stilbenes and Inflammation

Stilbenes are polyphenolic allelochemicals synthesized by plants, especially grapes, peanuts, rhubarb, berries, etc., to defend themselves under stressful conditions. They are now exploited in medicine for their antioxidant, anti-proliferative and anti-inflammatory properties. Inflammation is the immune system's response to invading bacteria, toxic chemicals or even nutrient-deprived conditions. It is characterized by the release of cytokines which can wreak havoc on healthy tissues, worsening the disease condition. Stilbenes modulate NF-κB, MAPK and JAK/STAT pathways, and reduce the transcription of inflammatory factors which result in maintenance of homeostatic conditions. Resveratrol, the most studied stilbene, lowers the Michaelis constant of SIRT1, and occupies the substrate binding pocket. Gigantol interferes with the complement system. Besides these, oxyresveratrol, pterostilbene, polydatin, viniferins, etc., are front runners as drug candidates due to their diverse effects from different functional groups that affect bioavailability and molecular interactions. However, they each have different thresholds for toxicity to various cells of the human body, and thus a careful review of their properties must be conducted. In animal models of autoinflammatory diseases, the mode of application of stilbenes is important to their absorption and curative effects, as seen with topical and microemulsion gel methods. This review covers the diversity seen among stilbenes in the plant kingdom and their mechanism of action on the different inflammatory pathways. In detail, macrophages' contribution to inflamed conditions in the liver, the cardiac, connective and neural tissues, in the nephrons, intestine, lungs and in myriad other body cells is explored, along with detailed explanation on how stilbenes alleviate the symptoms specific to body site. A section on the bioavailability of stilbenes is included for understanding the limitations of the natural compounds as directly used drugs due to their rapid metabolism. Current delivery mechanisms include sulphonamides, or using specially designed synthetic drugs. It is hoped that further research may be fueled by this comprehensive work that makes a compelling argument for the exploitation of these compounds in medicine.

Topics: Animals; Fruit; Humans; Inflammation; Resveratrol; Stilbenes; Vitis

Flavonoids, stilbenes, lignans, and phenolic acids, classes of polyphenols found in grape pomace (GP), were investigated as an important alternative source for active substances that could be used in the management of oxidative stress and inflammation. The benefic antioxidant and anti-inflammatory actions of GP are presented in the literature, but they are derived from a large variety of experimental

Topics: Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; C-Reactive Protein; Catalase; Dinoprostone; Flavonoids; Glutathione; Glutathione Peroxidase; Inflammation; Interferons; Interleukin-6; Interleukin-8; Lignans; NF-kappa B; Nitric Oxide Synthase Type III; Oxidative Stress; Plant Extracts; Polyphenols; Reactive Oxygen Species; Stilbenes; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha; Vitis

Topics: Animals; Benzoquinones; Biological Products; Biomimetics; Caffeic Acids; Curcumin; Cytokines; Exosomes; Humans; Inflammation; Inflammatory Bowel Diseases; Insecta; Macromolecular Substances; Nanomedicine; Oxidative Stress; Phenylethyl Alcohol; Phytochemicals; Plant Extracts; Polysaccharides; Quercetin; Resveratrol; Stilbenes; Transcription Factors; Translational Research, Biomedical; Vasoactive Intestinal Peptide; Zingiber officinale

Heterotopic ossification (HO) is associated with inflammation. The goal of this review is to examine recent findings on the roles of inflammation and the immune system in HO. We examine how inflammation changes in fibrodysplasia ossificans progressiva, in traumatic HO, and in other clinical conditions of HO. We also discuss how inflammation may be a target for treating HO.. Both genetic and acquired forms of HO show similarities in their inflammatory cell types and signaling pathways. These include macrophages, mast cells, and adaptive immune cells, along with hypoxia signaling pathways, mesenchymal stem cell differentiation signaling pathways, vascular signaling pathways, and inflammatory cytokines. Because there are common inflammatory mediators across various types of HO, these mediators may serve as common targets for blocking HO. Future research may focus on identifying new inflammatory targets and testing combinatorial therapies based on these results.

Topics: Adaptive Immunity; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthroplasty, Replacement, Hip; Blast Injuries; Brain Injuries, Traumatic; Burns; Cell Differentiation; Cytokines; Humans; Hypoxia; Immunosuppressive Agents; Inflammation; Janus Kinase Inhibitors; Macrophages; Mast Cells; Mesenchymal Stem Cells; Myositis Ossificans; Ossification, Heterotopic; Postoperative Complications; Pyrazoles; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Signal Transduction; Sirolimus; Spinal Cord Injuries; Stilbenes; Wounds and Injuries

Over the past years, several studies have found that foods rich in polyphenols protect against age-related disease, such as atherosclerosis, cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes (T2D), hypertension and Alzheimer's disease. Resveratrol and pterostilbene, the polyphenol found in grape and blueberries, have beneficial effects as anti-aging compounds through modulating the hallmarks of aging, including oxidative damage, inflammation, telomere attrition and cell senescence. In this review, we discuss the relationship between resveratrol and pterostilbene and possible aging biomarker, including oxidative stress, inflammation, and high-calorie diets. Moreover, we also discuss the positive effect of resveratrol and pterostilbene on lifespan, aged-related disease, and health maintenance. Furthermore, we summarize a variety of important mechanisms modulated by resveratrol and pterostilbene possibly involved in attenuating age-associated disorders. Overall, we describe resveratrol and pterostilbene potential for prevention or treatment of several age-related diseases by modulating age-related mechanisms. © 2017 BioFactors, 44(1):69-82, 2018.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Cardiovascular Diseases; Cataract; Cellular Senescence; Humans; Inflammation; Longevity; Neoplasms; Neurodegenerative Diseases; NF-E2-Related Factor 2; Osteoporosis; Oxidative Stress; Resveratrol; Sirtuin 1; Stilbenes; Telomere Homeostasis

Phenolics, which are secondary metabolites of plants, exhibit remarkable bioactivities. In this contribution, we have focused on their protective effect against chronic diseases rather than their antioxidant activities, which have been widely discussed in the literature. A large body of epidemiological studies has proven the bioactivities of phenolics in both standard compounds and natural extracts: namely, anticancer, anti-inflammatory, and antibacterial activities as well as reducing diabetes, cardiovascular disease, and neurodegenerative disease. Phenolics also display anti-analgesic, anti-allergic, and anti-Alzheimer's properties. Thus, this review provides crucial information for better understanding the bioactivities of phenolics in foods and fills a gap in the existing collective and overall knowledge in the field.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Bacterial Infections; Chalcones; Coumaric Acids; Edible Grain; Flavonoids; Fruit; Humans; Hydroxybenzoates; Inflammation; Neoplasms; Stilbenes; Vegetables

Inflammation is the principal response invoked by the body to address injuries. Despite inflammation constituting a crucial component of tissue repair, it is well known that unchecked or chronic inflammation becomes deleterious, leading to progressive tissue damage. Studies over the past years focused on foods rich in polyphenols with anti-inflammatory and immunomodulatory properties, since inflammation was recognized to play a central role in several diseases. In this review, we discuss the beneficial effects of resveratrol, the most widely investigated polyphenol, on cancer and neurodegenerative, respiratory, metabolic, and cardiovascular diseases. We highlight how resveratrol, despite its unfavorable pharmacokinetics, can modulate the inflammatory pathways underlying those diseases, and we identify future opportunities for the evaluation of its clinical feasibility.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Inflammation; Mice; Neoplasms; Obesity; Rats; Respiratory Tract Diseases; Resveratrol; Stilbenes

Endometriosis is characterized by the existence of endometrial tissue and stroma exterior to the uterus. Despite the high prevalence, the etiology of endometriosis remains elusive. The search for the most promising compounds for treatment of endometriosis has led to the identification of resveratrol. Resveratrol, a plant-derived polyphenolic phytoalexin, demonstrates broad-spectrum health beneficial effects, including anti-proliferative, anti-inflammatory, antineoplastic and antioxidant. Because of these properties and its wide distribution in plants, resveratrol is proposed as a great potential to treat endometriosis. In animal models of endometriosis, resveratrol supplementation has displayed beneficial results as it decreased the number and volume of endometrial implants, suppressed proliferation, vascularization, inflammation, cell survival and increased apoptosis. On the other hand, resveratrol treatment in-vitro studies, reduced invasiveness of endometriotic stromal cells (ESCs) and suppressed their inflammatory responses. In this review, we will summarize the recent studies in in-vitro and animal studies on resveratrol and endometriosis.

Topics: Animals; Biological Availability; Endometriosis; Female; Humans; Inflammation; Oxidative Stress; Resveratrol; Stilbenes

Natural products or nutraceuticals promote anti-aging, anti-cancer and other health-enhancing effects. A key target of the effects of natural products may be the regulation of the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway. This review will focus on the effects of curcumin (CUR), berberine (BBR) and resveratrol (RES), on the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway, with a special focus on GSK-3. These natural products may regulate the pathway by multiple mechanisms including: reactive oxygen species (ROS), cytokine receptors, mirco-RNAs (miRs) and many others. CUR is present the root of turmeric (Curcuma longa). CUR is used in the treatment of many disorders, especially in those involving inflammatory processes which may contribute to abnormal proliferation and promote cancer growth. BBR is also isolated from various plants (Berberis coptis and others) and is used in traditional medicine to treat multiple diseases/conditions including: diabetes, hyperlipidemia, cancer and bacterial infections. RES is present in red grapes, other fruits and berries such as blueberries and raspberries. RES may have some anti-diabetic and anti-cancer effects. Understanding the effects of these natural products on the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway may enhance their usage as anti-proliferative agent which may be beneficial for many health problems.

Topics: Berberine; Cardiovascular Diseases; Curcumin; Gene Expression Regulation; Glycogen Synthase Kinase 3; Humans; Inflammation; Mechanistic Target of Rapamycin Complex 1; Neoplasms; Neurodegenerative Diseases; Osteoarthritis; Phosphatidylinositol 3-Kinases; Protective Agents; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Resveratrol; Signal Transduction; Stilbenes

As a sugar additive, fructose is widely used in processed foods and beverages. Excessive fructose consumption can cause hepatic steatosis and dyslipidemia, leading to the development of metabolic syndrome. Recent research revealed that fructose-induced nonalcoholic fatty liver disease (NAFLD) is related to several pathological processes, including: (1) augmenting lipogenesis; (2) leading to mitochondrial dysfunction; (3) stimulating the activation of inflammatory pathways; and (4) causing insulin resistance. Cellular signaling research indicated that partial factors play significant roles in fructose-induced NAFLD, involving liver X receptor (LXR)α, sterol regulatory element binding protein (SREBP)-1/1c, acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), peroxisome proliferator-activated receptor α (PPARα), leptin nuclear factor-erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), c-Jun amino terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3K) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Until now, a series of natural products have been reported as regulators of NAFLD in vivo and in vitro. This paper reviews the natural products (e.g., curcumin, resveratrol, and (-)-epicatechin) and their mechanisms of ameliorating fructose-induced NAFLD over the past years. Although, as lead compounds, natural products usually have fewer activities compared with synthesized compounds, it will shed light on studies aiming to discover new drugs for NAFLD.

Topics: Animals; Biological Products; Catechin; Curcumin; Fructose; Humans; Inflammation; Insulin Resistance; Lipogenesis; Mitochondria; Non-alcoholic Fatty Liver Disease; Resveratrol; Stilbenes

Parkinson's disease (PD) is a mysterious, chronic, multi-factorial and progressive disorder of the nervous system that is characterized by the selective loss of dopamine-producing cells of the substantia nigra leading to dopamine deficiency in the striatum. PD is exemplified by oxidative stress, α-synuclein accumulation, mitochondrial dysfunction, defective ubiquitin proteasome system, aberrant autophagy, inflammation, and atypical apoptosis, which eventually lead to slowness of movement, resting tremor, stiffness, and loss of balance. Despite incomprehensible etiology, timely diagnosis, and permanent cure, a handful of synthetic and natural agents rescue from the symptomatic features and delay disease progression. At low doses, a natural polyphenol, trans-3,5,4'-trihydroxystilbene (resveratrol), delays neurodegeneration in the cellular and animal models and lessens oxidative stress, mitochondrial dysfunction, aberrant apoptosis, and defective autophagy. The present article explains neuroprotective efficacy, advantages, and downsides of resveratrol in the conventional and preclinical models. This piece of writing also examines its probable neuroprotective mechanisms and constraints of realistic recital in clinical investigations and likely endeavors to minimize apprehensions.

Topics: Animals; Humans; Inflammation; Neuroprotective Agents; Neurotoxins; Parkinsonian Disorders; Resveratrol; Stilbenes; Translational Research, Biomedical

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by deposition of amyloid plaques and neurofibrillary tangles, as well as microglial and astroglial activation, and, finally, leading to neuronal dysfunction and death. Current treatments for AD primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for the treatment of AD patients. This review will provide an overview of the antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of a variety of nutraceuticals including curcumin, apigenin, docosahexaenoic acid, epigallocatechin gallate, α-lipoic acid and resveratrol and their potential for AD prevention and treatment. We suggest that therapeutic use of these compounds might lead to a safe strategy to delay the onset of AD or slow down its progression. The continuing investigation of the potential of these substances is necessary as they are promising compounds to yield a possible remedy for this pervasive disease.

Topics: Alzheimer Disease; Animals; Antioxidants; Biological Products; Chronic Disease; Curcumin; Fish Oils; Humans; Inflammation; Neurodegenerative Diseases; Neurofibrillary Tangles; Neuroprotective Agents; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes

Resveratrol is a naturally occurring stilbene endowed with multiple health-promoting effects. It is produced by certain plants including several dietary sources such as grapes, apples, raspberries, blueberries, plums, peanuts, and products derived therefrom (e.g., wine). Resveratrol can be isolated and purified from these biological sources or synthesized in a few steps with an overall high yield. This compound and its glucoside, the trans-polydatin piceid, have received worldwide attention for their beneficial effects on cardiovascular, inflammatory, neurodegenerative, metabolic, and age-related diseases. These health-promoting effects are particularly attractive given the prevalence of resveratrol-based nutraceuticals and the paradoxical epidemiologic observation that wine consumption is inversely correlated to the incidence of coronary heart disease. However, the notion of resveratrol as a "magic bullet" was recently challenged by clinical trials showing that this polyphenol does not have a substantial influence on health status and mortality risk. In the present review, we discuss the proposed therapeutic attributes and the mode of molecular actions of resveratrol. We also cover recent pharmacologic efforts to improve the poor bioavailability of resveratrol and influence the transition between body systems in humans. We conclude with some thoughts about future research directions that might be meaningful for resolving controversies surrounding resveratrol.

Topics: Coronary Disease; Diet; Dietary Supplements; Fruit; Glycosides; Humans; Inflammation; Metabolic Diseases; Neurodegenerative Diseases; Phytotherapy; Plant Extracts; Polyphenols; Resveratrol; Stilbenes; Wine

Changes to somatic sensory pathways caused by peripheral tissue, inflammation or injury can result in behavioral hypersensitivity and pathological pain, such as hyperalgesia. Resveratrol, a plant polyphenol found in red wine and various food products, is known to have several beneficial biological actions. Recent reports indicate that resveratrol can modulate neuronal excitability, including nociceptive sensory transmission. As such, it is possible that this dietary constituent could be a complementary alternative medicine (CAM) candidate, specifically a therapeutic agent. The focus of this review is on the mechanisms underlying the modulatory effects of resveratrol on nociceptive neuronal activity associated with pain relief. In addition, we discuss the contribution of resveratrol to the relief of nociceptive and/or pathological pain and its potential role as a functional food and a CAM.

Topics: Animals; Dietary Supplements; Inflammation; Nociceptors; Pain Management; Resveratrol; Stilbenes

Resveratrol, a natural polyphenolic molecule with several biological activities, is a well recognized anti-oxidant, anti-aging and cancer chemopreventive agent. Moreover, resveratrol anti-inflammatory and antifibrotic properties have been demonstrated both in vitro and in different animal models of inflammatory pathologies, including bowel and liver diseases. We review the evidence of resveratrol protective role in respiratory diseases such as acute lung injury, asthma, chronic obstructive pulmonary disease and lung fibrosis. We conclude that resveratrol and its derivatives may act as a therapeutic agents in respiratory diseases and pertinent clinical trials should be performed.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Asthma; Disease Models, Animal; Fibrosis; Humans; Inflammation; Liver Diseases; Lung; Mice; Pulmonary Disease, Chronic Obstructive; Resveratrol; Stilbenes

Throughout the Western world obesity prevalence is steadily increasing, and associated metabolic co-morbidities are projected to rise during the years to come. As weight loss and weight maintenance remains a major problem, new strategies to protect against obesity-related morbidity are needed. There is a clear association between obesity, low-grade inflammation and obesity-associated diseases, thus, the development of new anti-inflammatory substances is urgently needed as these may ultimately pave the way for novel treatments of obesity and lifestyle-related diseases. A candidate molecule is the polyphenolic compound resveratrol, and in the present review, we provide an overview of the field, and discuss the future scientific perspectives. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Humans; Inflammation; Obesity; Resveratrol; Stilbenes; Translational Research, Biomedical

Resveratrol, a constituent of grapes and various other plants, has been an attractive compound for biomedical studies because moderate long-term drinking of red wine is associated with a reduced risk of lifestyle-related diseases, such as cardiovascular diseases and cancer. Resveratrol is as a phytoalexin, cyclooxygenase (COX) suppressor, and an activator of peroxisome proliferatoractivated receptor (PPAR) and SIRT1. As a major phytoalexin, resveratrol is produced by plants in response to various environmental stresses, such as pathogens and ultraviolet (UV) radiation, and promotes resistance to these stresses. A similar active ingredient, salicylic acid (SA), is also produced by plants. Aspirin, acetylated SA, is a major nonsteroidal anti-inflammatory drug (NSAID) because it inhibits COX activity in humans. The jasmonic acid (JA) pathway in plants and the COX pathway in humans are both defense systems against environmental stresses and involve lipid mediators derived from phospholipids. We can hypothesize that there is a molecular basis for the mutually beneficial relationship between plants and humans, which is important for understanding the mode of action of resveratrol in inflammation. Here we provide a review of the studies on resveratrol, especially with respect to the role of COX and PPAR in inflammation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Humans; Inflammation; Inflammation Mediators; Resveratrol; Stilbenes

Aging is an inevitable and multifactorial biological process. Free radicals have been implicated in aging processes; it is hypothesized that they cause cumulative oxidative damage to crucial macromolecules and are responsible for failure of multiple physiological mechanisms. However, recent investigations have also suggested that free radicals can act as modulators of several signaling pathways such as those related to sirtuins. Caloric restriction is a non-genetic manipulation that extends lifespan of several species and improves healthspan; the belief that many of these benefits are due to the induction of sirtuins has led to the search for sirtuin activators, especially sirtuin 1, the most studied. Resveratrol, a polyphenol found in red grapes, was first known for its antioxidant and antifungal properties, and subsequently has been reported several biological effects, including the activation of sirtuins. Endogenously-produced melatonin, a powerful free radical scavenger, declines with age and its loss contributes to degenerative conditions of aging. Recently, it was reported that melatonin also activates sirtuins, in addition to other functions, such as regulator of circadian rhythms or anti-inflammatory properties. The fact that melatonin and resveratrol are present in various foods, exhibiting possible synergistic effects, suggests the use of dietary ingredients to promote health and longevity.

Topics: Animals; Antioxidants; Caloric Restriction; Humans; Inflammation; Longevity; Melatonin; Resveratrol; Sirtuin 1; Stilbenes

This review presents recent evidence implicating microRNAs (miRNAs) in the beneficial effects of resveratrol (trihydroxystilbene), a nonflavonoid plant polyphenol, with emphasis on its anti-inflammatory effects. Many diseases and pathologies have been linked, directly or indirectly, to inflammation. These include infections, injuries, atherosclerosis, diabetes mellitus, obesity, cancer, osteoarthritis, age-related macular degeneration, demyelination, and neurodegenerative diseases. Resveratrol can both decrease the secretion of proinflammatory cytokines (e.g., IL-6, IL-8, and TNF-α) and increase the production of anti-inflammatory cytokines; it also decreases the expression of adhesion proteins (e.g., ICAM-1) and leukocyte chemoattractants (e.g., MCP-1). Resveratrol's primary targets appear to be the transcription factors AP-1 and NF-κB, as well as the gene COX2. Although no mechanistic link between any particular miRNA and resveratrol has been identified, resveratrol effects depend at least in part upon the modification of the expression of a variety of miRNAs that can be anti-inflammatory (e.g., miR-663), proinflammatory (e.g., miR-155), tumor suppressing (e.g., miR-663), or oncogenic (e.g., miR-21).

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acids; Gene Expression; Humans; Immunity, Innate; Inflammation; Inflammation Mediators; Lipid Metabolism; MicroRNAs; Resveratrol; RNA Interference; Stilbenes

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a natural phytoalexin found in grape-skin, exerts multiple biological activities, including anti-inflammatory, antiproliferative and antioxidant effects. In the past few years, mounting evidence has suggested that resveratrol is neuroprotective against a number of neurological diseases. An important contributor to the pathogenesis of neurological disorders is neuroinflammation, of which microglial activation is an important hallmark. It is possible that M1/M2 polarization of microglia may play an important role in controlling the balance between promoting and resolving neuroinflammation in the CNS. Immunomodulatory strategies capable of redirecting the microglial response toward the neuroprotective M2 phenotype could offer attractive options for neurodegenerative diseases with inflammatory components. The neuroprotective actions of resveratrol seem to be attributable to its anti-inflammatory properties, due not only to its direct scavenger effects versus toxic molecules but also to a capacity to upregulate natural anti-inflammatory defences, thus counteracting excessive responses of classically activated M1 microglia. The goal of this review is to summarize recent insights into the therapeutic potential of resveratrol as a natural modulator of microgliamediated neurotoxicity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Humans; Inflammation; Microglia; Neurodegenerative Diseases; Neuroprotective Agents; Resveratrol; Stilbenes

Chronic viral infections like those caused by hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause disease that establishes an ongoing state of chronic inflammation. While there have been tremendous improvements towards curing HCV with directly acting antiviral agents (DAA) and keeping HIV viral loads below detection with antiretroviral therapy (ART), there is still a need to control inflammation in these diseases. Recent studies indicate that many natural products like curcumin, resveratrol and silymarin alter cellular metabolism and signal transduction pathways via enzymes such as adenosine monophosphate kinase (AMPK) and mechanistic target of rapamycin (mTOR), and these pathways directly influence cellular inflammatory status (such as NF-κB) and immune function. Natural products represent a vast toolkit to dissect and define how cellular metabolism controls cellular immune and inflammatory function.

Topics: Biological Products; Chronic Disease; Curcumin; Hepatitis C; HIV Infections; Humans; Immunity, Cellular; Immunologic Factors; Inflammation; Resveratrol; Silymarin; Stilbenes

The mammalian sirtuins (SIRT1-7) are NAD(+)-dependent lysine deacylases that play central roles in cell survival, inflammation, energy metabolism, and aging. Members of this family of enzymes are considered promising pharmaceutical targets for the treatment of age-related diseases including cancer, type 2 diabetes, inflammatory disorders, and Alzheimer's disease. SIRT1-activating compounds (STACs), which have been identified from a variety of chemical classes, provide health benefits in animal disease models. Recent data point to a common mechanism of allosteric activation by natural and synthetic STACs that involves the binding of STACs to a conserved N-terminal domain in SIRT1. Compared with polyphenols such as resveratrol, the synthetic STACs show greater potency, solubility, and target selectivity. Although considerable progress has been made regarding SIRT1 allosteric activation, key questions remain, including how the molecular contacts facilitate SIRT1 activation, whether other sirtuin family members will be amenable to activation, and whether STACs will ultimately prove safe and efficacious in humans.

Topics: Allosteric Regulation; Animals; Benzimidazoles; Disease Models, Animal; Humans; Inflammation; Molecular Targeted Therapy; Resveratrol; Sirtuins; Stilbenes

Under normal conditions, most of the central nervous system (CNS) is protected by the blood brain barrier (BBB) from systemic inflammation progression and from the infiltration of immune cells. As a consequence, the CNS developed an original way to provide surveillance, defense and repair, which relies on the complex process of neuroinflammation. Despite tight regulation, neuroinflammation is frequently the cause of irreversible nerve cell loss but it is also where the solution lies. Specific immune crosstalk taking place in the CNS needs to be decoded in order to identify the best therapeutic strategies aimed at helping the CNS restore homeostasis in difficult conditions such as in neurodegenerative disorders. This review deals with the double-edged sword nature of neuroinflammation and the use of resveratrol in various models as one of the most promising therapeutic molecules for preventing the consequences of nerve cell autodestruction.

Topics: Animals; Humans; Inflammation; Models, Biological; Neurodegenerative Diseases; Neuroprotective Agents; Resveratrol; Stilbenes

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

Adipose tissue has an important endocrine function in the regulation of whole-body metabolism. Obesity leads to a chronic low-grade inflammation of the adipose tissue, which disrupts this endocrine function and results in metabolic derangements, such as type-2 diabetes. Dietary bioactive compounds, such as polyphenols and certain fatty acids, are known to suppress both systemic and adipose tissue inflammation and have the potential to improve these obesity-associated metabolic disorders. Mechanistically, polyphenolic compounds including non-flavonoids, such as curcumin and resveratrol, and flavonoids, such as catechins (tea-polyphenols), quercetin and isoflavones, suppress nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinases (MAPK) pathways while activating the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway in adipose tissue. Dietary polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), conjugated linoleic acid (CLA) and monounsaturated fatty acids (MUFA), such as oleic acid, also impart anti-inflammatory effects through several mechanisms. These include activation of AMPK and peroxisome proliferator-activated receptor gamma (PPAR-γ), as well as suppression of toll-like receptors (TLRs) and NF-κB pathway. This review discusses the major molecular mechanisms of dietary polyphenols and fatty acids, alone or in combination, which are responsible for adipose tissue-associated anti-inflammatory effects.

Topics: Adipose Tissue; Curcumin; Endocrine Glands; Fatty Acids; Food; Humans; Inflammation; Insulin Resistance; Polyphenols; Quercetin; Resveratrol; Stilbenes

The nuclear factor E2-related factor 2 (Nrf2) plays an important role in cellular protection against cancer, renal, pulmonary, cardiovascular and neurodegenerative diseases where oxidative stress and inflammation are common conditions. The Nrf2 regulates the expression of detoxifying enzymes by recognizing the human Antioxidant Response Element (ARE) binding site and it can regulate antioxidant and anti-inflammatory cellular responses, playing an important protective role on the development of the diseases. Studies designed to investigate how effective Nrf2 activators or modulators are need to be initiated. Several recent studies have shown that nutritional compounds can modulate the activation of Nrf2-Keap1 system. This review aims to discuss some of the key nutritional compounds that promote the activation of Nrf2, which may have impact on the human health.

Topics: Antioxidants; Catechin; Diet Therapy; Disulfides; Gene Expression Regulation; Humans; Inflammation; NF-E2-Related Factor 2; Resveratrol; Signal Transduction; Stilbenes; Sulfinic Acids

Besides synthesizing nutritive substances (proteins, fats and carbohydrates) for energy and growth, plants produce numerous non-energetic so-called secondary metabolites (mainly polyphenols) that allow them to protect themselves against infections and other types of hostile environments. Interestingly, these polyphenols often provide cells with valuable bioactive properties for the maintenance of their functions and homeostasis (signaling, gene regulation, protection against acquired or infectious diseases, etc.) both in humans and animals. Namely, from a nutritional point of view, and based on epidemiological data, it is now well accepted that the regular consumption of green vegetables, fruits and fibers has protective effects against the onset of cancer as well as of inflammatory, neurodegenerative, metabolic and cardiovascular diseases, and consequently increases the overall longevity. In particular, grapevine plants produce large amounts of a wide variety of polyphenols. The most prominent of those-resveratrol-has been shown to impair or delay cardiovascular alterations, cancer, inflammation, aging, etc. Until recently, the molecular bases of the pleiotropic effects of resveratrol remained largely unclear despite numerous studies on a variety of signaling pathways and the transcriptional networks that they control. However, it has been recently proposed that the protective properties of resveratrol may arise from its modulation of small non-coding regulatory RNAs, namely microRNAs. The aim of this review is to present up-to-date data on the control of microRNA expression by dietary phytophenols in different types of human cells, and their impact on cell differentiation, cancer development and the regulation of the inflammatory response.

Topics: Animals; Antioxidants; Cardiovascular Diseases; Cell Differentiation; Cell Physiological Phenomena; Diet; Dietary Fiber; Fruit; Gene Expression; Homeostasis; Humans; Inflammation; MicroRNAs; Neoplasms; Phenols; Plants; Polyphenols; Resveratrol; Signal Transduction; Stilbenes; Vegetables

Resveratrol, a natural polyphenol, has gained attention in recent years because of its connection with the health benefits of red wine and its anticancer activity in vitro. Studies in animal models have demonstrated beneficial effects on glucose metabolism, vascular function and anti-inflammatory and antioxidant properties. Human studies designed to understand the role of resveratrol in the prevention and treatment of age-related conditions such as diabetes, heart disease, and cancer have recently been undertaken.. We searched PubMed for original articles that reported studies of resveratrol in humans, using search terms, including resveratrol, human studies, glucose metabolism, vascular function, and inflammation. We also searched the reference lists of identified articles for additional papers and sought expert opinion on relevant studies.. Resveratrol treatment has shown beneficial effects on glucose and lipid metabolism in some, but not all studies. Study population, resveratrol source, and dose have varied widely, potentially explaining inconsistent findings. Improvements were noted in endothelial function, systolic blood pressure, and markers of oxidative stress and inflammation in several studies.. Despite the strong preclinical evidence of positive cardiometabolic effects, studies to date have not confirmed resveratrol's benefit in humans. Study variability and methodological issues limit interpretation of available results. Additional research, focusing on subjects with defined metabolic defects and using a range of doses, is needed to advance the field.

Topics: Animals; Antioxidants; Cardiovascular Diseases; Glucose Metabolism Disorders; Humans; Inflammation; Oxidative Stress; Resveratrol; Stilbenes

Resveratrol, a phenolic compound found in various plants, including grapes, berries, and peanuts, shows promise for the treatment of cancer, aging, type 2 diabetes, and cardiovascular diseases. Resveratrol can promote transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) activation, increase the expression level of SIRT-1, which is a sirtuin family protein, and reduce mTOR pathway signaling. This compound has anti-inflammatory properties in that it inhibits or antagonizes the nuclear factor-κB (NF-κB) activity, which is a redox-sensitive transcription factor that coordinates the inflammatory response. Inflammation and oxidative stress, which are common features in patients with chronic kidney disease (CKD), are interrelated and associated with cardiovascular disease and the progression of CKD itself. Because of the modulation of the mechanisms involved in the inflammatory-oxidative stress cycle, resveratrol could play an important role in controlling CKD-related metabolic derangements. Although resveratrol supplementation in theory is a promising therapy in this patient group, there are no studies evaluating its effects. Thus, the present review aims to describe the role of resveratrol in inflammation and oxidative stress modulation and its possible benefits to patients with CKD.

Topics: Humans; Inflammation; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Multiprotein Complexes; Oxidative Stress; Renal Insufficiency, Chronic; Resveratrol; Stilbenes; TOR Serine-Threonine Kinases

A reduction in calorie intake [caloric restriction (CR)] appears to consistently decrease the biological rate of aging in a variety of organisms as well as protect against age-associated diseases including chronic inflammatory disorders such as cardiovascular disease and diabetes. Although the mechanisms behind this observation are not fully understood, identification of the main metabolic pathways affected by CR has generated interest in finding molecular targets that could be modulated by CR mimetics. This review describes the general concepts of CR and CR mimetics as well as discusses evidence related to their effects on inflammation and chronic inflammatory disorders. Additionally, emerging evidence related to the effects of CR on periodontal disease in non-human primates is presented. While the implementation of this type of dietary intervention appears to be challenging in our modern society where obesity is a major public health problem, CR mimetics could offer a promising alternative to control and perhaps prevent several chronic inflammatory disorders including periodontal disease.

Topics: Adaptive Immunity; Animals; Biomimetics; Caloric Restriction; Cardiovascular Diseases; Chronic Disease; Diabetes Mellitus; Humans; Immunity, Innate; Inflammation; Inflammation Mediators; Insulin-Like Growth Factor I; Metformin; Periodontitis; Resveratrol; Signal Transduction; Sirolimus; Sirtuins; Stilbenes; TOR Serine-Threonine Kinases

Interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) are key cytokines that drive the production of inflammatory mediators and matrix-degrading enzymes in osteoarthritis (OA). These proinflammatory cytokines bind to their respective cell surface receptors and activate inflammatory signaling pathways culminating with the activation of nuclear factor κB (NF-κB), a transcription factor that can be triggered by a host of stress-related stimuli including, excessive mechanical stress and ECM degradation products. Once activated, NF-κB regulates the expression of many cytokines, chemokines, adhesion molecules, inflammatory mediators, and several matrix-degrading enzymes. Therefore, proinflammatory cytokines, their cell surface receptors, NF-κB and downstream signaling pathways are therapeutic targets in OA. This paper critically reviews the recent literature and outlines the potential prophylactic properties of plant-derived phytochemicals such as curcumin and resveratrol for targeting NF-κB signaling and inflammation in OA to determine whether these phytochemicals can be used as functional foods.

Topics: Angiogenesis Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Cartilage, Articular; Chondrocytes; Curcumin; Humans; Inflammation; Interleukin-1beta; Joints; Osteoarthritis; Phytochemicals; Phytotherapy; Resveratrol; Stilbenes; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Sirtuins are highly conserved NAD(+)-dependent enzymes that have beneficial effects against age-related diseases. Aging is the major unifying risk factor for all neurodegenerative disorders. Sirtuins modulate major biological pathways, such as stress response, protein aggregation, and inflammatory processes, that are involved in age-related neurodegenerative diseases. Therefore, sirtuins have been widely studied in the context of the nervous system and neurodegeneration. They are especially interesting because it is possible to alter the activities of sirtuins using small molecules that could be developed into drugs. Indeed, it has been shown that manipulation of SIRT1 activity genetically or pharmacologically impacts neurodegenerative disease models. This review summarizes recent research in sirtuin neurobiology and neurodegenerative diseases and analyzes the potential of therapeutic applications based on sirtuin research.

Topics: Aging; Animals; Drug Discovery; Humans; Inflammation; Neurodegenerative Diseases; Resveratrol; Sirtuins; Stilbenes; Stress, Physiological; Yeasts

Age-related macular degeneration (AMD) is the most common reason for blindness in developed countries. AMD essentially involves chronic oxidative stress, increased accumulation of lipofuscin in retinal pigment epithelial (RPE) cells, and extracellular drusen formation, as well as presence of chronic inflammation in the retina. The capacity to prevent the accumulation of cellular cytotoxic protein aggregates is decreased in senescent cells, which may evoke lipofuscin accumulation into lysosomes in postmitotic RPE cells. The formation of lipofuscin, in turn, decreases the lysosomal enzyme activity and impairs the autophagic clearance of damaged proteins destined for cellular removal. 5'-Adenosine monophosphate-activated protein kinase (AMPK) is a well-known inhibitor of mammalian target of rapamycin (mTOR) that subsequently evokes induction of autophagy. This review examines the novel potential therapeutic targets on the AMPK-mTOR axis and the ways in which autophagy clearance can suppress or prevent RPE degeneration and development of AMD.

Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Humans; Inflammation; Lipofuscin; Lysosomes; Mice; Mice, Inbred BALB C; Microscopy, Confocal; Models, Biological; Oxidative Stress; Resveratrol; Retina; Retinal Pigment Epithelium; Stilbenes; TOR Serine-Threonine Kinases

Respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are a significant and increasing global health problem. These diseases are characterized by airway inflammation, which develops in response to various stimuli. In asthma, inflammation is driven by exposure to a variety of triggers, including allergens and viruses, which activate components of both the innate and acquired immune responses. In COPD, exposure to cigarette smoke is the primary stimulus of airway inflammation. Activation of airway inflammatory cells leads to the release of excessive quantities of reactive oxygen species (ROS), resulting in oxidative stress. Antioxidants provide protection against the damaging effects of oxidative stress and thus may be useful in the management of inflammatory airways disease. Resveratrol, a polyphenol that demonstrates both antioxidative and anti-inflammatory functions, has been shown to improve outcomes in a variety of diseases, in particular, in cancer. We review the evidence for a protective role of resveratrol in respiratory disease. Mechanisms of resveratrol action that may be relevant to respiratory disease are described. We conclude that resveratrol has potential as a therapeutic agent in respiratory disease, which should be further investigated.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Humans; Inflammation; Lung Diseases, Obstructive; Oxidative Stress; Resveratrol; Stilbenes

To review the pathophysiology, pharmacology, and current or future therapies under study for use in treating diabetes mellitus, inflammation associated with diabetes mellitus, and/or obesity related to diabetes mellitus, through 1 of 4 investigational pathways: adiponectin, ghrelin, resveratrol, or leptin.. A literature search using MEDLINE (1966-December 12, 2009), PubMed (1950-December 12, 2009), Science Direct (1994-December 12, 2009), and International Pharmaceutical Abstracts (1970-December 12, 2009) was performed using the terms adiponectin, ghrelin, resveratrol, leptin, inflammation, obesity, and diabetes mellitus. English-language, original research, and review articles were examined, and citations from these articles were assessed as well.. Clinical studies and in vitro studies were included in addition to any Phase 1, 2, or 3 clinical trials.. Mechanistic pathways regarding adiponectin, ghrelin, resveratrol, and leptin are of interest as future treatment options for diabetes mellitus. Each of these pathways has produced significant in vitro and in vivo clinical data warranting further research as a possible treatment pathway for diabetes-related inflammation and/or obesity reduction. While research is still underway to determine the exact effects these pathways have on metabolic function, current data suggest that each of these compounds may be of interest for future therapies.. While several pathways under investigation may offer additional benefits in the treatment of diabetes mellitus and associated impairments, further investigation is necessary for both investigational and approved therapies to ensure that the impact in new pathways does not increase risks to patient safety and outcomes.

Topics: Adiponectin; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Antioxidants; Diabetes Mellitus; Ghrelin; Humans; Hypoglycemic Agents; Inflammation; Leptin; Obesity; Resveratrol; Stilbenes

Excess production of reactive oxygen species in the brain has been implicated as a common underlying risk factor for the pathogenesis of a number of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. In recent years, there is considerable interest concerning investigation of antioxidative and anti-inflammatory effects of phenolic compounds from different botanical sources. In this review, we first describe oxidative mechanisms associated with stroke, AD, and PD, and subsequently, we place emphasis on recent studies implicating neuroprotective effects of resveratrol, a polyphenolic compound derived from grapes and red wine. These studies show that the beneficial effects of resveratrol are not only limited to its antioxidant and anti-inflammatory action but also include activation of sirtuin 1 (SIRT1) and vitagenes, which can prevent the deleterious effects triggered by oxidative stress. In fact, SIRT1 activation by resveratrol is gaining importance in the development of innovative treatment strategies for stroke and other neurodegenerative disorders. The goal here is to provide a better understanding of the mode of action of resveratrol and its possible use as a potential therapeutic agent to ameliorate stroke damage as well as other age-related neurodegenerative disorders.

Topics: Alcohol-Induced Disorders, Nervous System; Animals; Antioxidants; Cell Death; Humans; Inflammation; Neurodegenerative Diseases; Neuroglia; Neurons; Oxidative Stress; Reactive Nitrogen Species; Reactive Oxygen Species; Resveratrol; Stilbenes; Stroke

Neuroinflammation is an important contributor to pathogenesis of neurological disorders, with microglial activation as a hallmark of neuroinflammation. Microglia serve the role of immune surveillance under normal conditions, but after brain damage or exposure to inflammation, microglia are activated and secrete pro-inflammatory and neurotoxic mediators. Sustained production of these factors contributes to neuronal damage. Therefore, inhibition of microglia-mediated neuroinflammation may become a promising therapeutic target for neurological disorders. Resveratrol, a non-flavonoid polyphenol rich in red wine and grapes, has beneficial health effects from its antioxidant, anticancer and anti-inflammatory properties. Recently, resveratrol has been shown to protect against various neurological disorders in experimental models, including brain ischemia, seizures, and neurodegenerative disease models. This minireview summarized the anti-inflammatory activities of resveratrol in the brain from both in vivo and in vitro studies, and highlighted the inhibition of activated microglia as a potential mechanism of neuroprotection. The release of various pro-inflammatory factors, the production of reactive oxygen species, and the activation of signal pathways leading to neuroinflammation were discussed in relation to microglial activation. Taken together, microglia are an important target for anti-inflammatory activities of resveratrol in the brain.

Topics: Animals; Anti-Inflammatory Agents; Brain; Cell Line; Humans; Inflammation; Microglia; Resveratrol; Stilbenes

This review focuses on molecular, cellular, and functional changes that occur in the vasculature during aging; explores the links between mitochondrial oxidative stress, inflammation, and development of vascular disease in the elderly patients; and provides a landscape of molecular mechanisms involved in cellular oxidative stress resistance, which could be targeted for the prevention or amelioration of unsuccessful vascular aging. Practical interventions for prevention of age-associated vascular dysfunction and disease in old age are considered here based on emerging knowledge of the effects of anti-inflammatory treatments, regular exercise, dietary interventions, and caloric restriction mimetics.

Topics: Aging; Animals; Apoptosis; Atherosclerosis; Blood Vessels; Caloric Restriction; Endothelium, Vascular; Exercise; Humans; Inflammation; Oxidative Stress; Resveratrol; Stem Cells; Stilbenes; Vascular Diseases

Topics: Animals; Antioxidants; Cardiovascular Diseases; Evidence-Based Medicine; Humans; Inflammation; Metabolic Syndrome; Neoplasms; Phytotherapy; Protective Agents; Resveratrol; Stilbenes

Topics: Animals; Apoptosis; Evidence-Based Medicine; Humans; Inflammation; Neoplasms; Phytotherapy; Protective Agents; Stilbenes

Plant-derived polyphenolic compounds, such as the stilbene resveratrol (trans-3,4',5-trihydroxystilbene), have been identified as potent anti-cancer agents. Extensive in vitro studies revealed multiple intracellular targets of resveratrol, which affect cell growth, inflammation, apoptosis, angiogenesis, and invasion and metastasis. These include tumor suppressors p53 and Rb; cell cycle regulators, cyclins, CDKs, p21WAF1, p27KIP and INK and the checkpoint kinases ATM/ATR; transcription factors NF-kappaB, AP-1, c-Jun, and c-Fos; angiogenic and metastatic factors, VEGF and matrix metalloprotease 2/9; cyclooxygenases for inflammation; and apoptotic and survival regulators, Bax, Bak, PUMA, Noxa, TRAIL, APAF, survivin, Akt, Bcl2 and Bcl-X(L). In addition to its well-documented anti-oxidant properties, there is increasing evidence that resveratrol exhibits pro-oxidant activity under certain experimental conditions, causing oxidative DNA damage that may lead to cell cycle arrest or apoptosis. This review summarizes in vitro mechanistic data available for resveratrol and discusses new potential anti-cancer targets and the antiproliferative mechanisms of resveratrol.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Cathepsins; Cell Cycle; Cell Division; Female; Humans; Inflammation; Leukemia; Lymphoma; Male; Neoplasms; Prostatic Neoplasms; Resveratrol; Safety; Stilbenes; Transcription Factors

Obesity is a multi-faceted disease, predisposing sufferers to numerous co-morbidities such as epithelial dysfunction and insulin resistance which ultimately result in CVD. Visceral adipose tissue in particular is associated with inflammation due to the release of pro-inflammatory cytokines by adipocytes. Inflammation seems to be rather central in causing damage to endothelial cells as well as exerting negative effects on glucose metabolism, ultimately leading to insulin resistance. Resveratrol is a naturally occurring phenolic substance which has been found to display anti-inflammatory, vasoprotective and insulin-sensitising effects, among others. The popularity of resveratrol use is escalating in the treatment of various ailments including obesity in adults. The use of the substance in childhood obesity is, however, a worrying factor, as no studies have as yet been performed on adolescent animals and there is evidence of kidney toxicity of resveratrol and its metabolites at intake levels below those currently approved as safe. Another cause for concern is the uncertainty surrounding long-term, low-dose administration of the substance in humans. The supplement should thus not be recommended for use in the prevention and treatment of obesity until conclusive research is established on the safety of long-term usage of resveratrol in both children and adults.

Topics: Adult; Animals; Antioxidants; Child; Drug Administration Schedule; Humans; Inflammation; Intra-Abdominal Fat; Kidney; Obesity; Phenols; Plant Extracts; Resveratrol; Stilbenes

Evidence from animal models and preliminary studies in humans indicates that calorie restriction (CR) delays cardiac aging and can prevent cardiovascular disease. These effects are mediated by a wide spectrum of biochemical and cellular adaptations, including redox homeostasis, mitochondrial function, inflammation, apoptosis, and autophagy. Despite the beneficial effects of CR, its large-scale implementation is challenged by applicability issues as well as health concerns. However, preclinical studies indicate that specific compounds, such as resveratrol, may mimic many of the effects of CR, thus potentially obviating the need for drastic food intake reductions. Results from ongoing clinical trials will reveal whether the intriguing alternative of CR mimetics represents a safe and effective strategy to promote cardiovascular health and delay cardiac aging in humans.

Topics: Aged; Animals; Antioxidants; Apoptosis; Autophagy; Caloric Restriction; Cardiovascular Diseases; Disease Models, Animal; Forecasting; Heart Diseases; Homeostasis; Humans; Inflammation; Inflammation Mediators; Mitochondria, Heart; Mitochondrial Diseases; Obesity; Oxidation-Reduction; Oxidative Stress; Resveratrol; Stilbenes

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Chromatin Assembly and Disassembly; Curcumin; Diet; Flavonoids; Inflammation; Oxidative Stress; Phenols; Polyphenols; Resveratrol; Stilbenes

Studies show that the plant polyphenol resveratrol can extend the life span of yeast, worms, flies, and fish. It also mitigates the metabolic dysfunction of mice fed high-fat diets. Resveratrol appears to mediate these effects partly by activating SIRT1, a deacetylase enzyme that regulates the activity of several transcriptional factors and enzymes responsive to nutrient availability. However, few foods contain resveratrol and humans metabolize it extensively, resulting in very low systemic bioavailability. Substantial research effort now focuses on identifying and testing more bioavailable and potent activators of SIRT1 for use as pharmacologic interventions in aging and age-related disorders.

