter, and phase 2 enzymes, i.e. the EpRE-regulated promoters of gastrointestinal glutathione peroxidase (GI-GPx) and heme oxygenase-1 (HO-1), examples of Nrf2-regulated genes. From the compounds tested, clove and thyme extracts as well as curcumin and resveratrol activated the PXR. PXR activation correlated with the activation of the CYP3A4 promoter in the case of thyme extract, curcumin, and resveratrol, but not in the case of clove extract. Allspice extract, EGCG, and quercetin did not activate PXR but enhanced CYP3A4 promoter activity. Thyme extract and quercetin activated the EpRE of HO-1. Both significantly activated the GI-GPx promoter, effects that depended on a functional EpRE. Resveratrol did not activate the isolated EpRE but enhanced the GI-GPx promoter activity, whereas clove extract even inhibited it. It is concluded that individual polyphenols as well as polyphenol-rich plant extracts may affect phase 1 and 2 enzyme expression by distinct mechanisms that must be elucidated, before potential health effects can reliably be predicted.

Topics: Catechin; Cell Line, Tumor; Curcumin; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dietary Supplements; Flavonoids; Gene Expression Regulation; Glutathione Peroxidase; Heme Oxygenase-1; Humans; Phenols; Plant Extracts; Polyphenols; Pregnane X Receptor; Promoter Regions, Genetic; Quercetin; Receptors, Steroid; Response Elements; Resveratrol; Stilbenes; Syzygium; Thymus Plant

Resveratrol and epigallocatechin-3-gallate (EGCG) are important candidates as chemopreventive agents by virtue of their ability to induce apoptosis in cancer cells. Casein kinase 2 (CK2) is a ubiquitous protein ser/thr kinase that plays diverse roles in cell proliferation and apoptosis. We have previously shown that overexpression of CK2 suppresses apoptosis induced by a variety of agents, whereas down-regulation of CK2 sensitizes cells to induction of apoptosis. We therefore investigated whether or not CK2 played a role in resveratrol and EGCG signaling in androgen-sensitive (ALVA-41) and androgen-insensitive (PC-3) prostate cancer cells. Resveratrol- and EGCG-induced apoptosis is associated with a significant down-regulation of CK2 activity and protein expression in both the ALVA-41 and PC-3 cells. Overexpression of CK2alpha protected prostatic cancer cells against resveratrol- and EGCG-induced apoptosis. Relatively low doses (10 mumol/L) of resveratrol and EGCG induced a modest proliferative response in cancer cells that could be switched to cell death by moderate inhibition of CK2. These findings characterize, for the first time, the effects of polyphenolic compounds on CK2 signaling in androgen-sensitive and androgen-insensitive prostatic carcinoma cells and suggest that resveratrol and EGCG may mediate their cellular activity, at least in part, via their targeting of CK2. Further, the data hint at the potential of using these polyphenols alongside CK2 inhibitors in combination chemotherapy.

Topics: Apoptosis; Casein Kinase II; Caspase 3; Catechin; Cell Proliferation; Drug Therapy, Combination; Humans; Immunoblotting; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Resveratrol; Signal Transduction; Stilbenes; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured

The present study was undertaken to test the hypothesis that dietary antioxidants protect DNA damage induced by peroxynitrite, a potent physiological inorganic toxin. The present study showed that dietary antioxidants such as (-)-epigallocatechin gallate, quercerin, rutin, resveratrol, and ursolic acid inhibit single strand breaks in supercoiled plasmid DNA induced by 3-morpholinosydnomine N-ethylcarbamide (SIN-1), a generator of peroxynitrite through the reaction between nitric oxide and superoxide anion. The formation of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in calf thymus DNA by SIN-1 was also inhibited by dietary antioxidants. When U937 cells were incubated with 1 mM SIN-1 bolus, a significant increase of 8-OH-dG level was observed. However, oxidative DNA damage was significantly lower in the cells pre-treated with dietary antioxidants when cells were exposed to SIN-1.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Catechin; Deoxyguanosine; Diet; DNA; DNA Damage; Free Radical Scavengers; Humans; Molsidomine; Peroxynitrous Acid; Resveratrol; Stilbenes; Triterpenes; U937 Cells; Ursolic Acid