Topics: Aging; Animals; Biological Availability; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Enzyme Activation; Enzyme Activators; Humans; Inflammation; Neurodegenerative Diseases; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes

Atherosclerosis, a progressive disease characterized by the accumulation of lipids and fibrous elements in the arteries, is a most important contributor to cardiovascular diseases. Resveratrol is a naturally occurring phytopolyphenol compound and shows the ability to reduce the risk of cardiovascular diseases. In this review, beneficial effects of resveratrol on the initiation and progression of atherosclerosis, including regulation of vasodilator and vasoconstrictor production, inhibition of oxidative stress/reactive oxygen species generation, anti-inflammation, inhibition of modification of low-density lipoproteins, anti-platelet aggregation, and its abilities to impede progression and modulate complications of atherosclerosis, are discussed.

Topics: Antioxidants; Atherosclerosis; Cholesterol, LDL; Humans; Inflammation; Oxidative Stress; Phytotherapy; Platelet Aggregation; Reactive Oxygen Species; Resveratrol; Stilbenes; Vasodilator Agents; Vitis

The aim of this review is to discuss the accumulating evidence that suggests that grape extracts and purified grape polyphenols possess a diverse array of biological actions and may be beneficial in the prevention of some inflammatory-mediated diseases including cardiovascular disease. The active components from grape extracts, which include the grape seed, grape skin, and grape juice, that have been identified thus far include polyphenols such as resveratrol, phenolic acids, anthocyanins, and flavonoids. All possess potent antioxidant properties and have been shown to decrease low-density lipoprotein-cholesterol oxidation and platelet aggregation. These compounds also possess a range of additional cardioprotective and vasoprotective properties including antiatherosclerotic, antiarrhythmic, and vasorelaxation actions. Although not exclusive, antioxidant properties of grape polyphenols are likely to be central to their mechanism(s) of action, which also include cellular signaling mechanisms and interactions at the genomic level. This review discusses some of the evidence favoring the consumption of grape extracts rich in polyphenols in the prevention of cardiovascular disease. Consumption of grape and grape extracts and/or grape products such as red wine may be beneficial in preventing the development of chronic degenerative diseases such as cardiovascular disease.

Topics: Antioxidants; Cardiovascular Diseases; Flavonoids; Fruit; Humans; Inflammation; Oxidative Stress; Phenols; Phytotherapy; Plant Preparations; Platelet Aggregation; Polyphenols; Resveratrol; Seeds; Stilbenes; Vasodilation; Vitis; Wine

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.

Topics: Aging; Cardiotonic Agents; Gene Expression Regulation; Gene Regulatory Networks; Inflammation; Intracellular Signaling Peptides and Proteins; Neoplasms; Platelet Aggregation; Resveratrol; Stilbenes; Transcription Factors

Resveratrol, a polyphenol found in numerous plant species, including mulberries, peanuts and grapes, has shown to possess chemopreventive properties against several cancers, and cardiovascular diseases. Recently, resveratrol has been shown to have positive effects on age longevity, lipid levels and a preventative quality against certain cancers and viral infections. Resveratrol induces apoptosis by up-regulating the expression of Bax, Bak, PUMA, Noxa, Bim, p53, TRAIL, TRAIL-R1/DR4 and TRAIL-R2/DR5 and simultaneously down-regulating the expression of Bcl-2, Bcl-XL, Mcl-1 and survivin. Resveratrol causes growth arrest at G1 and G1/S phases of cell cycle by inducing the expression of CDK inhibitors p21/WAF1/CIP1 and p27/KIP1. Resveratrol has also been shown to reduce inflammation via inhibition of prostaglandin production, cyclooxygenase-2 activity, and nuclear factor-kappaB activity. Modulation of cell signaling pathway by resveratrol explains its diverse bioactivities related with human health. Resveratrol also potentiates the apoptotic effects of cytokines, chemotherapeutic agents and gamma-radiation. Pharmacokinetic and pharmacodynamic studies demonstrated that the main target organs of resveratrol are liver and kidney, and it is metabolized by hydroxylation, glucuronidation, sulfation and hydrogenation. As a chemoprevention agent, resveratrol has been shown to inhibit tumor initiation, promotion, and progression. There is growing evidence that resveratrol can prevent or delay the onset of various cancers, heart diseases, ischemic and chemically induced injuries, pathological inflammation and viral infections. This review summarizes the molecular mechanisms of resveratrol and its clinical benefits for human diseases.

Topics: Cardiovascular Diseases; Cell Cycle; Chemoprevention; Chemotherapy, Adjuvant; Diabetes Mellitus; Gene Expression Regulation; Humans; Inflammation; Neoplasms; Neovascularization, Pathologic; Resveratrol; Signal Transduction; Stilbenes

Resveratrol (trans-3,4',5-trihydroxystilbene), a natural polyphenolic, non-flavonoid antioxidant, is a phytoalexin found in many plants including grapes, nuts and berries. Recent studies have documented that resveratrol has various health benefits, such as cardiovascular and cancer preventive properties. However, the experimental basis for such health benefit is not fully understood. One of the possible mechanisms for its protective activities is by down regulation of the inflammatory responses. That includes the inhibition of synthesis and release of pro-inflammatory mediators, modifications of eicosanoid synthesis, inhibition of some activated immune cells, or inhibiting the enzymes, such as cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2), which are responsible for the synthesis of pro-inflammatory mediators through the inhibitory effect of resveratrol on transcription factors like nuclear factor kappaB (NFkappaB) or activator protein-1 (AP-1). Being a phenolic compound, resveratrol certainly possesses a low bioavailability and most importantly, a rapid clearance from the plasma. Recent growing interest in varying protective nature of resveratrol may clinically also hold a respectable position as a better alternative for anti-inflammatory drugs. The purpose of this review is to provide evidence that resveratrol exhibits potent anti-inflammatory activity and also to explain the underling mechanism for both resveratrol- induced cardioprotective and anti-inflammatory properties. While it is true that the cardioprotective properties of resveratrol are likely attributable, at least in part, to its anti-inflammatory properties, the mechanisms discussed address foremost mechanisms for the anti-inflammatory activity which, in turn, is responsible for cardioprotection.

Topics: Anti-Inflammatory Agents; Cardiotonic Agents; Free Radicals; Humans; Inflammation; Inflammation Mediators; Models, Biological; Resveratrol; Stilbenes; Transcription Factors

Resveratrol (3,4',5-trihydroxystilbene, RESV) is a natural phenolic compound that exists as cis and trans isomers [c-RESV or (Z)-RESV and t-RESV or (E)-RESV, respectively]. t-RESV is a natural component of Vitis vinifera L. (Vitaceae), abundant in the skin of grapes (but not in the flesh) and in the leaf epidermis, and present in wines, especially red wines. In in vitro, ex vivo and in vivo experiments t-RESV exhibits a number of biological activities, including anti-inflammatory and anticarcinogenic properties. RESV also exists in wines as a cis isomer, which (unlike t-RESV) is not currently available commercially; as a result, little is known about this isomer's pharmacological activity. In this review, I will focus on the few comparative studies of the antioxidant effects of the two RESV isomers in different experimental models.

Topics: Animals; Antioxidants; Inflammation; Interferon-gamma; Kluyveromyces; Lipid Peroxidation; Lipopolysaccharides; Macrophages, Peritoneal; Mice; Rats; Reactive Oxygen Species; Resveratrol; Stereoisomerism; Stilbenes

Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans.

Topics: Aging; Animals; Heart Diseases; Humans; Inflammation; Myocardial Infarction; Neoplasms; Protective Agents; Resveratrol; Stilbenes; Stroke

Resveratrol is a phytoalexin found in many plants, mainly in grapes. It has been shown to prevent coronary heart diseases and to exert a variety of anti-cancer and anti-inflammatory effects.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Cardiovascular Diseases; Humans; Inflammation; Neoplasms; Resveratrol; Ribonucleotide Reductases; Stilbenes

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Arteriosclerosis; Biological Availability; Cell Division; Gene Transfer, Horizontal; Humans; Inflammation; Intestinal Absorption; Neoplasms; Resveratrol; Stilbenes; Vitis

Resveratrol, a polyphenol found in grapes, red wine, chocolate, and certain berries and roots, is considered to have antioxidant, anti-inflammatory, and anticancer effects in humans and is related to longevity in some lower organisms.. To determine whether resveratrol levels achieved with diet are associated with inflammation, cancer, cardiovascular disease, and mortality in humans.. Prospective cohort study, the Invecchiare in Chianti (InCHIANTI) Study ("Aging in the Chianti Region"), 1998 to 2009 conducted in 2 villages in the Chianti area in a population-based sample of 783 community-dwelling men and women 65 years or older.. Twenty-four-hour urinary resveratrol metabolites.. Primary outcome measure was all-cause mortality. Secondary outcomes were markers of inflammation (serum C-reactive protein [CRP], interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]) and prevalent and incident cancer and cardiovascular disease.. Mean (95% CI) log total urinary resveratrol metabolite concentrations were 7.08 (6.69-7.48) nmol/g of creatinine. During 9 years of follow-up, 268 (34.3%) of the participants died. From the lowest to the highest quartile of baseline total urinary resveratrol metabolites, the proportion of participants who died from all causes was 34.4%, 31.6%, 33.5%, and 37.4%, respectively (P = .67). Participants in the lowest quartile had a hazards ratio for mortality of 0.80 (95% CI, 0.54-1.17) compared with those in the highest quartile of total urinary resveratrol in a multivariable Cox proportional hazards model that adjusted for potential confounders. Resveratrol levels were not significantly associated with serum CRP, IL-6, IL-1β, TNF, prevalent or incident cardiovascular disease, or cancer.. In older community-dwelling adults, total urinary resveratrol metabolite concentration was not associated with inflammatory markers, cardiovascular disease, or cancer or predictive of all-cause mortality. Resveratrol levels achieved with a Western diet did not have a substantial influence on health status and mortality risk of the population in this study.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Female; Humans; Incidence; Inflammation; Italy; Male; Mortality; Neoplasms; Prevalence; Prospective Studies; Resveratrol; Stilbenes

In this study, we present a novel product consisted of red grape cells (RGC) grown in culture and evaluated its effect on human LDL oxidation (in vitro) and inflammatory stress (in an in vivo rat model). We analyzed RGC for its polyphenols content and characterized RGC-derived resveratrol (RES) and its properties; and finally, we characterized the pharmacokinetic profile of RGC-RES in human plasma. RGC has demonstrated a strong inhibitory effect on LDL oxidation with IC50 as low as 8.0 μg/ml. RGC significantly reduced rats inflamed paw size induced by carrageenan injection. LC/MS analysis has shown that the main polyphenol in RGC was RES with one hexose moiety. The human pharmacokinetic analysis (clinicaltrials.gov NCT01747252) revealed relatively high bioavailability and two distinctly separated plasma concentration peaks at 1 and 5 h. The present study demonstrates antioxidant and anti-inflammatory traits of RGC that warrants further research in both pre-clinical and clinical settings.

Topics: Adult; Animals; Biological Availability; Carrageenan; Cross-Over Studies; Edema; Humans; Indomethacin; Inflammation; Lipoproteins, LDL; Male; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Vitis

Numerous studies have shown that resveratrol (RES) exerts anti-inflammatory effects but human trials evidencing these effects in vivo are limited. Furthermore, the molecular mechanisms triggered in humans following the oral intake of RES are not yet understood. Therefore, the purpose of this study was to investigate the molecular changes in peripheral blood mononuclear cells (PBMCs) associated to the one-year daily intake of a RES enriched (8 mg) grape extract (GE-RES) in hypertensive male patients with type 2 diabetes mellitus (T2DM). We used microarrays and RT-PCR to analyze expression changes in genes and microRNAs (miRs) involved in the inflammatory response modulated by the consumption of GE-RES in comparison to a placebo and GE lacking RES. We also examined the changes in several serobiochemical variables, inflammatory and fibrinolytic markers. Our results showed that supplementation with GE or GE-RES did not affect body weight, blood pressure, glucose, HbA1c or lipids, beyond the values regulated by gold standard medication in these patients. We did not find either any significant change on serum inflammatory markers except for a significant reduction of ALP and IL-6 levels. The expression of the pro-inflammatory cytokines CCL3, IL-1β and TNF-α was significantly reduced and that of the transcriptional repressor LRRFIP-1 increased in PBMCs from patients taking the GE-RES extract. Also, a group of miRs involved in the regulation of the inflammatory response: miR-21, miR-181b, miR-663, miR-30c2, miR-155 and miR-34a were found to be highly correlated and altered in the group consuming the GE-RES for 12 months. Our results provide preliminary evidence that long-term supplementation with a grape extract containing RES downregulates the expression of key pro-inflammatory cytokines with the involvement of inflammation-related miRs in circulating immune cells of T2DM hypertensive medicated patients and support a beneficial immunomodulatory effect in these patients.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Coronary Artery Disease; Cytokines; Diabetes Mellitus, Type 2; Dietary Supplements; Gene Expression Regulation; Humans; Hypertension; Inflammation; Leukocytes, Mononuclear; Male; MicroRNAs; Middle Aged; Models, Molecular; Plant Extracts; Resveratrol; Stilbenes; Transcriptome; Vitis

Smokers are characterized by a low-grade systemic inflammatory state and an oxidant-antioxidant imbalance. Few human studies were conducted on the effects of resveratrol, a natural compound with anti-inflammatory and antioxidant properties, and no trial on smokers has been performed to date. We evaluated whether resveratrol has beneficial effects on markers of inflammation and oxidative stress in smokers.. A randomized, double- blind, cross-over trial was performed in 50 healthy adult smokers: 25 were randomly allocated to "resveratrol-first" (30-days: 500mg resveratrol/day, 30-days wash-out, 30-days placebo) and 25 to "placebo-first" (30-days placebo, 30-days wash-out, 30-days 500mg resveratrol/day). Resveratrol significantly reduced C-reactive protein (CRP) and triglyceride concentrations, and increased Total Antioxidant Status (TAS) values. After analyzing data with general linear models to assess period and carry-over effects, the ratios of the values after resveratrol to those after placebo were respectively: 0.47 (95%CI 0.38-0.59) -CRP- and 0.71 (95%CI 0.65-0.78) -triglycerides-, while TAS increased by 74.2 μmol/L (95%CI 60.8-87.6). Uric acid, glucose, insulin, cholesterol, liver enzyme concentrations, and weight, waist circumference, and blood pressure values did not significantly change after resveratrol supplementation.. Because resveratrol has anti-inflammatory, anti-oxidant, and hypotriglyceridemic effects, its supplementation may beneficially affect the increased cardiovascular risk of healthy smokers.

Topics: Adult; Anti-Inflammatory Agents; Antioxidants; C-Reactive Protein; Cardiovascular Diseases; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Female; Humans; Inflammation; Male; Middle Aged; Oxidative Stress; Placebo Effect; Resveratrol; Risk Factors; Smoking; Stilbenes; Triglycerides

Palovarotene is an oral γ-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement. REPAIR (Retinoid treatment of Emphysema in Patients on the α(1)-antitrypsin International Registry), was an investigator-initiated, double-blind, placebo-controlled randomised study to assess the safety and efficacy of 5 mg·day(-1) palovarotene given for 1 year to 262 patients with severe α(1)-antitrypsin deficiency and emphysema confirmed by computed tomography. Change in volume-adjusted 15th percentile point lung density from baseline in 1 year was the primary end-point; functional end-points were also regularly assessed. We randomly assigned 133 and 129 patients to placebo or palovarotene, respectively. Both groups were well matched for all baseline characteristics, including respiratory medications. 88% and 85% of patients completed 1 year of treatment with placebo and palovarotene, respectively. Palovarotene was generally well tolerated. In the study completers population, the placebo-corrected difference of lung density was -0.45 HU at week 28 (p=0.64) and -0.25 HU at week 52 (p=0.94). A nonsignificant treatment difference in most functional parameters of the lung in favour of the drug was observed over time suggesting potential pharmacological effects of palovarotene. Palovarotene 5 mg·day(-1) over 1 yr failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe α(1)-antitrypsin deficiency.

Topics: Adult; Aged; Animals; Double-Blind Method; Emphysema; Female; Forced Expiratory Volume; Gases; Genotype; Humans; Inflammation; Least-Squares Analysis; Male; Middle Aged; Placebos; Pyrazoles; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Smoking; Stilbenes; Tomography, X-Ray Computed

The search for complementary treatments in primary prevention of cardiovascular disease (CVD) is a high-priority challenge. Grape and wine polyphenol resveratrol confers CV benefits, in part by exerting anti-inflammatory effects. However, the evidence in human long-term clinical trials has yet to be established. We aimed to investigate the effects of a dietary resveratrol-rich grape supplement on the inflammatory and fibrinolytic status of subjects at high risk of CVD and treated according to current guidelines for primary prevention of CVD. Seventy-five patients undergoing primary prevention of CVD participated in this triple-blinded, randomized, parallel, dose-response, placebo-controlled, 1-year follow-up trial. Patients, allocated in 3 groups, consumed placebo (maltodextrin), a resveratrol-rich grape supplement (resveratrol 8 mg), or a conventional grape supplement lacking resveratrol, for the first 6 months and a double dose for the next 6 months. In contrast to placebo and conventional grape supplement, the resveratrol-rich grape supplement significantly decreased high-sensitivity C-reactive protein (-26%, p = 0.03), tumor necrosis factor-α (-19.8%, p = 0.01), plasminogen activator inhibitor type 1 (-16.8%, p = 0.03), and interleukin-6/interleukin-10 ratio (-24%, p = 0.04) and increased anti-inflammatory interleukin-10 (19.8%, p = 0.00). Adiponectin (6.5%, p = 0.07) and soluble intercellular adhesion molecule-1 (-5.7%, p = 0.06) tended to increase and decrease, respectively. No adverse effects were observed in any patient. In conclusion, 1-year consumption of a resveratrol-rich grape supplement improved the inflammatory and fibrinolytic status in patients who were on statins for primary prevention of CVD and at high CVD risk (i.e., with diabetes or hypercholesterolemia plus ≥1 other CV risk factor). Our results show for the first time that a dietary intervention with grape resveratrol could complement the gold standard therapy in the primary prevention of CVD.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Dietary Supplements; Double-Blind Method; Female; Fibrinolysis; Fruit; Humans; Inflammation; Male; Middle Aged; Phytotherapy; Plant Extracts; Resveratrol; Stilbenes; Time Factors; Vitis

Topics: Animals; Brain-Gut Axis; Cognitive Dysfunction; Diabetes Mellitus; Inflammation; Mice; Neuroinflammatory Diseases; NF-kappa B; Stilbenes; Toll-Like Receptor 4

Acute lung injury (ALI) is a major pathophysiological problem defined by severe inflammation and acute disease with substantial morbidity and death. It is known that lipopolysaccharide (LPS) induces ALI by causing oxidative stress and inflammation. The goal of this study was to investigate the protective effect of astringin on LPS-induced ALI and probable pathways. Astringin is a stilbenoid, the 3-β-D-glucoside of piceatannol, mainly found in the bark of Picea sitchensis. The findings showed that astringin prevented LPS-induced cellular damage by reducing the generation of oxidative stress in LPS-stimulated A549 lung epithelial cells. Furthermore, astringin extensively decreased the production of inflammatory factors such as TNF-α, IL-1β, and IL-6. In addition, the western blot results revealed that the ability of astringin to reduce oxidative stress and the generation of inflammatory cytokines by inhibiting the ROS-mediated PI3K/AKT/NF-κB pathway could be the reason for its protective effect against LPS-induced ALI. Overall, the results suggest that astringin could be a possible inhibitor of ALI triggered by LPS for pediatric lung injury.

Topics: Acute Lung Injury; Child; Glucosides; Humans; Inflammation; Lipopolysaccharides; Lung; NF-kappa B; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Stilbenes

Aflatoxin B1 (AFB1) is an extremely hazardous food/feed pollutant, posing a serious threat to health of human and animals. Particularly, exposure to AFB1 provokes enterocytes oxidative stress and inflammation, which lead to intestinal damage. Polydatin (PD), a stilbenoid glucoside, is known to possess antioxidant and anti-inflammatory properties and is being investigated for use in various disorders. The present study was intended at investigating the protective efficacy of polydatin against AFB1-induced ileum damage in mice. Kunming male mice received oral gavage of AFB1 (300 μg/kg body weight/day) and PD (100 mg/kg body weight/day) for 18 days. The results showed that mice exposed to AFB1 exhibited the impaired morphology, the suppressed disaccharidase activities, the down-regulated mRNA expressions of tight junction protein genes, oxidative stress, inflammation and the up-regulated mRNA expressions of genes related to mitophagy in the ileum, whereas PD treatment reversed the AFB1-induced disruption of ileal structure, digestion, barrier function, redox and immune status. The findings of the present study suggested that PD may have a potential benefit in preventing AFB1-induced ileum damage.

Topics: Aflatoxin B1; Animals; Body Weight; Glucosides; Humans; Ileum; Inflammation; Liver; Male; Mice; Oxidative Stress; RNA, Messenger; Stilbenes

Stilbenoid compounds have been described to have anti-inflammatory properties in animal models. To study how stilbenoid compounds affect inflammatory signaling. We found that DSS induces severe changes in the bacteriome of the. Taken together, we show that the stilbenoids PS and PSMME have anti-inflammatory properties

Topics: Animals; Ankyrins; Anti-Inflammatory Agents; Drosophila; Drosophila melanogaster; Inflammation; Intestines; NF-kappa B; Stilbenes

Pterostilbene is a revesterol analog with a long bioavailability and having potent anti-inflammatory activity in animal studies. In this study, we tried to scrutinize the anti-arthritic effect of pterostilbene against complete Freund's adjuvant (CFA)-induced arthritis model in rats. CFA was used for induction of the RA, and rats were divided into groups depending on different doses of pterostilbene given. Hepatic, antioxidant, rheumatoid factor (RF), myeloperoxidase (MPO), inflammatory cytokines, anti-collagen(C)II-Ig, inflammatory mediators, and gut microbiota were estimated. Pterostilbene significantly (p < .001) decreased the paw swelling, arthritic score, and increased the body weight. Besides altered the antioxidant, inflammatory mediators, anti-collagen (C)II Ig, and inflammatory cytokines. Furthermore, pterostilbene treatment helps to restore the ecosystem of gut microbiota in rats by reducing the relative abundance of Helicobacter, Desulfovibrio, Lachnospiraceae, and Mucispirillium. Based on the findings, we can say that pterostilbene has an anti-arthritic effect via suppressing inflammatory responses and altering intestinal bacteria. PRACTICAL APPLICATIONS: Arthritis is the painful disease and affected most of the people worldwide. In this experimental study, we estimated the anti-arthritic effect of pterostilbene against CFA-induced arthritis in rats. Pterostilbene noticeably suppressed the paw thickness, arthritic score, and organ index. Pterostilbene substantially altered the oxidative stress and inflammatory reaction. Pterostilbene considerably modulated the gut microbiota, suggesting the anti-arthritic effect.

Topics: Animals; Antioxidants; Arthritis, Experimental; Cytokines; Ecosystem; Freund's Adjuvant; Gastrointestinal Microbiome; Inflammation; Inflammation Mediators; Oxidative Stress; Rats; Stilbenes

Dysfunction of the blood-brain barrier (BBB) is involved in the pathogenesis of many cerebral diseases. Oxidative stress and inflammation are contributing factors for BBB injury. Piceatannol, a natural ingredient found in various plants, such as grapes, white tea, and passion fruit, plays an important role in antioxidant and anti-inflammatory responses. In this study, we examined the protective effects of piceatannol on lipopolysaccharide (LPS) insult in mouse brain endothelial cell line (bEnd.3) cells and the underlying mechanisms. The results showed that piceatannol mitigated the upregulated expression of adhesion molecules (ICAM-1 and VCAM-1) and iNOS in LPS-treated bEnd.3 cells. Moreover, piceatannol prevented the generation of reactive oxygen species in bEnd.3 cells stimulated with LPS. Mechanism investigations suggested that piceatannol inhibited NF-κB and MAPK activation. Taken together, these observations suggest that piceatannol reduces inflammation and oxidative stress through inactivating the NF-κB and MAPK signaling pathways on cerebral endothelial cells in vitro.

Topics: Antioxidants; Brain; Cell Adhesion Molecules; Cell Line; Endothelial Cells; Gene Expression Regulation; Inflammation; Lipopolysaccharides; MAP Kinase Signaling System; Molecular Structure; NF-kappa B; Oxidative Stress; Protective Agents; Stilbenes

Pterostilbene (PTE), a common polyphenol compound, exerts an anti-inflammatory effect in many diseases, including acute lung injury (ALI).. This study explores the potential mechanism of PTE pre-treatment against lipopolysaccharide (LPS)-induced ALI.. Sixty Sprague-Dawley rats were divided into control, ALI, 10 mg/kg PTE + LPS, 20 mg/kg PTE + LPS, and 40 mg/kg PTE + LPS groups. At 24 h before LPS instillation, PTE was administered orally. At 2 h before LPS instillation, PTE was again administered orally. After 24 h of LPS treatment, the rats were euthanized. The levels of inflammatory cells and inflammatory factors in the bronchoalveolar lavage fluid (BALF), the expression of nuclear receptor subfamily 4 group A member 1 (NR4A1), and the nuclear factor (NF)-κB pathway-related protein levels were detected. NR4A1 agonist was used to further investigate the mechanism of PTE pre-treatment.. After PTE pre-treatment, the LPS induced inflammation was controlled and the survival rate was increased to 100% from 70% after LPS treatment 24 h. For lung injury score, it decreased to 1.5 from 3.5 after treating 40 mg/kg PTE. Compared with the control group, the expression of NR4A1 in the ALI group was decreased by 20-40%. However, the 40 mg/kg PTE pre-treatment increased the NR4A1 expression by 20-40% in the lung tissue. The results obtained with pre-treatment NR4A1 agonist were similar to those obtained by pre-treatment 40 mg/kg PTE.. PTE pre-treatment might represent an appropriate therapeutic target and strategy for preventing ALI induced by LPS.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Inflammation; Lipopolysaccharides; Male; Nuclear Receptor Subfamily 4, Group A, Member 1; Rats; Rats, Sprague-Dawley; Stilbenes

Rheumatoid arthritis (RA) is a chronic inflammatory disease that mainly targets the synovial membrane, thus causing stiffness, deformity and dysfunction of joints. To date, no effective anti‑inflammatory treatments are available for RA. Piceatannol (PIC) is a natural derivative of resveratrol, which has been reported to attenuate the inflammatory response. To evaluate the effect of PIC on RA and to determine the underlying molecular target of PIC, both

Topics: Animals; Apoptosis; Arthritis, Rheumatoid; Cell Proliferation; Cells, Cultured; Fibroblasts; Humans; Inflammation; MAP Kinase Signaling System; NF-kappa B; Rats; Stilbenes; Synoviocytes

Heterotopic ossification (HO) is a common disease characterized by pain, dysfunction and calcification. The mechanisms underlying HO have not been completely elucidated. Palovarotene, a retinoic acid receptor γ agonist, significantly inhibits the formation of HO in vivo. However, its specific mechanism of action remains unclear. Therefore, we aimed to evaluate the signalling pathways related to the formation of HO as well as the mechanism of palovarotene action. We constructed in vitro and in vivo models of HO. Osteogenic differentiation of bone mesenchymal stem cells (BMSCs) was observed by alizarin red and alkaline phosphatase staining assays in vitro. X-ray and haematoxylin-eosin staining were performed in vivo. Western blots and reverse transcription-polymerase chain reaction were performed to determine the levels of osteogenic- and inflammation-related genes. Immunofluorescence and immunocytochemistry were used to assess the levels of p65, the core molecule of the nuclear factor κ-B (NF-κB) signalling pathway. We demonstrated that, in vitro, under inflammatory stimulation, pathological calcium deposition increased in BMSCs. The levels of osteogenesis- and inflammation-related genes were also upregulated, along with an enhanced expression of p65. Immunofluorescence assays revealed that p65 entered the nucleus, thereby stimulating the downstream effectors of the NF-κB pathway. The above trends were reversed after palovarotene treatment. In conclusion, the NF-κB signalling pathway played an important role in HO, and palovarotene could alleviate HO by blocking the NF-κB cascade. Our results may provide a theoretical basis for palovarotene in the treatment of HO. Further studies on the side effects of palovarotene are warranted in the future.

Topics: Animals; Cell Differentiation; Humans; Inflammation; Mesenchymal Stem Cells; NF-kappa B; Ossification, Heterotopic; Osteogenesis; Pyrazoles; Signal Transduction; Stilbenes

Alzheimer's disease (AD) is a neurodegenerative disease in elderly population. Pterostilbene (PTS) is a resveratrol analog with neuroprotective activity. However, the biological mechanisms of PTS in AD progression are largely uncertain. An animal model of AD was established using streptozotocin (STZ)-treated C57BL/6J mice. Monoamine oxidase B (MAOB) expression was analyzed by bioinformatics analysis and detected by western blotting assay. The memory impairment was investigated by Morris water maze test. The levels of Tau hyperphosphorylation and death-related proteins were detected by western blotting analysis. The levels of amyloid β (Aβ)

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; bcl-2-Associated X Protein; Caspase 3; Disease Models, Animal; Humans; Inflammation; Interleukin-6; Mice; Mice, Inbred C57BL; Monoamine Oxidase; Neurodegenerative Diseases; NF-kappa B; Reactive Oxygen Species; Resveratrol; Stilbenes; Streptozocin; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Oxyresveratrol (OXY) has been reported for its anti-inflammatory activity; however, the pharmaceutical applications of this compound are limited by its physicochemical properties and poor pharmacokinetic profiles. The use of an ester prodrug is a promising strategy to overcome these obstacles. In previous researches, several carboxylate esters of OXY were synthesized and oxyresveratrol tetraacetate (OXY-TAc) was reported to possess anti-melanogenic and anti-skin-aging properties. In this study, in addition to OXY-TAc, two novel ester prodrugs of OXY, oxyresveratrol tetrapropionate (OXY-TPr), and oxyresveratrol tetrabutyrate (OXY-TBu), were synthesized. Results from the Caco-2-permeation assay suggested that synthesized ester prodrugs can improve the membrane-permeation ability of OXY. The OXY-TAc exhibited the most significant profile, then this prodrug was chosen to observe anti-inflammatory activities with lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Our results showed that OXY-Tac significantly alleviated secretion of several pro-inflammatory mediators (nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), mitigated expression of enzyme-regulated inflammation (inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)), and suppressed the MAPK cascades. Interestingly, the observed anti-inflammatory activities of OXY-TAc were more remarkable than those of its parent compound OXY. Taken together, we demonstrated that OXY-TAc improved physicochemical and pharmacokinetic profiles and enhanced the pharmacological effects of OXY. Hence, the results in the present study would strongly support the clinical utilities of OXY-TAc for the treatment of inflammation-related disorders.

Topics: Animals; Anti-Inflammatory Agents; Caco-2 Cells; Cyclooxygenase 2; Esters; Humans; Inflammation; Lipopolysaccharides; Macrophages; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Plant Extracts; Prodrugs; RAW 264.7 Cells; Stilbenes

Osteoarthritis (OA) is a highly prevalent chronic joint disease that involves extracellular matrix (ECM) degradation and articular cartilage inflammation. Polydatin (PD) can alleviate inflammatory reactions in numerous diseases. The present study aimed to investigate the chondroprotective and anti-inflammatory effects of PD on interleukin (IL)- 1β-treated chondrocytes in vitro and anterior cruciate ligament transection-induced rat OA models in vivo. Primary chondrocytes were isolated from SD rats and cultured. Only second-passage cells were used for subsequent experiments. Counting kit-8, quantitative real-time polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, and immunofluorescence were used to detect relevant indices. Rat OA models were established to obtain in vivo data. PD treatment decreased the production of nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and IL-6 during IL-1β-stimulated chondrocyte inflammation. Moreover, PD upregulated aggrecan and collagen II expression, whereas downregulated a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and matrix metalloproteinase-13 (MMP-13) expression on IL-1β-mediated chondrocytes. Additionally, PD reduced IL-1β-stimulated NF-κB and Wnt/β-catenin activation and nuclear translocation. The results of histological analysis and scoring revealed that OA in the rat models was effectively ameliorated by the intra-articular injection of PD. PD suppressed IL-1β-stimulated iNOS, COX-2, NO, and PGE2 production, TNF-α, IL-6, collagen X, MMP-13, and ADAMTS-5 expression, collagen II and aggrecan degeneration by inhibiting NF-κB and Wnt/β-catenin signaling in vitro. PD also mitigated OA progression in the rat models, thereby providing reliable data that PD could serve as a promising candidate for OA therapy.

Topics: Aggrecans; Animals; Anti-Inflammatory Agents; beta Catenin; Cartilage, Articular; Cells, Cultured; Chondrocytes; Cyclooxygenase 2; Dinoprostone; Disintegrins; Glucosides; Inflammation; Interleukin-6; Matrix Metalloproteinase 13; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Stilbenes; Thrombospondins; Tumor Necrosis Factor-alpha; Wnt Signaling Pathway

Heart failure is one of the diseases with the highest mortality in the world, and inflammation is the main cause for its occurrence and development. The stilbene skeleton of resveratrol has been shown to have excellent anti-inflammatory and antioxidant activities. In order to continue our research on dihydropyrazole derivatives, a series of novel (E)-4-methyl-2-(3-phenyl-5-(4-styrylphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole derivatives were designed and synthesized according to the principle of molecular hybridization for evaluation their anti-inflammatory and antioxidation activities. We screened their anti-inflammatory abilities in RAW264.7 cells and analyzed the preliminary structure-activity relationship, and explored the related molecular mechanisms. We further used doxorubicin (DOX)-induced heart failure model to explore the protective role of our compound in vivo. Our results showed that compound F5 exhibited the most potent activity and was superior to the positive control. It reversed the expression of lipopolysaccharide (LPS)-regulated inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and superoxide dismutase 1 (SOD1) in RAW264.7 cells. In addition, compound F5 also inhibited DOX-induced inflammation and reactive oxygen species by modulating the p38/nuclear factor kappa B (NF-κB) signaling pathway in H9C2 cells. In vivo results showed that compound F5 ameliorated DOX-caused damage, such as reduced left ventricular ejection fraction, severe inflammation, fibrosis and oxidative stress in heart. In conclusion, compound F5 could be used as a promising agent for the treatment of heart failure through attenuating oxidative stress and inflammation.

Topics: Animals; Anti-Inflammatory Agents; Cyclooxygenase 2; Doxorubicin; Heart Failure; Inflammation; Lipopolysaccharides; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; RAW 264.7 Cells; Signal Transduction; Stilbenes; Stroke Volume; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Topics: Animals; Diabetes Mellitus, Experimental; Fibrosis; Hyperglycemia; Hypoglycemic Agents; Inflammation; Male; Rats; Rats, Sprague-Dawley; Stilbenes

Tetrahydroxy stilbene glycoside (TSG) is a main active compound in Polygonum multiflorum. Acetaminophen (APAP) is a well-known analgesic and antipyretic drug. It is considered to be safe within a therapeutic range, in case of acute intoxication hepatotoxicity occurs. This present study aims to observe TSG-provided alleviation on APAP-induced hepatoxicity in C57BL/6 mice. APAP performs extensive necrosis and dissolves nucleus suggesting liver damage from hepatic histopathology. Serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase analysis and liver histological evaluation showed that TSG reduced the hepatotoxicity induced by a toxic dose of APAP. Moreover, TSG alone had no hepatotoxicity. TSG eliminated hepatic glutathione depletion and cysteine adducts formation. It also reduced the expression of interleukin-10 and lowered the production of reactive oxygen species in liver tissues. Luminex was used to detect cytokine production in different groups. Herein, we used an untargeted metabolomics approach by performing ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry on treated mice to identify metabolic disruptions under APAP and TSG. Major alterations were observed for purine metabolism, amino acid metabolism, and fatty acid metabolism. These data provide metabolic evidence and biomarkers in the liver that the ABC transporters, Glycine serine and threonine metabolism, and Choline metabolism in cancer changed the most. These targets of metabolites have the potential to improve our understanding of homeostatic. Meanwhile, these metabolites revealed that TSG can alleviate inflammation caused by APAP and promote the activity of intrinsic antioxidants. In summary, TSG can regulate lipid metabolism, promote the production of antioxidant enzymes, and decrease the inflammatory response.

Topics: Acetaminophen; Animals; Chromatography, High Pressure Liquid; Cytokines; Data Analysis; Discriminant Analysis; Glycosides; Inflammation; Least-Squares Analysis; Liver; Male; Mass Spectrometry; Metabolomics; Mice, Inbred C57BL; Multivariate Analysis; Oxidative Stress; Signal Transduction; Stilbenes

Nuclear factor erythroid-2 related factor 2 (Nrf2) is involved in mitigating various oxidative stress- and inflammation-induced diseases, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Isorhapontigenin (ISO), from the Chinese herb Gnetum cleistostachyum, exhibits antioxidant and anti-inflammatory properties. In this study, we explored the protective effects of ISO in ALI and its underlying molecular mechanisms. ISO significantly mitigated ALI by reducing the lung wet/dry weight ratio, protein concentration in the bronchoalveolar lavage fluid (BALF), and the levels of myeloperoxidase and malondialdehyde. ISO also improved the superoxide dismutase and glutathione activity in vivo. Moreover, ISO effectively ameliorated the changes in IL-1β, IL-6, and TNF-α concentrations in BALF, prevented IκB degradation, and inhibited the phosphorylation of NF-κB p65 subunit in lung tissues; furthermore, it enhanced the nuclear translocation of Nrf2 and inhibited IL-1β, IL-6, TNF-α, iNOS, COX-2, and ROS production in lipopolysaccharide-treated RAW264.7 cells. The protective effects of ISO in ALI were significantly reversed in ML385-treated RAW264.7 cells and the mouse model, indicating its role in Nrf2-activation. In conclusion, ISO effectively ameliorated lipopolysaccharide-induced ALI by reducing inflammation and oxidative stress, primarily through activation of Nrf2 signaling.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Cells, Cultured; Humans; Inflammation; Lipopolysaccharides; Mice; NF-E2-Related Factor 2; Oxidative Stress; Signal Transduction; Stilbenes

Polydatin (PD) has a broad range of pharmacological activities; however, its effects on diabetic liver damage are poorly studies. This work is aimed to explore possible protective effects of polydatin-loaded chitosan nanoparticles (PD-CSNPs) or PD against liver damage associated with diabetes. Diabetes was induced in rats using nicotinamide/streptozotocin treatment. Diabetic rats were then divided into six groups: normal control rats, diabetic control rats, and rats orally treated with PD, PD-CSNPs, equivalent unloaded CSNPs, or metformin daily for 4 weeks. Treatment with PD and PD-CSNPs significantly reduced the blood glucose content, lipid peroxidation in the liver, and activities of serum transaminases and carbohydrate metabolism enzymes (including succinate dehydrogenase and pyruvate kinase); by contrast, liver glycogen content, glutathione concentration, and activities of the antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase, and glucose-6-phosphate dehydrogenase) were markedly increased compared with the control diabetic rats. Furthermore, expression of the tumor necrosis factor α and interleukin-1β mRNAs was significantly downregulated, while expression of glucose transporter 2 and glucokinase mRNAs was strongly upregulated vs. control diabetic rats. We concluded that PD-CSNPs and PD ameliorate diabetic liver damage by modulating glucose transporter 2 expression, affecting the activity of carbohydrate metabolism enzymes, and suppressing oxidative stress and inflammation, PD-CSNPs being more efficient than PD, probably due to higher bioavailability and prolonged release.

Topics: Animals; Chitosan; Diabetes Mellitus, Experimental; Glucose; Glucosides; Inflammation; Lipid Peroxidation; Liver; Male; Metformin; Nanoparticles; Niacinamide; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Stilbenes; Streptozocin

The COVID-19 pandemic as the largest global public health crisis is now considered as an emergency at the World Health Organization (WHO). As there is no specific therapy for SARS-CoV-2 infection at present and also because of the long time it takes to discover a new drug and the urgent need to respond urgently to a pandemic infection. Perhaps the best way right now is to find an FDA-approved drug to treat this infection. Oxidative stress and inflammation play a vital role in the progression of tissue injury in COVID-19 patients; furthermore, the G6PD activation is related to increased oxidative inflammation in acute pulmonary injury. In this regard, we propose a new insight that may be a good strategy for this urgency. Exploiting G6PD through inhibiting G6PD activity by modifying redox balance, metabolic switching and protein-protein interactions can be proposed as a new approach to improving patients in severe stage of COVID 19 through various mechanisms. Polydatin is isolated from many plants such as Polygonum, peanuts, grapes, red wines and many daily diets that can be used in severe stage of COVID-19 as a G6PD inhibitor. Furthermore, polydatin possesses various biological activities such as anti-inflammatory, antioxidant, immunoregulatory, nephroprotective, hepatoprotective, anti-arrhythmic and anti-tumor. Our hypothesis is that the consumption of antioxidants such as Polydatin (a glucoside of resveratrol) as a complementary therapeutic approach may be effective in reducing oxidative stress and inflammation in patients with COVID-19.

Topics: Anti-Inflammatory Agents; Antioxidants; COVID-19; COVID-19 Drug Treatment; Glucosephosphate Dehydrogenase; Glucosides; Humans; Inflammation; Lung; Magnoliopsida; Oxidative Stress; Pandemics; Phytotherapy; Plant Extracts; Resveratrol; SARS-CoV-2; Stilbenes

Pinosylvin is a natural stilbenoid found particularly in Scots pine. Stilbenoids are a group of phenolic compounds identified as protective agents against pathogens for many plants. Stilbenoids also possess health-promoting properties in humans; for instance, they are anti-inflammatory through their suppressing action on proinflammatory M1-type macrophage activation. Macrophages respond to environmental changes by polarizing towards proinflammatory M1 phenotype in infection and inflammatory diseases, or towards anti-inflammatory M2 phenotype, mediating resolution of inflammation and repair. In the present study, we investigated the effects of pinosylvin on M2-type macrophage activation, aiming to test the hypothesis that pinosylvin could polarize macrophages from M1 to M2 phenotype to support resolution of inflammation. We used lipopolysaccharide (LPS) to induce M1 phenotype and interleukin-4 (IL-4) to induce M2 phenotype in J774 murine and U937 human macrophages, and we measured expression of M1 and M2-markers. Interestingly, along with inhibiting the expression of M1-type markers, pinosylvin had an enhancing effect on the M2-type activation, shown as an increased expression of arginase-1 (Arg-1) and mannose receptor C type 1 (MRC1) in murine macrophages, and C-C motif chemokine ligands 17 and 26 (CCL17 and CCL26) in human macrophages. In IL-4-treated macrophages, pinosylvin enhanced PPAR-γ expression but had no effect on STAT6 phosphorylation. The results show, for the first time, that pinosylvin shifts macrophage polarization from the pro-inflammatory M1 phenotype towards M2 phenotype, supporting resolution of inflammation and repair.

Topics: Animals; Anti-Inflammatory Agents; Cell Polarity; Humans; Inflammation; Interleukin-4; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Phenotype; Pinus sylvestris; Plant Extracts; RNA, Messenger; Signal Transduction; Stilbenes; U937 Cells

The worldwide prevalence of obesity has significantly increased over the past few decades. It is currently believed that obesity is a risk factor for developing inflammatory bowel disease. Pterostilbene (PTS), a naturally occurring stilbene from blueberries, is known to have anticancer, anti-inflammation, antifibrosis, and antiobesity effects. The preventive effect of PTS on the susceptibility of high-fat diet (HFD) to dextran sulfate sodium (DSS)-induced colitis in mice was investigated. Beginning at 5 weeks of age, C57BL/6J mice were fed a normal diet, 50% HFD alone, or containing PTS, and DSS (2.5%, w/v) was given in drinking water at week 9 and week 11. The results demonstrated that PTS significantly attenuated HFD and DSS-induced plasma interleukin-6 accumulation. Moreover, PTS suppressed HFD/DSS-induced formation of aberrant crypt foci and reduced the colon weight-to-length ratio in HFD/DSS-induced colitis mice. Furthermore, PTS inhibited interleukin-1β (IL-1β), the C/EBP homologous protein (CHOP), cyclooxygenase-2, and transforming growth factor beta-1 (TGF-β1)/mothers against decapentaplegic homolog 2 expression and maintained mucin2 (Muc2) and E-cadherin expressions. In addition, post-treatment with PTS also decreased the colon weight-to-length ratio and loss of Muc2. Moreover, the CHOP, IL-1β, matrix metalloproteinase-2, and TGF-β1 expressions were significantly decreased in HFD/DSS-induced colitis mice after post-treatment with PTS. In conclusion, the results of the present study suggest that PTS is of significant interest for the prevention of HFD/DSS-induced colitis in C57BL/6J mice.

Topics: Animals; Colitis; Colon; Dextran Sulfate; Diet, High-Fat; Disease Models, Animal; Fibrosis; Inflammation; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Stilbenes

Sepsis-induced myocardial dysfunction (SIMD) represents one of the serious complications secondary to sepsis, which is a leading cause of the high mortality rate among septic cases. Subsequent cardiomyocyte apoptosis, together with the uncontrolled inflammatory response, has been suggested to be closely related to SIMD. Piceatannol (PIC) is verified with potent anti-apoptotic and anti-inflammatory effects, but its function and molecular mechanism in SIMD remain unknown so far. This study aimed to explore the potential role and mechanism of action of PIC in resisting SIMD. The interaction of PIC with JAK2 proteins was evaluated by molecular docking, molecular dynamics (MD) simulation and surface plasmon resonance imaging (SPRi). The cecal ligation and puncture-induced septicemia mice and the LPS-stimulated H9C2 cardiomyocytes were prepared as the models in vivo and in vitro, separately. Molecular docking showed that JAK2-PIC complex had the -8.279 kcal/mol binding energy. MD simulations showed that JAK2-PIC binding was stable. SPRi analysis also showed that PIC has a strong binding affinity to JAK2. PIC treatment significantly ameliorated the cardiac function, attenuated the sepsis-induced myocardial loss, and suppressed the myocardial inflammatory responses both in vivo and in vitro. Further detection revealed that PIC inhibited the activation of the JAK2/STAT3 signaling, which was tightly associated with apoptosis and inflammation. Importantly, pre-incubation with a JAK2 inhibitor (AG490) partially blocked the cardioprotective effects of PIC. Collectively, the findings demonstrated that PIC restored the impaired cardiac function by attenuating the sepsis-induced apoptosis and inflammation via suppressing the JAK2/STAT3 pathway both in septic mice and H9C2 cardiomyocytes.

Topics: Animals; Apoptosis; Cardiomyopathies; Cardiotonic Agents; Cell Line; Disease Models, Animal; Inflammation; Janus Kinase 2; Male; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Dynamics Simulation; Myocytes, Cardiac; Rats; Sepsis; Signal Transduction; STAT3 Transcription Factor; Stilbenes; Tyrphostins

Pterostilbene (Pts) may be used for allergic asthma treatment. The AMPK/Sirt1 and Nrf2/HO-1 pathways are potential targets for asthma treatement. However, the relationship between Pts and AMPK/Sirt1 and Nrf2/HO-1 pathways in asthma is unclear. Herein, we aim to explore the pharmacological effects of Pts on oxidative stress and allergic inflammatory response as well as the mechanism involving AMPK/Sirt1 and Nrf2/HO-1 pathways.. Asthma model was established in mice with ovalbumin (OVA). The model mice were treated by different concentrations of Pts. Lung pathological changes were observed through histological staining. In vitro, lipopolysaccharide (LPS)-stimulated 16HBE cells were treated with Pts. The siAMPKα2, siSirt1 and siNrf2 knockdown, and treatment with compound C, EX-527 or ML385 were also performed in 16HBE cells. Enzyme-linked immunosorbent assay was used to detect interleukin-4 (IL-4), IL-13, IL-5, total and OVA specific immunoglobulin E (IgE), and interferon γ (IFN-γ). Pneumonography was used to measure the airway hyperreactivity (AHR). Superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) levels were also detected. Immunohistochemistry, Western blot and immunofluorescence were used to measure protein levels.. Pts significantly attenuated lung inflammatory cell infiltration and goblet cell proliferation. Meanwhile, Pts treatment could reduce IL-4, IL-13, IL-5, and IgE (total and OVA specific) levels in the asthma model mice. However, IFN-γ in bronchoalveolar lavage fluid was elevated. In addition, Pts reduced AHR. We also found that Pts treatment promoted serum SOD and CAT, and reduced MDA. In vitro results showed that Pts treatment promoted iNOS, TNF-α, COX-2, IL-1β, and IL-6 expressions in 16HBE cells, prolonged G0/G1 phase of the cell cycle, and resulted in a shortened G2M phase. Moreover, we found that Pts promoted the phosphorylation of AMPK in 16HBE, and meanwhile inhibited the increase of ROS induced by LPS. Additionally, Pts treatment inhibited p-AMPK, Sirt1, Nrf2 and HO-1, which in turn leads to the alleviation of AMPK/Sirt1 and Nrf2/HO-1 pathways.. Pts alleviated oxidative stress and allergic airway inflammation via regulation of AMPK/Sirt1and Nrf2/HO-1 signaling pathways.

Topics: AMP-Activated Protein Kinases; Animals; Cytokines; Inflammation; Lung; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; Oxidative Stress; Sirtuin 1; Stilbenes

2,3,5,4'-Tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG) is the main active component of Polygoni Multiflori Radix, a root of the homonymous plant widely used in traditional Chinese medicine. TSG has protective effects on the liver, reduces cholesterol and possesses anti-oxidant, anti-tumor, and anti-atherosclerotic properties. However, the pharmacological effects and mechanisms of action of Polygonum multiflorum on atherosclerosis (AS) have not been studied yet.. The aim of this research was to study the effects of Polygoni Multiflori Radix Praeparata (PMRP) and its major active chemical constituent TSG on AS in ApoE-deficient (ApoE. High fat diet induced AS in ApoE. TSG markedly inhibited AS plaque formation in ApoE. PMRP and TSG improved lipid accumulation and inflammation, and regulated the intestinal microbial imbalance in ApoE

Topics: Administration, Oral; Animals; Aorta; Atherosclerosis; Chemokine CCL2; Diet, High-Fat; Disease Models, Animal; Drugs, Chinese Herbal; Gastrointestinal Microbiome; Glucosides; Humans; Inflammation; Intercellular Adhesion Molecule-1; Lipoproteins, LDL; Male; Mice; Mice, Knockout, ApoE; Polygonum; Stilbenes; Triglycerides; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Infrasound is a major threat to global health by causing injuries of the central nervous system (CNS). However, there remains no effective therapeutic agent for preventing infrasound-caused CNS injury. 2,3,5,4'-Tetrahydroxystilbene-2-O-. A mouse model with CNS (oxidative stress-induced inflammation and neuronal apoptosis) injuries was established when the mouse was exposed to the infrasound of 16 Hz at 130 dB for 2 h each day and the duration of treatment was 8 d. The mice were divided into the control (CG, healthy mice), the model (MG, model mice), and the THSG (EG, experimental group, model mice treated with THSG) groups. The learning and memory impairments caused by infrasound were examined using a Morris water maze test. Lipid profiles, antioxidant biomarkers, and inflammatory cytokines in hippocampus tissue were measured by using corresponding ELISA kits. Meanwhile, BCL-2/BAX/caspase-3 signaling pathway was measured in the hippocampi and prefrontal cortex of the mouse brain using real-time qPCR and Western blot. Nissl's stain was used to measure neuronal necrosis in the hippocampi and prefrontal cortex of the mouse brain.. THSG significantly ameliorated the learning and memory impairments caused by infrasound. On the other hand, THSG improved lipid profiles, increased antioxidant properties by affecting the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA), and displayed anti-inflammatory action via the downregulation of IL- (interleukin-) 6, IL-8, IL-10, TNF- (tumor necrosis factor-). THSG may be an effective anti-infrasound drug against CNS injury by improving antioxidant, anti-inflammatory, antiapoptosis, and antinecrosis capacities. Further research is still needed to confirm the exact molecular mechanism.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Central Nervous System; Cytokines; Disease Models, Animal; Glucosides; Inflammation; Male; Mice; Stilbenes; Ultrasonic Waves

Topics: Animals; Anti-Inflammatory Agents; Artocarpus; Cell Survival; Cyclooxygenase 2; Cytokines; Inflammation; Lipopolysaccharides; Macrophages; Mice; Mitogen-Activated Protein Kinases; NF-kappa B; Nitric Oxide; Phosphatidylinositol 3-Kinases; Phosphorylation; Plant Extracts; RAW 264.7 Cells; Signal Transduction; Stilbenes

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Inflammation; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Microglia; Plant Extracts; Resveratrol; Stilbenes

Neuroinflammation are involved in the pathogenesis of many neurodegenerative disorders. In our screening of natural effective neuroinflammatory inhibitors from natural products, stilbenes, such as resveratrol and its analogues, have received considerable attention over the last several decades as anti-neuroinflammatory agents. Then, Bletilla striata attracted our attention due to its abundant stilbenes portion, PE fraction. So, three new stilbenes: dusuanlansin E1 (23a), dusuanlansin E2 (23b), 3-hydroxy-5-methoxybibenzyl-3'-O-β-d-glucopyranoside (27), and 30 known stilbene compounds were isolated from B. striata. These structures of the compounds were established on the basis of extensive spectroscopic analysis including 1D and 2D NMR and circular dichroism (CD) data. Furthermore, all the isolated components were tested in vitro for their inhibitory effects on the nitric oxide generation in LPS-stimulated BV2 cells. As a result, compounds 2, 5, 6, 16, 17 can greatly inhibit the NO production without cytotoxicity. In addition, SARs between stilbenes and anti-neuroinflammation effects were discussed briefly. In conclusion, stilbenes were characteristic constituents of the tubers of B. striata with potential anti- neuroinflammatory effects.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Inflammation; Lipopolysaccharides; Mice; Microglia; Nitric Oxide; Orchidaceae; Plant Tubers; Stilbenes

The lack of effective Alzheimer's disease treatment is becoming a challenge for researchers and prompts numerous attempts to search for and develop better therapeutic solutions. Compounds that affect several routes of the neurodegeneration cascade leading to the development of disease are of particular interest. An example of such substances is resveratrol and its synthetic and natural derivatives, which have gained popularity in recent years and show promise as a possible new therapeutic option in the approach to Alzheimer's disease treatment. In this article, the state of the art evidence on the role of resveratrol (RSV) in neuroprotection is presented; research results are summarized and the importance of resveratrol and its derivatives in the treatment of Alzheimer's disease are underlined. It also focuses on various modifications of the resveratrol molecule that should be taken into account in the design of future research on drugs against Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzofurans; Blood-Brain Barrier; Central Nervous System Diseases; Humans; Inflammation; Metabolic Diseases; Neuroprotection; Oxidative Stress; Resveratrol; Stilbenes; tau Proteins

Early pulmonary fibrosis after acute lung injury leads to poor prognosis and high mortality. Pterostilbene (Pts), a bioactive component in blueberries, possesses anti-inflammatory, antioxidative and antifibrotic properties. However, the effects of Pts on lipopolysaccharide (LPS)-induced pulmonary fibrosis are still unknown. In our study, the Pts group showed lower lung injury and fibrosis scores, and lower levels of hydroxyproline and protein (collagen I and transforming growth factor-β) than the scores and levels in mice treated with LPS. MMP-1 was the degrading enzyme of collagen I and LPS caused the inhibition of MMP-1, disturbing the degradation of collagen. Additionally, Pts remarkably reversed the LPS-induced inhibition of interleukin-10 and the release of tumor necrosis factor-α, interleukin-6 and interleukin-1β. In terms of cellular pathways, Pts treatment ameliorated LPS-activated nuclear factor kappa B (NF-κB) and NOD-like receptor NLRP3 signaling. Besides, LPS-induced low levels of A20 could be activated by Pts. In addition, Pts treatment reversed the high levels of Caspase-3, poly ADP-ribose polymerase (PARP) and Bcl2-associated X protein (Bax) expression and the low levels of B cell lymphoma/lewkmia-2 (Bcl2) that had been induced by LPS. Moreover, oxidative stress is also involved in the pathogenesis of fibrosis. Our findings indicate that LPS injection triggered the production of myeloperoxidase (MPO) and malondialdehyde (MDA) and the depletion of superoxide dismutase (SOD) and glutathione (GSH), and that these effects were notably reversed by treatment with Pts. In addition, Pts induced the dissociation of Kelch-like epichlorohydrin-associated protein-1 (Keap-1) and NF-E2 related factor-2 (Nrf2) and the activation of downstream genes (heme oxygenase-1, NAD(P)H:quinine oxidoreductase, glutamate-cysteine ligase catalytic subunit and glutamate-cysteine ligase modifier). In conclusion, oxidative stress, apoptosis and inflammation are involved in early pulmonary fibrosis and Pts exerts a protective effect by activating Keap-1/Nrf2, inhibiting caspase-dependent A20/NF-κB and NLRP3 signaling pathways.

Topics: Animals; Antioxidants; Apoptosis; Blueberry Plants; Disease Models, Animal; Inflammation; Lipopolysaccharides; Mice; Mice, Inbred Strains; Oxidative Stress; Phytotherapy; Pulmonary Fibrosis; Rabbits; Random Allocation; Stilbenes

In general, anti-inflammatory treatment is considered for multiple liver diseases despite the etiology. But current drugs for alleviating liver inflammation have defects, making it necessary to develop more potent and safer drugs for liver injury. In this study, we screened a series of (dihydro-)stilbene or (dihydro-)phenanthrene derivatives extracted from Pholidota chinensis for their potential biological activities. Among 31 compounds, the dihydro-stilbene gigantol exerted most potent protective effects on human hepatocytes against lithocholic acid toxicity, and exhibited solid antioxidative and anti-inflammatory effect in vitro. In mice with CCl

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antioxidants; Bibenzyls; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Complement Membrane Attack Complex; Guaiacol; Hepatocytes; Humans; Inflammation; Lipid Peroxidation; Lithocholic Acid; Liver; Male; Mice, Inbred ICR; Oxidative Stress; Phenanthrenes; Proteome; Rats, Sprague-Dawley; Stilbenes

Ischemic stroke is a severe neurological disease without known effective therapy. Microglia-mediated neuroinflammation plays an important role in ischemic stroke. Therefore, finding a safe and effective microglial activation inhibitor might lead to an effective therapeutic strategy against ischemic stroke. In this project, our goal was to explore both the mechanism and effect of pterostilbene in MCAO/R rats. The potential effect of pterostilbene on ischemic stroke was tested using MCAO/R rats and its effect on microglial activation was tested in LPS-stimulated BV-2 cells. In vivo, pterostilbene decreased the neurological scores, brain water content and infarct volume in MCAO/R rats. Pterostilbene increased the number of mature neurons, decreased the number of activated microglia, and reduced iNOS and IL-1β mRNA expression. Pterostilbene inhibited phosphorylated-IκBα expression, thus promoting IκBα expression and inhibiting ROS overexpression. In vitro, pterostilbene inhibited the expression of inflammatory cytokines and suppressed NAPDH activity as well as activation of both the NF-κB pathway and ROS production. To our knowledge, our study is the first to demonstrate that pterostilbene-mediated alleviation of cerebral ischemia and reperfusion injury in rats may be correlated with the inhibition of the ROS/NF-κB-mediated inflammatory pathway in microglia, indicating the potential for the use of pterostilbene as a candidate therapeutic compound for ischemic stroke.

Topics: Animals; Brain; Brain Ischemia; Cell Line; Disease Models, Animal; Gene Expression Regulation; Inflammation; Interleukin-1beta; Macrophage Activation; Male; Microglia; NF-kappa B; NF-KappaB Inhibitor alpha; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger; Stilbenes; Stroke

Oxidative stress and inflammation have long been considered to be responsible for the development and progression of diabetic retinopathy. On the other hand, rhaponticin (RN) has received scientific attention due to its various pharmacological properties. Keeping all these in view, the present study was performed to investigate the potential protective effects of RN on the retina in diabetic rats. Rats were randomly divided into three groups: control group rats, diabetic group rats, diabetic + RN (20 mg/kg body weight for 28 days through oral route) group rats. RN supplementation to diabetic rats significantly prevent the reduction of final body weight loss, reduced weekly fasting blood glucose levels and HbA1c levels with a significant increase in serum insulin levels. quantitative polymerase chain reaction and immunohistochemical analysis found upregulation of Nrf2, NQO-1, HO-1 and upregulation of Keap1 genes and protein distribution along with significantly reduced levels of malondialdehyde and increased activity of superoxide dismutase, catalase and glutathione peroxidase in RN-treated diabetic rats as compared to diabetic rats. Furthermore, treatment of diabetic rats with RN showed downregulated expression of tumour necrosis factor-α, matrix metalloproteinase-2 and upregulated expression of interleukin-10 (IL-10) and TIMP-1 in the retina. RN treatment decreased nuclear factor kappa-light-chain-enhancer of activated B cells distribution and increased IL-10 protein distribution in the retinae of diabetic rats. In addition, RN treatment ameliorated morphological changes observed in retinae of diabetic rats. Altogether, these results provided clear evidence that treatment of diabetic rats with RN attenuated diabetic retinal changes through its hypoglycaemic, antioxidant and anti-inflammatory effects.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Glycated Hemoglobin; Heme Oxygenase-1; Inflammation; Male; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Rats; Rats, Wistar; Retina; Signal Transduction; Stilbenes

Macaranga Thou. (Euphorbiaceae) is a large genus that comprises over 300 species distributed between Western Africa and the islands of the South Pacific. Plants of this genus have a long-standing history of use in traditional medicine for different purposes, including the treatment of inflammation. Fresh and dried leaves of certain Macaranga species (e.g. M. tanarius (L.) Müll.Arg.), have been used to treat cuts, bruises, boils, swellings, sores and covering of wounds in general. Several reports described Macaranga spp. being a rich source of polyphenols, such as prenylated stilbenoids and flavonoids, mostly responsible for its biological activity. Similarly, an abundant content of prenylated stilbenes was also described in M. siamensis S.J.Davies, species recently identified (2001) in Thailand. While the respective biological activity of the prenylated stilbenes from M. siamensis was poorly investigated to date, our recent study pointed out the interest as the natural source of several novel anti-inflammatory stilbenoids isolated from this species.. This work investigated the potential anti-inflammatory effects of the stilbenoid macasiamenene F (MF) isolated from M. siamensis S.J.Davies (Euphorbiaceae) on the lipopolysaccharide (LPS)-induced inflammation-like response of monocytes and microglia, major cells involved in the peripheral and central inflammatory response, respectively.. LPS-induced stimulation of TLR4 signaling led to the activation of inflammatory pathways in in vitro models of THP-1 and THP-1-XBlue™-MD2-CD14 human monocytes, BV-2 mouse microglia, and an ex vivo model of brain-sorted mouse microglia. The ability of the stilbenoid MF to intervene in the IкB/NF-кB and MAPKs/AP-1 inflammatory cascade was investigated. The gene and protein expressions of the pro-inflammatory cytokines IL-1β and TNF-α were evaluated at the transcription and translation levels. The protective effect of MF against LPS-triggered microglial loss was assessed by cell counting and the LDH assay.. MF demonstrated beneficial effects, reducing both monocyte and microglial inflammation as assessed in vitro. It efficiently inhibited the degradation of IкBα, thereby reducing the NF-кB activity and TNF-α expression in human monocytes. Furthermore, the LPS-induced expression of IL-1β and TNF-α in microglia was dampened by pre-, co-, or post-treatment with MF. In addition to its anti-inflammatory effect, MF demonstrated a cytoprotective effect against the LPS-induced death of BV-2 microglia.. Our research into anti-inflammatory and protective effects of MF has shown that it is a promising candidate for further in vitro and in vivo investigations of MF interventions with respect to acute and chronic inflammation, including potentially beneficial effects on the inflammatory component of brain diseases such as stroke and Alzheimer's disease.

Topics: Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Cells, Cultured; Cytoprotection; Dose-Response Relationship, Drug; Euphorbiaceae; Humans; Inflammation; Inflammation Mediators; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Microglia; Monocytes; Plant Extracts; Prenylation; Stilbenes

Microglial inflammation plays an important part in the progression of multiple neurological diseases, including neurodegenerative diseases, stroke, depression, and traumatic encephalopathy. Here, we aimed to explore the role of pterostilbene (PTE) in the microglial inflammatory response and subsequent damage of cocultured neural cells and partially explain the underlying mechanisms. In the coculture system of lipopolysaccharide-activated BV-2 microglia and SH-SY5Y neuroblastoma, PTE (only given to BV-2) exhibited protection on SH-SY5Y cells, evidenced by improved SH-SY5Y morphology and viability and LDH release. It also attenuated SH-SY5Y apoptosis and oxidative stress, evidenced by TUNEL and DCFH-DA staining, as well as MDA, SOD, and GSH levels. Moreover, PTE upregulated SIRT-1 expression and suppressed acetylation of NF-

Topics: Cell Culture Techniques; Humans; Inflammation; Microglia; Signal Transduction; Sirtuin 1; Stilbenes

Oxyresveratrol (OXY), a major phytochemical component derived from several plants, has been proved to have several pharmacological properties. However, the role of OXY in regulating neuroinflammation is still unclear. Here, we focused mainly on the anti-neuroinflammatory effects at the cellular level of OXY in the interleukin-1 beta (IL-1β)-stimulated HMC3 human microglial cell line. We demonstrated that OXY strongly decreased the release of IL-6 and MCP-1 from HMC3 cells stimulated with IL-1β. Nevertheless, IL-1β could not induce the secretion of TNF-α and CXCL10 in this specific cell line, and that OXY did not have any effects on reducing the basal level of these cytokines in the sample culture supernatants. The densitometry analysis of immunoreactive bands from Western blot clearly indicated that IL-1β does not trigger the nuclear factor-kappa B (NF-κB) signaling. We discovered that OXY exerted its anti-inflammatory role in IL-1β-induced HMC3 cells by suppressing IL-1β-induced activation of the PI3K/AKT/p70S6K pathway. Explicitly, the presence of OXY for only 4 h could strongly inhibit AKT phosphorylation. In addition, OXY had moderate effects on inhibiting the activation of ERK1/2. Results from immunofluorescence study further confirmed that OXY inhibited the phosphorylation of AKT and ERK1/2 MAPK upon IL-1β stimulation in individual cells. These findings suggest that the possible anti-inflammatory mechanisms of OXY in IL-1β-induced HMC3 cells are mainly through its ability to suppress the PI3K/AKT/p70S6K and ERK1/2 MAPK signal transduction cascades. In conclusion, our study provided accumulated data that OXY is able to suppress IL-1β stimulation signaling in human microglial cells, and we believe that OXY could be a probable pharmacologic agent for altering microglial function in the treatment of neuroinflammation.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cell Survival; Cells, Cultured; Chemokine CCL2; Chemokine CXCL10; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Microglia; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Plant Extracts; Proto-Oncogene Proteins c-akt; Stilbenes; Tumor Necrosis Factor-alpha

Mycoplasma gallisepticum (MG) infection is the main cause of chronic respiratory disease (CRD) characterized by severe respiratory inflammation in chickens. Polydatin (PD) is a resveratrol glycoside isolated from Polygonum cuspidatum, which has prominent anti-inflammatory effect. The purpose of this study was to investigate the therapeutic effect of PD against MG-induced inflammation in chicken and its underlying mechanism. Histopathological analysis showed that PD treatment (15, 30, and 45 mg/kg) apparently alleviated MG-induced pathological changes of chicken embryonic lung. In chicken embryo fibroblast (DF-1) cells, PD treatment (15, 30, and 60 μg/mL) could effectively suppress MG propagation, promote MG-infected cell proliferation and cell cycle progress, and inhibit MG-induced cell apoptosis. ELISA and qPCR assays showed that PD treatment significantly suppressed the expression of interleukin-6 (IL-6), IL-1β and tumor necrosis factor-α (TNF-α) induced by MG both in vivo and in vitro. Besides, molecular studies indicated that the MG-induced levels of toll-like receptor-6 TLR6, myeloid differentiation-88 (MyD88) and nuclear factor κB (NF-κB) were significantly decreased by PD treatment. Moreover, immunofluorescence analysis showed that PD treatment restrained the MG-induced NF-κB-p65 nuclear translocation. Taken together, these results indicate the protective effects of PD against MG-induced inflammation injury in chicken were mainly by inhibiting the TLR6/MyD88/NF-κB pathway.

Topics: Animals; Chick Embryo; Chickens; Glucosides; Inflammation; Mycoplasma gallisepticum; Myeloid Differentiation Factor 88; NF-kappa B; Stilbenes; Toll-Like Receptor 6; Tumor Necrosis Factor-alpha

Osteoarthritis (OA) is a common cause of joint pain and physical disability in the elderly. It is highly associated with local inflammatory reactions and cartilage degradation. Isorhapontigenin (ISO), a natural compound existing in various plants, has shown prominent anti-inflammatory and anti-oxidative properties in several inflammatory diseases. However, the effects of ISO on OA remain to be elucidated. Here, we investigated the effects of ISO on interleukin-1β (IL-1β)-treated rat chondrocytes and cartilage explants. Our results revealed that ISO could suppress the IL-1β-induced elevated levels of nitric oxide (NO), inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2), and cyclooxygenase-2 (COX2). Besides, ISO could also inhibit the IL-1β-induced up-regulation of cartilage matrix catabolic enzymes such as matrix metalloproteinases (MMPs) and aggrecanase-2 (ADAMTS5). Moreover, the IL-1β-induced downregulation of collagen II and aggrecan could be reversed by ISO. Furthermore, ISO prevented rat cartilage explant damage induced by IL-1β. Mechanistically, ISO worked partly by suppressing mitogen-activated protein kinase (MAPK)-associated ERK and p38 pathways. Taken together, our study indicated the anti-inflammatory potential of ISO on IL-1β-treated rat chondrocytes, providing a new idea for OA treatment.

Topics: Animals; Anti-Inflammatory Agents; Cartilage; Chondrocytes; Inflammation; Interleukin-1beta; Matrix Metalloproteinases; Mitogen-Activated Protein Kinases; Osteoarthritis; Rats; Stilbenes

Topics: Animals; Cell Line; Chemical and Drug Induced Liver Injury; Cytokines; Dose-Response Relationship, Drug; Fibrin; Gene Expression Regulation; Humans; Inflammation; Macrolides; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Specific Pathogen-Free Organisms; Stilbenes; Thromboplastin

Inflammatory is one of the main cause of aortic valve stenosis (AS), so discovering novel biomarkers for the targeted therapy of inflammation could be an attractive strategy in AS prevention. The objectives of our study were to clarify the modulatory role of resistin and silent information regulator 1 (SIRT1) before and after surgery and also to evaluate the therapeutic effects of resveratrol.. Nineteen AS patients and 15 healthy subjects were studied as the case and control groups, respectively. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured to determine the levels of resistin and SIRT1 and the effects of resveratrol on them.. Significant increase in resistin expression was observed in the patients compare to the control (p ≤0.01), and this upregulation was augmented 72 h following surgery (p ≤0.01). The SIRT1 expression decreased in the AS group compare to the control but this reduction was not significant. Aortic valve replacement caused a higher decrease in the protein (p ≤0.01) and mRNA level (p ≤0.05) of SIRT1. Resveratrol in the AS group significantly diminished the resistin level (p ≤0.05) but increased the SIRT1 level (p ≤0.001).. In our patients with AS, the resistin level was increased, whereas the expression of SIRT1 was reduced and surgery augmented these alterations. Resveratrol improved inflammation in the PBMCs of the patients through the SIRT1/resistin pathway. These findings suggest that pharmacological therapy with resveratrol might be a novel approach to alleviating inflammation in patients with AS.

Topics: Adult; Aged; Animals; Aortic Valve Stenosis; Biomarkers; Enzyme Inhibitors; Female; Humans; Inflammation; Leukocytes, Mononuclear; Male; Middle Aged; Resistin; Resveratrol; RNA, Messenger; Sirtuin 1; Stilbenes; Up-Regulation

Astrocyte-mediated inflammation and oxidative stress elicit cerebral ischemia-reperfusion (IR) injury after stroke. Nuclear factor (NF)-κB activates astrocytes and generates pro-inflammatory factors. The purpose of the present study is to elucidate the effect of pterostilbene (PTE, a natural stilbene) on astrocytic inflammation and neuronal oxidative injury following cerebral ischemia-reperfusion injury. A middle cerebral artery occlusion-reperfusion (MCAO/R) mouse model and HT22/U251 co-culture model subjected to oxygen-glucose deprivation and re-introduction (OGD/R) were employed, with or without PTE treatment. The data showed that PTE delivery immediately after reperfusion, at 1 h after occlusion, decreased infarct volume, brain edema, and neuronal apoptosis and improved long-term neurological function. PTE decreased oxidation (i.e., production of reactive oxygen species, malondialdehyde) and inflammatory mediators (tumor necrosis factor-α, interleukin-1β, and interleukin-6) and increased anti-oxidative enzyme activities (i.e., of superoxide dismutase, glutathione peroxidase), by inhibiting phosphorylation and nuclear translocation of NF-κB. In conclusion, PTE attenuated astrocyte-mediated inflammation and oxidative injury following IR via NF-κB inhibition. Overall, PTE is a promising neuroprotective agent.

Topics: Animals; Apoptosis; Astrocytes; Brain; Inflammation; Inflammation Mediators; Male; Mice; Neurons; NF-kappa B; Oxidation-Reduction; Phosphorylation; Reperfusion Injury; Stilbenes

The present study was designed to investigate the protective effect of moracin on primary culture of nucleus pulposus cells in intervertebral disc and explore the underlying mechanism. Moracin treatment significantly inhibited the LPS-induced inflammatory cytokine accumulation (IL-1β, IL-6 and TNF-α) in nucleus pulposus cells. And moracin also dramatically decreased MDA activity, and increased the levels of SOD and CAT induced by LPS challenge. Moreover, the expressions of Nrf-2 and HO-1 were decreased and the protein levels of p-NF-κBp65, p-IκBα, p-smad-3 and TGF-β were increased by LPS challenge, which were significantly reversed after moracin treatments. Moracin treatments also decreased the levels of matrix degradation enzymes (MMP-3, MMP-13) as indicated by RT-PCR analysis. However, Nrf-2 knockdown abolished these protective effects of moracin. Together, our results demonstrated the ability of moracin to antagonize LPS-mediated inflammation in primary culture of nucleus pulposus in intervertebral disc by partly regulating the Nrf2/HO-1 and NF-κB/TGF-β pathway in nucleus pulposus cells.

Topics: Benzofurans; Heme Oxygenase (Decyclizing); Humans; Inflammation; Lipopolysaccharides; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; NF-E2-Related Factor 2; NF-kappa B; Nucleus Pulposus; Stilbenes; Transforming Growth Factor beta

Polydatin (PD), an active component of Chinese herbs, is reported to have many biological functions, such as cardioprotective actions, anti-inflammatory activities, and antitumor effects. In this study, we investigated the effects of PD on body weight control, glucose and lipid metabolic regulation, and anti-inflammation in a high-fat-diet- (HFD-) induced obese mice model. After treatment of PD (100 mg/kg/d for 4 weeks), HFD mice reduced body weight, retroperitoneal fat mass, and adipose cell sizes; significantly lowered serum total cholesterol triglyceride (TG) and low-density lipoprotein (LDL) levels; and increased high-density lipoprotein (HDL) levels compared with the HFD control mice. Further studies showed that PD downregulated the mRNA and protein expressions of peroxisome proliferator-activated receptor gamma (PPAR

Topics: Adipose Tissue; Administration, Oral; Animals; Diet, High-Fat; Energy Metabolism; Glucosides; Inflammation; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; PPAR gamma; Stilbenes

To investigate the effect of polydatin on glucose transporter, blood glucose homeostasis and renal injury in streptozotocin (STZ)-induced diabetic rats. The in vitro inhibitory effect of polydatin on sodium-glucose cotransporter-1 (SGLT1) and 2 (SGLT2) was determined using HEK293 cells. The inhibitory effect of polydatin on GLUT1 and GLUT4 was evaluated using 3T3-L1 adipocytes. Streptozotocin-induced diabetic rats were used for this study. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), urea nitrogen, serum creatinine and urinary protein were determined using biochemical analyzer. Histopathological examination was performed on renal tissue. Serum levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1) and C-reactive protein (CRP) were also determined. Polydatin significantly inhibited SGLT1/2 and exhibited high selectivity for both GLUT1 and GLUT4. It significantly and dose-dependently decreased hyperglycemia, enhanced urine glucose excretion in the diabetic rats. The polydatin treatment significantly ameliorated symptoms of DN such as polyuria, polydipsia and hyperphagia. The hypoglycemic effect of polydatin was maintained throughout the treatment period. In addition,the levels of IL-1β, TNF-α, MCP-1 and CRP were significantly reduced in treated group. Treatment with polydatin significantly ameliorated most of the structural and morphological changes induced by STZ. Moreover, the levels of urinary protein, serum creatinine and urea nitrogen were significantly reduced after treatment with polydatin.  As a potential dual inhibitor of SGLT1/2, polydatin has high selectivity for GLUT1 and GLUT4. Its long-term administration delays the development of DN, protects renal function and ameliorates renal tissue injury.

Topics: 3T3-L1 Cells; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Glucose Transporter Type 1; Glucose Transporter Type 4; Glucosides; HEK293 Cells; Humans; Hyperglycemia; Inflammation; Mice; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Stilbenes

As Alzheimer's disease (AD) induces several cellular and molecular damages, it could be interesting to use multi-target molecules for therapeutics. We previously published that trans ε-viniferin induced the disaggregation of Aβ42 peptide and inhibited the inflammatory response in primary cellular model of AD. Here, effects of this stilbenoid were evaluated in transgenic APPswePS1dE9 mice. We report that trans ε-viniferin could go through the blood brain barrier, reduces size and density of amyloid deposits and decreases reactivity of astrocytes and microglia, after a weekly intraperitoneal injection at 10 mg/kg from 3 to 6 months of age.

Topics: Alzheimer Disease; Animals; Astrocytes; Benzofurans; Disease Models, Animal; Female; Inflammation; Male; Mice; Mice, Transgenic; Microglia; Plaque, Amyloid; Stilbenes

Tetrahydroxy stilbene glucoside (TSG) has been reported to exert a cytoprotective effect against various toxicants. However, the function and mechanism of TSG in palmitic acid (PA)-induced inflammation and apoptosis in cardiomyocytes are still unknown. The present study was designed to investigate the post-transcriptional mechanism in TSG-treated cardiomyocytes' inflammation and apoptosis induced by PA.. The mRNA and protein levels were assayed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. Cell proliferation was analyzed by CCK-8 assay. Annexin V-fluorescein isothiocyanate/polyimide (annexin V-FITC/PI) staining was used to evaluate apoptosis using flow cytometry.. TSG restricted the detrimental effects, including the activated inflammatory response and apoptosis, of PA in cardiomyocytes, as well as the up-regulation of miR-129-3p and down-regulation of p-Smad3 expression. In addition, bioinformatics and experimental analysis suggested that Smad3 was a direct target of miR-129-3p, which could inhibit or enhance the expression of p-Smad by transfection with miR-129-3p mimics or inhibitors, respectively. Furthermore, our results demonstrated that overexpression of Smad3 reversed the inhibition of inflammation and apoptosis by overexpression of miR-129-3p in PA-stimulated cardiomyocytes.. TSG targeted to miR-129-3p/Smad3 signaling inhibited PA-induced inflammation and apoptosis in cardiomyocytes.

Topics: Animals; Apoptosis; Cell Line; Glucosides; Inflammation; MicroRNAs; Myocytes, Cardiac; Palmitic Acid; Protective Agents; Rats; Signal Transduction; Smad3 Protein; Stilbenes

Oligostilbenes are polyphenol oligomers derived from resveratrol and are commonly produced by members of the Gnetaceae family, and many researchers have focused on their anti-inflammatory activities. The EtOAc fraction of a Gnetum latifolium extract showed inhibitory activity against neuroinflammation induced by the transfection of Aβ

Topics: Animals; Cell Survival; Cells, Cultured; Density Functional Theory; Dose-Response Relationship, Drug; Gnetum; Inflammation; Mice; Molecular Conformation; Nitric Oxide; Plant Leaves; Stilbenes; Structure-Activity Relationship

Topics: Cell Line; Enzyme Inhibitors; Humans; Inflammation; Lipoxygenases; NF-kappa B; Prenylation; Prostaglandin-Endoperoxide Synthases; Signal Transduction; Stilbenes; Transcription Factor AP-1

Diabetic cardiomyopathy (DCM) is one of the leading causes of morbidity and mortality in diabetic patients. Piceatannol (PIC) has protective effects against cardiovascular disease; however, it remains unknown whether it also protects against DCM. A Cell Counting Kit-8 (CCK-8) assay was used to evaluate the effects of PIC on the viability of high glucose (HG)-induced H9C2 cells. Protein expression and mRNA levels were detected by western blotting and real-time polymerase chain reaction (RT-PCR), respectively. In vivo, physical and biochemical analyses, together with transthoracic echocardiography and hemodynamic measurements, were used to detect the effects of PIC treatment on cardiac function in DCM rats. Reactive oxygen species production was determined using an ELISA kit, and inflammatory cytokines were detected by RT-PCR. Pathological changes were assessed by hematoxylin-eosin staining, immunohistochemical staining, and TUNEL staining. According to the results, PIC treatment improved cell viability and inhibited cell apoptosis in HG-induced H9C2 cardiac myoblasts. In addition, PIC not only attenuated the over-production of interleukin-6 (IL-6) (P < 0.05) and tumor necrosis factor alpha (TNF-α) (P < 0.05), but also improved the expression of nuclear factor E2-related factor 2 (Nrf2) (P < 0.05) and heme oxygenase-1 (HO-1) (P < 0.01). Importantly, knockdown of Nrf2 suppressed PIC-mediated activation of the Nrf2/HO-1 pathway and abolished its anti-inflammatory effects. In vivo, oral administration of PIC suppressed STZ-induced inflammation, oxidative stress hypertrophy, fibrosis(myocardial collagen volume fraction in 5 mg/kg and 10 mg/kg PIC group was decreased 25.83% and 55.61% compared with the DM group), and apoptosis(Caspase-3 level in 5 mg/kg and 10 mg/kg PIC group was decreased 13.21% and 33.91% compared with the DM group), thereby relieving cardiac dysfunction and improving both fibrosis and pathological changes in cardiac tissues of diabetic rats. These findings define for the first time that the effects of PIC against DCM can be attributed to its role in inflammation and oxidative stress inhibition.

Topics: Animals; Cell Line; Diabetic Cardiomyopathies; Heme Oxygenase-1; Humans; Inflammation; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Rats; Signal Transduction; Stilbenes

Resveratrol is a polyphenol that has gained momentum in therapeutics in the last few years.. In this study, we hypothesised that resveratrol could act prophylactically and/or treat inflammatory lesions of the oral cavity after being delivered by two different formulations of buccal mucoadhesive tablets (F1 and F2, which differed in terms of viscosity agents used).. This hypothesis was assessed through permeation studies, to verify diffusion of the drug through the buccal mucosa using a porcine model to predict human in vivo behaviour.. F2 (tablet with less viscosity agent) presented better permeation than F1, but the amount of drug that crossed the mucosa was still low compared to the amount retained within it (35.90 µg found in the receptor medium and 15.63 mg quantified within the mucosa).. This accounted for a local effect rather than a systemic one, which is desirable for local processes, such as oral mucositis, lichen planus, erythema multiforme, nicotinic stomatitis, recurrent aphthous stomatitis, among others. In this sense, resveratrol-loaded mucoadhesive tablets appear to be a prominent alternative to prevent and/or cure inflammatory lesions of the oral cavity.

Topics: Adhesiveness; Administration, Buccal; Animals; Chemistry, Pharmaceutical; Drug Delivery Systems; Inflammation; Mouth; Mouth Mucosa; Permeability; Resveratrol; Stilbenes; Stomatitis; Swine; Tablets; Viscosity

The aim of this study was to evaluate the potential effects of 2,3,4',5-tetrahydroxystilbene-2-O-β-d-glucoside (TSG) on the development of atherosclerotic plaque in ApoE

Topics: Animals; Apolipoproteins E; Atherosclerosis; Biological Transport; Cholesterol; Fatty Liver; Foam Cells; Glucosides; Hyperlipidemias; Inflammation; Lipid Metabolism; Macrophages; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; RAW 264.7 Cells; Stilbenes

Arachidin-1 [trans-4-(3-methyl-1-butenyl)-3,5,3',4'-tetrahydroxystilbene] is a polyphenol produced by peanut kernels during germination. The aim of the present study was to investigate the mechanism underlying the anti-inflammatory effect of arachidin-1 in endothelial cells (ECs). The results of cell adhesion and western blotting assays demonstrated that arachidin-1 attenuated tumor necrosis factor (TNF)-α-induced monocyte/EC adhesion and intercellular adhesion molecule-1 (ICAM-1) expression. Arachidin-1 was demonstrated to exert its inhibitory effects by the attenuation of TNF-α-induced nuclear factor-κB (NF-κB) nuclear translocation and inhibitor of κB-α (IκBα) degradation. Furthermore, arachidin-1 upregulated nuclear factor-E2-related factor-2 (Nrf-2), a known mediator of phase II enzyme expression, and increased the transcriptional activity of antioxidant response element. Transfection of ECs with Nrf-2 siRNA blocked the inhibitory effect of arachidin-1 on ICAM-1 expression, NF-κB nuclear translocation and IκBα degradation. In addition, arachidin-1 induced the expression of the phase II enzymes thioredoxin-1, thioredoxin reductase-1, heme oxygenase-1, glutamyl-cysteine synthetase and glutathione S-transferase. Following arachidin-1 pretreatment, the H2O2-induced generation of reactive oxygen species was reduced. Therefore, the present results indicate that arachidin-1 suppresses TNF-α-induced inflammation in ECs through the upregulation of Nrf-2-related phase II enzyme expression.

Topics: Active Transport, Cell Nucleus; Arachis; Endothelial Cells; Gene Expression Regulation; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen Peroxide; Inflammation; Intercellular Adhesion Molecule-1; Metabolic Detoxication, Phase II; NF-E2-Related Factor 2; NF-kappa B; NF-KappaB Inhibitor alpha; Reactive Oxygen Species; RNA, Small Interfering; Stilbenes; Transfection; Tumor Necrosis Factor-alpha

CYP1B1 and CYP1A1 are important extra-hepatic cytochromes, expressed in the colon and involved in the metabolism of dietary constituents and exogenous compounds. CYP1B1 expression is increased by pro-inflammatory cytokines, and it has been recently implicated in regulation of blood brain barrier function. We investigated its involvement in the increased permeability of the intestinal epithelial barrier observed in inflammatory conditions.. Epithelial monolayers formed by human T84 colon carcinoma cells cultured on transwells, were disrupted by incubation with IFNγ (10 ng·mL. IFNγ disrupts the barrier integrity of the T84 monolayers and increases CYP1B1 and HIF1α mRNA expression. CYP1B1 induction is inhibited by the NF-κB inhibitor ammonium pyrrolidinedithiocarbamate (100 μM) but not by the HIF1α inhibitor 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (50 μM). Inhibition of CYP1B1 with the selective inhibitor 2,4,3',5'-tetramethoxystilbene (100 nM) partly reverses the effects of IFNγ on epithelial permeability.. These data suggest that increased expression of CYP1B1 is involved in the effects of IFNγ on epithelial permeability. Inhibition of CYP1B1 counteracts the alterations of epithelial barrier integrity induced by IFNγ and could thus have a therapeutic potential in disorders of intestinal permeability associated with inflammation.

Topics: Cell Line, Tumor; Colonic Neoplasms; Cytochrome P-450 CYP1B1; Electric Impedance; Humans; Inflammation; Interferon-gamma; Intestinal Mucosa; Permeability; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes

Oxyresveratrol and its glycoside are important natural active materials. As an effective tyrosine kinase inhibitor, oxyresveratrol may prevent herpes virus infection, inflammation and oxidative stress, as well as protect nerves. In addition, it is known to inhibit cell apoptosis following cerebral ischemia. In recent years, oxyresveratrol and its glycoside have been widely investigated, and their useful biological activities have been explored, indicating that they may be worthy of further comprehensive research. The aim of the present study was to evaluate the photoprotective effects of oxyresveratrol and its ability to abrogate inflammation and oxidative stress in a rat model of spinal cord injury (SCI). The authors identified that oxyresveratrol significantly reversed the SCI‑induced inhibition of Basso, Beattie, and Bresnahan scores, inhibited the SCI‑mediated increase in spinal cord water content, significantly suppressed SCI‑induced nuclear factor‑κB/p65, tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6 activities and reversed the malondialdehyde, superoxide dismutase, glutathione (GSH) and GSH peroxidase activities in SCI rats. SCI‑induced granulocyte‑macrophage colony‑stimulating factor (GM‑CSF), inducible nitric oxide synthase (iNOS) and cyclo‑oxygenase‑2 (COX‑2) protein expression was significantly suppressed by oxyresveratrol, and SCI‑mediated inhibition of nuclear factor (erythroid‑derived 2)‑like 2 (Nrf2) protein expression was significantly increased by oxyresveratrol. In conclusion, these results suggest that the effects of oxyresveratrol restores SCI, and abrogates inflammation and oxidative stress in rat model of SCI via the GM‑CSF, iNOS, COX‑2 and Nrf2 signaling pathway.

Topics: Animals; Antioxidants; Disease Models, Animal; Drug Administration Schedule; Female; Gene Expression Regulation; Glutathione Peroxidase; Granulocyte-Macrophage Colony-Stimulating Factor; Inflammation; Injections, Intraperitoneal; Interleukin-1beta; Interleukin-6; Locomotion; Malondialdehyde; Neuroprotective Agents; Nitric Oxide Synthase Type II; Oxidative Stress; Plant Extracts; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries; Stilbenes; Superoxide Dismutase; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Sepsis is characterized by injury to the microvasculature and the microvascular endothelial cells, leading to barrier dysfunction. However, the specific role of injury in septic endothelial barrier dysfunction remains to be elucidated. In the present study, it was hypothesized that endothelial cell inflammatory injury is likely required for barrier dysfunction under septic conditions in vitro. 2,3,5,4'‑Tetrahydroxystilbene‑2‑O‑β‑D‑glucoside (TSG), a compound extracted from Chinese herbs, is able to inhibit the inflammatory injury of septic‑serum in endothelial cells. In the present study, cell viability was assayed by CCK‑8 method; mRNA and protein expression was identified by RT‑qPCR, western blot or Elisa, respectively and the production of reactive oxygen species was observed by a fluorescence microscope. The present study indicated that septic serum significantly decreased the cell viability of pulmonary aortic endothelial cells (PAECs) following co‑cultivation for 6 h, which occurred in a time‑dependent manner. TSG notably increased the viability of PAECs in a time‑ and concentration‑dependent manner. Further investigations revealed that septic serum increased the secretion of interleukin (IL)‑1β, IL‑6 and C‑reactive protein in PAECs, whereas pretreatment with TSG significantly decreased the secretion of these inflammatory factors. These data indicated that septic serum increased inflammatory injury to the PAECs, and TSG decreased this injury via the reactive oxygen species‑mitogen‑activated protein kinase‑nuclear factor‑κB signaling pathway.