Human neutrophil elastase (HNE) is a serine protease, which is present in its active form in inflamed tissue as well as in psoriatic lesions. In extension of our research on natural compounds as inhibitors of HNE or of its release, several phenolics of different size were tested. The ellagitannins agrimoniin and pedunculagin were the most potent direct HNE inhibitors (IC (50) = 0.9 and 2.8 microM, respectively). Ligand docking calculations provided evidence that inhibition may occur in an unspecific manner. Agrimoniin also showed anti-proliferative effects in the ATP assay (IC (50) = 3.2 microM), suggesting that this type of tannin could have beneficial effects in the treatment of diseases such as psoriasis. Tests with other phenolics combined with ligand docking experiments revealed that, besides the presence of ORTHO-dihydroxy groups, a specific lipophilic shape is necessary for an inhibitory activity. The phenolic genistein deserves special interest as an inhibitor of elastase release because its effect was remarkably potent (IC (50) = 0.6 microM).

Topics: Catechin; Genistein; Humans; Hydrolyzable Tannins; Leukocyte Elastase; Phenols; Phenylethyl Alcohol; Plant Extracts; Proteinase Inhibitory Proteins, Secretory; Resveratrol; Stilbenes

Ionizing radiation is widely used in radiotherapy, in order to promote an apoptotic response in cancerous cells. Since the need to find new substances that would enhance the radiation-induced apoptosis in cancerous cells is great, we studied the effect of epigallocatechin-gallate (EGCG, a tea component), resveratrol (a wine component) and curcuma on cell proliferation and radiation-induced apoptosis in the human leukaemic cell line, EOL-1, derived from a patient with eosinophilic leukaemia. Cells were X-irradiated with 0, 2, 4, 6 or 8 Gy and cultured in the presence of EGCG, resveratrol or curcuma (concentrations ranging from 0 to 200 microM) for 1, 2 or 3 days of culture. Cell proliferation was measured using trypan blue exclusion. Apoptosis was evaluated using light microscopy (morphology study after May-Grunwald Giemsa staining) and flow cytometry (annexin-V staining). Irradiation alone induced a dose-related reduction in cell proliferation and the appearance of polyploid cells in EOL-1 cells. Additionally, EOL-1 cells underwent a dose-related increase of apoptosis which, from the second day on, was accompanied by a dose-related increase of necrosis. When cells were exposed to EGCG, resveratrol or curcuma alone, a decrease in cell proliferation was observed, beginning from 25 microM EGCG and 50 microM resveratrol and curcuma, while an increase in the percentage of apoptotic cells was noted from 50 microM EGCG, 100 microM resveratrol and curcuma in EOL-1 cells, after only one day of culture. Simultaneous exposure to X-irradiation and, EGCG, resveratrol or curcuma resulted in a synergistic decrease of cell proliferation as well as in a synergistic increase of apoptosis and necrosis. These results suggest that, depending on the concentration, EGCG, resveratrol and curcuma enhance radiation-induced apoptosis in the leukaemic cell line, EOL-1 (EGCG >resveratrol >curcuma). In order to further characterise the radiation-induced apoptosis of this leukaemic cell line, other flow cytometrical analyses are in progress.