Topics: Animals; Aorta; Cell Survival; Cells, Cultured; Cytokines; Endothelial Cells; Glucosides; Inflammation; Lung; Male; Mitogen-Activated Protein Kinases; NF-kappa B; Phosphorylation; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Sepsis; Signal Transduction; Stilbenes; Superoxides

Cardiovascular risk factors can negatively influence late endothelial progenitor cell (EPCs) number and functions, thus EPCs biology is a clinical implications for cardiovascular diseases. The present study aimed to investigate the potential protective effects of resveratrol (RES) on tumor necrosis factor (TNF)‑α‑induced inflammatory damage in late endothelial progenitor cells (EPCs) and to elucidate the underlying mechanisms. Late EPCs at passages 3‑5 were pretreated with RES at a concentration of 20 µmol/l for 12 h and subsequently incubated with TNF‑α (10 ng/ml) for 24 h. The adhesion, migration, proliferation and vasculogenesis of EPCs were subsequently detected. Furthermore, the mRNA expression levels of intercellular adhesion molecule‑1 (ICAM‑1) and monocyte chemoattractant protein‑1 (MCP‑1) were measured by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). Nitric oxide (NO) levels in the supernatant were determined using a colorimetric assay kit. Additionally, the mRNA and protein expression of Krüppel‑like factor‑2 (KLF2) was determined by RT‑qPCR and western blot analysis, respectively. The results indicated that TNF‑α markedly inhibited the proliferation, adhesion, migration and vasculogenesis of late EPCs. However, RES ameliorated the effects induced by TNF‑α. Furthermore, exposure of EPCs to TNF‑α decreased the levels of NO secretion and KLF2 expression at the mRNA and protein levels, but upregulated the levels of inflammatory factors, including ICAM‑1 and MCP‑1, compared with the control group. RES significantly inhibited TNF‑α‑induced inflammatory damage through upregulation of KLF2 expression and downregulation of the expression of ICAM‑1 and MCP‑1. In conclusion, RES may exert protective effects on the cardiovascular system, as demonstrated by the amelioration of TNF-α-induced inflammation in EPCs following RES treatment, and may therefore be used in the future for the prevention of cardiovascular disease.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cell Adhesion; Cell Movement; Cell Proliferation; Cells, Cultured; Chemokine CCL2; Endothelial Progenitor Cells; Female; Gene Expression Regulation; Inflammation; Intercellular Adhesion Molecule-1; Kruppel-Like Transcription Factors; Male; Neovascularization, Physiologic; Nitric Oxide; Rats; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

Oxidative stress has a pivotal role in the pathogenesis of diabetes-associated cardiovascular problems, which has remained a primary cause of the increased morbidity and mortality in diabetic patients. It is of paramount importance to prevent the diabetes-associated cardiac complications by reducing oxidative stress with the help of nutritional or pharmacological agents. Pterostilbene (PT), the primary antioxidant in blueberries, has recently gained attention for its promising health benefits in metabolic and cardiac diseases. However, the mechanism whereby PT reduces diabetic cardiac complications is currently unknown.. Sprague-Dawley rats were fed with 65% fructose diet with or without PT (20 mg kg. Fructose-fed rats demonstrated cardiac hypertrophy, hypertension, enhanced myocardial oxidative stress, inflammation and increased NF-κB expression. Administration of PT significantly decreased cardiac hypertrophy, hypertension, oxidative stress, inflammation, NF-κB expression and NLRP3 inflammasome. We demonstrated that PT improved mitochondrial biogenesis as evidenced by increased protein expression of PGC-1α, complex III and complex V in fructose-fed diabetic rats. Further, PT increased protein expressions of AMPK, Nrf2, HO-1 in cardiac tissues, which may account for the prevention of cardiac oxidative stress and inflammation in fructose-fed rats.. Collectively, PT reduced cardiac oxidative stress and inflammation in diabetic rats through stimulation of AMPK/Nrf2/HO-1 signalling.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Antioxidants; Blood Glucose; Diabetes Mellitus; Diabetic Cardiomyopathies; Disease Models, Animal; Fructose; Heme Oxygenase (Decyclizing); Hemodynamics; Inflammasomes; Inflammation; Inflammation Mediators; Male; Mitochondria, Heart; Myocardium; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Rats, Sprague-Dawley; Signal Transduction; Stilbenes

Inhibiting β-amyloid (Aβ)-induced microglial activation is proposed as an effective strategy for the treatment of Alzheimer's disease. Tetrahydroxystilbene glycoside (TSG) is the main active ingredient of Polygonum multiflorum and has a wide range of biological properties, including antiinflammation. Here, we focused on the function and regulatory mechanism of TSG in Aβ-induced N9 and BV2 cells. The results showed that Aβ treatment induced the activation of microglia cells and the production of inflammatory molecules, including inducible nitric oxide synthase, nitric oxide, cyclooxygenase 2, and prostaglandin E2, which were significantly inhibited by TSG pretreatment. Furthermore, we found Aβ exposure increased the levels of microglial M1 markers, interleukin (IL)-1β, IL-6, and tumor necrosis factor α, and the pretreatment of TSG suppressed the increase of M1 markers and enhanced the levels of M2 markers, including IL-10, brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, and arginase-1. PU.1 overexpression was found to eradicate the anti-inflammatory effects of TSG in Aβ-induced microglial cells. Taken together, these findings indicate that TSG attenuates Aβ-induced microglial activation and polarizes microglia towards M2 phenotype, which may be closely associated with the regulation of PU.1.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Arginase; Brain-Derived Neurotrophic Factor; Cells, Cultured; Glucosides; Inflammation; Interleukin-1beta; Mice; Microglia; NF-kappa B; Nitric Oxide Synthase Type II; Stilbenes; Tumor Necrosis Factor-alpha

Desoxyrhapontigenin (DRG), a stilbene compound from Rheum undulatum, has been found to exhibit various pharmacological activities, however, its impact on osteoclast formation has not been investigated. The present study investigated the effect of DRG on receptor activator of nuclear factor‑κB ligand (RANKL)‑induced osteoclast differentiation in mouse bone marrow macrophages (BMMs) and inflammation‑induced bone loss in vivo. BMMs or RAW264.7 cells were treated with DRG, followed by an evaluation of cell viability, RANKL‑induced osteoclast differentiation, actin‑ring formation and resorption pits activity. The effects of DRG on the RANKL‑induced phosphorylation of MAPK and the expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and c‑Fos were evaluated using western blot analysis once the BMMs were exposed to RANKL and DRG. The expression levels of osteoclast marker genes were also evaluated using western blot analysis and reverse transcription‑quantitative polymerase chain reaction A lipopolysaccharide (LPS)‑induced murine bone loss model was used to evaluate the protective effect of DRG on inflammation‑induced bone‑loss. The results demonstrated that DRG suppressed the RANKL‑induced differentiation of BMMs into osteoclasts, osteoclast actin‑ring formation and bone resorption activity in a dose‑dependent manner. Furthermore, DRG significantly inhibited LPS‑induced bone loss in a mouse model. At the molecular level, DRG inhibited the RANKL‑induced activation of extracellular signal‑regulated kinase, the expression of c‑Fos, and the induction of NFATc1, a crucial transcription factor for osteoclast formation. DRG decreased the expression levels of osteoclast marker genes, including matrix metalloproteinase‑9, tartrate‑resistant acid phosphatase and cathepsin K. In conclusion, these findings suggested that DRG inhibited the differentiation of BMMs into mature osteoclasts by suppressing the RANKL‑induced activator protein‑1 and NFATc1 signaling pathways, and may be a potential candidate for treating and/or preventing osteoclast‑associated diseases, including osteoporosis.

Topics: Actins; Animals; Bone Marrow Cells; Bone Resorption; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Inflammation; Macrophages; Mice; NFATC Transcription Factors; Osteoclasts; Osteogenesis; Phosphorylation; Proto-Oncogene Proteins c-fos; RANK Ligand; RAW 264.7 Cells; Stilbenes

Pterostilbene (Pte) and 4′-Methoxyresveratrol (4MR) are methylated derivatives of resveratrol. We investigated the anti-inflammatory effect of Pte and 4MR in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages. Both Pte and 4MR significantly reduced LPS-induced nitric oxide release by inhibiting the inducible nitric oxide synthase mRNA expression. Moreover, both of them inhibited LPS-induced mRNA expression of inflammatory cytokines including monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6 and IL-1β, and tumor necrosis factor α (TNF-α), and attenuated LPS-induced nuclear factor-κB (NF-κB) activation by decreasing p65 phosphorylation. In addition, 4MR but not Pte inhibited LPS-induced the activator protein (AP)-1 pathway in RAW 264.7 macrophages. Further study suggested that Pte had an inhibitory effect on extracellular regulated protein kinases (ERK) and p38 activation, but not on c-Jun N-terminal kinase (JNK), while 4MR had an inhibitory effect on JNK and p38 activation, but not on ERK. Taken together, our data suggested that Pte induced anti-inflammatory activity by blocking mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, while 4MR showed anti-inflammatory activity through suppression of MAPK, AP-1, and NF-κB signaling pathways in LPS-treated RAW 264.7 macrophages.

Topics: Animals; Anti-Inflammatory Agents; Cell Survival; Cytokines; Inflammation; Macrophages; Mice; Mitogen-Activated Protein Kinases; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; RAW 264.7 Cells; Resveratrol; Signal Transduction; Stilbenes; Transcription Factor AP-1

Resveratrol (RSV) has been reported as a promising oral supplementation for osteoarthritis treatment, while the mechanism of its action is still unclear. The specific aim of this study is to decode one of the mechanisms by which RSV protects chondrocyte.. Mouse chondrogenic cell line ATDC5 was treated with 30 µM RSV for 24 h, and 10 µg/ml LPS for 12 h, after which cell viability, apoptosis, and the release of pro-inflammatory cytokines were assessed. The expression of miR-146b in ATDC5 cells was silenced by the specific inhibitor transfection, and then cell viability, apoptosis and inflammation were re-assessed.. The IC50 value of LPS in ATDC5 cells was about 10.27 µg/ml. LPS with a dosage of 10 µg/ml repressed cell viability, induced apoptosis, and increased the release of IL-1β, IL-6 and TNF-α. RSV pre-treatment (30 µM) significantly alleviated LPS-induced apoptosis and inflammation. More importantly, miR-146b was up-regulated by RSV, and the protective functions of RSV on ATDC5 cells were attenuated by miR-146b silence. Further, NF-κB and p38MAPK pathways were activated by LPS, and were deactivated by RSV. Besides, RSV-induced the deactivation of NF-κB and p38MAPK pathways was reversed by miR-146b silence.. Our findings suggest that RSV protects ATDC5 cells from LPS-induced inflammatory and apoptotic injury via up-regulation of miR-146b and thereby deactivation of NF-κB and p38MAPK pathways.

Topics: Animals; Cell Line; Chondrocytes; Cytokines; Inflammation; Lipopolysaccharides; MAP Kinase Signaling System; Mice; MicroRNAs; Resveratrol; Stilbenes; Up-Regulation

Resveratrol, a natural phenolic compound, provides neuroprotective effects, however, the specific mechanisms of action remain to be elucidated. The purpose of the present study was to examine the neuroprotective effect of resveratrol on spinal cord injury (SCI) and the potential molecular mechanisms of action. A rat model of SCI was induced using Allen's method, and resveratrol (100 mg/kg) was intraperitoneally injected 1 day following surgery. The recovery of neurological function was assessed using the Basso, Beattie, Bresnahan scoring system and an inclined plane test. The concentrations of pro‑ and anti‑inflammatory factors were measured using ELISA. The expression and location of autophagy markers were measured using western blot and immunofluorescence analyses. The results suggested that resveratrol administration resulted in functional improvement of locomotor activity and reduced neuroinflammation following the induction of SCI. In addition, autophagy was activated following SCI, as demonstrated by the significantly increased ratio of microtubule‑associated protein light chain 3 (LC3)‑II/LC3‑I and expression of Beclin‑1 in the injured spinal cord. Of note, the enhancement of phosphorylated (p)‑AMP‑activated protein kinase (AMPK) and the reduction of p‑mammalian target of rapamycin (mTOR) following SCI indicated that the SCI‑induced activation of autophagy was associated with the AMPK/mTOR signaling pathway. Resveratrol treatment further enhanced the activation of autophagy via the AMPK/mTOR pathway following SCI. By contrast, the autophagic inhibitor, 3‑methyladenine, partially inhibited the neuroprotective effects of resveratrol treatment. Together, these findings suggested that resveratrol promoted functional recovery and inhibited neuroinflammation through the activation of autophagy mediated by the AMPK/mTOR pathway following SCI.

Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Inflammation; Male; Rats; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Spinal Cord Injuries; Stilbenes; TOR Serine-Threonine Kinases

Exposure to carbon black nanoparticles (CBNPs), a well-known industrial production, promotes pulmonary toxicity through inflammation and oxidative stress. Recent studies show that some polyphenols exert their antioxidant properties through regulation of protein kinase C-α (PKC-α) and NADPH oxidase (Nox) signaling. Resveratrol, a dietary polyphenol in fruits, possesses various health beneficial effects including anti-inflammatory and antioxidative properties. In this study, we aimed to elucidate the involvement of PKC-α and Nox in CBNPs-induced inflammation and oxidative stress, and to investigate the protective effects of resveratrol on CBNP-induced inflammation and oxidative stress in human lung epithelial A549 cells.. The production of reactive oxygen species (ROS) and the change of mitochondrial membrane potential (ΔΨm) were measured by flow cytometry. Nitric oxide (NO) was measured using the Griess reagent, and prostaglandin E. In lung epithelial A549 cells, CBNPs significantly enhanced oxidative stress by upregulation of Nox2 and membrane expression of p67. Resveratrol attenuated CBNPs-induced oxidative and inflammatory factors in lung epithelial A549 cells, at least in part via inhibiting PKC-α- and Nox-related signaling.

Topics: A549 Cells; Down-Regulation; Humans; Inflammation; Lung; NADPH Oxidases; Nanoparticles; Oxidative Stress; Protein Kinase C-alpha; Reactive Oxygen Species; Resveratrol; Soot; Stilbenes

Oxidative stress is a critical factor in nonalcoholic fatty liver disease pathogenesis. MicroRNA-200a (miR-200a) is reported to target Kelch-like ECH-associated protein 1 (Keap1), which regulates nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant pathway. Polydatin (3,4',5-trihydroxy-stilbene-3-β-D-glucoside), a polyphenol found in the rhizome of Polygonum cuspidatum, have anti-oxidative, anti-inflammatory and anti-hyperlipidemic effects. However, whether miR-200a controls Keap1/Nrf2 pathway in fructose-induced liver inflammation and lipid deposition and the blockade of polydatin are still not clear. Here, we detected miR-200a down-regulation, Keap1 up-regulation, Nrf2 antioxidant pathway inactivation, ROS-driven thioredoxin-interacting protein (TXNIP) over-expression, NOD-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome activation and dysregulation of peroxisome proliferator activated receptor-α (PPAR-α), carnitine palmitoyl transferase-1 (CPT-1), sterol regulatory element binging protein 1 (SREBP-1) and stearoyl-CoA desaturase-1 (SCD-1) in rat livers, BRL-3A and HepG2 cells under high fructose induction. Furthermore, the data from the treatment or transfection of miR-200a minic, Keap1 and TXNIP siRNA, Nrf2 activator and ROS inhibitor demonstrated that fructose-induced miR-200a low-expression increased Keap1 to block Nrf2 antioxidant pathway, and then enhanced ROS-driven TXNIP to activate NLRP3 inflammasome and disturb lipid metabolism-related proteins, causing inflammation and lipid deposition in BRL-3A cells. We also found that polydatin up-regulated miR-200a to inhibit Keap1 and activate Nrf2 antioxidant pathway, resulting in attenuation of these disturbances in these animal and cell models. These findings provide a novel pathological mechanism of fructose-induced redox status imbalance and suggest that the enhancement of miR-200a to control Keap1/Nrf2 pathway by polydatin is a therapeutic strategy for fructose-associated liver inflammation and lipid deposition.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cell Line; Drugs, Chinese Herbal; Fructose; Glucosides; Inflammation; Kelch-Like ECH-Associated Protein 1; Lipids; Liver; Male; MicroRNAs; NF-E2-Related Factor 2; Oxidative Stress; Rats, Sprague-Dawley; Signal Transduction; Stilbenes

Topics: Cell Line; Cell Survival; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; DNA Methyltransferase 3B; Epigenomics; Glucose Oxidase; Humans; Inflammation; Lipopolysaccharides; Long Interspersed Nucleotide Elements; Methylation; Oxidative Stress; Resveratrol; Sirtuin 1; Stilbenes

Resveratrol (RES) is a natural anti-inflammatory and antioxidant compound with poor water solubility and oral bioavailability. The present study takes the advantages of nanocarriers combined with a ligand (galactose) anchoring to orally deliver RES in an attempt to improve its bioavailability and pharmacological activity.. RES-loaded galactosylated nanoparticles (RES-GNPs) were prepared by solvent diffusion technique using poly(lactic-co-glycolic acid), synthesized. The resulting RES-GNPs were 108.4 nm around in particle size with a polydispersity index of 0.217. Furthermore, RES-GNPs possessed a high EE and a slow drug release in water. After oral administration, RES-GNPs significantly enhanced the oral bioavailability of RES, up to 335.7% relative to RES suspensions. In situ single-pass intestinal perfusion and cellular uptake experiments showed that GNPs could improve the intestinal permeability and transcellular transport of RES. Moreover, the anti-inflammatory efficacy of RES-GNPs in RAW 264.7 cells model was superior to free RES and RES-GNPs.. The results indicate that RES-GNPs can effectively promote the intestinal absorption of RES and strengthen its bioactivity, which may be a promising system for the treatment of inflammatory diseases.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Biological Availability; Caco-2 Cells; Drug Liberation; Endocytosis; Galactosamine; Humans; Inflammation; Intestinal Absorption; Intestinal Mucosa; Lactic Acid; Male; Nanoparticles; Particle Size; Permeability; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Proton Magnetic Resonance Spectroscopy; Rats, Sprague-Dawley; Resveratrol; Solubility; Stilbenes

The maladaptive response of aged microglia to surgery and consequent neuroinflammation plays a key pathogenic role in postoperative cognitive dysfunction (POCD). Here, we assessed the preventive effect of resveratrol (RESV) for POCD in aged rats. The emulsified form of RESV (e-RESV) was selected to improve its oral and brain bioavailability. Animals were assigned to one of four groups: e-RESV (80 mg/kg) versus vehicle treatment by abdominal surgery versus isoflurane anesthesia alone (n = 8 in each group). The dose-dependent effects of e-RESV were also assessed in dose range of 0-60 mg/kg. Either vehicle or e-RESV was administered intragastrically 24 h before surgery. Seven days after procedure, cognitive function was evaluated using a novel object recognition test, followed by measurement of hippocampal pro-inflammatory cytokine levels. Our results showed that pre-treatment with e-RESV attenuated the surgery-induced cognitive impairment and related hippocampal neuroinflammation at 40 mg/kg or higher doses. Additionally, the ex-vivo experiments revealed that the preemptive e-RESV regimen reduced the hippocampal microglial immune reactivity to lipopolysaccharide. Furthermore, e-RESV induced neuroprotective benefits were inhibited by the concomitant administration of sirtinol, a specific SIRT1 inhibitor. Our findings imply the preventive potential of e-RESV for POCD via the SIRT1 signaling pathway.

Topics: Administration, Oral; Aging; Animals; Biological Availability; Cognitive Dysfunction; Cytokines; Dose-Response Relationship, Drug; Emulsions; Hippocampus; Inflammation; Inflammation Mediators; Male; Microglia; Postoperative Complications; Rats, Wistar; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes

Heme oxygenase-1 (HO-1) can exert anti-inflammatory and antioxidant effects. Acute lung injury (ALI) is associated with increased inflammation and influx of proinflammatory cells and mediators in the airspaces and lung parenchyma. In this study, we demonstrate that pterostilbene 4'-

Topics: Acute Lung Injury; Animals; Antioxidants; Disease Models, Animal; Enzyme Induction; Epithelial Cells; Glucosides; Heme Oxygenase-1; Humans; Inflammation; Lipopolysaccharides; Lung; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Pseudomonas aeruginosa; RAW 264.7 Cells; RNA, Messenger; Stilbenes; Up-Regulation

Asthma is an inflammatory disease caused by an imbalance of Th1 and Th2 cells. In general, asthma is characterized by a stronger Th2 response. Most conventional asthma treatment focuses on improving airway flow or suppression of airway inflammation. To reduce the side effects of currently used asthma medicines, we have conducted studies on natural products that have no side effects. 2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucoside (TSG), the main compound of

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Count; Cytokines; Disease Models, Animal; Female; Glucosides; Immunoglobulin Class Switching; Inflammation; Inflammation Mediators; Lung; Mice, Inbred C57BL; Ovalbumin; Protective Agents; Respiratory Hypersensitivity; Stilbenes; Th1 Cells; Th2 Cells

Resveratrol (RSV) is a natural compound exhibiting anti-inflammatory effect, but the anti-inflammatory mechanism has not been fully understood. This study is aimed to evaluate the anti-inflammatory activity and mechanism of RSV in lipopolysaccharides-induced rats' model. The visceral wet/dry weight ratios and the changes of hematologic and biochemical indices indicated that LPS- stimulation mainly caused damages to liver and lung, while pretreatment with RSV could alleviate the lesions. The cytokine assays showed that RSV could markedly decrease the production of proinflammatory mediators and cytokines (IL-1, IL-1β, IL-6, NO, iNOS and COX-2), and increase the expression of anti-inflammatory mediator (IL-10). RSV could inhibit TLR4 signaling pathway by down-regulating the mRNA levels of MyD88 and TRAF6, and suppressing the TLR4 protein. RSV could inhibit the signaling cascades of NF-κBp65 and MAPKs through down-regulating the mRNA levels of IκBα, p38MAPK, JNK, ERK1, ERK2 and ERK5 in liver and lung, and suppressing the dynamic changes of proteins and phosphorylated proteins including IκBα, NF-κBp65, p38MAPK, JNK, ERK1/2 and ERK5 from tissue's cytoplasm to nucleus. In conclusion, RSV possessed a therapeutic effect on LPS-induced inflammation in rats and the mechanism mainly attributed to suppressing the signaling cascades of NF-κBp65 and MAPKs by inhibiting the TLR4 signaling pathway.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Female; Inflammation; Lipopolysaccharides; Liver; Male; Mitogen-Activated Protein Kinases; Models, Biological; Pulmonary Edema; Rats; Resveratrol; Signal Transduction; Stilbenes; Toll-Like Receptor 4; Transcription Factor RelA

Resveratrol, an edible polyphenolic phytoalexin, improves endothelial dysfunction and attenuates inflammation. However, the mechanisms have not been thoroughly elucidated. Therefore, we investigated the molecular basis of the effects of resveratrol on TNF-α-induced ICAM-1 expression in HUVECs. The resveratrol treatment significantly attenuated the TNF-α-induced ICAM-1 expression. The inhibition of p38 phosphorylation mediated the reduction in ICAM-1 expression caused by resveratrol. Resveratrol also decreased TNF-α-induced IκB phosphorylation and the phosphorylation, acetylation, and translocation of NF-κB p65. Moreover, resveratrol induced the AMPK phosphorylation and the SIRT1 expression in TNF-α-treated HUVECs. Furthermore, TNF-α significantly suppressed miR-221/-222 expression, which was reversed by resveratrol. miR-221/-222 overexpression decreased p38/NF-κB and ICAM-1 expression, which resulted in reduced monocyte adhesion to TNF-α-treated ECs. In a mouse model of acute TNF-α-induced inflammation, resveratrol effectively attenuated ICAM-1 expression in the aortic ECs of TNF-α-treated wild-type mice. These beneficial effects of resveratrol were lost in miR-221/222 knockout mice. Our data showed that resveratrol counteracted the TNF-α-mediated reduction in miR-221/222 expression and decreased the TNF-α-induced activation of p38 MAPK and NF-κB, thereby suppressing ICAM-1 expression and monocyte adhesion. Collectively, our results show that resveratrol attenuates endothelial inflammation by reducing ICAM-1 expression and that the protective effect was mediated partly through the miR-221/222/AMPK/p38/NF-κB pathway.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Cell Adhesion; Disease Models, Animal; Gene Expression Regulation; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Monocytes; p38 Mitogen-Activated Protein Kinases; Peritonitis; Primary Cell Culture; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Chronic obstructive pulmonary disease (COPD) is a corticosteroid-resistant airway inflammatory condition. Resveratrol exhibits anti-inflammatory activities in COPD but has weak potency and poor pharmacokinetics. This study aimed to evaluate the potential of isorhapontigenin, another dietary polyphenol, as a novel anti-inflammatory agent for COPD by examining its effects in vitro and pharmacokinetics in vivo.. Primary human airway epithelial cells derived from healthy and COPD subjects, and A549 epithelial cells were incubated with isorhapontigenin or resveratrol and stimulated with IL-1β in the presence or absence of cigarette smoke extract. Effects of isorhapontigenin and resveratrol on the release of IL-6 and chemokine (C-X-C motif) ligand 8 (CXCL8), and the activation of NF-κB, activator protein-1 (AP-1), MAPKs and PI3K/Akt/FoxO3A pathways were determined and compared with those of dexamethasone. The pharmacokinetic profiles of isorhapontigenin, after i.v. or oral administration, were assessed in Sprague-Dawley rats.. Isorhapontigenin, an orally bioavailable dietary polyphenol, displayed superior anti-inflammatory effects compared with resveratrol. Furthermore, it suppressed the PI3K/Akt pathway that is insensitive to corticosteroids. These favourable efficacy and pharmacokinetic properties support its further development as a novel anti-inflammatory agent for COPD.

Topics: Administration, Oral; Adrenal Cortex Hormones; Aged; Animals; Anti-Inflammatory Agents; Biological Availability; Cell Survival; Dose-Response Relationship, Drug; Epithelial Cells; Female; Humans; Inflammation; Injections, Intravenous; Male; Molecular Structure; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Respiratory System; Resveratrol; Stilbenes; Structure-Activity Relationship; Tumor Cells, Cultured

In recent years, there has been a dramatic increase in the number and variety of electronic devices that emit electromagnetic waves. Because people live and work in close proximity to these pieces of electrical equipment, there is growing concern surrounding the destruction of homeostasis by electromagnetic field exposure. In the present study, the effects of 60 Hz 0.8 mT extremely low-frequency electromagnetic fields (ELF-EMF) on a macrophage cell line (RAW 264.7) were examined. Under defined ELF-EMF exposure conditions, the production of nitric oxide and pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6, were increased in RAW 264.7 cells and the expression of those genes was also upregulated. However, cell proliferation was not altered. Translocation of NF-κB (nuclear factor kappa B), molecules that act downstream of the pro-inflammatory cytokines, were increased to the nucleus under ELF-EMF exposure conditions. In addition, we found that ELF-EMF exposure elevated activation of nuclear factor of activated T cells (NFAT) 2, as well as positively affected the influx of calcium. Furthermore, with both the presence of a potent antioxidant (Resveratrol) and downregulation of the antioxidant-related gene Prx-1 (Peroxiredoxin-1), ELF-EMF was associated with higher inflammatory responses of macrophages. These results suggest that an ELF-EMF amplifies inflammatory responses through enhanced macrophage activation and can decrease the effectiveness of antioxidants. Bioelectromagnetics. 38:374-385, 2017. © 2017 Wiley Periodicals, Inc.

Topics: Animals; Antioxidants; Cytokines; Down-Regulation; Electromagnetic Fields; Gene Knockdown Techniques; Homeodomain Proteins; Homeostasis; Inflammation; Mice; NF-kappa B; NFATC Transcription Factors; RAW 264.7 Cells; Resveratrol; Signal Transduction; Stilbenes

Resveratrol is a natural polyphenol extracted from mangy plants. It has been reported that resveratrol show multitudinous positive role in biology such as anti-oxidant, anti-nociception and anti-inflammatory effects. Therefore, the present study devotes to test the effect of resveratrol on LPS-induced mastitis in mice. Resveratrol was administered intraperitoneally 1 h before LPS treatment. And the anti-inflammatory effect of resveratrol was measured by histopathological examination, MPO assay, real-time PCR and western blotting analysis. The results showed that resveratrol significantly reduced the LPS-induced mammary histopathological changes. Meanwhile, it sharply attenuated the activity of MPO. The result also indicated that the resveratrol can decrease the expression of pro-inflammatory cytokines TNF-α and IL-1β. From the results of western blotting, resveratrol suppressed the expression of phosphorylation of p65 and IκB from NF-κB signal pathway and phosphorylation of p38 and ERK from MAPK signal pathway. These findings suggested that resveratrol may inhibit the inflammatory response in the mastitis.

Topics: Animals; Anti-Inflammatory Agents; Blotting, Western; Cytokines; Disease Models, Animal; Female; Inflammation; Interleukin-1beta; Lipopolysaccharides; Mammary Glands, Animal; MAP Kinase Signaling System; Mastitis; Mice; Mice, Inbred BALB C; NF-kappa B; Peroxidase; Phosphorylation; Real-Time Polymerase Chain Reaction; Resveratrol; Signal Transduction; Stilbenes; Tumor Necrosis Factor-alpha

Pterostilbene has been reported as a potential drug to inhibit oxidative stress and inflammation. However, the effect of pterostilbene on chondrocytes and osteoarthritis remains to be elucidated. We sought to investigate whether pterostilbene could protect chondrocytes from inflammation and ROS production through factor erythroid 2-related factor 2 (Nrf2) activation. The pterostilbene toxicity on chondrocytes collected from cartilages of Sprague-Dawley rats was assessed by CCK-8 test. Immunofluorescence and Western blotting explored the nuclear translocation of Nrf2. Nrf2 expression was silenced by siRNA to evaluate the involvement of Nrf2 in the effect of pterostilbene on chondrocytes. Finally, osteoarthritis model was established by the transection of anterior cruciate ligament and partial medial meniscectomy in rats, and then these rats received pterostilbene 30 mg/kg, daily, p.o. for 8 weeks. Histology and immunohistochemistry were used to assess histopathological change and Nrf2 expression in cartilage. Nuclear translocation of Nrf2 was stimulated by pterostilbene without cellular toxicity. Pterostilbene inhibited the level of COX-2, iNOS, PGE2, and NO, as well as the mitochondrial and total intracellular ROS production induced by IL-1β in chondrocytes, partially reversed by the Nrf2 silencing. Pterostilbene prevented cartilage degeneration and promoted the nuclear translocation of Nrf2 in cartilage. These results suggest that pterostilbene could inhibit the IL-1β-induced inflammation and ROS production in chondrocytes by stimulating the nuclear translocation of Nrf2.

Topics: Animals; Cartilage; Cell Survival; Cells, Cultured; Chondrocytes; Cyclooxygenase 2; Immunohistochemistry; Inflammation; Interleukin-1beta; Male; NF-E2-Related Factor 2; Nitric Oxide Synthase Type II; Nitrites; Osteoarthritis; Protein Transport; Rats; Reactive Oxygen Species; RNA, Small Interfering; Signal Transduction; Stilbenes

Resveratrol and curcumin, as natural flavones products, have good therapeutic effect in acute and chronic inflammation; on the other hand, tetramethylpyrazine (TMP) has angiogenesis and vessel protection effect as well as anti-inflammatory function. In this paper, the anti-inflammatory effect of the tetramethylpyrazine, resveratrol and curcumin (TRC) combination in acute and chronic inflammation was reported in vivo.. The dose of the combined three natural products was optimized based on the acute paw swelling mouse model with a Uniform Design methodology. The therapeutic effect of TRC combination on chronic inflammation was investigated by using the collagen-induced arthritis (CIA) rat model based upon the following indexes: the volume of paw swelling, arthritis score, serum mediators and histological examination as well as immunohistochemical staining. The levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) in serum were measured and the pathological sections of liver and kidney were analysed. LD. The results showed this formulation could provide a novel potent treatment for acute and chronic inflammation (RA) without side effect like gastric injury occurring in NSAIDs.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Aspartate Aminotransferases; Cartilage; Curcumin; Cytokines; Drug Combinations; Edema; Female; Inflammation; Joints; Kidney; Liver; Male; Mice; NF-kappa B; Phytotherapy; Plant Extracts; Pyrazines; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Cyclophosphamide (CyP), an efficient anticancer drug, may damage normal human cells. Resveratrol (RES), a natural polyphenol, has a diverse pharmacological properties.. To test possible protective effect of RES on multi-organ damage caused by CyP.. RES (10 mg/kg/day) was administered orally for 8 days. In independent rat groups, CyP toxicity was induced via a single dose of 150 mg/kg i.p. 3 days before the end of experiment, with or without RES treatment.. Compared to control, CyP caused significant increase in organ-to-body weight ratios of heart, kidney and liver, with deterioration in their functional parameters; namely serum creatine kinase, blood urea nitrogen, creatinine, alanine aminotransferase and aspartate aminotransferase. CyP also caused distortion in these organs' histology, with significant tissue oxidative stress, manifested by decrease in reduced glutathione and catalase, as well as increase in malondialdehyde and nitric oxide levels. Furthermore, CyP caused multi-organ inflammatory effects as shown by increased tumor necrosis factor-α levels, as well as up-regulation of nuclear factor-κB expressions. Using RES concurrently with CyP restored heart, kidney and liver functional parameters, as well as their normal histology. RES also reversed oxidative stress, as well as inflammatory signs caused by CyP alone.. RES may be beneficial adjuvant that confers multi-organ protection against CyP toxicity via antioxidant and anti-inflammatory mechanisms.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Antioxidants; Aspartate Aminotransferases; Blood Urea Nitrogen; Creatine Kinase; Creatinine; Cyclophosphamide; Inflammation; Male; Malondialdehyde; NF-kappa B; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha; Up-Regulation

Brown adipose tissue thermogenesis at the cost of energy is not only important for the development of obesity, but also possesses great promise in anti-obesity treatment. Uncoupling protein 1 (UCP1) expression has been reported to be under control of the intracellular deacetylase SIRT1. Here, we investigated the effect and mechanism of inflammation and sirtuin-1 (SIRT1) activation on the induction of thermogenic genes in immortalized brown adipocytes incubated with LPS or IL1β and mice with elevated inflammatory tone. In vitro stimulation of brown adipocytes with dibutyryl cyclic adenosine monophosthate (dbcAMP) reduced the expression of

Topics: Adipocytes, Brown; Animals; Cell Cycle Proteins; Cell Line; Down-Regulation; Inflammation; Interleukin-1beta; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Resveratrol; Sirtuin 1; Stilbenes; Uncoupling Protein 1

Recent studies suggest an anti-inflammatory activity of oxyresveratrol, a stilbene extracted from Cortex mori root used in traditional Chinese medicine that also presents estrogen-like activity. We herein tested the hypothesis that oxyreservatrol exerts an anti-inflammatory effect through its estrogenic-like function. In MCF-7 cells, oxyresveratrol significantly induced proliferation, which was accompanied with estrogen receptor (ER)-mediated transcriptional activation, increased estrogen-targeted gene expression (e.g., pS2, PGR, and CTSD), and increased ERα/β proteins. The estrogen-like effect of oxyresveratrol was reversed by the ER inhibitor ICI 182780. Strong ER-binding activities of oxyresveratrol were revealed by negative docking scores. The LPS-induced inflammatory response (e.g., upregulated IκB-α phosphorylation, NF-κB nuclear translocation, and cytokine messenger RNA expression) was significantly suppressed in an ER-dependent manner by oxyresveratrol in RAW264.7 cells. These results suggest that oxyresveratrol may function as an ER agonist and modulate NF-κB signaling.

Topics: Animals; Anti-Inflammatory Agents; Cell Proliferation; Humans; Inflammation; Lipopolysaccharides; MCF-7 Cells; Mice; NF-kappa B; Phytoestrogens; Plant Extracts; RAW 264.7 Cells; Receptors, Estrogen; Signal Transduction; Stilbenes

Extracellular vesicles (EVs) are nanoscale membrane-formed compartments naturally secreted from cells, which are intercellular mediators regulating physiology and pathogenesis, therefore they could be a novel therapeutic carrier for targeted delivery. However, the translation of EVs is hindered by the heterogeneous composition, low yield, inefficient drug loading and unlikely scalability. Here we report a strategy to generate EVs using nitrogen cavitation (NC-EVs) that instantly disrupts neutrophils to form nanosized membrane vesicles. NC-EVs are similar to naturally secreted EVs (NS-EVs), but contain less subcellular organelles and nuclear acids. The production of NC-EVs was increased by 16 folds and is easy to scale up for clinical use compared to NS-EVs. To examine the usefulness of NC-EVs as a drug delivery platform, piceatannol (an anti-inflammation drug) was remotely loaded in NC-EVs via the pH gradient. We found that piceatannol-loaded NC-EVs dramatically alleviated acute lung inflammation/injury and sepsis induced by lipopolysaccharide (LPS). Our studies reveal that nitrogen cavitation is a novel approach to efficiently generate EVs from any cell type and could be exploited for personalized nanomedicine.

Topics: Animals; Cell-Derived Microparticles; Cells, Cultured; Extracellular Vesicles; HL-60 Cells; Humans; Inflammation; Lipopolysaccharides; Mice; Neutrophils; Sepsis; Stilbenes

Piceatannol, a bioactive component in grape and blueberry, was examined for its potential in decreasing the inflammatory activities in adipocytes using a cocultured adipocyte and macrophage system, and suppressing tumor necrosis factor-α (TNF-α)-mediated inflammation and the related insulin resistance using a 3T3-L1 adipocyte model. Piceatannol at 10 μM significantly reduced the release of inflammatory cytokines of TNF-α and monocyte chemoattractant protein-1 (MCP-1) by 19 and 31% in the cocultured system, respectively. Pretreatment with piceatannol also inhibited TNF-α-induced expression of interleukin-6 (IL-6) and MCP-1 at both mRNA and protein levels in the 3T3-L1 adipocytes. Piceatannol also partially improved the malfunction of insulin-stimulated glucose uptake, which was reduced by TNF-α in 3T3-L1 adipocytes. Furthermore, the inhibitions were mediated by significant blocking of IκBα phosphorylation and nuclear factor-κB (NF-κB) activation through suppressing nuclear translocation of NF-κB p65 along with c-Jun N-terminal kinase (JNK)-mitogen activated protein kinase (MAPK) activation. In addition, the Akt-dependent forkhead box O1 (FoxO1) signaling pathway was involved in the restoration of insulin-stimulated glucose uptake through suppressing the down-regulation of phosphorylation of Akt and FoxO1 expressions. These results suggested the potential of piceatannol in improving chronic inflammatory condition and insulin sensitivity in obese adipose tissues.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Chemokine CCL2; Forkhead Box Protein O1; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Mice; Phosphorylation; Plant Extracts; Stilbenes; Tumor Necrosis Factor-alpha

Aseptic loosening is the most common cause of total hip arthroplasty (THA) failure, and osteolysis induced by wear particles plays a major role in aseptic loosening. Various pathways in multiple cell types contribute to the pathogenesis of osteolysis, but the role of Sirtuin 1 (SIRT1), which can regulate inflammatory responses through its deacetylation, has never been investigated. We hypothesized that the downregulation of SIRT1 in macrophages induced by metal nanoparticles was one of the reasons for osteolysis in THA failure. In this study, the expression of SIRT1 was examined in macrophages stimulated with metal nanoparticles from materials used in prosthetics and in specimens from patients suffering from aseptic loosening. To address whether SIRT1 downregulation triggers these inflammatory responses, the effects of the SIRT1 activator resveratrol on the expression of inflammatory cytokines in metal nanoparticle-stimulated macrophages were tested. The results demonstrated that SIRT1 expression was significantly downregulated in metal nanoparticle-stimulated macrophages and clinical specimens of prosthesis loosening. Pharmacological activation of SIRT1 dramatically reduced the particle-induced expression of inflammatory cytokines in vitro and osteolysis in vivo. Furthermore, SIRT1 regulated particle-induced inflammatory responses through nuclear factor kappa B (NF-κB) acetylation. Thus, the results of this study suggest that SIRT1 plays a key role in metal nanoparticle-induced inflammatory responses and that targeting the SIRT1 pathway may lead to novel therapeutic approaches for the treatment of aseptic prosthesis loosening.

Topics: Acetylation; Aged, 80 and over; Animals; Arthroplasty, Replacement, Hip; Cytokines; Female; Humans; Inflammation; Macrophages; Male; Metal Nanoparticles; Mice, Inbred C57BL; Middle Aged; NF-kappa B; Osteolysis; Prostheses and Implants; Prosthesis Failure; Resveratrol; Sirtuin 1; Stilbenes

Trans-resveratrol (tRESV), a polyphenol with antioxidant properties, is common in many food sources, hence easily accessible for study as a maternal dietary supplement in perinatal asphyxia (PA). Hypoxic-ischemic encephalopathy secondary to PA affects especially vulnerable brain areas such as hippocampus and is a leading cause of neonatal morbidity. The purpose of this study is to identify new epigenetic mechanisms of brain inflammation and injury related to PA and to explore the benefit of tRESV enriched maternal diet. The hippocampal interleukin 1 beta (IL-1b), tumour necrosis factor alpha (TNFα) and S-100B protein, at 24-48h after 90min of asphyxia were assessed in postnatal day 6 rats whose mothers received either standard or tRESV enriched diet. The expression of non-coding microRNAs miR124, miR132, miR134, miR146 and miR15a as epigenetic markers of hippocampus response to PA was determined 24h post-asphyxia. Our results indicate that neural response to PA could be epigenetically controlled and that tRESV reduces asphyxia-related neuroinflammation and neural injury. Moreover, tRESV could increase, through epigenetic mechanisms, the tolerance to asphyxia, with possible impact on the neuronal maturation. Our data support the neuroprotective quality of tRESV when used as a supplement in the maternal diet on the offspring's outcome in PA.

Topics: Animals; Animals, Newborn; Asphyxia Neonatorum; Dietary Supplements; Disease Models, Animal; Epigenesis, Genetic; Female; Hippocampus; Inflammation; Neuroprotective Agents; Pregnancy; Rats; Rats, Wistar; Resveratrol; Stilbenes

Tapinarof (GSK2894512) is a naturally derived topical treatment with demonstrated efficacy for patients with psoriasis and atopic dermatitis, although the biologic target and mechanism of action had been unknown. We demonstrate that the anti-inflammatory properties of tapinarof are mediated through activation of the aryl hydrocarbon receptor (AhR). We show that tapinarof binds and activates AhR in multiple cell types, including cells of the target tissue-human skin. In addition, tapinarof moderates proinflammatory cytokine expression in stimulated peripheral blood CD4+ T cells and ex vivo human skin, and impacts barrier gene expression in primary human keratinocytes; both of these processes are likely to be downstream of AhR activation based on current evidence. That the anti-inflammatory properties of tapinarof derive from AhR agonism is conclusively demonstrated using the mouse model of imiquimod-induced psoriasiform skin lesions. Topical treatment of AhR-sufficient mice with tapinarof leads to compound-driven reductions in erythema, epidermal thickening, and tissue cytokine levels. In contrast, tapinarof has no impact on imiquimod-induced skin inflammation in AhR-deficient mice. In summary, these studies identify tapinarof as an AhR agonist and confirm that its efficacy is dependent on AhR.

Topics: Administration, Topical; Animals; Basic Helix-Loop-Helix Transcription Factors; Cells, Cultured; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Humans; Inflammation; Mice; Psoriasis; Receptors, Aryl Hydrocarbon; Resorcinols; Skin; Stilbenes

The phenolic substance resveratrol (RES) is a plant metabolite known to modulate numerous physiological functions and to exert beneficial effects as a cancer-chemopreventing agent and on neurological, hepatic, and cardiovascular systems. Since the compound affects the lifespan of yeast and flies it might be an anti-aging substance. Mechanistically, RES is involved in down regulating the inflammatory response. The pleiotropic effects of RES in cells of the immune and endothelial system were examined in this study.. RES had cell-specific and context-dependent effects, in particular on the expression of IL-1β, IL-6, CCL4/MIP-1β and CXCL10/IP-10. It enhanced cellular features that mirror increased alertness to disturbed immune homeostasis in the vascular-endothelial compartment (e.g. increased production of IL-1β or IL-6), whereas it blunted inflammatory mediators in macrophages and consequently chronic inflammation. We infer from the present in vitro study, that RES has unique properties in the regulation of inflammatory and immune responses, which are controlled in a complex hierarchical and temporal order.

Topics: Animals; Chemokines; Cytokines; Endothelial Cells; Humans; Inflammation; Macrophages; Mice; Monocytes; RAW 264.7 Cells; Resveratrol; Stilbenes

Impact of ROS in development of hyperalgesia has recently motivated scientists to focus on ROS as novel target of anti-hyperalgesic interventions. However, role of ROS in molecular signaling of hyperalgesia is still poorly understood. The present study is aimed to analyze the effect of dietary antioxidant resveratrol on antioxidant defense system, ROS level and TNFR1-ERK signaling pathway during early and late phase of inflammatory hyperalgesia.. Hyperalgesia was assessed by paw withdrawal latency test in complete Freund's adjuvant-induced hyperalgesic rats. Activities of antioxidant enzymes were measured by in-gel assays, ROS level was measured by DCFH. Anti-hyperalgesic effect of resveratrol was observed by paw withdrawal latency test. ROS level was increased in paw skin as well as spinal cord during early phase which was further increased in paw skin, but remained constant in spinal cord up to late phase. Resveratrol differentially regulated the activities of SOD, catalase and GPx in paw skin as well as spinal cord of hyperalgesic rats in both phases. Activities were normalized back showing anti-hyperalgesic effect of resveratrol. Upregulated ERK signaling was modulated by resveratrol, whereas TNFR1 level remained unchanged.. Overall results suggest that resveratrol alleviates inflammatory hyperalgesia by downregulation of ERK activation, modulation of ROS and differential regulation of antioxidant enzymes during early and late phases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Freund's Adjuvant; Hyperalgesia; Inflammation; MAP Kinase Signaling System; Pain Measurement; Rats; Reactive Oxygen Species; Receptors, Tumor Necrosis Factor, Type I; Resveratrol; Stilbenes

The present study focused on the therapeutic effects of resveratrol in a rat model of blunt chest trauma-induced acute lung injury and the potential role of endocan as a biomarker of inflammation. They were randomly divided into the following four groups (n = 7 in each group): control group (no treatment or trauma); trauma group (trauma-induced group); resveratrol group (resveratrol [0.3 mg/kg] administered via the i.p. route group); and resveratrol + trauma group (resveratrol [0.3 mg/kg] administered via the i.p. route 1 h prior to the induction of trauma At the end of the 24 h, all the experimental rats were sacrificed. Lung lobe and blood samples were collected for biochemical, histopathological, and immunohistochemical investigations. Serum endocan levels were found to be significantly higher in the travma, resveratrol, and resveratrol + trauma groups than in the control group (p < 0.001, p < 0.001, p < 0.001). Moreover, in resveratrol + trauma group, endocan showed a significant increase compared to trauma and resveratrol group (p < 0.001, p < 0.001). Serum MDA level was significantly higher in the trauma group than in the control group (p = 0.017). SOD showed a significant increase in resveratrol and resveratrol + trauma groups compared to control group (p < 0.001, p < 0.001). The present study suggested that resveratrol exerted antioxidant properties in a rat model of lung injury after blunt chest trauma. Thus, it may have therapeutic potential in cases of blunt chest trauma-induced lung injury. Serum levels of endocan were not correlated with the inflammation response. The clinical use of endocan as a biomarker of inflammation in lung injury caused by blunt chest trauma is not recommended.

Topics: Acute Lung Injury; Animals; Antioxidants; Biomarkers; Inflammation; Proteoglycans; Rats; Resveratrol; Stilbenes; Thoracic Injuries; Wounds, Nonpenetrating

Polyphenols such as apigenin, kaempferol or resveratrol are typically found in plants, including fruits, vegetables, herbs and spices, which have a wide range of biological functions such as antioxidative, anti-inflammatory, vasodilative, anticoagulative and proapoptotic. Discovering such multifunctional compounds in widely consumed plant-based products - ones that both inhibit the release of TNF-α from tissue macrophages and at the same time enhance the secretion of IL-10 - would be an important signpost in the quest for effective pharmacological treatment of numerous diseases that have an inflammatory etiology. The aim of the study is to investigate the impact of biologically active polyphenols such as apigenin, resveratrol and kaempferol on gene expression and protein secretion of IL-10 and TNF-α in line RAW-264.7. Cells were cultured under standard conditions. IL-10 and TNF-α genes expression were examined using QRT-PCR and to assess cytokines concentration ELISA have been used. Apigenin, kaempferol and resveratrol at a dose 30μM significantly decrease the TNF-α expression and secretion. Apigenin decrease the IL-10 expression and secretion. Furthermore, increase in IL-10 secretion after administration of kaempferol and resveratrol were observed. In the process of administration of tested compounds before LPS, which activate macrophages, decrease of TNF-α secretion after apigenin and kaempferol and increase of IL-10 secretion after resveratrol were observed. The results of present work indicate that 1) apigenin, resveratrol and kaempferol may reduce the intensity of inflammatory processes by inhibiting the secretion of proinflammatory cytokine TNF-α, and resveratrol and kaempferol additionally by increasing the secretion of anti-inflammatory cytokine IL-10 2) the studies indicate the potentially beneficial - anti-inflammatory - impact of diet rich in products including apigenin, resveratrol and kaempferol.

Topics: Animals; Anti-Inflammatory Agents; Apigenin; Cell Line; Cytokines; Gene Expression; Inflammation; Interleukin-10; Kaempferols; Lipopolysaccharides; Macrophages; Mice; RAW 264.7 Cells; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

Topics: Animals; Inflammation; Male; Mustard Plant; Plant Oils; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Resveratrol; Stilbenes; Trigeminal Nucleus, Spinal

Is resveratrol able to prevent the lipopolysaccharide (LPS)-induced preterm labor in 15-day pregnant BALB/c mice?. Resveratrol prevented the LPS-induced onset of preterm labor in 64% of the cases and showed anti-inflammatory and tocolytic effects by downregulating COX-2 and iNOS expression and NOS activity, and by changing the uterine prostaglandin and endocannabinoid profiling.. Genital tract infections by Gram-negative bacteria are a common complication in human pregnancy and have been shown to increase risk of preterm delivery. Bacterial LPS elicits a strong maternal inflammatory response that results in preterm delivery and fetal death in a murine model endotoxin-induced preterm labor.. An in vivo animal study was conducted. On Day 15 of pregnancy, mice received at 8:00 h a dose of vehicle (40% ethanol in saline solution) or resveratrol (3 mg/kg in vehicle) via oral gavage followed by two doses of LPS or vehicle administered intraperitoneally (i.p.), the first one at 10:00 h (0.17 mg/kg in 0.1 ml of sterile saline solution) and the second at 13:00 h (0.5 mg/kg in 0.1 ml of sterile saline solution). The mice were closely observed for any signs of morbidity (piloerection, decreased movement, and diarrhea), vaginal bleeding or preterm delivery. The beginning of preterm delivery was defined by early delivery of the first pup. Normal term labor occurs on Day 19 of gestation.. Time of labor, pregnancy outcome and morphological features were evaluated after LPS and/or resveratrol administration. Uterine stripes were collected 5 h after the last LPS injection and prostaglandin and endocannabinoid profiling was analyzed by mass spectrometry. Nitric oxide synthase (NOS) activity was measured by radioconversion assay. Cyclooxygenase-2 (Cox-2) and 15-hydroxyprostaglandin dehydrogenase (15-Pgdh) mRNA levels were analyzed by RT-PCR whilst the protein expression of inducible nitric oxide synthase (iNOS), COX-1 and COX-2 were studied by western blot.. In vivo treatment of 15-day pregnant BALB/c mice with resveratrol prevented the LPS-induced preterm birth in 64% of the cases, whereas only 15% of mice with LPS alone escaped preterm birth. Treatment with resveratrol resulted in a reduced NOS activity (P < 0.05) in the uterus of LPS-treated mice. Similarly, resveratrol reduced the expression of LPS-induced pro-inflammatory agents such as iNOS (P < 0.05), COX-2 (P < 0.05), prostaglandin E2 (PGE2) (P < 0.05) and anandamide (AEA) (P < 0.05). Moreover, resveratrol administration resulted in changes in the uterine endocannabinoid profiling altered by LPS.. N/A.. Since our experimental design involves the use of mice, the extrapolation of the results presented here to humans is limited.. Our findings provide evidence for the tocolytic effects of resveratrol.. Dr Ana María Franchi was funded by Agencia Nacional para la Promoción Científica y Tecnológica (PICT 2013/0097) and by Consejo Nacional de Investigaciones Científicas y Técnicas (PIP 2012/0061). Dr Heather B. Bradshaw was funded by NIH (DA006668). The authors have no competing interests.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Endocannabinoids; Female; Inflammation; Lipopolysaccharides; Mice, Inbred BALB C; Obstetric Labor, Premature; Pregnancy; Prostaglandins; Protective Agents; Resveratrol; Stilbenes; Uterus

Tetrahydroxy stilbene glucoside (TSG) is one of the main active ingredients of Polygonum multiflorum and performs various types of biological activity, particularly anti‑inflammatory and anti‑oxidative activities. However, the beneficial effect of TSG in H2O2‑induced human brain microvascular endothelial cell (HBMEC) dysfunction has not been fully elucidated. In the present study, H2O2‑induced oxidative stress and inflammatory responses, and the pharmacological effect of TSG were investigated. The results demonstrated that H2O2 appeared to exert a cytotoxic effect on HBMECs, as the cell viability was significantly inhibited in H2O2‑treated HBMECs. Conversely, TSG did not exert a toxic effect on HBMECs, and TSG inhibited H2O2‑induced HBMEC cytotoxicity in a dose‑dependent manner. Furthermore, the findings indicated that TSG restricted the oxidative stress caused by H2O2 via inhibition of malondialdehyde and reactive oxygen species, and upregulation of superoxide dismutase and glutathione. H2O2‑induced injury was associated with enhancing the levels of inflammatory cytokines, tumor necrosis factor‑α, interleukin (IL)‑6 and IL‑1β in the cultured HBMECs, which were attenuated by TSG treatment. Furthermore, the findings demonstrated that TSG inhibited necrosis factor‑κB protein expression levels, which, as an upstream transcription factor, may regulate inflammatory responses. Thus, TSG protected HBMECs from H2O2‑induced dysfunction by inhibiting oxidative stress and inflammatory responses.

Topics: Brain; Cell Proliferation; Cell Survival; DNA Damage; Endothelial Cells; Glucosides; Humans; Hydrogen Peroxide; Inflammation; Oxidative Stress; Reactive Oxygen Species; Stilbenes

Oxidative stress and inflammation are hypothesized to contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Resveratrol (trans-3,5,4'-trihydroxystilbene) is known for its antioxidant and anti-inflammatory properties. The study aimed to investigate the effects of resveratrol in a rat model with COPD on the regulation of oxidative stress and inflammation via the activation of Sirtuin1 (SIRTl) and proliferator-activated receptor-γ coactivator-1α (PGC-1α). Thirty Wistar rats were randomly divided into three groups: control group, COPD group and resveratrol intervention group. The COPD model was established by instilling with lipopolysaccharide (LPS) and challenging with cigarette smoke (CS). The levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) in serum were measured. The levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured. The expression levels of SIRT1 and PGC-1α in the lung tissues were examined by immunohistochemistry as well as real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) and western blotting analysis. After the treatment with resveratrol (50 mg/kg), compared with the COPD group, alleviation of inflammation and reconstruction in the small airways of the lungs were seen. Resveratrol might be correlated not only with the lower level of MDA and the higher activity of SOD, but also with the upregulation of SIRT1 and PGC-1α expression. Resveratrol treatment decreased serum levels of IL-6 and IL-8. Our findings indicate that resveratrol had a therapeutic effect in our rat COPD model, which is related to the inhibition of oxidative stress and inflammatory response. The mechanism may be related to the activation and upgrading of the SIRT1/PGC-1α signaling pathways. Thus resveratrol might be a therapeutic modality in COPD.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Gene Expression Regulation; Inflammation; Interleukin-6; Interleukin-8; Lipopolysaccharides; Lung; Malondialdehyde; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pulmonary Disease, Chronic Obstructive; Rats; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Superoxide Dismutase

Topics: Down-Regulation; Humans; Inflammation; Oryza; Reactive Oxygen Species; Resveratrol; Skin Aging; Stilbenes; Ultraviolet Rays

Polydatin(PD) shows anti-allergic inflammatory effect, and this study investigated its underlying mechanisms in in vitro and in vivo models. IgE-mediated passive cutaneous anaphylaxis (PCA) and passive systemic anaphylaxis (PSA) models were used to confirm PD effect in vivo. Various signaling pathway proteins in mast cell were examined. RT-PCR, ELISA and western blotting were applied when appropriate. Activity of Lyn and Fyn kinases in vitro was measured using the Kinase Enzyme System. PD dose-dependently reduced the pigmentation of Evans blue in the PCA model and decreased the concentration of serum histamine in PSA model, and attenuated the degranulation of mast cells without generating cytotoxicity. PD decreased pro-inflammatory cytokine expression (TNF-α, IL-4, IL-1β, and IL-8). PD directly inhibited activity of Lyn and Syk kinases and down-regulated downstream signaling pathway including MAPK, PI3K/AKT and NF-kB. In addition, PD also targets Nrf2/HO-1 pathway to inhibit mast cell-derived allergic inflammatory reactions. In conclusion, the study demonstrates that PD is a possible therapeutic candidate for allergic inflammatory diseases. It directly inhibited activity of Lyn and Syk kinases and down-regulates the signaling pathway of MAPK, PI3K/AKT and NF-κB, and up-regulates the signaling pathway of Nrf2/HO-1 to inhibit the degranulation of mast cells.

Topics: Anaphylaxis; Animals; Cell Degranulation; Cytokines; Dermatitis, Atopic; Extracellular Signal-Regulated MAP Kinases; Glucosides; Heme Oxygenase-1; Inflammation; Male; MAP Kinase Signaling System; Mast Cells; Membrane Proteins; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Stilbenes

Growing evidence suggests that inflammatory processes may be involved in depressive disorders. Inflammation is known to induce mitochondrial dysfunction in the nervous system. However, whether mitochondrial dysfunction is involved in the occurrence of inflammation-induced depressive-like behavior remains to be investigated. The present study aims to firstly, clarify whether mitochondrial dysfunction contributes to lipopolysaccharide (LPS)-induced depression-like behavior in mice and secondly, determine whether the anti-oxidant resveratrol alleviates inflammation-induced depressive-like behavior through the prevention of mitochondrial dysfunction in the hippocampus. We found that the administration of LPS led to mitochondrial oxidative stress and dysfunction as evidenced by increased mitochondrial superoxide production and decreased mitochondrial membrane potential and ATP production in the hippocampus. These effects were attenuated by intracerebroventricular (ICV) Injection of the mitochondria-targeted antioxidant Mito-TEMPO. LPS-treated mice displayed depressive-like behaviors as evidenced by reduced sucrose preference, increased immobility time and decreased struggling time in the forced swimming test. Both Mito-TEMPO and resveratrol could significantly improve the LPS-induced depressive-like behaviors. In contrast, ICV Injection of rotenone, the mitochondrial respiratory chain inhibitor, induced mitochondrial oxidative stress and dysfunction in the hippocampus, and resulted in depressive-like behaviors. Moreover, resveratrol alleviated the LPS-induced apoptosis of hippocampal cells. The antidepressant action of resveratrol was accomplished through the interruption of mitochondrial oxidative stress and the prevention of cell apoptosis in the hippocampus. These findings support the potential for resveratrol as a possible pharmacological agent for depression treatment in the future.

Topics: Animals; Antidepressive Agents; Antioxidants; Apoptosis; Cyclic N-Oxides; Depression; Disease Models, Animal; Food Preferences; Hippocampus; Inflammation; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred ICR; Mitochondria; Resveratrol; Rotenone; Stilbenes; Swimming; Uncoupling Agents

While Lymphotoxin α (TNF-β), a product of lymphocytes, is known to play a pivotal role in inflammatory joint environment, resveratrol has been shown to possess anti-inflammatory and chondroprotective effects via activation of the histondeacetylase Sirt1. Whether TNF-β induction of inflammatory pathways in primary human chondrocytes (PCH) can be modulated by resveratrol, was investigated. Monolayer and alginate cultures of PCH were treated with TNF-β, anti-TNF-β, nicotinamide (NAM), antisense oligonucleotides against Sirt1 (Sirt1-ASO) and/or resveratrol and co-cultured with T-lymphocytes. We found that resveratrol suppressed, similar to anti-TNF-β, TNF-β-induced increased adhesiveness in an inflammatory microenvironment of T-lymphocytes and PCH. In contrast, knockdown of Sirt1 by mRNA abolished the inhibitory effects of resveratrol on the TNF-β-induced adhesiveness, suggesting the essential role of this enzyme for resveratrol-mediated anti-inflammatory signaling. Similar results were obtained in PCH stimulated with TNF-α. Sirt1-ASO, NAM or TNF-β, similar to T-lymphocytes induced inflammatory microenvironment by down-regulation of cartilage-specific proteins, Sox9, Ki67 and enhanced NF-κB-regulated gene products involved in inflammatory and degradative processes in cartilage (MMP-9/-13, COX-2, caspase-3), NF-κB activation and its translocation to the nucleus. Moreover, resveratrol reversed the TNF-β-, NAM-, T-lymphocytes-induced up-regulation of various NF-κB-regulated gene products. Down-regulation of Sirt1 by mRNA interference abrogated the effect of resveratrol on TNF-β-induced effects. Ultrastructural and cell viability assay investigations revealed that resveratrol revoked TNF-β-induced dose-dependent degradative/apoptotic morphological changes, cell viability and proliferation in PCH. Taken together, suppression of TNF-β-induced inflammatory microenvironment in PCH by resveratrol/Sirt1 might be a novel therapeutic approach for targeting inflammation during rheumatoid arthritis.

Topics: Apoptosis; Cartilage, Articular; Cells, Cultured; Chondrocytes; Down-Regulation; Gene Knockdown Techniques; Humans; Inflammation; Lymphotoxin-alpha; NF-kappa B; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Tumor Necrosis Factor-alpha; Up-Regulation

To explore the effect of high glucose-based peritoneal dialysis fluids on NLRP3-IL-1β in human peritoneal mesothelial cells.. HMrSV5 cells (SV40 immortalized human peritoneal mesothelial cell line) were grown in type I collagen-coated dishes in DMEM/F12 containing 10% fetal calf serum (FCS). All experiments on HMrSV5 cells were performed between passages 5 and 10. The cells were divided into 7 groups: control, 1.5% dextrose, 2.5% dextrose, 4.25% dextrose, rotenone, thenoyltrifluoroacetone (TTFA), and antimycin A. Immunoblotting was used to evaluate the expression of IL-1β. Small interfering RNA (siRNA) targeting NLRP3 was used to downregulate the expression of NLRP3 and Western blot was used to evaluate the expression of IL-1β in human peritoneal mesothelial cells exposed to 4.25% dextrose. In the meanwhile, resveratrol (RSV) was used to induce autophagy, 3-methyladenine (3-MA) and siRNA against Beclin 1 or ATG5 were used to block auto-phagy, flow cytometric was used to analyze the respiring (mitotracker deep red), total (mitotracker green) and reactive oxygen species (ROS)-generating mitochondria (mitoSOX); Western blot was used to evaluate the expression of IL-1β.. The IL-1β relative expressions were 0, 0.175±0.082, 0.418±0.163, 2.357±0.288, 2.642±0.358, 3.271±0.462, and 0.123±0.091, indicating that the cells exposed to high glucose-based peritoneal dialysis fluids and cells treated with mitochondria respiratory chain key enzyme complex I, and complex III inhibitors increased the IL-1β expression. And we found that NLRP3 knock-down significantly blocked the upregulation of IL-1β. In addition, the fluorescence intensity of total mitochondria and ROS-generating mitochondria in the following groups: control, negative control, RSV, 3-MA, ATG5 siRNA, Beclin1 siRNA were 1.76±0.42, 1.83±0.55, 1.85±0.62, 7.36±0.92, 5.35±0.77, 5.06±0.62 and 821.68±95.12, 868.15±102.82, 723.39±92.56, 1 660.08±113.65, 1 433.01±107.24, 1 562.36±112.88 respectively. The increased concentrations of mitochondrial ROS and IL-1β upregulation were confirmed in the inhibition but not the induction of auto-phagy. We also found that downregulation of ATG5 and Beclin1 sensitized cells for the release of IL-1β induced by MSU (monosodium urate) or nigericin which was the NLRP3 inflammasome activator. RSV treatment attentuated this effect.. Long-term application of high glucose-based peritoneal dialysis fluids can trigger the consistent activation of NLRP3-IL-1β in peritoneal mesothelial cells. Timely initiation of autophagy may block the NLRP3-IL-1β activation and provide a basis for the further development of a potential therapeutic strategy for delay of chronic inflammation and peritoneal fibrosis associated with peritoneal dialysis.

Topics: Autophagy; Blotting, Western; Carrier Proteins; Cell Line; Dialysis Solutions; Glucose; Humans; Inflammasomes; Inflammation; Interleukin-1beta; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Peritoneal Dialysis; Peritoneum; Reactive Oxygen Species; Resveratrol; Stilbenes

The DNAX adaptor protein 12 (DAP12) is a transmembrane adaptor molecule that signals through the activation of Syk (Spleen Tyrosine Kinase) in myeloid cells. The purpose of this study is to investigate the role of DAP12 and Syk pathways in inflammatory bowel diseases (IBDs).. DAP12 deficient and DAP12 transgenic, overexpressing an increased amount of DAP12, mice and Syk deficient mice in the C57/BL6 background were used for these studies. Colitis was induced by administering mice with dextran sulfate sodium (DSS), in drinking water, or 2,4,6-trinitrobenzene sulfonic acid (TNBS), by intrarectal enema.. Abundant expression of DAP12 and Syk was detected in colon samples obtained from Crohn's disease patients with expression restricted to immune cells infiltrating the colonic wall. In rodents development of DSS colitis as measured by assessing severity of wasting diseases, global colitis score,and macroscopic and histology scores was robustly attenuated in DAP12-/- and Syk-/- mice. In contrast, DAP12 overexpression resulted in a striking exacerbation of colon damage caused by DSS. Induction of colon expression of proinflammatory cytokines and chemokines in response to DSS administration was attenuated in DAP12-/- and Syk-/- mice, whereas opposite results were observed in DAP12 transgenic mice. Treating wild-type mice with a DAP-12 inhibitor or a Syk inhibitor caused a robust attenuation of colitis induced by DSS and TNBS.. DAP12 and Syk are essential mediators in inflammation-driven immune dysfunction in murine colitides. Because DAP12 and Syk expression is upregulated in patients with active disease, present findings suggest a beneficial role for DAP12 and Syk inhibitors in IBD.

Topics: Adaptor Proteins, Signal Transducing; Adult; Animals; Antipruritics; Colitis; Cytokines; Disease Models, Animal; Female; Humans; Inflammation; Inflammatory Bowel Diseases; Intestinal Diseases; Ketotifen; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Stilbenes; Syk Kinase

Multiple sclerosis (MS) is a demyelinating neurodegenerative disease, representing a major cause of neurological disability in young adults. Resveratrol is a stilbenoid polyphenol, known to pass blood brain barrier and exhibit antioxidant, anti-inflammatory, and neuroprotective effects in several brain injuries. Cuprizone model of MS is particularly beneficial in studying demyelination/remyelination. Our study examined the potential neuroprotective and pro-remyelination effects of resveratrol in cuprizone-intoxicated C57Bl/6 mice. Mice were fed with chow containing 0.7 % cuprizone for 7 days, followed by 3 weeks on 0.2 % cuprizone diet. Resveratrol (250 mg/kg/day, p.o.) was given for 3 weeks starting from the second week. At the end of the experiment, animals were tested on rotarod to evaluate changes in balance and motor coordination. Mice were then sacrificed to measure the brain content of glutathione, lipid peroxidation products, adenosine triphosphate, and phospho-inhibitory subunit of nuclear factor κB-α. The activities of cytochrome oxidase and superoxide dismutase were also assessed. The gene expression of myelin basic protein, 2',3'-cyclic nucleotide 3' phosphodiesterase, oligodendrocyte transcription factor-1 (Olig1), NF-κB p65 subunit, and tumor necrosis factor-α was also estimated. Luxol fast blue/periodic acid-Schiff stained brain sections were blindly scored to assess the myelin status. Resveratrol effectively enhanced motor coordination and balance, reversed cuprizone-induced demyelination, improved mitochondrial function, alleviated oxidative stress, and inhibited NF-κB signaling. Interestingly, resveratrol increased Olig1 expression that is positively correlated to active remyelination. The present study may be the first to indicate a pro-remyelinative effect for resveratrol which might represent a potential additive benefit in treating MS.

Topics: Animals; Biomarkers; Brain; Cuprizone; Disease Models, Animal; Inflammation; Male; Mice, Inbred C57BL; Mitochondria; Motor Activity; Multiple Sclerosis; Myelin Sheath; Oxidative Stress; Remyelination; Resveratrol; Stilbenes

Resveratrol-phospholipid complex (Phytosome®) (RSVP) was found better aqueous soluble and permeable than free resveratrol (RSV). RSVPs were incorporated in polymeric patch prepared by solvent casting method using Eudragit RL 100, PVP K30, and PEG 400 for application on dermal sites for sustained treating of inflammation. Prepared patches were evaluated for various physicochemical properties, surface morphology by SEM, TEM, and compatibility of patch components by FT-IR and DSC studies. Optimized formulation (F9) gave 95.79 ± 3.02% drug release and 51.36% (4.28 ± 0.48 mg/cm

Topics: Acrylic Resins; Administration, Cutaneous; Animals; Anti-Inflammatory Agents; Carrageenan; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Delivery Systems; Edema; Inflammation; Male; Permeability; Phospholipids; Polyethylene Glycols; Polymers; Rabbits; Rats; Rats, Wistar; Resveratrol; Skin; Skin Absorption; Stilbenes; Transdermal Patch

Diabetic nephropathy is one of the major microvascular complications of diabetes mellitus which ultimately gives rise to cardiovascular diseases. Prolonged hyperglycaemia and chronic renal inflammation are the two key players in the development and progression of diabetic nephropathy. Nuclear factor kB (NF-kB)-mediated inflammatory cascade is a strong contributor to the renovascular inflammation in diabetic nephropathy. Here, we studied the effects of piceatannol, a potent NF-kB inhibitor, on various oxidative stress markers and NF-kB dependent diabetic renoinflammatory cascades in rat induced by alloxan (ALX). Experimental diabetes was induced in male Wistar rats by a single intraperitoneal dose, 150 mg/kg body-weight (b.w.) of ALX. Diabetic rats were treated with Piceatannol (PCTNL) at a dose of 30 and 50 mg/kg b.w. After 14 days of oral treatment, PCTNL significantly restored blood sugar level, glomerular filtration rate, serum markers and plasma lipids. PCTNL administration also reversed the declined activity of cellular antioxidant machineries namely superoxide dismutase and glutathione and the elevated levels of malondialdehyde and nitric oxide. Moreover, piceatannol-treated groups showed marked inhibition of renal pro-inflammatory cytokines and NF-kB p65/p50 binding to DNA. Renal histopathological investigations also supported its ameliorative effects against diabetic kidney damage. Importantly, effects were more prominent at a dose of 50 mg/kg, and in terms of body-weight gain, PCTNL failed to effect significantly. However, overall findings clearly demonstrated that PCTNL provides remarkable renoprotection in diabetes by abrogating oxidative stress and NF-kB activation - and might be helpful in early stage of diabetic nephropathy.

Topics: Alloxan; Animals; Antioxidants; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Glutathione; Inflammation; Kidney; Male; Malondialdehyde; NF-kappa B; Oxidative Stress; Rats; Rats, Wistar; Stilbenes; Superoxide Dismutase

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Heart; Inflammation; Interleukin-1beta; Male; Myocardium; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Stilbenes; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Inflammation and oxidative stress (OS) are key points in age progression. Both processes impact negatively in cognition and in brain functions. Resveratrol (RV) has been postulated as a potent antioxidant natural compound, with rejuvenating properties. Inducing a metabolic stress by high-fat (HF) diet in aged C56/BL6 (24 months) led to cognitive disturbances compared with control age mated and with young mice. These changes were prevented by RV. Molecular determinations demonstrated a significant increase in some inflammatory parameters (TNF-α, Cxcl10, IL-1, IL-6, and Ccl3) in old mice, but slight changes in OS machinery. RV mainly induced the recovery of the metabolically stressed animals. The study of key markers involved in senescence and rejuvenation (mitochondrial biogenesis and Sirt1-AMPK-PGC1-α) demonstrated that RV is also able to modulate the changes in these cellular metabolic pathways. Moreover, changes of epigenetic marks (methylation and acetylation) that are depending on OS were demonstrated. On the whole, results showed the importance of integrative role of different cellular mechanisms in the deleterious effects of age in cognition and the beneficial role of RV. The work presented in this study showed a wide range of processes modified in old age and by metabolic stress, weighting the importance of each one and the role of RV as a possible strategy for fighting against.

Topics: 5-Methylcytosine; Animals; Biomarkers; Body Weight; Cognitive Dysfunction; Energy Intake; Gene Expression Regulation; Glucose Tolerance Test; Inflammation; Male; Maze Learning; Memory; Mice, Inbred C57BL; Neuroprotective Agents; Oxidative Phosphorylation; Oxidative Stress; Resveratrol; Stilbenes; Stress, Physiological

Neuronal dysfunction caused by neuroinflammation triggered by the stimulation of matrix metalloproteinases and the subsequent release of pro-inflammatory cytokines, as a result of oxidative stress and mitochondrial dysfunction, is one of the probable mechanisms involved in the pathogenesis of autism spectrum disorders (ASD). The aim of the present study was to explore the ameliorative potential of resveratrol on neuroinflammation in the experimental paradigm of neuroinflammatory model of ASD in rats.. 1M Propanoic acid (PPA) (4 μl) was infused over 10 min into the anterior portion of the lateral ventricle to induce ASD like symptoms in rats. Resveratrol (5, 10 and 15 mg/kg) was administered starting from the 2nd day of the surgery and continued upto 28th day. Rats were tested for various behavioural paradigms such as social interaction, stereotypy, locomotor activity, anxiety, novelty, depression, spatial learning, memory, repetitive and pervasive behaviour between the 7th day and 28th day. In addition, biochemical tests for oxidative stress, mitochondrial complexes, TNF-α and MMP-9 were also assessed.. Treatment with resveratrol for four weeks restored, significantly and dose dependently, all the neurological, sensory, behavioural, biochemical and molecular deficits in PPA induced autistic phenotype in rats.. The major finding of the study is that resveratrol restored the core and associated symptoms of autistic phenotype by suppressing oxidative-nitrosative stress, mitochondrial dysfunction, TNF-α and MMP-9 expression in PPA induced ASD in rats. Therefore, resveratrol might serve as an adjunct potential therapeutic agent for amelioration of neurobehavioural and biochemical deficits associated with autism spectrum disorders.

Topics: Animals; Autism Spectrum Disorder; Disease Models, Animal; Inflammation; Male; Memory; Motor Activity; Neuroprotective Agents; Oxidative Stress; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

Resveratrol has been shown to exert anti-inflammatory and anti-oxidant effects in a variety of cell types, however, its role in prevention of inflammatory responses mediated by palmitate in skeletal muscle cells remains unexplored. In the present study, we investigated the effects of resveratrol on palmitate-induced inflammation and elucidated the underlying mechanisms in skeletal muscle cells. The results showed that palmitate significantly enhanced TNF-α and IL-6 mRNA expression and protein secretion from C2C12 cells at 12, 24, and 36 h treatments. Increased expression of cytokines was accompanied by an enhanced phosphorylation of JNK, P38, ERK1/2, and IKKα/IKKβ. In addition, JNK and P38 inhibitors could significantly attenuate palmitate-induced mRNA expression of TNF-α and IL-6, respectively, whereas NF-κB inhibitor reduced the expression of both cytokines in palmitate-treated cells. Resveratrol pretreatment significantly prevented palmitate-induced TNF-α and IL-6 mRNA expression and protein secretion in C2C12 cells. Importantly, pre-treatment of the cells with resveratrol completely abrogated the phosphorylation of ERK1/2, JNK, and IKKα/IKKβ in palmitate treated cells. The protection from palmitate-induced inflammation by resveratrol was accompanied by a decrease in the generation of reactive oxygen species (ROS). N-acetyl cysteine (NAC), a known scavenger of ROS, could protect palmitate-induced expression of TNF-α and IL-6. Furthermore, inhibition of SIRT1 by shRNA or sirtinol demonstrated that the anti-inflammatory effect of resveratrol in muscle cells is mediated through a SIRT1-independent mechanism. Taken together, these findings suggest that resveratrol may represent a promising therapy for prevention of inflammation in skeletal muscle cells. J. Cell. Biochem. 118: 2654-2663, 2017. © 2017 Wiley Periodicals, Inc.

Topics: Animals; Cell Line; Inflammation; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mice; Muscle Fibers, Skeletal; Muscle Proteins; NF-kappa B; Oxidative Stress; Palmitic Acid; Resveratrol; Sirtuin 1; Stilbenes

Aging is a physiological state in which a progressive decline in organ functions is accompanied by the development of age-related diseases. Resveratrol supplementation has been shown to exert anti-inflammatory and antioxidant effects in various mammalian models of aging. Senescence-accelerated mice (SAM) are commonly used as animal models to investigate the aging process. In the present study, the effects of inflammation, oxidative stress and apoptosis in pancreas of two different types of SAM (SAMR1 or resistant to aging, and SAMP8 or prone to aging) have been analysed, as well as the effect of resveratrol administration (5mg/kg/day) on these parameters in the SAMP8 strain. mRNA expressions of sirtuin 1 and FoxO factors were found to be decreased with aging in SAMP8 mice. An increase in inflammatory status and nuclear-factor kappa B (NFκB) protein expression was also observed in old mice, together with a decrease of anti-apoptotic markers and antioxidant-enzyme activity. Resveratrol administration was able to increase sirtuin 1 mRNA expression, as well as decreasing NFκB expression and reducing the proinflammatory and prooxidant status associated with age. In conclusion, resveratrol was able to modulate the inflammatory, oxidative and apoptotic status related to aging, thereby exerting a protective effect on pancreas age-induced damage.

Topics: Aging; Animals; Antioxidants; Apoptosis; Inflammation; Male; Mice; NF-kappa B; Oxidative Stress; Pancreas; Resveratrol; RNA, Messenger; Sirtuin 1; Stilbenes

Carbon monoxide (CO) exerts protective effects on hepatic ischemia/reperfusion injury (IRI), but the underlying molecular mechanisms are not fully understood. High-mobility group box 1 (HMGB1) is an important mediator of injury and inflammation in hepatic IRI. Here, we investigated whether CO could attenuate hepatic IRI via inhibition of HMGB1 release, particularly through sirtuin 1 (SIRT1). CO was released by treatment with carbon monoxide-releasing molecule (CORM)-2. CORM-2-delivered CO ameliorated hepatic IRI, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory responses, and less severe ischemia/reperfusion-associated histopathologic changes. Treatment with CORM-2 significantly inhibited IRI-induced HMGB1 translocation and release. SIRT1 expression was increased by CORM-2 pretreatment. When CORM-2-induced SIRT1 expression was inhibited using EX527, HMGB1 translocation and release were increased and hepatic IRI was worsened, whereas SIRT1 activation by resveratrol reversed this trend. In vitro, CORM-2 reduced hypoxia/reoxygenation-induced HMGB1 translocation and release, these inhibitions were blocked by SIRT1 inhibition using EX527 or SIRT1 small interfering RNA both in alpha mouse liver 12 cells and RAW264.7 macrophages. Moreover, SIRT1 directly interacted with and deacetylated HMGB1. IRI increased HMGB1 acetylation, which was abolished by CORM-2 treatment via SIRT1. In conclusion, these results suggest that CO may increase SIRT1 expression, which may decrease HMGB1 acetylation and subsequently reduce its translocation and release, thereby protecting against hepatic IRI. Liver Transplantation 23 510-526 2017 AASLD.

Topics: Acetylation; Animals; Carbazoles; Carbon Monoxide; HMGB1 Protein; Inflammation; Liver; Liver Transplantation; Male; Mice; Organometallic Compounds; Protective Agents; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Reperfusion Injury; Resveratrol; Sirtuin 1; Stilbenes

The aim of this study was to investigate the role of resveratrol on subacute systemic inflammation-induced dysfunction of cognitive memory in mice and its underlying mechanism. Male ICR mice were trained in a water maze for four days of acquisition training and one day of probe trial. Subacute treatment with lipopolysaccharide (LPS) (1 mg/kg) by intraperitoneal injection for 5 days was used to establish a systemic inflammatory model. All mice were sacrificed after probe testing, then the expression of glial fibrillary acidic protein (GFAP), synaptophysin, and sirtuin1 (SIRT1) in hippocampi were determined using immunohistochemistry or western blot analysis. Morris water maze tests indicated that hippocampus-dependent spatial learning and memory were impaired in LPS-treated group. Resveratrol attenuated LPS-induced memory deficit in dose-dependent manner. Immunohistochemistry and western blot analysis revealed that LPS increased hippocampal GFAP expression and inhibited synaptophysin expression, which were prevented by resveratrol treatment. Treatment with LPS declined the SIRT1 protein expression in the hippocampus, which could be prevented by resveratrol. The protective effect of resveratrol could be abolished by a specific SIRT1 inhibitor. Our findings add new experimental data for potential therapeutic effects of resveratrol in the brain in a model of subacute systemic inflammation-induced astrocyte activation, synaptic alteration and cognitive decline.

Topics: Animals; Astrocytes; Blotting, Western; Glial Fibrillary Acidic Protein; Hippocampus; Hyperalgesia; Immunohistochemistry; Inflammation; Lipopolysaccharides; Male; Maze Learning; Memory Disorders; Mice, Inbred ICR; Microglia; Models, Biological; Resveratrol; Sirtuin 1; Spatial Memory; Stilbenes; Synaptophysin

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Blotting, Western; Diet, High-Fat; Enzyme-Linked Immunosorbent Assay; Inflammation; Male; Mice; Mice, Inbred C57BL; Obesity; Osteoarthritis; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stilbenes

Gestational diabetes mellitus (GDM), which complicates up to 20% of all pregnancies, is associated with low-grade maternal inflammation and peripheral insulin resistance. Sterile inflammation and infection are key mediators of this inflammation and peripheral insulin resistance. Resveratrol, a stilbene-type phytophenol, has been implicated to exert beneficial properties including potent anti-inflammatory and antidiabetic effects in non-pregnant humans and experimental animal models of GDM. However, studies showing the effects of resveratrol on inflammation and insulin resistance associated with GDM in human tissues have been limited. In this study, human placenta, adipose (omental and subcutaneous) tissue and skeletal muscle were stimulated with pro-inflammatory cytokines TNF-α and IL-1β, the bacterial product lipopolysaccharide (LPS) and the synthetic viral dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) to induce a GDM-like model. Treatment with resveratrol significantly reduced the expression and secretion of pro-inflammatory cytokines IL-6, IL-1α, IL-1β and pro-inflammatory chemokines IL-8 and MCP-1 in human placenta and omental and subcutaneous adipose tissue. Resveratrol also significantly restored the defects in the insulin signalling pathway and glucose uptake induced by TNF-α, LPS and poly(I:C). Collectively, these findings suggest that resveratrol reduces inflammation and insulin resistance induced by chemical and microbial products. Resveratrol may be a useful preventative therapeutic for pregnancies complicated by inflammation and insulin resistance, like GDM.

Topics: Adipose Tissue; Diabetes, Gestational; Female; Humans; Infant; Inflammation; Insulin; Insulin Resistance; Muscle, Skeletal; Placenta; Pregnancy; Resveratrol; Signal Transduction; Stilbenes

The aim of the study was to evaluate the vascular anti-inflammatory effects of polyphenolic extracts from two typical South Italy red wines, the specific contribution of individual polyphenols and the underlying mechanisms of action.. Human endothelial cells were incubated with increasing concentrations (1-50 μg/mL) of Primitivo and Negroamaro polyphenolic extracts (PWPE and NWPE, respectively) or pure polyphenols (1-25 μmol/L), including hydroxycinnamic acids (p-coumaric, caffeic and caftaric acids), flavonols (kaempferol, quercetin, myricetin) or stilbenes (trans-resveratrol, trans-piceid) before stimulation with lipopolysaccharide. Through multiple assays, we analyzed the endothelial-monocyte adhesion, the endothelial expression of adhesion molecules (ICAM-1, VCAM-1 and E-Selectin), monocyte chemoattractant protein-1 (MCP-1) and macrophage colony-stimulating factor (M-CSF), as well as ROS intracellular levels and the activation of NF-κB and AP-1.. Both PWPE and NWPE, already at 1 μg/mL, inhibited monocyte adhesion to stimulated endothelial cells, a key event in triggering vascular inflammation. They down-regulated the expression of adhesion molecules, ICAM-1, VCAM-1, E-Selectin, as well as MCP-1 and M-CSF, at mRNA and protein levels. All polyphenols reduced intracellular ROS, and everything, except caftaric acid, inhibited the endothelial expression of adhesion molecules and MCP-1, although with different potency. Flavonols and resveratrol significantly reduced also the endothelial expression and release of M-CSF. The decrease in endothelial inflammatory gene expression was related to the inhibition of NF-κB and AP-1 activation but not to intracellular oxidative stress.. This study showed multiple anti-inflammatory and anti-atherosclerotic properties of red wine polyphenolic extracts and indentified specific bioactive polyphenols which could counteract inflammatory diseases including atherosclerosis.

Topics: Anti-Inflammatory Agents; Atherosclerosis; Cell Adhesion; Chemokine CCL2; Coumaric Acids; E-Selectin; Endothelial Cells; Flavonols; Humans; Inflammation; Intercellular Adhesion Molecule-1; Italy; NF-kappa B; Oxidative Stress; Polyphenols; RNA, Messenger; Stilbenes; Transcription Factor AP-1; Vascular Cell Adhesion Molecule-1; Wine

Resveratrol is a phytoalexin with beneficial effects on human health. The aim of the present study was to investigate the effects of resveratrol on endothelial dysfunction involved in insulin signaling and inflammation.. Endothelial cells were stimulated with palmitate (PA) to induce insulin resistance characterized by a loss of insulin-mediated nitric oxide (NO) production. Diabetes was induced in rats by fructose feeding. The effects of resveratrol and the mechanisms involved were investigated using an aortic relaxation assay and Western blot analysis.. In endothelial cells, 0.1-10 μmol/L resveratrol suppressed IκB kinase β (IKKβ)/nuclear factor-κB phosphorylation, as well as tumor necrosis factor-α and interleukin-6 production, and restored the insulin receptor substrate-1 (Irs-1)/Akt/endothelial NO synthase signaling pathway. Furthermore, resveratrol effectively inhibited the mitogenic actions of insulin by decreasing the secretion of endothelin-1 and plasminogen activator inhibitor-1. It also positively regulated AMP-activated kinase (AMPK) and sirtuin 1 (SIRT1) activation, which contributed to the inhibition of inflammation implicated in endothelial insulin resistance. Stimulation with PA and long term-fructose feeding impaired insulin-mediated vessel dilation in rat aorta, whereas pretreatment of aortic rings with resveratrol (0.1-10 μmol/L) or treatment of rats with 5 or 20 mg/kg resveratrol counteracted these changes.. The results indicate that resveratrol inhibits inflammation and facilitates insulin phosphatidylinositol 3-kinase signaling by beneficial modulation of IRS-1 function partly via regulation of AMPK and SIRT1 activity in the endothelium.

Topics: AMP-Activated Protein Kinases; Animals; Blotting, Western; Cytokines; Diabetes Mellitus, Experimental; Endothelium, Vascular; Fructose; Gene Expression Regulation; Inflammation; Insulin Resistance; Male; Microscopy, Fluorescence; Nitric Oxide; Phosphorylation; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Vasodilation

Topics: Acute Disease; Animals; Calcium; Calcium Channels; HEK293 Cells; Humans; Inflammation; Inhibitory Concentration 50; Isothiocyanates; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Stilbenes; Transient Receptor Potential Channels; TRPA1 Cation Channel

Resveratrol (RSV) has beneficial effects on renal diseases, but its underlying mechanisms are still unclear. In the present study, we investigate the renoprotective effects of RSV on obesity-related renal diseases and clarify the potential mechanisms. Male C57BL/6J mice were fed with high-fat diet (HFD) with or without 400 mg/kg RSV treatment for 12 weeks. Feeding HFD induced renal injuries, but treating them with RSV significantly decreased glomerular volume (p < 0.05), glycogen (p < 0.01) and collagen (p < 0.05) in renal tissues. Although slightly changed body weight and fasting blood glucose, RSV attenuated renal dysfunction, including decreased levels of blood urea nitrogen (p < 0.05), urea protein (p < 0.01), and microalbuminuria (p < 0.01). Furthermore, RSV treatment markedly reduced gene expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and inducible nitric oxide synthase (iNOS) (all p < 0.05), 4-Hydroxynonenal expression (p < 0.01), and lipid accumulation. Mechanistically, RSV enhanced the expression of lipolytic genes, peroxisome proliferator-activated receptor (PPAR)-α (p < 0.001), carnitine palmitoyltransferase (CPT)-1 (p < 0.05), and medium-chain acyl-coenzyme A dehydrogenase (MCAD) (p < 0.01), but had no effect on lipogenic genes, PPAR-γ and sterol regulatory element-binding protein (SREBP)-1c. RSV also obviously increased renal PPAR-α protein expression (p < 0.001) and the phosphorylation of AMPK level. Collectively, these results support the therapeutic effects of RSV on high-fat diet-induced renal damages at least partially through targeting on PPAR-α signaling pathway.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Inflammation; Kidney; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; PPAR alpha; Resveratrol; Signal Transduction; Stilbenes

Metalloproteinase-13 is the major type II collagenase that directly implicates cartilage matrix destruction. Metalloproteinase-13 is inducted and activated by interleukin-1β, which is a commonly observed proinflammatory cytokine in the joint cavity of arthritic patients. Depression of interleukin-1β function can inhibit metalloproteinase-13 expression and protect the cartilage extracellular matrix. In this study, resveratrol release microspheres were developed, and the direct function of the released resveratrol on the interleukin-1β was discussed. The resveratrol-loaded microspheres were fabricated using oil-in-water emulsion and solution-evaporation methods. The particle size and the encapsulation efficiency for the techniques, which used different fabrication conditions, were within 8.3-63.9 μm and 37%-82%, respectively. The effect of drug release lasted for more than 650 h in a PBS solution at 37℃. Human bone mesenchymal stem cells were chosen for cell experiments. Interleukin-1β was used to induce an inflammatory condition. The effect of sustained resveratrol release from the microspheres on the cells' gene expression was observed using the transwell co-culturing method. The results indicated that metalloproteinase-13 mRNA expression was upregulated after interleukin-1β induction. The released resveratrol directly inhibited the function of interleukin-1β and thus downregulated metalloproteinase-13 mRNA expression. Moreover, the upregulation of Col2, aggrecan and Sox9 mRNA expressions, which are major chondrocyte markers, was observed after resveratrol was released into the culture medium. Resveratrol was observed to maintain the cells' chondrogenic gene expression when subject to the inflammation condition. The sustained released resveratrol inhibited interleukin-1β-inducted metalloproteinase-13 activation and promoted chondrocyte differentiation. This drug-loading microsphere is a promising candidate for arthritis therapy.

Topics: Antioxidants; Arthritis; Cell Differentiation; Cell Proliferation; Cell Survival; Cells, Cultured; Chondrocytes; Coculture Techniques; Drug Carriers; Drug Delivery Systems; Humans; Inflammation; Interleukin-1beta; Lactic Acid; Matrix Metalloproteinase 13; Matrix Metalloproteinase 8; Mesenchymal Stem Cells; Microspheres; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Resveratrol; SOX9 Transcription Factor; Stilbenes

The stability and longevity of recordings obtained from intracortical microelectrodes continues to remain an area of concern for neural interfacing applications. The limited longevity of microelectrode performance has been associated with the integrity of the blood brain barrier (BBB) and the neuroinflammatory response to the microelectrode. Here, we report the investigation of an additive approach that targets both mechanical and chemical factors believed to contribute to chronic BBB instability and the neuroinflammatory response associated with implanted intracortical microelectrodes. The implants investigated were based on a mechanically adaptive, compliant nanocomposite (NC), which reduces the tissue response and tissue strain. This material was doped with various concentrations of the antioxidant resveratrol with the objective of local and rapid delivery. In vitro analysis of resveratrol release, antioxidant activity, and cytotoxicity suggested that a resveratrol content of 0.01% was optimal for in vivo assessment. Thus, probes made from the neat NC reference and probes containing resveratrol (NC Res) were implanted into the cortical tissue of rats for up to sixteen weeks. Histochemical analysis suggested that at three days post-implantation, neither materials nor therapeutic approaches (independently or in combination) could alter the initial wound healing response. However, at two weeks post-implantation, the NC Res implant showed a reduction in activated microglia/macrophages and improvement in neuron density at the tissue-implant interface when compared to the neat NC reference. However, sixteen weeks post-implantation, when the antioxidant was exhausted, NC Res and the neat NC reference exhibited similar tissue responses. The data show that NC Res provides short-term, short-lived benefits due to the antioxidant release, and a long-term reduction in neuroinflammation on account of is mechanical adaptive, compliant nature. Together, these results demonstrate that local delivery of resveratrol can provide an additive advantage by providing a consistent reduction in the tissue response.

Topics: Animals; Blood-Brain Barrier; Cerebral Cortex; Drug Delivery Systems; Inflammation; Macrophages; Male; Microelectrodes; Microglia; Nanocomposites; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. Here we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous) together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b, whereas the increased macrophage infiltration was unaltered) without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin/delta0-15glucose) from 13.73 to 22.40 pmol/mmol (P < 0.001). This aberration in insulin and glucose homeostasis was normalized by resveratrol.. Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion.