Topics: Annexin A5; Apoptosis; Catechin; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Curcuma; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Eosinophils; Flow Cytometry; Humans; Leukemia; Necrosis; Plant Extracts; Radiation Tolerance; Radiation, Ionizing; Resveratrol; Signal Transduction; Stilbenes; Time Factors; X-Rays

NADPH-cytochrome P-450 reductase (P-450 reductase) plays a crucial role in the metabolism of many endogenic compounds and xenobiotics detoxication. The enzyme is also involved in the toxicity of some clinically important antitumour drugs (doxorubicin) and pesticides (paraquat). P-450 reductase activates them to their more toxic metabolites via one electron reduction which triggers free radical cascade. In some cases however, such transformation is essential to produce therapeutic effect in anticancer drugs. The main purpose of the paper was to evaluate the effect of three natural compounds found in human diet: (-)-epigallocatechin gallate (EGCG), quercetin and resveratrol on P-450 reductase activity. The activity of the enzyme was determined spectrophotometrically by measurement of the rate of cytochrome c reduction at 550 nm, in vitro, using human heart, liver and lung microsomes. It was found that quercetin increased the P-450 reductase activity in human organs at all tested doses. The activity of microcosms in all organs was enhanced according to the concentrations of quercetin, which increased the activity in the order lung>heart>liver. Addition of EGCG to the reaction mixture enhanced the P-450 reductase activity in the following order: liver>heart>lung. However, no significant effect of resveratrol on P-450 reductase activity was observed. It seems that the presence of quercetin and EGCG in the diet may increase P-450 reductase activity during doxorubicin therapy with subsequent increased risk of toxicity. A beneficial effect may be obtained in anticancer therapy with bioreductive agents like tirapazamine.

Topics: Anti-Bacterial Agents; Antioxidants; Catechin; Diet; Doxorubicin; Enzyme Activation; Heart; Herbicides; Humans; In Vitro Techniques; Liver; Lung; Male; Microsomes, Liver; Myocardium; NADPH-Ferrihemoprotein Reductase; Paraquat; Quercetin; Resveratrol; Stilbenes

The effect of some polyphenols (resveratrol, catechin, epigallocatechin-3-gallate, and quercetin) and beverages (red wine and green tea) on the enzymatic activity of pepsin during the digestion of three different substrates (pork meat, insoluble azocasein, and denatured hemoglobin) has been investigated. The tested polyphenols and beverages increase the initial velocity of the reaction, and the activating effect is concentration dependent. The order of effectiveness of polyphenols in increasing the initial velocity of the reaction is resveratrol > or = quercetin > epigallocatechin-3-gallate > catechin. The kinetic data obtained with soluble denatured hemoglobin show that the K(m) for the substrate is not changed, whereas the V(max) of the reaction is increased. Pepsin activity follows a simple Michaelis-Menten kinetic suggesting that k(3) is increased by polyphenols. To the authors' knowledge, the present study is the first demonstration that some polyphenols and related beverages are able to enhance the enzymatic activity of pepsin.

Topics: Animals; Caseins; Catechin; Digestion; Enzyme Activation; Flavonoids; Gastric Mucosa; Hemoglobins; Kinetics; Meat; Pepsin A; Phenols; Polyphenols; Protein Denaturation; Quercetin; Resveratrol; Stilbenes; Swine; Tea; Wine

This study investigated the in vitro effects of the polyphenols resveratrol, mangiferin and (-)-epigallocatechin-3-gallate (EGCG) on the histiophagous ciliate Philasterides dicentrarchi, which causes fatal scuticociliatosis in farmed turbot Scophthalmus maximus L. Of the 3 polyphenols, resveratrol showed strongest antiprotozoal activity, reducing ciliate density after 1 wk culture by, on average, 91% at 50 microM, and 96% at 500 microM. EGCG reduced ciliate density by, on average, 93% at 500 microM, with no significant effect at 50 microM. Mangiferin reduced ciliate density by, on average, 56% at 500 microM, again with no significant effect at 50 microM. In view of these findings, we discuss the potential utility of chemotherapy with polyphenols as a strategy for the control of scuticociliatosis in farmed turbot.