Topics: Adipose Tissue; Animals; Antioxidants; Blood Glucose; Body Weight; Epididymis; Gene Expression Profiling; Glucose; Glucose Tolerance Test; Homeostasis; Inflammation; Insulin; Insulin Resistance; Insulin Secretion; Leukocytes; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Osmosis; Resveratrol; Stilbenes

It has been suggested that continuous exposure of peritoneal mesothelial cells (PMCs) to high glucose-containing peritoneal dialysis (PD) solutions may result in peritoneal inflammatory injury and impairment of local peritoneal host defence. Here, we investigated the effect of glucose-based PD solutions on mitochondrial reactive oxygen species (ROS) and nod-like receptor 3 (NLRP3) inflammasome activation in human PMCs (HPMCs). Exposure of HPMCs to high glucose-based PD solutions resulted in ROS production, which can trigger NLRP3 activation, leading to IL-1β secretion. Additionally, resveratrol (RSV) treatment induced mitophagy/autophagy via adenosine monophosphate-activated protein kinase (AMPK) activation. Increased mitochondrial ROS concentrations and IL-1β upregulation were confirmed following inhibition (siRNA against Beclin1 and ATG5 or autophagy inhibitor 3MA), but not induction (RSV), of mitophagy/autophagy. Furthermore, we observed that ATG5 and Beclin1 downregulation sensitised cells to IL-1β release induced by MSU or nigericin, which is an NLRP3 inflammasome activator. RSV treatment attenuated this effect. Taken together, this study may provide a potential therapeutic strategy for peritoneal inflammatory injury via NLRP3 inflammasome activation triggered by mitochondrial ROS.

Topics: Autophagy; Carrier Proteins; Cells, Cultured; Epithelial Cells; Humans; Inflammasomes; Inflammation; Mitochondria; Mitophagy; NLR Family, Pyrin Domain-Containing 3 Protein; Reactive Oxygen Species; Resveratrol; Stilbenes

This study hypothesized that resveratrol, a silencing information regulator 1 (SIRT1) activator, would counteract the inflammatory signaling associated with radiotherapy-induced premature ovarian failure (POF). Immature female Sprague-Dawley rats were subjected to a single dose of γ-radiation to induce POF and treated with resveratrol (25mg/kg) once daily for two weeks before and three days post irradiation. Resveratrol preserves the entire ovarian follicle pool manifested by increasing serum anti-Müllerian hormone (AMH) levels. Radiation triggered inflammatory process in the ovary through enhanced NF-κB and poly(ADP-ribose) polymerase (PARP)-1 expression which convinced the expression of inflammatory markers including IL-6, IL-8, and visfatin mRNA levels, as well as inducible nitric oxide synthase and cyclooxygenase-2 protein expression with a concomitant reduction in IL-10 mRNA levels. Resveratrol significantly counteracted the effect of radiation and upregulated the gene expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and SIRT1. Resveratrol-activated SIRT1 expression was associated with inhibition of PARP-1 and NF-κB expression-mediated inflammatory cytokines. Our findings suggest that resveratrol restored ovarian function through increasing AMH levels, and diminishing ovarian inflammation, predominantly via upregulation of PPAR-γ and SIRT1 expression leading to inhibition of NF-κB provoked inflammatory cytokines.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Cytokines; Female; Gamma Rays; Inflammation; Nitric Oxide Synthase Type II; Ovarian Follicle; Ovarian Reserve; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; PPAR gamma; Primary Ovarian Insufficiency; Radiation Injuries, Experimental; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Transcription Factor RelA

Resveratrol has been reported to inhibit monoamine oxidases (MAO). Many substrates or inhibitors of neuronal MAO interact also with other amine oxidases (AO) in peripheral organs, such as semicarbazide-sensitive AO (SSAO), known as primary amine oxidase, absent in neurones, but abundant in adipocytes. We asked whether phenolic compounds (resveratrol, pterostilbene, quercetin, and caffeic acid) behave as MAO and SSAO inhibitors. AO activity was determined in human adipose tissue. Computational docking and glucose uptake assays were performed in 3D models of human AO proteins and in adipocytes, respectively. Phenolic compounds fully inhibited the fluorescent detection of H2O2 generated during MAO and SSAO activation by tyramine and benzylamine. They also quenched H2O2-induced fluorescence in absence of biological material and were unable to abolish the oxidation of radiolabelled tyramine and benzylamine. Thus, phenolic compounds hampered H2O2 detection but did not block AO activity. Only resveratrol and quercetin partially impaired MAO-dependent [(14)C]-tyramine oxidation and behaved as MAO inhibitors. Phenolic compounds counteracted the H2O2-dependent benzylamine-stimulated glucose transport. This indicates that various phenolic compounds block downstream effects of H2O2 produced by biogenic or exogenous amine oxidation without directly inhibiting AO. Phenolic compounds remain of interest regarding their capacity to limit oxidative stress rather than inhibiting AO.

Topics: Adipocytes; Adipose Tissue; Adolescent; Adult; Aged; Amine Oxidase (Copper-Containing); Anti-Inflammatory Agents; Antioxidants; Benzylamines; Caffeic Acids; Diet; Female; Fluorometry; Hexoses; Humans; Hydrogen Peroxide; Inflammation; Middle Aged; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Oxidative Stress; Oxygen; Phenols; Quercetin; Resveratrol; Stilbenes; Tyramine; Young Adult

The natural polyphenol compound resveratrol (RSV) is considered to have a broad spectrum of beneficial biological activities upon human health. However, the exact effect of RSV on steatosis (a phenotype of non-alcoholic fatty liver [NAFL]) or fibrosis and inflammation (major phenotypes of non-alcoholic steatohepatitis [NASH]) is not known. Our data showed that administration of RSV (2 or 20 mg/kg/day) did not suppress steatosis in a high-fat diet-induced model of NAFL in mice. In contrast, identical concentrations of RSV dramatically inhibited inflammation and fibrosis in a low-dose lipopolysaccharide-induced model of NASH. These data suggested that RSV administration-mediated improvement of inflammation and fibrosis was due to the inhibition of LPS reactivity controlled by CD14 expression in Kupffer cells. These findings suggest that RSV could be a candidate agent for the treatment of NASH.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Disease Models, Animal; Fibrosis; Fluorescent Antibody Technique; Gene Expression; Humans; Immunoblotting; Inflammation; Interleukin-6; Lipopolysaccharide Receptors; Lipopolysaccharides; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor; Stilbenes; Tumor Necrosis Factor-alpha

Topics: Humans; Inflammation; MicroRNAs; Resveratrol; Stilbenes

Diets rich in fruits and vegetables (FV), which contain (poly)phenols, protect against age-related inflammation and chronic diseases. T-lymphocytes contribute to systemic cytokine production and are modulated by FV intake. Little is known about the relative potency of different (poly)phenols in modulating cytokine release by lymphocytes. We compared thirty-one (poly)phenols and six (poly)phenol mixtures for effects on pro-inflammatory cytokine release by Jurkat T-lymphocytes. Test compounds were incubated with Jurkat cells for 48 h at 1 and 30 µm, with or without phorbol ester treatment at 24 h to induce cytokine release. Three test compounds that reduced cytokine release were further incubated with primary lymphocytes at 0·2 and 1 µm for 24 h, with lipopolysaccharide added at 5 h. Cytokine release was measured, and generation of H2O2 by test compounds was determined to assess any potential correlations with cytokine release. A number of (poly)phenols significantly altered cytokine release from Jurkat cells (P<0·05), but H2O2 generation did not correlate with cytokine release. Resveratrol, isorhamnetin, curcumin, vanillic acid and specific (poly)phenol mixtures reduced pro-inflammatory cytokine release from T-lymphocytes, and there was evidence for interaction between (poly)phenols to further modulate cytokine release. The release of interferon-γ induced protein 10 by primary lymphocytes was significantly reduced following treatment with 1 µm isorhamnetin (P<0·05). These results suggest that (poly)phenols derived from onions, turmeric, red grapes, green tea and açai berries may help reduce the release of pro-inflammatory mediators in people at risk of chronic inflammation.

Topics: Cell Survival; Chronic Disease; Curcuma; Curcumin; Cytokines; Euterpe; Female; Humans; Hydrogen Peroxide; Inflammation; Jurkat Cells; Lipopolysaccharides; Lymphocytes; Middle Aged; Onions; Polyphenols; Quercetin; Resveratrol; Stilbenes; Tea; Vanillic Acid; Vitis

Low-grade inflammation negatively affects bone. Resveratrol is a natural compound proven to possess both anti-inflammatory and bone protective properties. However, it is uncertain if the bone effects are mediated though anti-inflammatory effects. Firstly, we investigated if resveratrol affects proliferation and differentiation of human bone marrow-derived mesenchymal stem cells. Secondly, we investigated if inflammation negatively affects proliferation and differentiation, and if resveratrol counteracts this through anti-inflammatory effects. Mesenchymal stem cells were obtained from bone marrow aspiration in 13 healthy individuals and cultured towards the osteoblast cell lineage. The cells were stimulated with resveratrol, lipopolysaccharide (LPS), LPS + resveratrol, or vehicle (control) for 21 days. Compared to control, resveratrol decreased cell number by 35 % (p < 0.05) and induced differentiation (a 3-fold increase in alkaline phosphatase (p < 0.002), while P1NP and OPG showed similar trends). LPS induced inflammation with a 44-fold increase in interleukin-6 (p < 0.05) and an extremely prominent increase in interleukin-8 production (p < 0.05) relative to control. In addition, LPS increased cell count (p < 0.05) and decreased differentiation (a reduction in P1NP production (p < 0.02)). Co-stimulation with LPS + resveratrol did not reduce interleukin-6 or interleukin-8, but nonetheless, cell count was reduced (p < 0.05) and alkaline phosphatase, P1NP, and OPG increased (p < 0.05 for all). Thus, resveratrol stimulates osteoblast differentiation independently of inflammation.

Topics: Cell Differentiation; Cell Lineage; Humans; Inflammation; Mesenchymal Stem Cells; Osteoblasts; Osteocalcin; Osteogenesis; Resveratrol; Stilbenes

The mechanisms leading to neuronal death in Parkinson's disease (PD) are not fully elucidated; however, mounting evidence implicates endoplasmic reticulum (ER) stress, oxidative damage, and inflammatory changes are the crucial factors in its pathogenesis. This study was undertaken to investigate the modulatory effects of resveratrol on ER stress-mediated apoptosis, inflammatory and oxidative stress markers in a rat model of rotenone-induced PD. mRNA expression levels of ER stress markers; C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78), were estimated in the rat brain using quantitative real-time PCR. Caspase-3 activity, IL-1β levels and Nuclear Factor Erythroid 2-related factor (Nrf2) DNA-binding activity were estimated by ELISA, while glutathione peroxidase and Xanthine oxidase activities, as well as protein carbonyl contents in the rat brain were evaluated spectrophotometrically. Our data revealed that Resveratrol ameliorated rotenone-induced ER stress by downregulating CHOP and GRP78 genes expression and hampered caspase-3 activity in the brain of rotenone exposed rats. It also restored redox balance as evident by suppressing Xanthine oxidase activity and protein carbonyls formation; in addition to preservation of intracellular antioxidants status via activating glutathione peroxidase and Nrf2 signaling pathway. In conclusion; our study launched promising avenues for the potential use of resveratrol as a neuroprotective therapeutic agent in Parkinson's disease.

Topics: Animals; Apoptosis; Biomarkers; Caspase 3; Chemically-Induced Disorders; Disease Models, Animal; Endoplasmic Reticulum Stress; Enzyme Activation; Gene Expression Regulation; HSP70 Heat-Shock Proteins; Inflammation; Male; Membrane Proteins; Parkinson Disease; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Resveratrol; Rotenone; Stilbenes; Transcription Factor CHOP

Resveratrol, a polyphenol phytoalexine, has been shown to play a neuroprotective role in the neurodegenerative process in Alzheimer's disease (AD) and improve memory function in dementia. However, the in vivo effect of resveratrol in normal aging models of learning and memory has not yet been evaluated. Therefore, the present neurobehavioral study was undertaken to evaluate the effect of resveratrol on cognitive impairment induced by aging in passive avoidance and Morris water maze (MWM) tests. Male Wistar albino rats were divided into four groups: young control (4month), young resveratrol (4month+RESV), old control (24month) and old resveratrol (24month+RESV). Resveratrol (50mg/kg/day) was given to the 4month+RESV and 24month+RESV groups orally for 12weeks. There was no significant difference between the groups for the first day of latency, while in aged rats, the second day of latency was significantly shortened compared to the young group in the passive avoidance test (p<0.05). Additionally, in the MWM test, the results showed a decrease in the time spent in the escape platform's quadrant in the probe test in aged rats (p<0.05). The administration of resveratrol at 50mg/kg/day increased the retention scores in the passive avoidance test and the time spent in the escape platform's quadrant in the MWM task (p<0.05). Furthermore resveratrol attenuated the protein levels of TNFα and IL1β in the 24-month group. These findings indicate that aging impairs emotional and spatial learning-memory and resveratrol reverses the effect of age-related learning and memory impairment. The results of this study suggest that resveratrol is effective in preventing cognitive deficit in aged rats by inhibiting the production of inflammatory cytokines.

Topics: Aging; Animals; Anti-Inflammatory Agents, Non-Steroidal; Avoidance Learning; Behavior, Animal; Cognitive Dysfunction; Cytokines; Disease Models, Animal; Inflammation; Male; Rats, Wistar; Resveratrol; Spatial Learning; Stilbenes

Hypoxic activation of hypoxia-inducible factor 1α (HIF-1α) and fibrosis in adipose tissue contribute to adipose dysfunction. This study was designed to investigate the effects of metformin and resveratrol on the regulation of HIF-1α and fibrosis in hypoxic adipose tissue.. Mice were fed a high-fat diet to induce hypoxia and fibrosis in adipose tissue; adipose tissue incubated in vitro in 1% O2 showed a similar change. The effects of metformin and resveratrol on hypoxia, HIF-1α accumulation, endoplasmic reticulum stress and gene expressions of extracellular matrix components and pro-inflammatory cytokines were examined.. Oral administration of metformin or resveratrol prevented hypoxia and reduced HIF-1α accumulation with dephosphorylation of inositol-requiring enzyme 1α and eukaryotic initiation factor 2α, indicative of suppression of hypoxic HIF-1α activation and endoplasmic reticulum stress. Metformin and resveratrol down-regulated gene expressions of Col3α, Col6α, elastin and lysyl oxidase and thereby reduced collagen deposition in adipose tissue. The increased gene expressions of TNF-α, IL-6, monocyte chemoattractant protein 1 and F4/80 were also down-regulated by metformin and resveratrol. Metformin and resveratrol had similar effects in adipose tissue exposed to 1% O2 . Metformin reduced ATP production and prevented the reduction in oxygen tension in 3T3-L1 cells, suggesting that it prevented hypoxia by limiting oxygen consumption, whereas resveratrol reduced HIF-1α accumulation by promoting its proteasomal degradation via the regulation of AMPK/SIRT1.. Hypoxia and fibrosis are early causes of adipose dysfunction in obesity. Both metformin and resveratrol effectively inhibited HIF-1α activation-induced fibrosis and inflammation in adipose tissue, although by different mechanisms.

Topics: 3T3-L1 Cells; Adipose Tissue; Animals; Cells, Cultured; Dose-Response Relationship, Drug; Fibrosis; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Male; Metformin; Mice; Mice, Inbred ICR; Resveratrol; Stilbenes; Structure-Activity Relationship

The effects of high-fructose diet on adipose tissue insulin signaling and inflammatory process have been poorly documented. In this study, we examined the influences of long-term fructose intake and resveratrol supplementation on the expression of genes involved in insulin signaling and the levels of inflammatory cytokines and sex hormones in the white adipose tissues of male and female rats. Consumption of high-fructose diet for 24 weeks increased the expression of genes involved in insulin signaling including IR, IRS-1, IRS-2, Akt, PI3K, eNOS, mTOR, and PPARγ, despite induction of proinflammatory markers, iNOS, TNFα, IL-1β, IL-18, MDA, and ALT, as well as anti-inflammatory factors, IL-10 and Nrf2 in adipose tissues from males and females. Total and free testosterone concentrations of adipose tissues were impaired in males but increased in females, although there were no changes in their blood levels. Resveratrol supplementation markedly restored the levels of MDA, IL6, IL-10, and IL-18, as well as iNOS, Nrf2, and PI3K mRNA, in adipose tissues of both genders. Dietary fructose activates both insulin signaling and inflammatory pathway in the adipose tissues of male and female rats proposing no correlation between the tissue insulin signaling and inflammation. Resveratrol has partly modulatory effects on fructose-induced changes.

Topics: Adipose Tissue, White; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Dietary Carbohydrates; Female; Fructose; Gonadal Steroid Hormones; Inflammation; Insulin; Male; Rats; Rats, Wistar; Resveratrol; Signal Transduction; Stilbenes

Resveratrol, a component of red wine, has been reported to decrease prostaglandin E2 production by inhibiting the cyclooxygenase-2 cascade and to modulate various voltage-dependent ion channels, suggesting that resveratrol could attenuate inflammatory hyperalgesia. However, the effects of resveratrol on inflammation-induced hyperexcitability of nociceptive neurons in vivo remain to be determined. Thus, the aim of the present study was to determine whether daily systemic administration of resveratrol to rats attenuates the inflammation-induced hyperexcitability of spinal trigeminal nucleus caudalis wide-dynamic range neurons associated with hyperalgesia.. Inflammation was induced by injection of complete Freund's adjuvant into the whisker pad. The threshold of escape from mechanical stimulation applied to whisker pad in inflamed rats was significantly lower than in control rats. The decreased mechanical threshold in inflamed rats was restored to control levels by daily systemic administration of resveratrol (2 mg/kg, i.p.). The mean discharge frequency of spinal trigeminal nucleus caudalis wide-dynamic range neurons to both nonnoxious and noxious mechanical stimuli in inflamed rats was significantly decreased after resveratrol administration. In addition, the increased mean spontaneous discharge of spinal trigeminal nucleus caudalis wide-dynamic range neurons in inflamed rats was significantly decreased after resveratrol administration. Similarly, resveratrol significantly diminished noxious pinch-evoked mean after discharge frequency and occurrence in inflamed rats. Finally, resveratrol restored the expanded mean size of the receptive field in inflamed rats to control levels.. These results suggest that chronic administration of resveratrol attenuates inflammation-induced mechanical inflammatory hyperalgesia and that this effect is due primarily to the suppression of spinal trigeminal nucleus caudalis wide dynamic range neuron hyperexcitability via inhibition of both peripheral and central cyclooxygenase-2 cascade signaling pathways. These findings support the idea of resveratrol as a potential complementary and alternative medicine for the treatment of trigeminal inflammatory hyperalgesia without side effects.

Topics: Animals; Hyperalgesia; Inflammation; Male; Neurons; Rats, Wistar; Resveratrol; Stilbenes; Trigeminal Nucleus, Spinal

Previous studies have shown positive effects of long-term resveratrol (RSV) supplementation in preventing pancreatic beta cell dysfunction, arterial stiffening and metabolic decline induced by high-fat/high-sugar (HFS) diet in nonhuman primates. Here, the analysis was extended to examine whether RSV may reduce dietary stress toxicity in the cerebral cortex of the same cohort of treated animals. Middle-aged male rhesus monkeys were fed for 2 years with HFS alone or combined with RSV, after which whole-genome microarray analysis of cerebral cortex tissue was carried out along with ELISA, immunofluorescence, and biochemical analyses to examine markers of vascular health and inflammation in the cerebral cortices. A number of genes and pathways that were differentially modulated in these dietary interventions indicated an exacerbation of neuroinflammation (e.g., oxidative stress markers, apoptosis, NF-κB activation) in HFS-fed animals and protection by RSV treatment. The decreased expression of mitochondrial aldehyde dehydrogenase 2, dysregulation in endothelial nitric oxide synthase, and reduced capillary density induced by HFS stress were rescued by RSV supplementation. Our results suggest that long-term RSV treatment confers neuroprotection against cerebral vascular dysfunction during nutrient stress.

Topics: Animals; Apoptosis; Cerebral Cortex; Diet, High-Fat; Dietary Sucrose; Gene Expression Profiling; Inflammation; Macaca mulatta; Male; Neuroprotective Agents; NF-kappa B; Nitric Oxide Synthase Type III; Oxidative Stress; Resveratrol; Stilbenes

Palmitoylethanolamide (PEA), a special food for medical purposes, has anti-inflammatory and neuroprotective effects. Nevertheless, PEA lacks direct ability to prevent free radical formation. Polydatin (PLD), a natural precursor of resveratrol, has antioxidant activity. The combination of PEA and PLD could have beneficial effects on oxidative stress induced by inflammatory processes. In the present study, we compared the effects of micronized PEA (PEA-m) and PLD association (PEA-m+PLD) with a new co-micronized composite containing PEA and PLD (m(PEA/PLD)) in the rat paw model of carrageenan (CAR)-induced acute inflammation. Intraplantar injection of CAR led to a time-dependent development of peripheral inflammation, in terms of paw edema, cytokine release in paw exudates, nitrotyrosine formation, inducible nitric oxide synthase and cyclooxygenase-2 expression. m(PEA/PLD) reduced all measured parameters. Thermal hyperalgesia and mechanical allodynia were also markedly reduced. At the spinal cord level, manganese superoxide dismutase (MnSOD) was found to be nitrated and subsequently deactivated. Further, m(PEA/PLD) treatment increased spinal MnSOD expression, prevented IkB-α degradation and nuclear factor-κB translocation, suggesting a possible role on central sensitization. m(PEA/PLD) showed more robust anti-inflammatory and anti-hyperalgesic effects compared to the simple association of PEA-m and PLD. This composite formulation approach opens a new therapeutic strategy for the development of novel non-narcotic anti-hyperalgesic agents.

Topics: Active Transport, Cell Nucleus; Administration, Oral; Amides; Animals; Carrageenan; Cell Line, Tumor; Cell Nucleus; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Drug Compounding; Drug Interactions; Edema; Ethanolamines; Gene Expression Regulation, Enzymologic; Glucosides; Hyperalgesia; Inflammation; Male; Neutrophil Infiltration; NF-KappaB Inhibitor alpha; Nitric Oxide Synthase Type II; Palmitic Acids; Proteolysis; Rats; Rats, Sprague-Dawley; Stilbenes; Superoxide Dismutase; Transcription Factor RelA; Tyrosine

Micro-inflammation plays an important role in the pathogenesis of spontaneously hypertensive rat (SHR). In the present study, we investigated the therapeutic potential of resveratrol (RSV), a polyphenol with anti-fibrosis activity in hypertensive renal damage model. In SHR renal damage model, RSV treatment blunted the increase in urine albumin excretion, urinary β2-microglobulin (β2-MG), attenuated the decrease in creatinine clearance rate (CCR). The glomerular sclerosis index (1.54±0.33 compared with 0.36±0.07) and tubulointerstitial fibrosis (1.57±0.31 compared with 0.19±0.04) were significantly higher in SHRs compared with Wistar Kyoto rats (WKYs), which were significantly lower by RSV treatment. The increases in mesangium accumulation and the expression of renal collagen type I (Col I), fibronectin (Fn), plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor-β1 (TGF-β1) in SHR were also reduced by RSV treatment. Nuclear factor κB (NF-κB) expression was increased in the cytoplasm and nuclei of the SHR kidneys, which was significantly decreased by RSV treatment. Furthermore, the protein level of IκB-α significantly decreased in the kidneys of the SHR when compared with the WKYs. RSV treatment partially restored the decreased IκB-α level. In SHR kidney, increased expression of interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein 1 (MCP-1) were observed. These changes were attenuated by RSV treatment. No changes in blood pressure were detected between SHR group and SHR + RSV group. Taken together, the present study demonstrated that RSV treatment may significantly attenuate renal damage in the SHR model of chronic kidney disease (CKD). The renal protective effect is associated with inhibition of IL-6, ICAM-1 and MCP-1 expression via the regulation of the nuclear translocation of NF-κB, which suggesting that micro-inflammation may be a potential therapeutic target of hypertensive renal damage.

Topics: Acute Kidney Injury; Animals; beta 2-Microglobulin; Blood Pressure; Collagen Type I; Disease Models, Animal; Fibronectins; Fibrosis; Gene Expression Regulation; Humans; Hypertension; Inflammation; Kidney; Plasminogen Activator Inhibitor 1; Rats; Resveratrol; Stilbenes; Transforming Growth Factor beta1

Monocyte-to-macrophage differentiation promotes an inflammatory environment within the arterial vessel wall that causes a mal-adaptive immune response, which contributes to the progression of atheromatous plaque formation. In the current study, we show that resveratrol, a well-known antioxidant, dose-dependently attenuated phorbol myristate acetate (PMA)-induced monocyte-to-macrophage differentiation, as measured by cell adhesion, increase in cell size, and scavenger receptor expression in THP-1 monocytes. Also, resveratrol significantly inhibited PMA-induced pro-inflammatory cytokine/chemokine and matrix metalloprotease (MMP-9) production. This inhibitory effect of resveratrol on monocyte differentiation results from its ability to restore intracellular glutathione (GSH) status, as resveratrol in the presence of buthionine sulfoximine (BSO) failed to affect monocyte differentiation. Furthermore, PMA-induced monocyte differentiation and inflammation was greatly inhibited when cells were co-treated with N-Acetyl-l-cysteine (NAC), a GSH precursor, while the presence of BSO aggravated these processes. These results also show that resveratrol mediated up-regulation of GSH is due to AMP-activated protein kinase (AMPK)-α activation, as compound C (AMPK inhibitor) treatment drastically depleted intracellular GSH and exacerbated PMA-induced monocyte differentiation and pro-inflammatory cytokine production. More importantly, chronic administration of resveratrol efficiently prevented monocyte infiltration and markedly diminished angiotensin (Ang)-II-induced atheromatous plaque formation in apolipoprotein-E knockout (ApoE(-/-)) mice. We conclude that, intracellular GSH status plays a critical role in regulating monocyte-to-macrophage differentiation and inflammation and resveratrol, by restoring GSH levels, inhibits these processes. Taken together, these results suggest that resveratrol can attenuate atherosclerosis, at least, in part, by inhibiting monocyte differentiation and pro-inflammatory cytokines production.

Topics: Acetylcysteine; AMP-Activated Protein Kinases; Animals; Antioxidants; Apolipoproteins E; Atherosclerosis; Buthionine Sulfoximine; Cell Differentiation; Glutathione; Homeostasis; Humans; Inflammation; Macrophages; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Monocytes; Resveratrol; Stilbenes; Tetradecanoylphorbol Acetate

Machado-Joseph disease (MJD) is a neurodegenerative disorder characterized by an abnormal expansion of the CAG triplet in the ATXN3 gene, translating into a polyglutamine tract within the ataxin-3 protein. The available treatments only ameliorate symptomatology and do not block disease progression. In this study we find that caloric restriction dramatically rescues the motor incoordination, imbalance and the associated neuropathology in transgenic MJD mice. We further show that caloric restriction rescues SIRT1 levels in transgenic MJD mice, whereas silencing SIRT1 is sufficient to prevent the beneficial effects on MJD pathology. In addition, the re-establishment of SIRT1 levels in MJD mouse model, through the gene delivery approach, significantly ameliorates neuropathology, reducing neuroinflammation and activating autophagy. Furthermore, the pharmacological activation of SIRT1 with resveratrol significantly reduces motor incoordination of MJD mice. The pharmacological SIRT1 activation could provide important benefits to treat MJD patients.

Topics: Animals; Ataxin-3; Autophagy; Caloric Restriction; Cell Line, Tumor; Cerebellum; Disease Models, Animal; Gait; Inflammation; Machado-Joseph Disease; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Mutant Proteins; Nervous System; Neurons; Resveratrol; RNA, Messenger; Sirtuin 1; Stilbenes

State of the art. Osteoarthritis (OA) is a chronic articular disease characterized by cartilage degradation and osteophyte formation. OA physiopathology is multifactorial and involves mechanical and hereditary factors. So far, there is neither preventive medicine to delay cartilage breakdown nor curative treatment. Objectives. To investigate pro-inflammatory paracrine interactions between human primary chondrocytes and macrophages following interleukin-1-β (IL-1β) treatment; to evaluate the molecular mechanism responsible for the inhibitory effect of resveratrol. Results. The activation of NF-κB in chondrocytes by IL-1β induced IL-6 secretion. The latter will then activate STAT3 protein in macrophages. Moreover, STAT3 was able to positively regulate IL-6 secretion, as confirmed by the doubling level of IL-6 in the coculture compared to macrophage monoculture. These experiments confirm the usefulness of the coculture model in the inflammatory arthritis-linked process as a closer biological situation to the synovial joint than separated chondrocytes and macrophages. Il also demonstrated the presence of an inflammatory amplification loop induced by IL-1β. Resveratrol showed a strong inhibitory effect on the pro-inflammatory marker secretion. The decrease of IL-6 secretion is dependent on the NFκB inhibition in the chondrocytes. Such reduction of the IL-6 level can limit STAT3 activation in the macrophages, leading to the interruption of the inflammatory amplification loop. Conclusion. These results increase our understanding of the anti-inflammatory actions of resveratrol and open new potential approaches to prevent and treat osteoarthritis.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Cells, Cultured; Chondrocytes; Coculture Techniques; Humans; Inflammation; Interleukin-1beta; Macrophages; Resveratrol; Stilbenes; Time Factors

Macrophages play a central role in atherosclerosis development and progression, hence, targeting macrophage activity is considered an attractive therapeutic. Recently, we documented nanomedicinal delivery of the anti-inflammatory compound prednisolone to atherosclerotic plaque macrophages in patients, which did however not translate into therapeutic efficacy. This unanticipated finding calls for in-depth screening of drugs intended for targeting plaque macrophages.. We evaluated the effect of several candidate drugs on macrophage activity, rating overall performance with respect to changes in cytokine release, oxidative stress, lipid handling, endoplasmic reticulum (ER) stress, and proliferation of macrophages. Using this in vitro approach, we observed that the anti-inflammatory effect of prednisolone was counterbalanced by multiple adverse effects on other key pathways. Conversely, pterostilbene, T0901317 and simvastatin had an overall anti-atherogenic effect on multiple pathways, suggesting their potential for liposomal delivery.. This dedicated assay setup provides a framework for high-throughput assessment. Further in vivo studies are warranted to determine the predictive value of this macrophage-based screening approach and its potential value in nanomedicinal drug development for cardiovascular patients.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Cell Proliferation; Cytokines; Endoplasmic Reticulum Stress; High-Throughput Screening Assays; Humans; Hydrocarbons, Fluorinated; Inflammation; Inflammation Mediators; Lipid Metabolism; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; NF-kappa B; Oxidative Stress; Plaque, Atherosclerotic; Prednisolone; RAW 264.7 Cells; Reactive Oxygen Species; Signal Transduction; Simvastatin; Stilbenes; Sulfonamides; Transfection

Inflammation plays an important role in polycystic kidney disease (PKD). The current study aimed to examine the efficacy of the anti-inflammatory compound resveratrol in PKD and to investigate its underlying mechanism of action.. Male Han:SPRD (Cy/+) rats with PKD were treated with 200 mg/kg/day resveratrol or vehicle by gavage for 5 weeks. Human autosomal dominant (AD) PKD cells, three-dimensional (3D) Madin-Darby canine kidney cells and zebrafish were treated with various concentrations of resveratrol or the nuclear factor κB (NF-κB) inhibitor QNZ.. Resveratrol treatment reduced blood urea nitrogen levels and creatinine levels by 20 and 24%, respectively, and decreased two-kidney/total body weight ratio by 15% and cyst volume density by 24% in Cy/+ rats. The proliferation index and the macrophage infiltration index were reduced by 40 and 43%, respectively, in resveratrol-treated cystic kidneys. Resveratrol reduced the levels of the pro-inflammatory factors monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and complement factor B (CFB) in Cy/+ rat kidneys in parallel with the decreased activity of NF-κB (p50/p65). The activation of NF-κB and its correlation with pro-inflammatory factor expression were confirmed in human ADPKD cells and kidney tissues. Resveratrol and QNZ inhibited the expression of MCP-1, TNF-α and CFB and reduced NF-κB activity in ADPKD cells. Moreover, NF-κB blockage minimized the inhibition of inflammatory factor production by resveratrol treatment. Furthermore, resveratrol or QNZ inhibited cyst formation in the 3D cyst and zebrafish models.. The NF-κB signaling pathway is activated and partly responsible for inflammation in polycystic kidney tissues. Targeting inflammation through resveratrol could be a new strategy for PKD treatment in the future.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Case-Control Studies; Chemokine CCL2; Disease Progression; Dogs; Humans; Inflammation; Madin Darby Canine Kidney Cells; Male; NF-kappa B; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Rats; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Stilbenes; Tumor Necrosis Factor-alpha; Zebrafish

Evidence shows beneficial effects of resveratrol (RES) on human health. However, its poor aqueous solubility limits therapeutic effectiveness. Thus, the use of nanostructured delivery systems for RES, such as a liquid-crystalline system (LCS), could be viable. The purpose of this study was to develop, characterize, and determine the in vivo effectiveness of a RES-loaded LCS. We studied an LCS containing silicon glycol copolymer, polyether functional siloxane, and the polymeric dispersion carbomer homopolymer type B (C974) in the ratio 20:55:25 with and without RES. Results obtained using polarized light microscopy, small-angle X-ray scattering, and rheology analysis showed that the RES-loaded LCS system presents a lamellar structure and behaves as a non-Newtonian fluid presenting pseudoplastic (the apparent viscosity decreases as the stress increases) and thixotropic (the apparent viscosity decreases with the duration of stress) behaviors. Cytotoxicity studies showed that the formulation components are noncytotoxic. Topical application of a RES-loaded LCS protected hairless mice from UVB-irradiation-induced skin damage by inhibiting edema, neutrophil recruitment, lipid hydroperoxide and superoxide anion production, gp91phox mRNA expression, and oxidative stress. The RES-loaded LCS maintained 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and ferric reducing abilities, catalase activity, reduced glutathione levels, and mRNA expression of glutathione peroxidase 1 and glutathione reductase. The RES-loaded LCS also up-regulated matrix metalloproteinase-9 activity, IL-10 production, and mRNA expression of transcription factor Nrf2 and heme oxygenase-1. Therefore, a RES-loaded LCS is a promising new therapeutic approach to mitigate skin photodamage.

Topics: Animals; Antioxidants; Benzothiazoles; Edema; Female; Glutathione; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Heme Oxygenase-1; Humans; Inflammation; Interleukin-10; Matrix Metalloproteinase 9; Mice; Mice, Hairless; Molecular Structure; Oxidative Stress; Resveratrol; Skin; Stilbenes; Sulfonic Acids; Superoxides; Ultraviolet Rays

Horses affected with gastrointestinal conditions such as colic or colitis are at substantial risk for translocation of bacterial components such as lipopolysaccharide (LPS, endotoxin) from the gastrointestinal tract into circulation resulting in systemic inflammation and subsequent morbidity and mortality. Therefore, there is a need for effective preventive and treatment strategies aimed at minimizing the host's inflammatory reaction to these pathogen-associated molecular patterns (PAMPs) from gastrointestinal disease. Resveratrol (RES, trans-3,5,4'-trihydroxystilbene) is a phytoalexin commonly found in fruits and beverages, including red wine. Health benefits associated with the consumption of red wine have been attributed to RES. Resveratrol has been significantly shown to exert a powerful anti-inflammatory effect in laboratory animals subjected to experimental endotoxemia/sepsis. Therefore, the objective of this study was to determine in vitro whether RES had an inhibitory effect on the production of tumor necrosis factor (TNF) in cultivated whole blood (Cwb) following stimulation by PAMPs. We hypothesized that RES would inhibit TNF production in Cwb following stimulation by LPS or lipoteichoic acid (LTA). Production of TNF bioactivity in Cwb was measured in the presence of phosphate buffered saline (control), ethanol (solvent control), dexamethasone (anti-inflammatory control), LPS, LTA, and three different concentrations of RES. Both LPS and LTA stimulated TNF production, and addition of dexamethasone was inhibitory to this effect. An anti-inflammatory effect for RES was not demonstrated under the current experimental conditions. Further studies are required to characterize the effect of RES on the equine innate immune system during systemic inflammation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Gene Expression Regulation; Horses; Immunity, Innate; Inflammation; Lipopolysaccharides; Phytoalexins; Resveratrol; Sesquiterpenes; Stilbenes; Teichoic Acids; Tumor Necrosis Factor-alpha

Inflammation derived from macrophages activation leads to various diseases. Synthetic modifications of resveratrol have been shown to have better anti-inflammatory activities. In this study, croton oil-induced mouse ear edema and lipopolysaccharides (LPS)-stimulated RAW264.7 macrophages were used to evaluate the anti-inflammatory effects of WL-09-5, a derivative of resveratrol. Furthermore, the activation of NF-κB was determined. Results showed that WL-09-5 significantly reduced the croton oil-induced ear edema, scavenged NO and ROS production, and reduced the levels of TNF-α, IL-6, and IL-1β. Furthermore, WL-09-5 may significantly inhibit the translocation of NF-κB in macrophage cells stimulated by LPS in a dose-dependent manner, which is a potent mechanism of its anti-inflammatory effects. In conclusion, WL-09-5 is an underlying candidate for inflammatory diseases that need further investigations.

Topics: Animals; Anti-Inflammatory Agents; Cyclooxygenase 2; Cytokines; Dinoprostone; Edema; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Macrophages; Mice; Molecular Structure; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Resveratrol; Signal Transduction; Stilbenes; Tumor Necrosis Factor-alpha

Atherosclerosis is a specific form of an artery wall thickens, a syndrome affecting arterial blood vessels due to a chronic inflammatory response in the walls of arteries, which is promoted by fat accumulation. Toll-like receptors (TLRs) play prominent roles in inflammatory responses. And TLR5 is overexpressed in several diseases. Here in our study, we investigated the effect of TLR5 in high fat-induced atherosclerosis via NF-κB signaling pathway modulating pro-inflammatory cytokines releasing. Our results found that high fat induced atherosclerosis in wild type mice with fat accumulation and inflammatory response through NF-κB activation. Contrastly, TLR5 knockout mice displayed lower fat accumulation and ameliorated inflammation after high fat feeding with NF-κB inactivation. In addition, pterostilbene, as a natural dimethyl ether derivative of resveratrol mainly from blueberries, has diverse pharmacological activities, especially anti-inflammation. Our study also found that pterostilbene displayed inhibited role in suppressing inflammatory response through inactivating NF-κB signaling pathway regulated by TLR5 down-regulation in high fat-induced mice. Moreover, in vitro experiments of vascular smooth muscle cells (VSMCs) challenged with LPS or TNF-α, further indicated that NF-κB was involved in atherosclerosis progression, leading to high secretion of pro-inflammatory cytokines. However, VSMCs from TLR5 deficient mice inhibited phosphorylated levels of NF-κB signalilng pathway, finally resulting in down-regulation of inflammatory cytokines. Notably, pterostilbene also displayed suppressed role in inflammatory response via NF-κB inactivity in LPS or TNF-α-induced VSMCs by decreasing TLR5 expression. The results above indicated a novel therapeutic strategy of pterostilbene to protect against atherosclerosis via TLR5 regulation for clinic treatment in the future.

Topics: Animals; Atherosclerosis; Diet, High-Fat; Gene Knockdown Techniques; Inflammation; Inflammation Mediators; Male; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NF-kappa B; Signal Transduction; Stilbenes; Toll-Like Receptor 5; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Tumor-associated macrophages (TAMs) polarized to the M2 phenotype play key roles in tumor progression in different cancer types, including lung cancer. MUC1 expression in various types of cancer is an indicator of poorer prognosis. Elevated MUC1 expression has been reported in inflammatory lung macrophages and is associated with lung cancer development. Here, we investigated the role of M2-polarized TAMs (M2-TAMs) in the generation of lung cancer stem cells (LCSCs) and tested pterostilbene, a small-molecule agent that modulates MUC1 expression in lung cancer cells, with the goal of subverting the microenvironment toward a favorable anti-tumor impact. We found that MUC1 was overexpressed in lung cancer patients, which was associated with poor survival rates. M2-TAMs and cancer cell lines were co-cultured in an experimental tumor microenvironment model. The expression levels of MUC1 and cancer stemness genes significantly increased in lung cancer cells in the presence of the M2-TAM cells. Intriguingly, pterostilbene dose-dependently suppressed self-renewal ability in M2-TAMs-co-cultured lung cancer cells, and this suppression was accompanied by downregulation of MUC1, NF-κB, CD133, β-catenin, and Sox2 expression. Moreover, MUC1-silenced M2-TAMs exhibited a significantly lower ability to promote LCSC generation and decreased levels of NF-κB, CD133, and Sox2. The results suggest that MUC1 plays an important role in TAM-induced LCSC progression. Pterostilbene may have therapeutic potential for modulating the unfavorable effects of TAMs in lung cancer progression.

Topics: A549 Cells; AC133 Antigen; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Separation; Coculture Techniques; Disease Progression; Flow Cytometry; Gene Expression Profiling; Gene Silencing; Humans; Immune System; Inflammation; Lung Neoplasms; Macrophages; Mucin-1; Neoplastic Stem Cells; Phenotype; Prognosis; Stilbenes; Treatment Outcome; Tumor Microenvironment

Sirtuin type 1 (Sirt1) and protein kinase B (Akt2) are associated with development of obesity and inflammation, but the molecular mechanisms of Sirt1 and Akt2 interaction on adipose inflammation remain unclear. To explore these mechanisms, a mouse model was used. Mice were fed with a high-fat diet (HFD) for 8 weeks, with interventions of resveratrol (RES) or nicotinamide (NAM) during the last 15 days. The HFD reduced Sirt1 mRNA in adipose tissue and elevated interleukin-6 (IL-6) expression. RES reduced the adipose tissue weight, increased the Sirt1 mRNA level, and reduced both mRNA and protein levels of IL-6, MCP-1, inducible nitric oxide synthase, and TNF-α by inhibiting phosphorylation of Akt2 in adipose tissue. Additionally, macrophage type I marker genes were reduced while macrophage type II marker genes were elevated by RES addition. Moreover, activation of Akt2 signal by using insulin significantly blunted the inhibitory effect of RES on adipose inflammation. Immunoprecipitation assay demonstrated that RES enhances the protein-protein interaction between Sirt1 and Akt2, but NAM inhibits this interaction. Furthermore, Sirt1 significantly reduced the levels of raptor and inactivated mammalian target of rapamycin (mTOR)C1 signal by interacting with Akt2, and confirmed that RES attenuated adipose inflammation by inhibiting the mTOR/S6K1 pathway via rapamycin.

Topics: Adaptor Proteins, Signal Transducing; Animals; Anti-Obesity Agents; Cells, Cultured; Diet, High-Fat; Enzyme Activation; Inflammation; Insulin; Male; Mice; Niacinamide; Obesity; Proto-Oncogene Proteins c-akt; Regulatory-Associated Protein of mTOR; Resveratrol; Ribosomal Protein S6 Kinases, 90-kDa; Signal Transduction; Sirtuin 1; Stilbenes; Subcutaneous Fat; TOR Serine-Threonine Kinases

Resveratrol is known to improve metabolic dysfunction associated with obesity. Visceral obesity is a sign of aging and is considered a risk factor for ischemic stroke. In this study, we investigated the effects of resveratrol on inflammation in visceral adipose tissue and the brain and its effects on ischemic brain injury in aged female mice. Mice treated with resveratrol (0.1 mg/kg, p.o.) for 10 days showed reduced levels of interleukin-1β and tumor necrosis factor-α, as well as a reduction in the size of adipocytes in visceral adipose tissue. Resveratrol also reduced interleukin-1β and tumor necrosis factor-α protein levels and immunoglobulin G extravasation in the brain. Mice treated with resveratrol demonstrated smaller infarct size, improved neurological function, and blunted peripheral inflammation at 3 days postischemic stroke. These results showed that resveratrol counteracted inflammation in visceral adipose tissue and in the brain and reduced stroke-induced brain injury and peripheral inflammation in aged female mice. Therefore, resveratrol administration can be a valuable strategy for the prevention of age-associated and disease-provoked inflammation in postmenopausal women.

Topics: Adipocytes; Animals; Brain; Brain Ischemia; Encephalitis; Female; Humans; Immunoglobulin G; Inflammation; Interleukin-1beta; Intra-Abdominal Fat; Mice, Inbred C57BL; Postmenopause; Resveratrol; Stilbenes; Stroke; Tumor Necrosis Factor-alpha

Increased molecular understanding of multifactorial diseases paves the way for novel therapeutic approaches requiring sophisticated carriers for intracellular delivery of actives. We designed and characterized self-assembling lipid-core nanocapsules for coencapsulation of two poorly soluble natural polyphenols curcumin and resveratrol. The polyphenols were identified as high-potential therapeutic candidates intervening in the intracellular inflammation cascade of chondrocytes during the progress of osteoarthritis. To elucidate the interplay between chondrocytes and nanocapsules and their therapeutic effect, we pursued a complementary analytical approach combining label-free visualization with biological assays. Primary human chondrocytes did not show any adverse effects upon nanocapsule application and coherent anti-Stokes Raman scattering images visualized their intracellular uptake. Further, by systematically blocking different uptake mechanisms, an energy independent uptake into the cells could be identified. Additionally, we tested the therapeutic effect of the polyphenol-loaded carriers on inflamed chondrocytes. Treatment with nanocapsules resulted in a major reduction of nitric oxide levels, a well-known apoptosis trigger during the course of osteoarthritis. For a more profound examination of this protective effect on joint cells, we pursued studies with atomic force microscopy investigations. Significant changes in the cell cytoskeleton as well as prominent dents in the cell membrane upon induced apoptosis were revealed. Interestingly, these effects could not be detected for chondrocytes which were pretreated with the nanocapsules. Overall, besides presenting a sophisticated carrier system for joint application, these results highlight the necessity of establishing combinatorial analytical approaches to elucidate cellular uptake, the interplay of codelivered drugs and their therapeutic effect on the subcellular level.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Chondrocytes; Curcumin; Drug Carriers; Grape Seed Extract; Humans; Inflammation; Microscopy, Atomic Force; Nanocapsules; Nonlinear Optical Microscopy; Particle Size; Polyphenols; Polysorbates; Resveratrol; Stilbenes; Vitis

This study aims to investigate the effects of metformin and resveratrol on muscle insulin resistance with emphasis on the regulation of lipolysis in hypoxic adipose tissue. ICR mice were fed with high fat diet (HFD) for 10days with administration of metformin, resveratrol, or intraperitoneal injection of digoxin. Adipose hypoxia, inflammation and cAMP/PKA-dependent lipolysis were investigated. Moreover, lipid deposition and insulin resistance were examined in the muscle. Metformin and resveratrol attenuated adipose hypoxia, inhibited HIF-1α expression and inflammation in the adipose tissue of HFD-fed mice. Metformin and resveratrol inhibited lipolysis through prevention of PKA/HSL activation by decreasing the accumulation of cAMP via preserving PDE3B. Metformin and resveratrol reduced FFAs influx and DAG accumulation, and thus improved insulin signaling in the muscle by inhibiting PKCθ translocation. This study presents a new view of regulating lipid metabolism to ameliorate insulin resistance and provides the clinical guiding significance for obesity and type 2 diabetes with metformin and resveratrol treatment.

Topics: 3T3-L1 Cells; Adipose Tissue; Administration, Oral; Animals; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diet, High-Fat; Diglycerides; Fatty Acids; Feeding Behavior; Glucose; Hypoxia; Inflammation; Insulin; Insulin Resistance; Lipolysis; Male; Metformin; Mice; Mice, Inbred ICR; Models, Biological; Muscles; Resveratrol; Signal Transduction; Stilbenes

Brain metastasis is one of the chief causes of mortality in breast cancer patients, but the mechanisms that drive this process remain poorly understood. Here, we report that brain metastatic cells expressing high levels of c-Met promote the metastatic process via inflammatory cytokine upregulation and vascular reprogramming. Activated c-Met signaling promoted adhesion of tumor cells to brain endothelial cells and enhanced neovascularization by inducing the secretion of IL8 and CXCL1. Additionally, stimulation of IL1β secretion by activation of c-Met induced tumor-associated astrocytes to secrete the c-Met ligand HGF. Thus, a feed-forward mechanism of cytokine release initiated and sustained by c-Met fed a vicious cycle that generated a favorable microenvironment for metastatic cells. Reinforcing our results, we found that pterostilbene, a compound that penetrates the blood-brain barrier, could suppress brain metastasis by targeting c-Met signaling. These findings suggest a potential utility of this natural compound for chemoprevention. Cancer Res; 76(17); 4970-80. ©2016 AACR.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Female; Heterografts; Humans; Inflammation; Mice; Mice, Nude; Neoplasm Invasiveness; Neovascularization, Pathologic; Proto-Oncogene Proteins c-met; Signal Transduction; Stilbenes; Transcriptome; Tumor Microenvironment

Adipose tissue inflammation is believed to play a pivotal role in the development obesity-related morbidities such as insulin resistance. However, it is not known how this (low-grade) inflammatory state develops. It has been proposed that the leakage of lipopolysaccharides (LPS), originating from the gut microbiota, through the gut epithelium could drive initiation of inflammation. To get a better understanding of which proteins and intracellular pathways are affected by LPS in adipocytes, we performed SILAC proteomic analysis and identified proteins that were altered in expression. Furthermore, we tested the anti-inflammatory compound resveratrol. A total of 927 proteins were quantified by the SILAC method and of these 57- and 64 were significantly up- and downregulated by LPS, respectively. Bioinformatic analysis (GO analysis) revealed that the upregulated proteins were especially involved in the pathways of respiratory electron transport chain and inflammation. The downregulated proteins were especially involved in protein glycosylation. One of the latter proteins, GALNT2, has previously been described to regulate the expression of liver lipases such as ANGPTL3 and apoC-III affecting lipid metabolism. Furthermore, LPS treatment reduced the protein levels of the insulin sensitizing adipokine, adiponectin, and proteins participating in the final steps of triglyceride- and cholesterol synthesis. Generally, resveratrol opposed the effect induced by LPS and, as such, functioning as an ameliorating factor in disease state. Using an unbiased proteomic approach, we present novel insight of how the proteome is altered in adipocytes in response to LPS as seen in obesity. We suggest that LPS partly exerts its detrimental effects by altering glycosylation processes of the cell, which is starting to emerge as important posttranscriptional regulators of protein expression. Furthermore, resveratrol could be a prime candidate in ameliorating dysfunctioning adipose tissue induced by inflammatory stimulation.

Topics: Adipocytes; Adipose Tissue; Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Angiopoietins; Gastrointestinal Microbiome; Gene Expression Regulation; Glycosylation; Humans; Inflammation; Insulin; Insulin Resistance; Lipid Metabolism; Lipogenesis; Lipopolysaccharides; N-Acetylgalactosaminyltransferases; Obesity; Polypeptide N-acetylgalactosaminyltransferase; Proteome; Proteomics; Resveratrol; Stilbenes

Artocarpus heterophyllus, a popular tropical fruit commonly known as the jackfruit tree, is normally planted in subtropical or tropical areas. Since a variety of phytochemicals isolated from A. heterophyllus have been found to possess potently anti-inflammatory, antiviral and antimalarial activities, researchers have devoted much interest to its potential pharmaceutical value. However, the exact mechanism underlying its anti-inflammatory activity is not well characterized. In this study, seven natural products isolated from A. heterophyllus, including 25-Hydroxycycloart-23-en-3-one (HY), Artocarpin (AR), Dadahol A (DA), Morachalcone A (MA), Artoheterophyllin B (AB), Cycloheterophyllin (CY) and Moracin C (MC) were collected. Lipopolysaccharide (LPS)-stimulated inflammatory response in RAW264.7 macrophages were used in this study. Among these compounds, MC significantly inhibited LPS-activated reactive oxygen species (ROS) and nitric oxide (NO) release without marked cytotoxicity. Furthermore, MC effectively reduced LPS stimulated up-regulation of mRNA and protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and serval pro-inflammatory cytokines (interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α)). Mechanistic studies revealed that the anti-inflammatory effect of MC was associated with the activation of the mitogen activated protein kinases (MAPKs) (including p38, ERK and JNK) and nuclear factor-κB (NF-κB) pathways, especially reducing the nuclear translocation of NF-κB p65 subunit as revealed by nuclear separation experiment and confocal microscopy.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Artocarpus; Benzofurans; Blotting, Western; Cell Proliferation; Cells, Cultured; Cytokines; Fluorescent Antibody Technique; HEK293 Cells; Humans; Inflammation; Lipopolysaccharides; Macrophages; Mice; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes

Toll-like receptor 4 (TLR4) has been proven to play a critical role in neuroinflammation and to represent an important therapeutic target following subarachnoid hemorrhage (SAH). Resveratrol (RSV), a natural occurring polyphenolic compound, has a powerful anti-inflammatory property. However, the underlying molecular mechanisms of RSV in protecting against early brain injury (EBI) after SAH remain obscure. The purpose of this study was to investigate the effects of RSV on the TLR4-related inflammatory signaling pathway and EBI in rats after SAH. A prechiasmatic cistern SAH model was used in our experiment. The expressions of TLR4, high-mobility group box 1 (HMGB1), myeloid differentiation factor 88 (MyD88), and nuclear factor-κB (NF-κB) were evaluated by Western blot and immunohistochemistry. The expressions of Iba-1 and pro-inflammatory cytokines in brain cortex were determined by Western blot, immunofluorescence staining, or enzyme-linked immunosorbent assay. Neural apoptosis, brain edema, and neurological function were further evaluated to investigate the development of EBI. We found that post-SAH treatment with RSV could markedly inhibit the expressions of TLR4, HMGB1, MyD88, and NF-κB. Meanwhile, RSV significantly reduced microglia activation, as well as inflammatory cytokines leading to the amelioration of neural apoptosis, brain edema, and neurological behavior impairment at 24 h after SAH. However, RSV treatment failed to alleviate brain edema and neurological deficits at 72 h after SAH. These results indicated that RSV treatment could alleviate EBI after SAH, at least in part, via inhibition of TLR4-mediated inflammatory signaling pathway.

Topics: Animals; Anti-Inflammatory Agents; Brain; Inflammation; Male; Myeloid Differentiation Factor 88; NF-kappa B; Rats; Resveratrol; Signal Transduction; Stilbenes; Subarachnoid Hemorrhage; Toll-Like Receptor 4

Many patients with diabetes are at increased risk of cognitive dysfunction and dementia. Resveratrol, a polyphenol found mainly in grapes and red wine, has antioxidant, anti-inflammatory, and neuroprotective activities. Studies demonstrated that resveratrol could prevent memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats. However, whether administration of resveratrol could modulate the structural synaptic plasticity in diabetic rats remains unknown. Therefore, we tested its influence against cognitive dysfunction as well as on hippocampal structural synaptic plasticity in streptozotocin-induced diabetic rats. Our results showed that the cognitive performances in diabetic group were markedly deteriorated, accompanied by noticeable alterations in oxidative as well as inflammation parameters, SYN and GAP-43 expression were reduced in the hippocampus. In contrast, chronic treatment with resveratrol (10, 20mg/kg) improved neuronal injury and cognitive performance by attenuating oxidative stress and inflammation as well as inhibiting synapse loss in diabetic rats. In conclusion, the present study suggested that oral supplementation of resveratrol might be a potential therapeutic strategy for the treatment and/or prevention of diabetic encephalopathy.

Topics: Animals; Antioxidants; Blood Glucose; Cognition; Cognition Disorders; Cognitive Dysfunction; Diabetes Complications; Diabetes Mellitus, Experimental; Hippocampus; Inflammation; Male; Maze Learning; Memory; Neuronal Plasticity; Oxidative Stress; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Superoxide Dismutase; Synapses

The present investigation reports the development of liposomes for the co-delivery of naturally occurring polyphenols, namely quercetin and resveratrol. Small, spherical, uni/bilamellar vesicles were produced, as demonstrated by light scattering, cryo-TEM, SAXS. The incorporation of quercetin and resveratrol in liposomes did not affect their intrinsic antioxidant activity, as DPPH radical was almost completely inhibited. The cellular uptake of the polyphenols was higher when they were formulated in liposomes, and especially when co-loaded rather than as single agents, which resulted in a superior ability to scavenge ROS in fibroblasts. The in vivo efficacy of the polyphenols in liposomes was assessed in a mouse model of skin lesion. The topical administration of liposomes led to a remarkable amelioration of the tissue damage, with a significant reduction of oedema and leukocyte infiltration. Therefore, the proposed approach based on polyphenol vesicular formulation may be of value in the treatment of inflammation/oxidative stress associated with pre-cancerous/cancerous skin lesions.

Topics: Administration, Topical; Animals; Antioxidants; Disease Models, Animal; Drug Combinations; Drug Delivery Systems; Dynamic Light Scattering; Female; Fibroblasts; Humans; Inflammation; Liposomes; Mice; Oxidative Stress; Quercetin; Reactive Oxygen Species; Resveratrol; Skin Neoplasms; Stilbenes

2,3,4',5-Tetrahydroxystilbene-2-O-β-d-glucoside (THSG) affects neuroinflammation-related neurodegenerative diseases and inhibits neuroinflammatory mediators. However, the detailed impacts and underlying mechanisms of THSG on neuroinflammatory responses are still unclear. The aim of this study was to investigate the anti-neuroinflammatory mechanism of THSG via AMPK/Nrf2 signaling pathways. This study showed that THSG attenuated LPS-induced iNOS, COX-2, TNF-α, and IL-6 activation in microglia. Furthermore, it was observed that activation of IκBα and NF-κB was significantly increased upon LPS stimulation, and suppressed by THSG treatment in a dose-dependent manner. The expression of HO-1 and NQO1, as well as Nrf2 activation, was induced by THSG in microglia. The promoter activity of ARE and HO-1 also increased in a dose-dependent manner following THSG treatment. Nrf2/HO-1/NQO1 has anti-inflammatory properties; the knock-down of Nrf2/HO-1/NQO1 by specific siRNA prevented the THSG-mediated inhibition of iNOS and COX-2 promoter activity. Consistent with this concept, the phosphorylation of LKB1, CaMKII, and AMPK were elevated after THSG treatment. The blockade of AMPK by a pharmacological inhibitor prevented THSG-induced HO-1 and NQO1 expression. The anti-inflammatory properties of THSG were also reversed by treatment with an AMPK inhibitor. In conclusion, we demonstrated that THSG attenuates the LPS-induced neuroinflammatory response mediated by AMPK/Nrf2 signaling pathways.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Apoptosis; Blotting, Western; Cell Proliferation; Cells, Cultured; Cytokines; Glucosides; Inflammation; Lipopolysaccharides; Mice; Mice, Inbred ICR; Microglia; NF-E2-Related Factor 2; NF-kappa B; Nitric Oxide; Phosphorylation; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Stilbenes

Chronic chagasic cardiomyopathy (CCM) is presented by increased oxidative/inflammatory stress and decreased mitochondrial bioenergetics. SIRT1 senses the redox changes and integrates mitochondrial metabolism and inflammation; and SIRT1 deficiency may be a major determinant in CCM. To test this, C57BL/6 mice were infected with Trypanosoma cruzi (Tc), treated with SIRT1 agonists (resveratrol or SRT1720), and monitored during chronic phase (~150 days post-infection). Resveratrol treatment was partially beneficial in controlling the pathologic processes in Chagas disease. The 3-weeks SRT1720 therapy provided significant benefits in restoring the left ventricular (LV) function (stroke volume, cardiac output, ejection fraction etc.) in chagasic mice, though cardiac hypertrophy presented by increased thickness of the interventricular septum and LV posterior wall, increased LV mass, and disproportionate synthesis of collagens was not controlled. SRT1720 treatment preserved the myocardial SIRT1 activity and PGC1α deacetylation (active-form) that were decreased by 53% and 9-fold respectively, in chagasic mice. Yet, SIRT1/PGC1α-dependent mitochondrial biogenesis (i.e., mitochondrial DNA content, and expression of subunits of the respiratory complexes and mtDNA replication machinery) was not improved in chronically-infected/SRT1720-treated mice. Instead, SRT1720 therapy resulted in 2-10-fold inhibition of Tc-induced oxidative (H2O2 and advanced oxidation protein products), nitrosative (inducible nitric oxide synthase, 4-hydroxynonenal, 3-nitrotyrosine), and inflammatory (IFNγ, IL1β, IL6 and TNFα) stress and inflammatory infiltrate in chagasic myocardium. These benefits were delivered through SIRT1-dependent inhibition of NFκB transcriptional activity. We conclude that Tc inhibition of SIRT1/PGC1α activity was not a key mechanism in mitochondrial biogenesis defects during Chagas disease. SRT1720-dependent SIRT1 activation led to suppression of NFκB transcriptional activity, and subsequently, oxidative/nitrosative and inflammatory pathology were subdued, and antioxidant status and LV function were enhanced in chronic chagasic cardiomyopathy.

Topics: Animals; Antioxidants; Blotting, Western; Chagas Cardiomyopathy; Disease Models, Animal; Heart; Heterocyclic Compounds, 4 or More Rings; Humans; Inflammation; Mice; Mice, Inbred C57BL; NF-kappa B; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Transcriptome; Trypanosoma cruzi

Myocardial fibrosis and inflammation are intricately linked in diabetic cardiomyopathy (DCM), and resveratrol has been shown to attenuate oxidative stress, inflammation, and fibrosis in several cell types or animal models. High mobility group box 1 (HMGB 1), a proinflammatory cytokine, has been reported to regulate fibrosis and inflammation in various organs. Then the present study aimed to reveal the expression of HMGB 1-mediated signaling pathway and oxidative stress in resveratrol-treated diabetic mice. The significant increase in serum HMGB 1 concentration in diabetic mice was attenuated by treatment with resveratrol. Similarly, western blot analysis revealed a significant increase of HMGB 1 protein in monocytes and heart tissues of diabetic mice, and resveratrol partly normalized the changes. In addition, resveratrol abrogated the increased expression of HMGB 1-mediated signaling pathway, oxidative stress, fibrosis, and inflammation in diabetic hearts. In conclusion, inhibition of HMGB 1-mediated signaling pathway and oxidative stress may contribute to resveratrol-induced anti-inflammatory and antifibrotic effects in DCM.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Fibrosis; Heart; HMGB1 Protein; Inflammation; Male; Membrane Glycoproteins; Mice; Monocytes; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Protective Agents; Resveratrol; Signal Transduction; Src Homology 2 Domain-Containing, Transforming Protein 1; Stilbenes

The aim of this study was to investigate the effect of natural antioxidants resveratrol and quercetin on oxidative stress and secondary cell damage in rats with acute spinal cord injury.. In this experimental study, 42 male Sprague-Dawley rats were used. Spinal cord injury was performed with clip compression method at level of T4-5. The study was conducted using 6 groups: control, trauma, trauma and solvent, trauma and resveratrol, trauma and quercetin, and trauma with combined resveratrol and quercetin. All rats were euthanized 48 hours after the procedure. Effects of resveratrol and quercetin on serum and tissue total antioxidant capacity and paraoxanase activity level were examined.. Compared to trauma group, there was a significant increase in total antioxidant capacity and paraoxanase activity level in resveratrol, quercetin, and combined treatment groups. There was no significant difference between resveratrol and quercetin groups with regard to total antioxidant capacity and paraoxanase activity level. Total antioxidant capacity and paraoxanase activity level were significantly higher in solvent group than trauma group. In histopathological evaluation, there was a decrease in polymorphonuclear leukocyte infiltration in solvent, resveratrol, quercetin, and combined treatment groups.. Biochemical and histological staining results of present study showed that resveratrol and quercetin may be effective in preventing secondary damage in spinal cord injury.

Topics: Animals; Antioxidants; Disease Models, Animal; Inflammation; Male; Oxidative Stress; Quercetin; Rats; Rats, Sprague-Dawley; Resveratrol; Spinal Cord Injuries; Stilbenes

Neutrophils are the first cells to achieve the sites of infection or inflammation in the lungs. The massive accumulation of these cells is associated with acute and chronic lung injury. Therefore, they have been implicated in the pathogenesis of many lung diseases through the release of reactive oxygen intermediates, proteolytic enzymes and Neutrophil Extracellular Traps (NETs). The excessive and continuous release of NETs, fibers composed by decondensed chromatin coated with neutrophil proteins, are associated to the impairment of lung function in different pathological settings. Flavonoids inhibit the respiratory burst of neutrophils in mammals. However, one of these flavonoids, resveratrol has a particular chemical property. It reduce Cu(II) to Cu(I) form with concomitant formation of reactive oxygen species, which can produce DNA breakage as reported in several in vitro models. We hypothesize that direct resveratrol administration in lungs can cleave DNA in NETs, improving lung function during acute airway infections or chronic inflammatory lung diseases. If the hypothesis is correct, the control of NET formation can be used to reduce the inflammatory environment in lung after neutrophil stimuli. Additionally, the production of proinflammatory cytokines by neutrophils could be also diminished by resveratrol administration. In this sense, this flavonoid provides a multifaceted opportunity for treatment of lung diseases with strong or chronic neutrophil activation.

Topics: Acute Lung Injury; Antioxidants; Chromatin; DNA Damage; Flavonoids; Humans; Inflammation; Lung; Models, Theoretical; Neutrophils; Reactive Oxygen Species; Respiratory Function Tests; Resveratrol; Stilbenes

Topics: Animals; Antioxidants; Hypertension, Pulmonary; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; NF-E2-Related Factor 2; Random Allocation; Rats; Reactive Oxygen Species; Resveratrol; Stilbenes; Thioredoxins

Oxidative stress (OS) is important in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA) and its experimental model--adjuvant arthritis (AA). Antioxidants are scarcely studied in autoimmunity, and future analyses are needed to assess its effects in ameliorating these diseases. Although there are studies about antioxidants effects on the course of RA, their role in combination therapy has not yet been studied in detail, especially on extra-articular manifestations of AA. During the 28-d administration of pinosylvin (PIN) in monotherapy and in combination with methotrexate (MTX) to AA rats, we evaluated the impact of the treatment on selected parameters. The experiment included: healthy controls, untreated AA, AA administered 50 mg/kg b.w. of PIN daily p.o., AA administered 0.4 mg/kg b.w. of MTX twice weekly p.o. and AA treated with a combination of PIN+MTX. AA was monitored using: hind paw volume, C-reactive protein, monocyte chemotactic protein-1 (MCP-1), thiobarbituric acid reactive substances (TBARS) and F2-isoprostanes in plasma, γ-glutamyltransferase activity in spleen, activity of lipoxygenase (LOX) in lung, heme oxygenase-1 (HO-1) and nuclear factor kappa B (NF-κB) in liver and lung. PIN monotherapy significantly improved the activation of NF-κB in liver and lung, HO-1 expression and activity of LOX in the lung, MCP-1 levels in plasma (on 14th d) and plasmatic levels of F2-isoprostanes. An important contribution of PIN to MTX effect was the reduction of OS (an increase of HO-1 expression in lung and reduction of plasmatic TBARS) and decrease of LOX activity in the lung.

Topics: Animals; Antirheumatic Agents; Arthritis, Experimental; Biomarkers; C-Reactive Protein; Chemokine CCL2; Drug Synergism; Drug Therapy, Combination; F2-Isoprostanes; gamma-Glutamyltransferase; Heme Oxygenase-1; Hindlimb; Inflammation; Lipoxygenase; Liver; Lung; Male; Methotrexate; NF-kappa B; Oxidative Stress; Rats; Rats, Inbred Lew; Spleen; Stilbenes; Thiobarbituric Acid Reactive Substances

Sleep fragmentation (SF) increases food intake and the risk of obesity, and recruits macrophages to visceral white adipose tissue (VWAT) promoting tissue inflammation and insulin resistance. Administration of resveratrol (Resv) has been associated with significant improvements in high-fat diet-induced obesity, inflammation and insulin resistance.. Male mice were subjected to SF or sleep control conditions for 8 weeks, and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin and leptin were obtained and VWAT insulin sensitivity tests were performed (phosphorylated AKT/total AKT), along with flow-cytometric assessments for VWAT macrophages (M1 and M2) and T-cell lymphocytes (CD4+, CD8+ and T regulatory cell (Treg)).. SF-Veh and SF-Resv mice showed increased food consumption and weight gain. However, although SF-Veh mice exhibited increased fasting insulin and leptin levels, and reduced VWAT p-AKT/AKT responses to insulin, such alterations were abrogated in SF-Resv-treated mice. Increases in M1, reduced M2 counts and increased tumor necrosis factor-α release emerged in SF-Veh macrophages compared with all other three groups. Similarly, increased CD8+ and reduced Treg lymphocyte counts were apparent in SF-Veh.. Resveratrol does not reverse the SF-induced increases in food intake and weight gain, but markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy in the context of sleep disorders manifesting metabolic morbidity.

Topics: Animals; Anti-Obesity Agents; Diet, High-Fat; Disease Models, Animal; Eating; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Male; Mice; Mice, Inbred C57BL; Obesity; Resveratrol; Sleep Apnea Syndromes; Stilbenes; Tumor Necrosis Factor-alpha; Weight Gain

The role of pterostilbene (Pte) in inflammation induced by ischemia/reperfusion is not well understood. The aim of this study was to investigate whether Pte modulates neutrophil accumulation and the induction of tumor necrosis factor-α (TNF-α) in an ischemia/reperfusion (I/R)-injured rat heart model. Rats were randomly exposed to a sham operation, myocardial ischemia/reperfusion (MI/R) alone, MI/R+Pte, MI/R+Pte+L-NAME and MI/R+Pte+ (methylene blue) MB. The results demonstrated that compared with MI/R, Pte reduced the area of myocardial infarction, the levels of myocardial myeloperoxidase, serum creatinine kinase and lactate dehydrogenase, and the production of serum and myocardial TNF-α. These Pte-induced effects were eliminated by the administration of L-NAME, a nitric oxide (NO) synthase inhibitor, and MB, a cyclic guanosine monophosphate (cGMP) inhibitor. In conclusion, Pte produces cardioprotective and anti-inflammatory effects. These effects may be associated with an increase in NO production, the inhibition of neutrophil accumulation, and induction of TNF-α and cGMP signaling pathways in myocardium subjected to MI/R.

Topics: Animals; Cardiotonic Agents; Creatine Kinase; Inflammation; L-Lactate Dehydrogenase; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Neutrophil Infiltration; Rats; Stilbenes; Tumor Necrosis Factor-alpha

The aim of our study was to evaluate the effectiveness of resveratrol in experimentally induced endometrial implants in rats through inhibiting angiogenesis and inflammation. Endometrial implants were surgically induced in 24 female Wistar-Albino rats in the first surgery. After confirmation of endometriotic foci in the second surgery, the rats were divided into resveratrol (seven rats), leuprolide acetate (eight rats), and control (seven rats) groups and medicated for 21 d. In the third surgery, the measurements of mean areas and histopathological analysis of endometriotic lesions, VEGF, and MCP-1 measurements in blood and peritoneal fluid samples, and immunohistochemical staining were evaluated. After treatment, significant reductions in mean areas of implants (p < 0.01) and decreased mean histopathological scores of the implants (p < 0.05), mean VEGF-staining scores of endometriotic implants (p = 0.01), and peritoneal fluid levels of VEGF and MCP-1 (p < 0.01, for VEGF and p < 0.01, for MCP-1) were found in the resveratrol and leuprolide acetate groups. Serum VEGF (p = 0.05) and MCP-1 (p = 0.01) levels after treatment were also significantly lower in the resveratrol and leuprolide acetate groups. Resveratrol appears to be a potential novel therapeutic agent in the treatment of endometriosis through inhibiting angiogenesis and inflammation. Further studies are needed to determine the optimum effective dose in humans and to evaluate other effects on reproductive physiology.

Topics: Angiogenesis Inhibitors; Animals; Ascitic Fluid; Disease Models, Animal; Endometriosis; Endometrium; Female; Inflammation; Leuprolide; Neovascularization, Pathologic; Rats; Rats, Wistar; Resveratrol; Stilbenes; Therapeutics

It has been previously reported that Toll‑like receptor 4 (TLR4)/NF‑κB signaling mediates early inflammation during myocardial ischemia and reperfusion. It has additionally been suggested that resveratrol produces cardioprotective and anti‑inflammatory effects. The aim of the present study was to investigate whether resveratrol could modulate TLR4/NF‑κB signaling, reduce neutrophil accumulation and TNF‑α induction in an ischemia/reperfusion injured rat heart model. Rats were randomly exposed to a sham operation, myocardial ischemia and reperfusion (MI/R), MI/R + resveratrol or MI/R + resveratrol + L‑NAME. The data showed that following MI/R, the expression of myocardial TLR4 and NF‑κB increased significantly in the area of induced ischemia. As compared with MI/R, resveratrol significantly attenuated the expression of TLR4 and NF‑κB and reduced the levels of myeloperoxidase, serum and myocardial TNF‑α production, myocardial infarct size and myocardial apoptosis induced by MI/R. All the effects of resveratrol were abolished upon application of L‑NAME, a nitric oxide (NO) synthase inhibitor. These data provide evidence that resveratrol inhibits TLR4/NF‑κB signaling in the rat heart subjected to MI/R, and the anti‑inflammatory effect of resveratrol is associated with NO production.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Disease Models, Animal; Down-Regulation; Heart; Inflammation; Male; Myocardial Reperfusion Injury; Myocardium; Neutrophils; NF-kappa B; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peroxidase; Rats; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Stilbenes; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Excessive inflammation is considered a critical factor in many human diseases. Oxyresveratrol(trans-2,3',4,5'-tetrahydroxystilbene), a natural hydroxystilbene, has been shown to possess antioxidant and free radical-scavenging activity. In this study, we investigated the effects of oxyresveratrol (OxyR) on the lipopolysaccharide (LPS)-induced production of inflammatory cytokines and mediators and further explored the mechanism of action in RAW264.7 murine macrophage cell line. Production of nitric oxide (NO), prostaglandin E2 (PGE2), messenger RNA (mRNA) and protein expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin 6 (IL-6), and granulocyte macrophage colony-stimulating factor (GM-CSF), phosphorylation of mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38), and the activation of nuclear factor κ-light chain enhancer of activated B cells (NFκB) with OxyR were assayed in LPS-stimulated RAW264.7 cells. OxyR inhibited the productions of NO, PGE2, IL-6, and GM-CSF significantly in LPS-stimulated RAW264.7 cells. OxyR suppressed mRNA and protein expressions of iNOS, COX-2, IL-6, and GM-CSF in LPS-stimulated RAW264.7 cells. OxyR suppressed the phosphorylation of Akt and JNK and p38 MAPKs and the translocation of NFκB p65 subunit into the nucleus. These results indicate that OxyR inhibits LPS-stimulated inflammatory responses though the blocking of MAPK and NFκB signaling pathway in macrophages, and suggest that OxyR possesses anti-inflammatory effects.

Topics: Animals; Cell Line; Cyclooxygenase 2; Dinoprostone; Granulocyte-Macrophage Colony-Stimulating Factor; Inflammation; Interleukin-6; Lipopolysaccharides; Macrophages; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphorylation; Plant Extracts; Protein Kinases; Stilbenes

The NLRP3 inflammasome is a caspase-1-containing multi-protein complex that controls the release of IL-1β and plays important roles in the development of inflammatory disease. Here, we report that resveratrol, a polyphenolic compound naturally produced by plants, inhibits NLRP3 inflammasome-derived IL-1β secretion and pyroptosis in macrophages. Resveratrol inhibits the activation step of the NLRP3 inflammasome by suppressing mitochondrial damage. Resveratrol also induces autophagy by activating p38, and macrophages treated with an autophagy inhibitor are resistant to the suppressive effects of resveratrol. In addition, resveratrol administration mitigates glomerular proliferation, glomerular sclerosis, and glomerular inflammation in a mouse model of progressive IgA nephropathy. These findings were associated with decreased renal mononuclear leukocyte infiltration, reduced renal superoxide anion levels, and inhibited renal NLRP3 inflammasome activation. Our data indicate that resveratrol suppresses NLRP3 inflammasome activation by preserving mitochondrial integrity and by augmenting autophagy.

Topics: Adaptor Proteins, Signal Transducing; Adenosine Triphosphate; Animals; Apoptosis Regulatory Proteins; Autophagy; Calcium-Binding Proteins; Carrier Proteins; Caspase 1; Cells, Cultured; Gene Expression Regulation; Inflammation; Interleukin-1beta; Macrophages; Mice; Mitochondria; Mitogen-Activated Protein Kinase Kinases; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphorylation; Protein Kinase C; Reactive Oxygen Species; Resveratrol; Stilbenes

The purpose of this study was to evaluate the effects of polydatin (PD) on cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions at protein and transcriptional levels, as well as the production of prostaglandin E2 (PGE2) and nitric oxide (NO) in lipopolysaccharide (LPS)-induced macrophage RAW 264.7 cells. To elucidate the underlying mechanism responsible for these symptoms, we investigated the phosphorylation of mitogen-activated protein kinase (MAPK) pathway and nuclear factor-κB (NF-κB) expression. NO was analyzed with the Griess method. PGE2 was measured by enzyme-linked immunosorbent assay (ELISA). iNOS and COX-2 messenger RNA (mRNA) were identified by qPCR assay. iNOS, COX-2, NF-κB, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 protein expressions were detected with Western blot. The results revealed that PD effectively inhibited NO and PGE2 production, and it is not surprising that PD reduced iNOS and COX-2 expression at protein and transcriptional levels. Additionally, PD significantly ameliorated the activation of NF-κB and the phosphorylation of MAPKs in LPS-induced RAW 264.7 macrophages. These findings suggested that PD exerted potent anti-inflammatory activity in macrophages.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Cell Survival; Cyclooxygenase 2; Dinoprostone; Drugs, Chinese Herbal; Extracellular Signal-Regulated MAP Kinases; Glucosides; Inflammation; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Macrophages; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; p38 Mitogen-Activated Protein Kinases; Phosphorylation; RAW 264.7 Cells; RNA, Messenger; Stilbenes; Transcription, Genetic

The aim of this study was to preliminarily investigate the effects of resveratrol on the treatment of systemic inflammatory response induced by severe burn wounding. Through the simulation experiment in vivo on burned mice and simulative experiment in vitro on mice macrophage respectively, differences of the related pro-inflammatory cytokines and SIRT1 expression levels between the resveratrol-treated group and the untreated control group were detected and analyzed. The results of the simulation experiment in vivo on burned mice manifested that the survival rate of the mice in the resveratrol-treated group was markedly higher than that of controls (p<0.05). Resveratrol could significantly reduce the levels of pro-inflammatory factors TNF-α, IL-1β, and IL-6 in serum (p<0.01) and greatly elevate the expression level of SIRT1 (p<0.01). The results of the simulative experiment in vitro on mice macrophage showed no significant difference in TNF-α, IL-1β, or IL-6 contents among three groups (C, mice macrophage control group; R, resveratrol-treated macrophage group; I, SIRT1-inhibitor-treated macrophage group). Whereas, after lipopolysaccharide (LPS) activation (L group), macrophage TNF-α, IL-1β, and IL-6 levels were significantly increased in L group, dramatically higher than those in L+R group (LPS and resveratrol treatment group) (p<0.01). After adding SITR1 inhibitor, three pro-inflammatory cytokines in L+R+I group all showed significant increases compared with those in L+R group (p<0.01). LPS activated macrophages were able to promote the expression of pro-inflammatory cytokines. By upregulating the expression levels of SIRT1, resveratrol could effectively inhibit the inflammation cascade reaction and increase the survival rate of severe burn with bacterial infections in a large extent.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Burns; Cells, Cultured; Female; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Pseudomonas aeruginosa; Pseudomonas Infections; Resveratrol; Sirtuin 1; Stilbenes; Survival Rate; Tumor Necrosis Factor-alpha

Acute kidney injury (AKI) is the most frequent and serious complication in sepsis, a potentially deadly inflammatory response induced by bacterial, viral, or fungal infection. LPS-induced AKI is associated with an abnormal inflammatory response, including renal endothelial dysfunction and renal inflammation. Resveratrol, a natural phytoalexin with low toxicity and anti-inflammatory properties, is known to protect endothelial cells and modulate the immune response in sepsis.. This study investigates the potential protective effects of resveratrol on AKI induced by LPS exposure of mice. Resveratrol was administered as a pre- and posttreatment, or as a posttreatment alone following LPS injection and compared to control groups. Resveratrol significantly improved kidney function and lowered serum and kidney tissue inflammatory cytokine levels. Consistently, resveratrol prevented endotoxin-induced disruption of endothelial cell permeability and inhibited inflammation of kidney tissue. Resveratrol treatment attenuated the effects of LPS on macrophages, with significant inhibition of activation, cytokine release, and Toll-like receptor 4 activation. Resveratrol treatment also resulted in decreased expression of iNOS, Bcl-2, and Bcl-xL in macrophages, which was linked with induction of apoptosis in macrophages.. Our studies suggest that resveratrol might represent a novel therapeutic agent to prevent and treat sepsis-induced AKI.

Topics: Acute Kidney Injury; Animals; Apoptosis; Capillary Permeability; Female; Inflammation; Kidney; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred C57BL; NF-kappa B; Resveratrol; Signal Transduction; Stilbenes; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Inflammation is a hallmark of aging. Caloric restriction and resveratrol (RSV) have shown important effects on prevention of oxidative stress and inflammation. Here, we investigate the progression of proinflammatory markers in liver during aging and the effect of RSV on inflammation markers in the liver of old male C57BL/6J mice. Young (2 months), mature (12 months) and old (18 months) mice were fed during 6 months with RSV. Levels of IL-1β, IL-6, IL-10, IL-17 and TNF-α were evaluated by ELISA in mice liver. Levels of pro-inflammatory cytokines, IL-1β, IL-6, IL-17 and TNF-α and also their respective mRNA increased in the liver from old mice. However, RSV decreased these levels in the case of IL-1β and TNF-α but only in old mice showing no effect on young and mature animals. This reduction was also found at the mRNA level. Levels of mRNA of the components of NALP-3 inflammasome, ASC, CASP-1, NALP-1 and NALP-3, also showed an age-dependent increase that was reversed by RSV. Furthermore, cyclooxygenase 2 levels, a marker of proinflammatory innate immune activity, were also upregulated in aged liver and reversed again by RSV. In conclusion, our study confirms that aging is accompanied by an increase in the proinflammatory pattern in the liver and that RSV reduces this pattern in old mice liver.

Topics: Aging; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Cytokines; Inflammation; Liver; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Resveratrol; RNA, Messenger; Stilbenes

Polydatin and resveratrol, as major active components in Polygonum cuspidatum, have anti-inflammatory, antioxidant and antitumor functions. However, the effect and mechanism of polydatin and resveratrol on enterovirus 71 (EV71) have not been reported. In this study, resveratrol revealed strong antiviral activity on EV71, while polydatin had weak effect. Neither polydatin nor resveratrol exhibited influence on viral attachment. Resveratrol could effectively inhibit the synthesis of EV71/VP1 and the phosphorylation of IKKα, IKKβ, IKKγ, IKBα, NF-κB p50 and NF-κB p65, respectively. Meanwhile, the remarkably increased secretion of IL-6 and TNF-α in EV71-infected rhabdosarcoma (RD) cells could be blocked by resveratrol. These results demonstrated that resveratrol inhibited EV71 replication and cytokine secretion in EV71-infected RD cells through blocking IKKs/NF-κB signaling pathway. Thus, resveratrol may have potent antiviral effect on EV71 infection.

Topics: Antiviral Agents; Cytokines; Dose-Response Relationship, Drug; Enterovirus A, Human; Glucosides; I-kappa B Kinase; Inflammation; Interleukin-6; NF-kappa B; Phosphorylation; Resveratrol; Rhabdomyosarcoma; Signal Transduction; Stilbenes; Tumor Necrosis Factor-alpha; Virus Replication

High dietary fructose is an important causative factor in the development of metabolic syndrome-associated glomerular podocyte oxidative stress and injury. Here, we identified microRNA-377 (miR-377) as a biomarker of oxidative stress in renal cortex of fructose-fed rats, which correlated with podocyte injury and albuminuria in metabolic syndrome. Fructose feeding increased miR-377 expression, decreased superoxide dismutase (SOD) expression and activity, and caused O2(-) and H2O2 overproduction in kidney cortex or glomeruli of rats. This reactive oxygen species induction increased p38 MAPK phosphorylation and thioredoxin-interacting protein (TXNIP) expression and activated the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome to produce interleukin-1β in kidney glomeruli of fructose-fed rats. These pathological processes were further evaluated in cultured differentiated podocytes exposed to 5mM fructose, or transfected with miR-377 mimic/inhibitor and TXNIP siRNA, or co-incubated with p38 MAPK inhibitor, demonstrating that miR-377 overexpression activates the O2(-)/p38 MAPK/TXNIP/NLRP3 inflammasome pathway to promote oxidative stress and inflammation in fructose-induced podocyte injury. Antioxidants pterostilbene and allopurinol were found to ameliorate fructose-induced hyperuricemia, podocyte injury, and albuminuria in rats. More importantly, pterostilbene and allopurinol inhibited podocyte miR-377 overexpression to increase SOD1 and SOD2 levels and suppress the O2(-)/p38 MAPK/TXNIP/NLRP3 inflammasome pathway activation in vivo and in vitro, consistent with the reduction of oxidative stress and inflammation. These findings suggest that miR-377 plays an important role in glomerular podocyte oxidative stress, inflammation, and injury driven by high fructose. Inhibition of miR-377 by antioxidants may be a promising therapeutic strategy for the prevention of metabolic syndrome-associated glomerular podocyte injury.

Topics: Allopurinol; Animals; Antioxidants; Blotting, Western; Carrier Proteins; Caspase 1; Cells, Cultured; Free Radical Scavengers; Fructose; Gene Expression Regulation; Hydrogen Peroxide; Immunoenzyme Techniques; Inflammation; Interleukin-1beta; Kidney Glomerulus; Male; MicroRNAs; Oxidative Stress; Podocytes; Pterocarpus; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Sweetening Agents

Compelling evidence supports the role of oxidative stress and renal interstitial inflammation in the pathogenesis of hypertension. Resveratrol is a polyphenolic stilbene, which can lower oxidative stress by activating the transcription factor nuclear factor-E2-related factor-2 (Nrf2), the master regulator of numerous genes encoding antioxidant and phase II-detoxifying enzymes and molecules. Given the role of oxidative stress and inflammation in the pathogenesis of hypertension, we conducted this study to test the hypothesis that long-term administration of resveratrol will attenuate renal inflammation and oxidative stress and, hence, progression of hypertension in the young spontaneously hypertensive rats (SHR). SHR and control [Wistar-Kyoto (WKY)] rats were treated for 9 wk with resveratrol or vehicle in their drinking water. Vehicle-treated SHR exhibited renal inflammatory injury and oxidative stress, as evidenced by glomerulosclerosis, tubulointerstitial injury, infiltration of inflammatory cells, and increased levels of renal 8-isoprostane and protein carbonylation. This was associated with reduced antioxidant capacity and downregulations of Nrf2 and phase II antioxidant enzyme glutathione-S-transferase (GST). Resveratrol treatment mitigated renal inflammation and injury, reduced oxidative stress, normalized antioxidant capacity, restored Nrf2 and GST activity, and attenuated the progression of hypertension in SHR. However, resveratrol had no effect on these parameters in WKY rats. In conclusion, development and progression of hypertension in the SHR are associated with inflammation, oxidative stress, and impaired Nrf2-GST activity in the kidney. Long-term administration of resveratrol restores Nrf2 expression, ameliorates inflammation, and attenuates development of hypertension in SHR. Clinical studies are needed to explore efficacy of resveratrol in human hypertension.

Topics: Animals; Antioxidants; Blood Pressure; Body Weight; Drinking; Eating; Hypertension; Inflammation; Kidney; Male; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Resveratrol; Stilbenes

Scots pine (Pinus sylvestris) is known to be rich in phenolic compounds, which may have anti-inflammatory properties. The present study investigated the anti-inflammatory effects of a knot extract from P. sylvestris and two stilbenes, pinosylvin and monomethylpinosylvin, isolated from the extract. Inflammation is characterized by increased release of pro-inflammatory and regulatory mediators including nitric oxide (NO) produced by the inducible nitric oxide synthase (iNOS) pathway. The knot extract (EC50 values of 3 and 3 μg/mL) as well as two of its constituents, pinosylvin (EC50 values of 13 and 15 μM) and monomethylpinosylvin (EC50 values of 8 and 12 μM), reduced NO production and iNOS expression in activated macrophages. They also inhibited the production of inflammatory cytokines IL-6 and MCP-1. More importantly, pinosylvin and monomethylpinosylvin exerted a clear anti-inflammatory effect (80% inhibition at the dose of 100 mg/kg) in the standard in vivo model, carrageenan-induced paw inflammation in the mouse, with the effect being comparable to that of a known iNOS inhibitor L-NIL. The results reveal that the Scots pine stilbenes pinosylvin and monomethylpinosylvin are potential anti-inflammatory compounds.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cell Line; Chemokine CCL2; Gene Expression; HEK293 Cells; Humans; Inflammation; Interleukin-6; Macrophages; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Pinus sylvestris; Plant Extracts; Stilbenes; Wood

The cardioprotective effects of resveratrol are well established in animal models of metabolic disease but are yet to be investigated in a combined model of hypertension and diabetes. This study investigated the ability of resveratrol's antioxidant and anti-inflammatory effects to prevent cardiovascular complications in the spontaneously hypertensive streptozotocin-induced diabetic rat. Diabetes was induced in eight-week-old male spontaneously hypertensive rats via a single intravenous injection of streptozotocin. Following this, resveratrol was administered orally for an eight-week period until the animals were sixteen weeks of age. Upon completion of the treatment regime assessments of oxidative stress, lipid peroxidation, inflammation, and cardiovascular function were made. Resveratrol administration to hypertensive-diabetic animals did not impact upon blood glucose or haemodynamics but significantly reduced oxidative stress, lipid peroxidation, and inflammatory cytokines. Reductions in systemic levels of oxidative stress and inflammation conferred improvements in vascular reactivity and left ventricular pump function and electrophysiology. This study demonstrates that resveratrol administration to hypertensive diabetic animals can elicit cardioprotective properties via antioxidant and anti-inflammatory effects. The observed preservation of cardiovascular function was independent of changes in blood glucose concentration and haemodynamics, suggesting that oxidative stress and inflammation are key components within the pathological cascade associated with hypertension and diabetes.

Topics: Acetylcholine; Animals; Blood Vessels; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Experimental; Drinking; In Vitro Techniques; Inflammation; Lipid Peroxidation; Male; Microelectrodes; Myocardial Contraction; Nitric Oxide; Nitroprusside; Norepinephrine; Oxidative Stress; Rats, Inbred SHR; Resveratrol; Stilbenes; Streptozocin; Ventricular Function

We investigated the effects of 4-17 month supplementation with ω-3 fatty acids and antioxidants (Smartfish drink; Smartfish AS, Oslo, Norway) in 12 patients with minor cognitive impairment (MCI) [minimental state examination (MMSE) ≥19], 2 patients with pre-MCI (normal MMSE), and 7 patients with Alzheimer disease (AD) (MMSE <19). We measured the phagocytosis of amyloid-β 1-42 (Aβ) by flow cytometry and microscopy, the transcription of inflammatory genes by RT-PCR, the production of resolvin D1 (RvD1) by enzyme immunoassay, and the cognitive status by MMSE. In patients with MCI and pre-MCI, phagocytosis of Aβ by monocytes increased from 530 to 1306 mean fluorescence intensity units (P = 0.016). The increase in patients with AD was not significant (N.S.). The lipidic mediator RvD1, which stimulates Aβ phagocytosis in vitro, increased in macrophages in 80% of patients with MCI and pre-MCI (mean increase 9.95 pg/ml) (N.S.). Transcription of inflammatory genes' mRNAs was increased in a subgroup of patients with low transcription at baseline, whereas it was not significantly changed in patients with high transcription at baseline. The mean MMSE score of patients with MCI and pre-MCI was 25.9 at baseline and 25.7 after 4-17 months (N.S.). Our study is the first to show significant immune and biochemical effects of ω-3 fatty acids with antioxidants in patients with MCI. Cognitive benefits of ω-3 supplementation in patients with MCI should be tested in a clinical trial.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Cholecalciferol; Cognitive Dysfunction; Dietary Supplements; Docosahexaenoic Acids; Fatty Acids, Omega-3; Female; Humans; Inflammation; Macrophages; Male; Mental Status Schedule; Middle Aged; Monocytes; Phagocytosis; Resveratrol; RNA, Messenger; Stilbenes

Chronic, low-grade systemic inflammation has been shown to play an important role in the development of obesity-related complications. Epididymal white adipose tissue (WAT) can influence testicular function through its endocrine function. The purpose of this study was to assess the effects of resveratrol on the epididymal WAT inflammatory response and on testicular steroidogenesis in obese individuals. Seven-week-old male C57BL/6J mice were fed a high-calorie and high-cholesterol diet (HCD group) or HCD supplemented with resveratrol (HCD+Res group) for 18 weeks. As we previously showed that resveratrol protects against Leydig cell steroidogenesis in HCD-induced obese mice, this study assessed macrophage infiltration in fat depots by measuring crown-like structure (CLS) density. Histological analysis showed that adipocyte size was significantly smaller and CLSs were less numerous in the HCD+Res group than the HCD group (P < 0.01). Additionally, resveratrol supplementation decreased Nfkb1 expression (P < 0.01) and increased the IκB-α protein abundance (P < 0.01) in epididymal WAT. Consistent with this alteration in NF-κB signaling, the expression of two classic proinflammatory cytokines, TNF-α (Tnfa) and IL-1β (Il1b), were significantly decreased in the HCD+Res group compared with the HCD group (P < 0.01). Significant differences were also found in the expression of sirtuin1 (Sirt1) (P < 0.01) and manganese superoxide dismutase (Sod2) (P < 0.01) between the HCD and HCD+Res groups. Our data suggest that resveratrol can attenuate obesity-induced inflammation and oxidative stress in epididymal WAT, which partly accounts for its beneficial effects in testicular steroidogenesis.