Topics: Analysis of Variance; Animals; Antiprotozoal Agents; Catechin; Dose-Response Relationship, Drug; Fish Diseases; Flatfishes; In Vitro Techniques; Oligohymenophorea; Protozoan Infections, Animal; Resveratrol; Stilbenes; Xanthones

Phenolic compounds EGCG [(-)-epigallocatechin-3-gallate], resveratrol (3,4',5-trihydroxy-trans-stilbene) and capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) are worth investigating for clinical application in cancer prevention and chemotherapy. Hypoxia-induced drug resistance is a major obstacle in the development of effective cancer chemotherapy. Therefore, we examined whether drug resistance to these phenolic compounds is acquired by hypoxia.. Hep3B hepatoma, Caki-1 renal carcinoma, SK-N-MC neuroblastoma, and HEK293 cell lines were cultured under normoxic or hypoxic conditions. Drug sensitivities to the phenolic compounds and expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and the multidrug resistance genes were examined in these cell lines.. Drug resistance was acquired 24 h after hypoxia and subsided 8 h after reoxygenation. Protein synthesis inhibitors abolished this drug resistance. A transfection study demonstrated that HIF-1alpha enhanced this hypoxia-induced resistance and that its dominant-negative isoform suppressed resistance acquisition. However, MDR1 and MRP1, which provide multidrug resistance to conventional anticancer agents, were not induced by hypoxia.. These results suggest that HIF-1alpha-dependent gene expression participates in the cellular process of the hypoxia-induced resistance to phenolic compounds.

Topics: Animals; Antineoplastic Agents; Antioxidants; Blotting, Western; Capsaicin; Catechin; Cell Line, Tumor; Cell Survival; DNA-Binding Proteins; Drug Resistance, Neoplasm; Hypoxia-Inducible Factor 1; Nuclear Proteins; Resveratrol; Stilbenes; Time Factors; Transcription Factors; Transfection

Prostate cancer is an important public health problem in the United States. Seven phytoestrogens found in common herbal products were screened for estrogen receptor binding and growth inhibition of androgen-insensitive (PC-3) and androgen-sensitive (LNCaP) human prostate tumor cells. In a competitive 3H-estradiol ligand binding assay using mouse uterine cytosol, 2.5 M quercetin, baicalein, genistein, epigallocatechin gallate (EGCG), and curcumin displaced > 85% of estradiol binding, whereas apigenin and resveratrol displaced > 40%. From growth inhibition studies in LNCaP cells, apigenin and curcumin were the most potent inhibitors of cell growth, and EGCG and baicalein were the least potent. In PC-3 cells, curcumin was the most potent inhibitor of cell growth, and EGCG was the least potent. In both cell lines, significant arrest of the cell cycle in S phase was induced by resveratrol and EGCG and in G2M phase by quercetin, baicalein, apigenin, genistein, and curcumin. Induction of apoptosis was induced by all of the 7 compounds in the 2 cell lines as shown by TUNEL and DNA fragmentation assays. Androgen responsiveness of the cell lines did not correlate with cellular response to the phytoestrogens. In conclusion, these 7 phytoestrogens, through different mechanisms, are effective inhibitors of prostate tumor cell growth.

Topics: Antineoplastic Agents, Hormonal; Catechin; Cell Cycle; Cell Division; Curcumin; DNA Fragmentation; Humans; Male; Phytoestrogens; Prostatic Neoplasms; Quercetin; Receptors, Estrogen; Resveratrol; Stilbenes; Tumor Cells, Cultured

DNA damage generated by oxygen-derived free radicals is related to mutagenesis, carcinogenesis and aging. In the last several years, hundreds of publications have confirmed that melatonin is a potent endogenous free radical scavenger. In the present in vitro study, we have examined the efficacy of three polyphenolic antioxidants, i.e. xanthurenic acid, resveratrol (3,4',5-trihydroxy-trans-stilbene) and (-)-epigallocatechin-3-gallate (EGCG) and two classical non-polyphenolic antioxidants, i.e. vitamin C (ascorbic acid) and alpha-lipoic acid (LA, 1,2-dithiolane-3-pentanoic acid) in inhibiting *OH-induced oxidative DNA damage. We compared the efficacy of these five antioxidants with the effectiveness of melatonin (N-acetyl-5-methoxytryptamine) and we also investigated the possible synergistic effects of melatonin with the other five molecules. Using high performance liquid chromatography (HPLC), the formation of 8-hydroxy-2-deoxyguanosine (8-OH-dG) in purified calf thymus DNA treated with the Fenton reagents, chromium(III) (as CrCl3) plus hydrogen peroxide (H2O2) (Cr(III)/H2O2), was measured in the presence or absence of the antioxidants alone or in combination with melatonin. 8-OH-dG is considered a biomarker of oxidative DNA damage. Among the antioxidants tested, melatonin was the most effective of these with an IC50 = 3.6 +/- 0.1 micro m. For the other antioxidants the IC50 values were as follows: xanthurenic acid (IC50 = 7.9 +/- 0.3), resveratrol (IC50 = 10.9 +/- 0.3), EGCG (IC50 = 5.7 +/- 0.3), vitamin C (IC50 = 16.9 +/- 0.5) and LA (IC50 = 38.8 +/- 0.7). These values differ from that of melatonin with a P < 0.01. Melatonin (1 micro M) reversed the pro-oxidant effect of resveratrol (0.5 micro M) and vitamin C (0.5 micro M), had an antagonistic effect when used in combination with EGCG (1 micro M) and it exhibited synergism in combination with vitamin C (0.5 micro M) and with LA (5 micro M).

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antioxidants; Ascorbic Acid; Catechin; Chromium; Deoxyguanosine; DNA Damage; Dose-Response Relationship, Drug; Drug Synergism; Hydrogen Peroxide; Inhibitory Concentration 50; Iron; Melatonin; Oxidative Stress; Resveratrol; Stilbenes; Thioctic Acid; Xanthurenates

The objective of the current study was to investigate the effect of resveratrol, a naturally occurring polyphenol with cancer chemopreventive properties, on polyamine metabolism in the human colonic adenocarcinoma cell line Caco-2. We demonstrated that inhibition of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, was due to attenuated ODC protein and mRNA levels (50-200 microM). The naturally occurring resveratrol analog piceatannol (100 microM) also diminished ODC activity, protein and mRNA levels, whereas the green tea polyphenol (-)-epigallocatechin gallate (EGCG; 100 microM) exerted only weak effects on ODC. The transcription factor c-Myc, a positive regulator of the odc gene was attenuated by resveratrol treatment and to a lesser extent by piceatannol and EGCG. S-Adenosylmethionine decarboxylase, an enzyme that synthesizes higher polyamines, was concomitantly inhibited by resveratrol and piceatannol treatment, whereas EGCG did not affect its activity. In addition resveratrol, piceatannol and EGCG enhanced spermidine/spermine N(1)-acetyltransferase activity, an enzyme that degrades polyamines in cooperation with polyamine oxidase. Intracellular levels of spermine and spermidine were not affected, whereas putrescine and N(8)-acetylspermidine concentrations increased after incubation with resveratrol. These events were paralleled by an increase of the activator protein-1 constituents c-Fos and c-Jun. Whereas DNA-binding activity of c-Jun remained unchanged, DNA-binding activity of c-Fos was significantly enhanced by resveratrol and piceatannol, but inhibited by EGCG. The data suggest that growth arrest by resveratrol is accompanied by inhibition of polyamine synthesis and increased polyamine catabolism. C-Fos seems to play a role in this context. Effects of piceatannol on polyamine synthesis were similar, but not as potent as those exerted by resveratrol.

Topics: Acetyltransferases; Adenocarcinoma; Adenosylmethionine Decarboxylase; Anticarcinogenic Agents; Base Sequence; Caco-2 Cells; Catechin; Colonic Neoplasms; DNA Primers; Gene Expression Regulation; Humans; Ornithine Decarboxylase; Polyamines; Proto-Oncogene Proteins c-fos; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes

Previously, inhibitors of CYP1A1 were rated as candidate chemopreventive agents against cancer mainly according to their effects on the 7-ethoxyresorufin O-deethylation (EROD) of diagnostic probe substrates. Surprisingly, several polyphenols including resveratrol, formerly identified as potent inhibitors by the EROD assay, exhibited no or weak inhibition of procarcinogen activation. We compared the effects of 11 representative natural polyphenols, which normally occur in food, on different activities of CYP1A1, namely epoxidation of 7,8-dihydrodiol-benzo[a]pyrene, the terminal step in the activation leading to the ultimate carcinogenic diolepoxides, hydroxylation of benzo[a]pyrene, and EROD. For the first time, a reconstituted system was used for the determination of IC(50) values, consisting of purified enzymes (human CYP1A1 and human NADPH-cytochrome P450 reductase) and dilaurylphosphatidylcholine. The results demonstrate that the inhibitory effects of dietary polyphenols on CYP1A1 activity depend on both the structure of the inhibitor and the type of the reaction and substrate used in the assay. Consequently, a potent EROD inhibition alone is insufficient to count a substance among the chemoprotective agents.

Topics: Anticarcinogenic Agents; Benzo(a)pyrene; Biotransformation; Carcinogens; Catechin; Cytochrome P-450 CYP1A1; Enzyme Inhibitors; Flavonoids; Humans; In Vitro Techniques; Phenols; Polymers; Resveratrol; Stilbenes

The reactivity of flavonoids as radical scavengers was investigated under kinetic considerations using radical polymerization of methyl methacrylates initiated by benzoyl peroxide. The number of radicals which are trapped by each molecule of phenol (the stoichiometric factors, n values) decreased in the order of epigallocatechin-3-O-gallate (ECG) (5.5) > catechin (3.5) > resveratrol (2.4) > quercetin (1.9) > n-propylgallate (1.5) > hesperetin (1.0). The inhibition rate constants (k(inh)) (1-3 x 10(3) 1/(mol s)) for the flavonoids were not different from each other, and, therefore, the radical scavenging activity depend on n values. The n values of the fully oxidized flavonoids were estimated from the frontier orbital theory, using PM3 semiempirical molecular orbital calculation. The experimental n values were consistent with the calculated values.

Topics: Catechin; Flavonoids; Free Radical Scavengers; Free Radicals; Hesperidin; Kinetics; Molecular Structure; Polymers; Propyl Gallate; Quercetin; Resveratrol; Stilbenes; Structure-Activity Relationship

Since several anti-cancer drugs interact with cell membrane lipids, the effects of anti-cancer dietary factors on liposomal membranes with different lipid composition were comparatively studied by measuring fluorescence polarization. Fluidity was imparted on both hydrophobic and hydrophilic regions of lipid bilayers by decreasing cholesterol and increasing unsaturated phosphatidylcholine in membranes. At 0.625-10 microM, (-)-epigallocatechin gallate, genistein, apigenin, resveratrol and a reference anti-cancer drug, doxorubicin, rigidified the tumor cell model membranes consisting of 20 mol% cholesterol and 80 mol% phosphatidylcholine with the acyl chain 18:1/16:0 ratio of 1.0, but not daidzein. They were more effective on the membrane core than the membrane surface. Quercetin showed a biphasic effect on the hydrophobic regions of membrane lipid bilayers to rigidify above 5 microM and fluidize below 2.5 microM. In contrast, anti-cancer dietary factors and doxorubicin were not or much less effective in rigidifying the normal cell model membranes consisting of 40 mol% cholesterol and 60 mol% phosphatidylcholine with the acyl chain 18:1/16:0 ratio of 0.5. The membrane-rigidifying effects were greater depending on a decrease of the cholesterol/phosphatidylcholine ratio and an increase of the phosphatidylcholine unsaturation degree. Membrane-active dietary factors and doxorubicin inhibited the growth of mouse myeloma cells at 10-100 microM, while the growth inhibition by membrane-inactive daidzein was relatively weak. Anti-cancer dietary factors appear to act on more fluid membranes like tumor cells as well as doxorubicin to induce rigidification, especially in the hydrocarbon core of membrane lipids, which is determined by the composition of cholesterol and unsaturated phospholipids.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apigenin; Catechin; Cell Division; Cell Membrane; Diet; Flavonoids; Fluorescence Polarization; Genistein; Isoflavones; Liposomes; Membrane Fluidity; Membrane Lipids; Mice; Multiple Myeloma; Phenols; Resveratrol; Stilbenes; Tumor Cells, Cultured

One of the proposed functions of phosphatidic acid (PA) formation from phospholipase D (PLD) activation in neutrophils is to promote degranulation induced by receptor agonists. The present study shows that the time course and dose response of PA formation and degranulation induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) differed. PLD activation and degranulation also exhibited different dose response to genistein and epigallocatechin gallate (EGCG), inhibitors of protein tyrosine kinases. Genistein inhibited PLD activity with an IC(50) value of 12.2 microM in fMLP- and 107 microM in phorbol myristate acetate (PMA)-stimulated cells. It required higher concentrations of genistein to inhibit degranulation than to inhibit PLD activity induced by fMLP. EGCG in the range of 40-400 microM had no effect on PLD activity but it inhibited the release of beta-glucuronidase and elastase by fMLP-stimulated cells. These results demonstrate differential regulation of PLD activity and degranulation of primary granules by genistein and EGCG in fMLP-stimulated neutrophils.

Topics: Catechin; Cell Degranulation; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Genistein; Glucuronidase; Humans; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pancreatic Elastase; Phosphatidic Acids; Phospholipase D; Resveratrol; Signal Transduction; Stilbenes; Tetradecanoylphorbol Acetate

Flavonoids are a class of polyphenolic compounds widely distributed in the plant kingdom, which display a variety of biological activities, including chemoprevention and tumor growth inhibition. Our aim was to investigate the effects of several polyphenols on the growth and metastatic potential of B16-BL6 melanoma cells in vivo. Intraperitoneal administration of quercetin, apigenin, (-)-epigallocathechin-3-gallate (EGCG), resveratrol, and the anti-estrogen tamoxifen, at the time of i.m. injection of B16-BL6 cells into syngeneic mice, resulted in a significant, dose-dependent delay of tumor growth, without toxicity. The relative descending order of potency was EGCG > apigenin = quercetin = tamoxifen > resveratrol > control. Furthermore, polyphenols significantly potentiated the inhibitory effect of a non-toxic dose of cisplatin. When tested for the ability to inhibit lung colonization, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the number of B16-BL6 colonies in the lungs in a dose-dependent manner, with quercetin and apigenin being more effective than tamoxifen. Interestingly, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the invasion of B16-BL6 cells in vitro, with quercetin and apigenin being more effective than tamoxifen. This suggests that anti-invasive activity is one of the mechanisms underlying inhibition of lung colonization by quercetin and apigenin. In conclusion, quercetin and apigenin inhibit melanoma growth and invasive and metastatic potential; therefore, they may constitute a valuable tool in the combination therapy of metastatic melanoma.

Topics: Animals; Anticarcinogenic Agents; Apigenin; Catechin; Cell Division; Curcumin; Female; Flavonoids; Growth Inhibitors; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neoplasm Transplantation; Quercetin; Resveratrol; Stilbenes; Tamoxifen; Tumor Cells, Cultured