Topics: Adipose Tissue, White; Animals; Blotting, Western; DNA Primers; Epididymis; Gonadal Steroid Hormones; Histological Techniques; Immunohistochemistry; Inflammation; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Oxidative Stress; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stilbenes

Atherosclerosis (AS) is an inflammatory disease involved in vascular inflammatory injury. The inflammasome is an important part of inflammatory diseases and participates in the vascular inflammatory injury. Resveratrol (RSV) possesses anti-inflammatory activities, but its effects on inflammasomes during vascular injury remain unclear. This study focused on the effects and mechanisms of RSV on inflammasomes during vascular injury.. Male Sprague-Dawley rats were treated with a purified diet or cholesterol-enriched diet combined with vitamin D2 (VD; 1.8 million units/kg/days, Po) and saline or RSV (50 mg/kg/days, Po) daily for 5 weeks. The concentrations and enzyme activities of related indicators were measured by a spectrophotometer or ELISA kit. Their gene and protein expression levels were analyzed by reverse transcription-polymerase chain reaction and Western blot, respectively.. Upon administration with RSV, rats with combined hyper cholesterol and VD demonstrated the following changes: the vascular histopathological changes were relieved, and the level of the von Willebrand factor decreased. The level of serum IL-1β, a marker of inflammasome activation, significantly decreased. The mRNA and protein expression levels of the three components of inflammasomes, namely, NOD-like receptor pyrin domain containing 3, apoptosis-associated speck-like protein containing a caspase-recruitment domain, and caspase-1, were downregulated. The effects of RSV were closely related to hypolipidemia (decrease in the levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol combined with the expression of the lectin-like ox-LDL receptor and increase in high-density lipoprotein cholesterol), antioxidation (decrease in MDA levels and increase in SOD and GPx activities), and anti-inflammation (downregulation of the expression of IL-1β, intracellular adhesion molecule-1, and monocyte chemotactic protein-1). The mechanisms for the downregulation of NF-κB p65 and p38 MAPK expression, as well as the upregulation of SIRT1 expression, were analyzed.. This study proved that RSV inhibited inflammasome activation to protect vascular injury in vivo. RSV exhibited therapeutic potential in the treatment of vascular injury.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Aorta, Thoracic; Atherosclerosis; Carrier Proteins; Caspase 1; Ergocalciferols; Hypercholesterolemia; Inflammasomes; Inflammation; Lipid Peroxidation; Lipids; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Vitamins

Resveratrol has been shown to mimic the beneficial effects of dietary restriction (DR). We previously reported that DR delays stroke onset and extends the lifespan in Stroke-Prone Spontaneously Hypertensive rats (SHRSP). Therefore, we examined whether resveratrol mimics DR and delays stroke onset in SHRSP.. Cerebrovascular endothelial cells (CVECs) from SHRSP were treated with resveratrol, and the inflammatory gene expression levels and NFκB protein levels were measured. In order to address the effects of resveratrol in vivo, SHRSP (male, 10 weeks of age) were fed an experimental diet containing several doses of resveratrol (0 - 0.05% (w/w)), after which we measured the plasma cytokine levels and examined the stroke onset and lifespan.. Treatment with resveratrol (100 μM, 24 hours) in CVECs from SHRSP significantly decreased the interleukin (IL)-1β-induced monocyte chemoattractant protein-1 (MCP-1) mRNA expression levels and p50 and p65 protein levels in the nuclear fraction. When the SHRSP were fed a diet containing resveratrol for one week, the resveratrol treatment did not affect the plasma lipid and glucose levels, body weight or weight of each tissue. Resveratrol slightly, but not significantly, decreased the plasma levels of IL-1β and MCP-1 compared with that observed in the control group. In addition, resveratrol decreased the IL-1β and MCP-1 mRNA expression levels in the brain versus the control animals. However, no doses of resveratrol delayed stroke onset or extended the lifespan in SHRSP.. In this study, resveratrol did not delay stroke onset in SHRSP, although it partially suppressed systemic and cerebral inflammation. These results suggest that resveratrol does not mimic the beneficial effects of DR on stroke in vivo.

Topics: Adenylate Kinase; Animals; Antioxidants; Blood Glucose; Blood Pressure; Body Weight; Cerebrovascular Circulation; Chemokine CCL2; Endothelial Cells; Inflammation; Interleukin-1beta; Male; Rats; Rats, Inbred SHR; Resveratrol; Signal Transduction; Stilbenes; Stroke

With its adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), Nod-like receptor family, pyrin domain containing 3 (NLRP3) forms the inflammasome and mediates inflammatory innate immune responses. Development of an anti-inflammatory drug targeting the NLRP3-inflammasome is urgently required because its aberrant activation often causes inflammatory diseases, including gout. We show that resveratrol, a natural polyphenol in grapes and wine, is a safe and effective phytochemical that inhibits NLRP3-inflammasome activation. Resveratrol inhibits the accumulation of acetylated α-tubulin caused by mitochondrial damage in macrophages stimulated with inducers of the NLRP3-inflammasome. Consequently, resveratrol inhibits the acetylated-α-tubulin-mediated spatial arrangement of mitochondria and their subsequent contact with the endoplasmic reticulum (ER), causing insufficient assembly of ASC on the mitochondria and NLRP3 on the ER. These findings indicate that resveratrol targets the generation of an optimal site for the assembly of NLRP3 and ASC, thus inhibiting NLRP3-inflammasome activation. Therefore, resveratrol could be an effective medication for the treatment of NLRP3-related inflammatory diseases.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Carrier Proteins; Caspases; Endoplasmic Reticulum; Female; Immunity, Innate; Inflammasomes; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Phytochemicals; Resveratrol; Signal Transduction; Stilbenes; Tubulin; Vitis; Wine

Pseudoachondroplasia (PSACH), a severe short-limb dwarfing condition, results from mutations that cause misfolding of the cartilage oligomeric matrix protein (COMP). Accumulated COMP in growth plate chondrocytes activates endoplasmic reticulum stress, leading to inflammation and chondrocyte death. Using a MT-COMP mouse model of PSACH that recapitulates the molecular and clinical PSACH phenotype, we previously reported that oxidative stress and inflammation play important and unappreciated roles in PSACH pathology. In this study, we assessed the ability of antioxidant and anti-inflammatory agents to affect skeletal and cellular pathology in our mouse model of PSACH. Treatment of MT-COMP mice with aspirin or resveratrol from birth to P28 decreased mutant COMP intracellular retention and chondrocyte cell death, and restored chondrocyte proliferation. Inflammatory markers associated with cartilage degradation and eosinophils were present in the joints of untreated juvenile MT-COMP mice, but were undetectable in treated mice. Most importantly, these treatments resulted in significantly increased femur length. This is the first and only therapeutic approach shown to mitigate both the chondrocyte and long-bone pathology of PSACH in a mouse model and suggests that reducing inflammation and oxidative stress early in the disease process may be a novel approach to treat this disorder.

Topics: Achondroplasia; Animals; Anti-Inflammatory Agents; Antioxidants; Aspirin; Cartilage Oligomeric Matrix Protein; Cell Proliferation; Chondrocytes; Disease Models, Animal; Growth Plate; Inflammation; Mice; Mutation; Resveratrol; Stilbenes

Methylglyoxal (MG) has been found to cause inflammation and insulin resistance in vitro and in vivo in recent studies. Resveratrol has been proposed as an effective treatment that helps lower the risk of developing complications of diabetes. To study the significance of glycosylation-related stress on the pathology of diabetes, the effects of resveratrol were examined in a mouse model of diabetes induced by MG. Resveratrol was given via oral gavage in MG-treated mice, and diabetes-related tests and markers were assessed using biochemical and immunohistochemical analyses. Treatment with resveratrol markedly improved blood glucose level from the oral glucose tolerance test and promoted nuclear factor erythroid 2-related factor-2 (Nrf2) phosphorylation (p < 0.05) in the pancreas of MG-treated mice. However, these effects were abolished by retinoic acid, Nrf2 inhibitor, in resveratrol and retinoic acid-treated and MG-induced mice. These findings support that resveratrol may be useful in the treatment of type-2 diabetes by protecting against pancreatic cell dysfunction.

Topics: Animals; Anti-Inflammatory Agents; Blood Glucose; Disease Models, Animal; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Liver; Male; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; Pancreas; Pancreatic Diseases; Phosphorylation; Pyruvaldehyde; Resveratrol; Stilbenes

Dysfunction of the retinal pigment epithelium (RPE) resulting from chronic inflammation is implicated in the pathogenesis of age-related macular degeneration (AMD). RPE cells adjacent to drusen deposits in the AMD eye are known to contain CXCL11, a chemokine involved in inflammatory cell recruitment. We investigated the CXCL11 production by the human RPE (ARPE-19) cells under inflammatory conditions and tested its response to resveratrol, a naturally occurring anti-inflammatory antioxidant. A proinflammatory cytokine mixture consisting of IFN-γ, IL-1β and TNF-α highly increased CXCL11 mRNA expression and CXCL11 protein secretion by ARPE-19 cells. Resveratrol substantially inhibited the proinflammatory cytokines-induced CXCL11 production while partially blocking nuclear factor-κB activation. This inhibitory action of resveratrol was also observed for the cytokines-induced expression of chemokines CXCL9, CCL2 and CCL5. Our results indicate that resveratrol could potentially attenuate RPE inflammatory response implicated in the pathogenesis of AMD.

Topics: Cell Line; Chemokine CXCL11; Gene Expression Regulation; Humans; Inflammation; NF-kappa B; Resveratrol; Retinal Pigment Epithelium; Stilbenes

Obesity, a sirtuin-1 (SIRT-1) -deficient state, increases morbidity and resource utilization in critically ill patients. SIRT-1 deficiency increases microvascular inflammation and mortality in early sepsis. The objective of the study was to study the effect of resveratrol (RSV), a SIRT-1 activator, on microvascular inflammation in obese septic mice.. ob/ob and C57Bl/6 (WT) mice were pretreated with RSV versus dimethyl sulfoxide (DMSO) (vehicle) prior to cecal ligation and puncture (sepsis). We studied (1) leukocyte/platelet adhesion, (2) E-selectin, ICAM-1, and SIRT-1 expression in small intestine, and (3) 7-day survival. A group of RSV-treated mice received SIRT-1 inhibitor (EX-527) with sepsis induction, and leukocyte/platelet adhesion and E-selectin/ICAM-1 expression were studied. We treated endothelial (HUVEC) cells with RSV to study E-selectin/ICAM-1 and p65-acetylation (AC-p65) in response to lipopolysaccharide (LPS).. RSV treatment decreased leukocyte/platelet adhesion and E-selectin/ICAM-1 expression with increased SIRT-1 expression in septic ob/ob and WT mice, decreased E-selectin/ICAM-1 expression via increased SIRT-1 expression, and decreased AC-p65 expression in HUVEC. EX-527 abolished RSV-induced attenuation of microvascular inflammation in ob/ob septic mice. Finally, ob/ob mice in the sepsis+RSV group had significantly increased 7-day survival versus the sepsis+vehicle group.. RSV increases SIRT-1 expression in ob/ob septic mice to reduce microvascular inflammation and improves survival.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cecum; Cell Adhesion Molecules; Female; Inflammation; Intercellular Adhesion Molecule-1; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Platelet Adhesiveness; Resveratrol; Sepsis; Sirtuin 1; Stilbenes

Spinal cord injury (SCI)-induced systemic inflammatory response affects multiple organs outside the spinal cord. Treatment options for such complications are lacking. We studied the potential protective effects of resveratrol on SCI-induced inflammatory damage in rat lungs. Sprague-Dawley rats were subjected to weight-drop impact at the T10 vertebral level with administration of resveratrol (100 mg/kg) or vehicle (via the intraperitoneal route) immediately after trauma. Lung injury was studied by measuring: vascular permeability-related pulmonary edema; histopathologic scores, neutrophil infiltration and concentrations of inflammatory cytokines in bronchoalveolar fluid; expression of inflammatory enzymes and sirtuin (SIRT) 1 as well as nuclear factor-kappa B (NF-κB) activity in pulmonary tissues. Resveratrol treatment significantly alleviated SCI-induced pulmonary edema as indicated by the ratio of the wet weight to dry weight of lung tissue and pulmonary permeability index. Resveratrol significantly reduced neutrophil infiltration and production of inflammatory mediators. Resveratrol treatment was accompanied by up-regulation of expression of SIRT1 and suppression of NF-κB activity in pulmonary tissues. These data suggest that resveratrol may protect the lungs from SCI-induced inflammatory damage, and could be used as a therapeutic option against pulmonary problems after SCI.

Topics: Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cytokines; Female; Inflammation; Lung; Lung Diseases; Oxidative Stress; Rats; Rats, Sprague-Dawley; Resveratrol; Sirtuin 1; Spinal Cord Injuries; Stilbenes

Inflammatory cytokines play a major role in spontaneous preterm birth. Resveratrol has strong anti-inflammatory effects, but its effect on preterm birth in vivo is unknown. We investigated whether resveratrol protects against preterm birth in the lipopolysaccharide (LPS)-induced preterm mouse model. Twelve-day-old pregnant mice were fed 20 to 40 mg/kg resveratrol daily. On day 15, 10 μg of LPS was injected into uterine cervices. Resveratrol administration significantly decreased the rate of preterm birth. Resveratrol administration abolished LPS-induced elevation of tumor necrosis factor α (TNF-α) and interleukin (IL) 1β but not IL-6 levels. The TNF-α messenger RNA levels were decreased in the cervices of resveratrol-administered mice compared with controls. Resveratrol treatment suppressed the elevation in TNF-α and IL-1β levels in LPS-exposed peritoneal macrophages. Further resveratrol treatment eradicated the proinflammatory cytokine-mediated elevation in cyclooxygenase 2 (COX-2) in peritoneal macrophages. Resveratrol may protect against pathological preterm birth by suppression of elevated proinflammatory cytokines and consequent elevation of COX-2 in macrophages.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Cyclooxygenase 2; Disease Models, Animal; Female; Gestational Age; Inflammation; Inflammation Mediators; Interleukin-1beta; Lipopolysaccharides; Macrophages, Peritoneal; Mice, Inbred C57BL; Pregnancy; Premature Birth; Resveratrol; Stilbenes; Time Factors; Tumor Necrosis Factor-alpha

Previous research demonstrated that resveratrol possesses promising properties for preventing obesity. Endoplasmic reticulum (ER) stress was proposed to be involved in the pathophysiology of both obesity and hepatic steatosis. In the current study, we hypothesized that resveratrol could protect against high-fat diet (HFD)-induced hepatic steatosis and ER stress and regulate the expression of genes related to hepatic steatosis. Rats were fed either a control diet or a HFD for 12 weeks. After 4 weeks, HFD-fed rats were treated with either resveratrol or vehicle for 8 weeks. Body weight, serum metabolic parameters, hepatic histopathology, and hepatic ER stress markers were evaluated. Moreover, an RT2 Profiler Fatty Liver PCR Array was performed to investigate the mRNA expressions of 84 genes related to hepatic steatosis. Our work showed that resveratrol prevented dyslipidemia and hepatic steatosis induced by HFD. Resveratrol significantly decreased activating transcription factor 4, C/EBP-homologous protein and immunoglobulin binding protein levels, which were elevated by the HFD. Resveratrol also decreased PKR-like ER kinase phosphorylation, although it was not affected by the HFD. Furthermore, resveratrol increased the expression of peroxisome proliferator-activated receptor δ, while decreasing the expression of ATP citrate lyase, suppressor of cytokine signaling-3, and interleukin-1β. Our data suggest that resveratrol can prevent hepatic ER stress and regulate the expression of peroxisome proliferator-activated receptor δ, ATP citrate lyase, suppressor of cytokine signaling-3, tumor necrosis factor α, and interleukin-1β in diet-induced obese rats, and these effects likely contribute to resveratrol's protective function against excessive accumulation of fat in the liver.

Topics: Animals; Diet, High-Fat; Dyslipidemias; Endoplasmic Reticulum Stress; Gene Expression; Inflammation; Insulin Resistance; Lipid Metabolism; Liver; Male; Non-alcoholic Fatty Liver Disease; Phytotherapy; Plant Extracts; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Diabetes mellitus is a heterogeneous metabolic disorder essentially characterized by deficiency of insulin secretion, insulin receptor or post-receptor events. This study aims to investigate the effects of resveratrol administration on the metabolic characteristics, hepatic functions, histopathological features and insulin signaling pathway components in streptozotocin induced diabetes. Male Wistar rats were randomly divided into four groups: (1) control/vehicle; (2) control/20mg/kg resveratrol; (3) diabetic/vehicle; and (4) diabetic/20mg/kg resveratrol. Histopathological examinations were carried out to reveal hepatic tissue damage and inflammation. In addition to hepatic glucose, lipid, insulin, ALT, AST, resistin and XOD contents, gene and protein expressions of insulin signaling pathway components such as insulin Rβ, IRS-1, IRS-2, eNOS, PI3K, Akt, and FOXO3a were analyzed by qRT-PCR and Western blot. The rats in the diabetes group had significantly lower terminal body weight and hepatic insulin level, but significantly higher hepatic glucose, total cholesterol, triglyceride and resistin concentrations. Diabetes triggered the inflammatory process in the liver tissues that was evidenced by histopathological deformations and increase in the hepatic ALT and AST levels. Hepatic inflammation was considerably associated with insulin signaling pathway ever since a significant down-regulation of insulin signaling components; IRS-1, IRS-2, PI3K, Akt and mTOR have been identified in the diabetic group. To some extent, resveratrol treatment reversed the diabetes-induced changes in the liver tissues. Taken together, resveratrol partly improved hepatic dysfunction induced by diabetes. This may be due to the healing activity of resveratrol on insulin signaling pathway, resistin levels and hepatic glucose-lipid contents.

Topics: Animals; Diabetes Mellitus, Experimental; Inflammation; Insulin; Liver; Male; Rats; Rats, Wistar; Resveratrol; Signal Transduction; Stilbenes; Streptozocin

In this study, the effects of combining ursolic acid + resveratrol, for possible combined inhibitory effects on skin tumor promotion, were evaluated. Ursolic acid, resveratrol, and the combination of ursolic acid + resveratrol were applied topically prior to 12-O-tetracanoylphorbol-13-acetate (TPA) treatment on mouse skin to examine their effect on TPA-induced signaling pathways, epidermal hyperproliferation, skin inflammation, inflammatory gene expression, and skin tumor promotion. The combination of ursolic acid + resveratrol produced a greater inhibition of TPA-induced epidermal hyperproliferation. The combination of ursolic acid + resveratrol inhibited TPA-induced signaling pathways, including EGFR, STAT3, Src, Akt, Cox-2, Fas, NF-κB, p38 MAPK, c-Jun, and JNK1/2 while increasing levels of tumor suppressors, such as p21 and PDCD4, to a greater extent compared with the groups treated with the individual compounds. Ursolic acid + resveratrol also induced a dramatic increase of p-AMPK-α(Thr172). Combined treatment with ursolic acid + resveratrol resulted in a greater inhibition of expression of proinflammatory cytokines, including Il1a, Il1b, and Il22. Furthermore, NF-κB, Egr-1, and AP-1 DNA binding activities after TPA treatment were dramatically decreased by the combination of ursolic acid + resveratrol. Treatment with ursolic acid + resveratrol during skin tumor promotion with TPA produced greater inhibition of tumor multiplicity and tumor size than with either agent alone. Collectively, the greater ability of the combination of ursolic acid + resveratrol to inhibit skin tumor promotion was due to the greater inhibitory effects on growth factor and inflammatory signaling, skin inflammation, and epidermal hyperproliferation induced by TPA treatment.

Topics: Animals; Anticarcinogenic Agents; Carcinogenesis; Cell Nucleus; Cell Proliferation; Cytosol; Female; Inflammation; Male; Mice; Mice, Inbred ICR; Protein Binding; Resveratrol; Signal Transduction; Skin; Skin Neoplasms; Stilbenes; Tetradecanoylphorbol Acetate; Triterpenes; Ursolic Acid

Although survival rate of infants born prematurely has been raised by supplemental oxygen treatment, it is followed by high morbidity of hyperoxia-induced bronchopulmonary dysplasia. In this study, the effect of resveratrol on the lung injury was evaluated in hyperoxia-exposed rats of preterm birth. The results demonstrated that hyperoxia led to thickened alveolar wall, simplified alveolar architecture and fibrosis. In addition, elevated methane dicarboxylic aldehyde level, decreased glutathione level and superoxide dismutase activity were also found in hyperoxic lungs, as well as the increased tumor necrosis factor-α, interleukin-1β and interleukin-6 in the bronchoalveolar lavage fluid. Fibrotic-associated proteins transforming growth factor-β1, α-smooth muscle actin, collagen I and fibronectin deposition were also found in interstitial substance of lungs. Furthermore, Wnt/β-catenin signalling was found to be active in hyperoxia-induced lungs. In addition, expression of SP-C was increased and T1α was decreased in hyperoxia-exposed lungs. Resveratrol intraperitoneal administration alleviated hyperoxia-induced histological injury of lungs, regulated redox balance, decreased pro-inflammatory cytokine release, and down-regulated expression of fibrotic-associated proteins. Furthermore, Wnt/β-catenin signalling was also suppressed by resveratrol, as represented by diminished expression of lymphoid enhancer factor-1, Wnt induced signalling protein-1 and cyclin D1. In addition, the increase of SP-C and decrease of T1α expression was prevented as well. The present study showed that resveratrol could protect lungs from hyperoxia-induced injury through its antioxidant, anti-inflammatory and anti-fibrotic effects. The transdifferentiation of alveolar epithelial type II cells to alveolar epithelial type I cells promotion and Wnt/β-catenin signalling suppression are also involved in the protective effect.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Antioxidants; Cell Hypoxia; Cytoprotection; Female; Inflammation; Lung; Oxidative Stress; Pregnancy; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Wnt Signaling Pathway

The production of excessive amounts of nitric oxide (NO) through inducible nitric oxide synthase (iNOS) contributes to organ injury, inflammation, and mortality after shock. Resveratrol (RSV) is a natural polyphenol that decreases shock-induced hepatic injury and inflammation. We hypothesized that RSV would mediate these effects by decreasing hepatocyte iNOS production.. Rat hepatocytes were isolated, cultured with varying concentrations of RSV, and then stimulated to induce iNOS with interleukin-1 and interferon. Induction of iNOS protein was measured by Western blot, iNOS mRNA by polymerase chain reaction, and NO production was measured by culture supernatant nitrite. Activation of intracellular signaling pathways involving Akt, c-Jun N-terminal kinase (JNK), and nuclear factor κB (NF-κB) were measured by Western blot using isoform-specific antibodies.. RSV decreased the expression of iNOS mRNA, protein, and supernatant nitrite in a dose-dependent manner. Our previous work demonstrated that Akt and JNK both inhibit hepatic iNOS production, whereas NF-κB increases iNOS expression. Analysis of signaling pathways in this study demonstrated that RSV increased JNK phosphorylation but decreased Akt phosphorylation and increased NF-κB activation.. RSV decreases cytokine-induced hepatocyte iNOS expression, possibly through up-regulation of the JNK signaling pathway. RSV merits further investigation to determine its mechanism as a compound that can decrease inflammation after shock.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Blotting, Western; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Hepatocytes; Inflammation; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Stilbenes; Up-Regulation

ω-3 PUFAs and polyphenols have multiple effects on inflammation in vivo and in vitro. The effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and resveratrol (RV) were investigated in LPS-stimulated peripheral blood leukocytes (PBLs) (i.e., acute inflammation) and IL-1β activated human chondrocytes (i.e., chronic inflammation). Inflammatory mediators including chemokines, cytokines, interleukins, and PGE2 were measured by multiplex analysis and gene expression was quantified by RT-PCR. In PBLs, RV decreased the secretion of PGE2, CCL5/RANTES, and CXCL8/IL-8 but increased IL-1β, IL-6, and IL-10. In contrast to RV, ω-3 PUFAs augmented the production of PGE2 and CXCL8/IL-8. EPA and DHA similarly affected the pattern of inflammatory mediators. Combination of RV and ω-3 PUFAs exerted synergistic effects on CCL5/RANTES and had additive effects on IL-6 or CXCL8/IL-8. Both ω-3 PUFAs and RV reduced catabolic gene expression (e.g., MMPs, ADAMTS-4, IL-1β, and IL-6) in activated chondrocytes. The data suggest that ω-3 PUFAs and RV differ in the regulation of acute inflammation of peripheral blood leukocytes but have common properties in modulating features related to chronic inflammation of chondrocytes.

Topics: Acute Disease; Chondrocytes; Chronic Disease; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Gene Expression Regulation; Humans; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Leukocytes; Lipopolysaccharides; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception and the attenuation of morphine antinociceptive tolerance. In this study, the authors investigated the impact of AMPK activation through resveratrol treatment on bone cancer pain.. The nociception was assessed by measuring the incidence of foot withdrawal in response to mechanical indentation in rats (n = 8). Cytokine expression was measured using quantitative polymerase chain reaction (n = 8). Cell signalings were assayed by western blot (n = 4) and immunohistochemistry (n = 5). The microglial cell line BV-2, primary astrocytes, and neuron-like SH-SY5Y cells were cultured to investigate the in vitro effects.. Resveratrol and 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide, the AMPK activators, significantly attenuated bone cancer pain in rats with tumor cell implantation (TCI; threshold of mechanical withdrawal, resveratrol vs. vehicle: 10.1 ± 0.56 vs. 4.1 ± 0.37; 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide vs. vehicle: 8.2 ± 0.17 vs. 4.1 ± 0.37, mean ± SEM); these effects were reversed by the AMPK inhibitor compound C (compound C vs. resveratrol: 6.2 ± 1.35 vs. 10.1 ± 0.56, mean ± SEM). Resveratrol has an AMPK-dependent inhibitory effect on TCI-evoked astrocyte and microglial activation. The antinociceptive effects of resveratrol were partially mediated by the reduced phosphorylation of mitogen-activated protein kinases and decreased production of proinflammatory cytokines in an AMPK-dependent manner. Furthermore, resveratrol potently inhibited inflammatory factors-mediated protein kinase B/mammalian target of rapamycin signaling in neurons. Acute pain evoked by proinflammatory cytokines in the spinal cord was significantly attenuated by resveratrol.. AMPK activation in the spinal glia by resveratrol may have utility in the treatment of TCI-induced neuroinflammation, and our results further implicate AMPK as a novel target for the attenuation of bone cancer pain.

Topics: AMP-Activated Protein Kinases; Animals; Bone Neoplasms; Cell Line, Tumor; Female; Humans; Inflammation; Mitogen-Activated Protein Kinases; Pain; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Local angiotensin II (AII) and sirtuin 1 (SIRT1) play a major role in the modulation of neuroinflammation, oxidative stress and aging-related dopaminergic vulnerability to damage. However, it is not known whether the modulation is related to reciprocal regulation between SIRT1 and AII. In the present study, a single intraventricular injection of AII increased nigral SIRT1 levels in young adult rats. Although AII activity is known to be increased in aged rats, levels of SIRT1 were significantly lower than in young controls. Treatment with the SIRT1-activating compound resveratrol increased nigral SIRT1 levels in aged rats. Levels of SIRT1 were significantly higher in aged wild type mice than in AII type-1 receptor (AT1) deficient mice. In cell culture studies, treatment with AII also induced a transitory increase in levels of SIRT1 in the MES 23.5 dopaminergic neuron and the N9 microglial cell lines. In aged rats, treatment with resveratrol induced a significant decrease in the expression of AT1 receptors and markers of NADPH-oxidase activation (p47phox). In aged transgenic mice over-expressing SIRT1, levels of AT1 and p47 phox were lower than in aged wild type controls. In vitro, the inhibitory effects of resveratrol on AII/AT1/NADPH-oxidase activity were confirmed in primary mesencephalic cultures, the N9 microglial cell line, and the dopaminergic neuron cell line MES 23.5, and they were blocked by the SIRT1 specific inhibitor EX527. The present findings show that SIRT1 and the axis AII/AT1/NADPH-oxidase regulate each other. This is impaired in aged animals and may be mitigated with sirtuin-activating compounds.

Topics: Aging; Angiotensin II; Animals; Brain; Cell Line; Dopaminergic Neurons; Gene Expression Regulation; Homozygote; Humans; Immunohistochemistry; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Fluorescence; NADPH Oxidases; Neurodegenerative Diseases; Neuroglia; Neurons; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Resveratrol; Sirtuin 1; Stilbenes; Substantia Nigra

The gut-liver axis is largely involved in the development of non-alcoholic fatty liver disease (NAFLD). We investigated whether 2, 3, 5, 4'-tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG) could reverse NAFLD induced by a high-fat diet (HFD) and whether it did so via the gut-liver axis. Results showed that TSG could reduce the accumulation of FFA and it did so by reducing the expression of L-FABP and FATP4. TSG regulated gut microbiota balanced and increased the protein expression of ZO-1 and occludin, which could improve the function of the intestinal mucosal barrier and reduce serum LPS content by about 25%. TSG reduced TL4 levels by 56% and NF-κB expression by 23% relative to the NAFLD model group. This suggests that prevention of NAFLD by TSG in HFD-fed rats is mediated by modulation of the gut microbiota and TLR4/NF-κB pathway, which may alleviate chronic low-grade inflammation by reducing the exogenous antigen load on the host.

Topics: Animals; Diet, High-Fat; Flow Cytometry; Glucosides; Inflammation; Intestinal Mucosa; Liver; Male; Microbiota; Non-alcoholic Fatty Liver Disease; Rats; Rats, Sprague-Dawley; Signal Transduction; Stilbenes

Current evidence supports that depression is accompanied by the activation of the inflammatory-response system, and overproduction of pro-inflammatory cytokines may play a role in the pathophysiology of depressive disorders. Resveratrol has anti-inflammatory, antioxidant and anti-depressant-like properties. Using an animal model of depression induced by a single administration of lipopolysaccharide (LPS), the present study investigated the effects of resveratrol on LPS-induced depressive-like behavior and inflammatory-response in adult mice. Our results showed that pretreatment with resveratrol (80mg/kg, i.p.) for 7 consecutive days reversed LPS-increased the immobility time in the forced swimming test and tail suspension test, and LPS-reduced sucrose preference test. Moreover, the antidepressant action of resveratrol was paralleled by significantly reducing the expression levels of pro-inflammatory cytokines, and up-regulating phosphorylated cAMP response-element-binding protein (pCREB)/brain-derived neurotrophic factor (BDNF) expression in prefrontal cortex (PFC) and hippocampus. In addition, resveratrol ameliorated LPS-induced NF-κB activation in the PFC and hippocampus. The results demonstrate that resveratrol may be an effective therapeutic agent for LPS-induced depressive-like behavior, partially due to its anti-inflammatory aptitude and by modulating pCREB and BDNF expression in the brain region of mice.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain; Brain-Derived Neurotrophic Factor; Cell Nucleus; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cytokines; Depression; Food Preferences; Hippocampus; Inflammation; Lipopolysaccharides; Male; Mice; Motor Activity; NF-kappa B; Prefrontal Cortex; Resveratrol; Signal Transduction; Stilbenes; Sucrose

A complicated interplay between resident mast cells and other recruited inflammatory cells contributes to the development and progression of allergic inflammation entailing the promotion of T helper 2 (Th2) cytokine responses. The current study examined whether resveratrol suppressed the production of inflammatory Th2 cytokines in cultured rat basophilic leukemia RBL-2H3 cells. Cells pre-treated with resveratrol nontoxic at 1–25 μM were sensitized with anti-dinitrophenyl (anti-DNP), and subsequently stimulated by dinitrophenyl-human serum albumin (DNP–HSA) antigen. Resveratrol dose-dependently diminished the secretion of interleukin (IL)-3, IL-4, IL-13 as well as tumor necrosis factor (TNF)-α by the antigen stimulation from sensitized cells. It was found that resveratrol mitigated the phosphorylation of p38 MAPK, ERK, and JNK elevated in mast cells exposed to Fc epsilon receptor I (FcεRI)-mediated immunoglobulin E (IgE)-antigen complex. The FcεRI aggregation was highly enhanced on the surface of mast cells following the HSA stimulation, which was retarded by treatment with 1–25 μM resveratrol. The IgE-receptor engagement rapidly induced tyrosine phosphorylation of c-Src-related focal adhesion protein paxillin involved in the cytoskeleton rearrangement. The FcεRI-mediated rapid activation of c-Src and paxillin was attenuated in a dose-dependent manner. In addition, the paxillin activation entailed p38 MAPK and ERK-responsive signaling, but the JNK activation was less involved. Consistently, oral administration of resveratrol reduced the tissue level of phosphorylated paxillin in the dorsal skin of DNP–HSA-challenged mice. The other tyrosine kinase Tyk2-STAT1 signaling was activated in the dorsal epidermis of antigen-exposed mice, which was associated with allergic inflammation. These results showed that resveratrol inhibited Th2 cytokines- and paxillin-linked allergic responses dependent upon MAPK signaling. Therefore, resveratrol may possess the therapeutic potential of targeting mast cells in preventing the development of allergic inflammation.

Topics: Animals; Cells, Cultured; Cytokines; Dinitrophenols; Disease Models, Animal; Dose-Response Relationship, Drug; Hypersensitivity; Immunoglobulin E; Inflammation; Male; MAP Kinase Signaling System; Mast Cells; Mice; Mice, Inbred BALB C; Molecular Targeted Therapy; Phosphorylation; Phytotherapy; Receptors, IgE; Resveratrol; Serum Albumin; Stilbenes; Th2 Cells

Antiepileptic drug therapy, though beneficial for restraining seizures, cannot thwart status epilepticus (SE) induced neurodegeneration or down-stream detrimental changes. We investigated the efficacy of resveratrol (RESV) for preventing SE-induced neurodegeneration, abnormal neurogenesis, oxidative stress and inflammation in the hippocampus. We induced SE in young rats and treated with either vehicle or RESV, commencing an hour after SE induction and continuing every hour for three-hours on SE day and twice daily thereafter for 3 days. Seizures were terminated in both groups two-hours after SE with a diazepam injection. In contrast to the vehicle-treated group, the hippocampus of animals receiving RESV during and after SE presented no loss of glutamatergic neurons in hippocampal cell layers, diminished loss of inhibitory interneurons expressing parvalbumin, somatostatin and neuropeptide Y in the dentate gyrus, reduced aberrant neurogenesis with preservation of reelin + interneurons, lowered concentration of oxidative stress byproduct malondialdehyde and pro-inflammatory cytokine tumor necrosis factor-alpha, normalized expression of oxidative stress responsive genes and diminished numbers of activated microglia. Thus, 4 days of RESV treatment after SE is efficacious for thwarting glutamatergic neuron degeneration, alleviating interneuron loss and abnormal neurogenesis, and suppressing oxidative stress and inflammation. These results have implications for restraining SE-induced chronic temporal lobe epilepsy.

Topics: Animals; Behavior, Animal; Cell Adhesion Molecules, Neuronal; Cell Death; Cognition; Extracellular Matrix Proteins; GABAergic Neurons; Gene Expression Regulation; Hippocampus; Inflammation; Interneurons; Longevity; Male; Microglia; Nerve Degeneration; Nerve Tissue Proteins; Neurogenesis; Neuropeptide Y; Oxidative Stress; Parvalbumins; Rats, Inbred F344; Reelin Protein; Resveratrol; Seizures; Serine Endopeptidases; Somatostatin; Status Epilepticus; Stilbenes; Tumor Necrosis Factor-alpha

In the present study we used a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model to analyze resveratrol neuroprotective effects. The MPTP-induced PD model is characterized by chronic inflammation, oxidative stress and loss of the dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). We observed that resveratrol treatment significantly reduced glial activation, decreasing the levels of IL-1β, IL-6 and TNF-α, as well as their respective receptors in the SNpc of MPTP-treated mice, as demonstrated by Western blotting, RT-PCR and quantitative PCR analysis. This reduction is related to possible neuroprotection as we also observed that resveratrol administration limited the decline of tyrosine hydroxylase-immunoreactivity induced in the striatum and SNpc by MPTP injection. Consistent with these data, resveratrol treatment up-regulated the expression of the suppressor of cytokine signaling-1 (SOCS-1), supporting the hypothesis that resveratrol protects DA neurons of the SNpc against MPTP-induced cell loss by regulating inflammatory reactions, possibly through SOCS-1 induction.

Topics: Animals; Cytokines; Dopaminergic Neurons; Immunohistochemistry; Inflammation; Macrophage Activation; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning; Neostriatum; Neuroglia; Neuroprotective Agents; Real-Time Polymerase Chain Reaction; Resveratrol; Stilbenes; Substantia Nigra; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins; Tyrosine 3-Monooxygenase; Up-Regulation

In this study, we aimed to investigate the therapeutic effects and involved mechanisms of resveratrol on an established non-alcoholic fatty liver disease (NAFLD) murine model. Wild-type and autophagic mediator ULK1 heterozygous knockout mice were induced to have NAFLD by high-fat diet for 8weeks. After that, resveratrol treatment was applied with the high-fat diet feeding for another 4weeks. Typical features of NAFLD, including histological changes, fibrosis, insulin resistance, oxidative status, and inflammation were characterized. After-treatment with resveratrol showed ameliorative effects on all measured features of NAFLD, from histology, insulin resistance, glucose tolerance to oxidative stress and inflammation. resveratrol treatment also reduced the activity of nuclear factor-κB (NF-κB) through the restoration of its inhibitor IκBα. Partial inhibition of ULK1 expression impaired the ameliorative effects of resveratrol on hepatic histology, fibrosis, oxidative status, inflammation, and NF-κB activity. In conclusion, resveratrol improved NAFLD-caused hepatic injury partially through regulating autophagic and IκBα-NF-κB pathways.

Topics: Animals; Autophagy; Diet, High-Fat; Disease Models, Animal; DNA Primers; Fatty Liver; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Oxidative Stress; Polymerase Chain Reaction; Resveratrol; Stilbenes

Resveratrol has been shown to exploit various biological activities, including an anti-inflammatory activity. However, resveratrol is metabolized by phase II enzymes post-absorption to predominantly form glucuronides and sulfates. To investigate the anti-inflammatory effects of resveratrol and its dominating sulfated and glucuronated metabolites formed in vivo, U-937 macrophages were chosen as an immune-competent model system, known to release cytokines upon lipopolysaccharide stimulation. U-937 cells were stimulated with lipopolysaccharides from Escherichia coli (E. coli-LPS) to evoke an inflammatory reaction, and pre- or co-incubated with 1 or 10 μM of resveratrol (RES), resveratrol-3-sulfate (R3S), resveratrol-disulfates (RDS), resveratrol-3-glucuronide or resveratrol-4'-glucuronide. Time dependent gene expression of IL-6, IL-1α/β and IL-1R by qPCR was studied at 1 h, 3 h, 6 h, 9 h, and 24 h of incubation, and the release of IL-6 and TNF-α, after 6 h was analysed by means of non-magnetic or magnetic bead analysis. As a result, 10 μM resveratrol completely inhibited the E. coli-LPS-induced release of IL-6, while resveratrol-3-sulfate and resveratrol-disulfates decreased it by respective 84.2 ± 29.4% and 52.3 ± 39.5%. Whereas TNF-α release was reduced by 48.1 ± 15.4%, 33.0 ± 10.0% and 46.7 ± 8.7% by RES, R3S and RDS, respectively. These results show that not only resveratrol but also resveratrol-3-sulfate and resveratrol-disulfates exhibit an anti-inflammatory potential by counteracting an inflammatory challenge in U-937 macrophages at plasma representative concentrations.

Topics: Anti-Inflammatory Agents; Down-Regulation; Humans; Inflammation; Interleukin-1; Interleukin-6; Lipopolysaccharides; Macrophages; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha; U937 Cells

In this study, resveratrol (RSV) - a potent sirtuin 1 activator - was found to have beneficial effects on glucolipid metabolism and improve inflammatory mediators and markers of oxidative stress. Diabetic (db/db) mice and non-diabetic C57BL/6J mice were used in the study. The db/db mice were treated with or without 0.3% RSV mixed with chow for 8 weeks. Dietary RSV significantly lowered blood glucose, plasma lipid and free fatty acid levels in db/db mice. RSV markedly inhibited the expression of intercellular adhesion molecule-1 (ICAM-1), endothelial vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) in the aorta and the blood plasma of db/db mice (p < 0.05). Levels of mac-3-positive macrophages (measure of the infiltration of activated macrophages) were lower in RSV-treated diabetic mice than in their untreated counterparts (p < 0.05). RSV treatment reduced the activity of the transcriptional regulator nuclear factor kappa B (NF-κB) in aortic tissues (p < 0.05). Thus, RSV treatment reduced ICAM-1, VCAM-1 and MCP-1 expression in the aorta and ICAM-1, VCAM-1 and MCP-1 levels in the plasma of diabetic mice. Since dietary supplementation with RSV also reduced NF-κB activities in the aorta, the therapeutic effects of RSV might be associated with the downregulation of NF-κB.

Topics: Animals; Antigens, Differentiation; Blood Glucose; Chemokine CCL2; Diabetes Complications; Diabetes Mellitus; Inflammation; Intercellular Adhesion Molecule-1; Macrophages; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Resveratrol; Signal Transduction; Stilbenes; Vascular Cell Adhesion Molecule-1

Recent studies show that resveratrol exerts beneficial effects on prevention of pulmonary hypertension. This study is performed to explore the effects of trimethoxystilbene, a novel resveratrol analog, on rat pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-induced pulmonary arterial hypertension (PAH) and the underlying mechanisms. Sprague-Dawley rats were placed in a chamber and exposed to 10% O(2) continuously for 4 weeks to induce PAH. The effects of trimethoxystilbene (5 or 10 mg/kg per day, intragastric [i.g.]) and resveratrol (as a positive control, 25 mg/kg per day, i.g.) on hypoxia-induced PAH vascular remodeling and right ventricle hypertrophy were evaluated. At the end of experiments, the index for pulmonary vascular remodeling and right ventricle hypertrophy, inflammatory cell infiltration in lung tissue, the plasma levels and lung tissue contents of hydrogen peroxide (H(2)O(2)), the mRNA and protein levels for NADPH oxidases (NOX2, NOX4) and vascular peroxidase 1 (VPO1) in pulmonary artery or right ventricle were measured. The results showed that trimethoxystilbene treatment significantly attenuated hypoxia-induced pulmonary vascular remodeling (such as decrease in the ratio of wall thickness to vessel external diameter) and right ventricle hypertrophy (such as decrease in the ratio of right ventricle weight to the length of the tibia), accompanied by downregulation of NOX2, NOX4, and VPO1 expression in pulmonary artery or right ventricle, decrease in H(2)O(2) production and inflammatory cell infiltration in lung tissue. Trimethoxystilbene is able to prevent pulmonary vascular remodeling and right ventricle hypertrophy in hypoxia-induced rat model of PAH, which is related to inhibition of the NOX/VPO1 pathway-mediated oxidative stress and the inflammatory reaction.

Topics: Animals; Hemeproteins; Hypertension, Pulmonary; Hypoxia; Inflammation; Male; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidase 4; NADPH Oxidases; Peroxidases; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Stilbenes; Ventricular Remodeling

TNF-α converting enzyme (TACE) processes the membrane TNF-α to release the bioactive soluble TNF-α. Several evidences suggest the involvement of TNF-α and TACE in inflammatory bowel disease (IBD). Tissue inhibitor of metalloproteinase (TIMP)-3, an endogenous inhibitor of TACE, is positively associated with silent information regulator (SIRT)-1. We aimed to study the expression of TACE, TIMP-3 and SIRT-1 at different stages of colitis and how TACE is regulated in response to SIRT-1 activation. Acute colitis was induced by 3.5% dextran sulfate sodium (DSS) in drinking water for 5days and levels of cytokines and mRNA expression of TACE, TIMP-3 and SIRT-1 were measured in colon at different time intervals. Next, the effect of SIRT-1 activator (resveratrol) or a selective TACE inhibitor (compound 11p) treatment was evaluated. Elevated levels of TNF-α, interleukin (IL)-6, IL-1β, interferon (IFN)-γ and IL-17 were observed during DSS exposure phase which restored to the normal level after DSS removal. A significant increase in TACE and suppression in TIMP-3 and SIRT-1 mRNA level was observed during DSS exposure phase which reverts back to normal towards the remission phase. Treatment with resveratrol significantly elevated SIRT-1 and TIMP-3 and suppressed TACE mRNA expression and was associated with amelioration of disease. Furthermore, treatment with selective TACE inhibitor significantly suppressed body weight loss, disease activity index, colonic myeloperoxidase activity and the elevated levels of cytokines after DSS challenge. These results strongly emphasize the involvement of TACE in colon inflammation and inhibition of TACE directly or indirectly via SIRT-1 activation ameliorates colitis.

Topics: Acute Disease; ADAM Proteins; ADAM17 Protein; Animals; Colitis; Colon; Cytokines; Dextran Sulfate; Female; Inflammation; Kinetics; Mice; Mice, Inbred C57BL; Resveratrol; Sirtuin 1; Stilbenes; Time Factors; Tissue Inhibitor of Metalloproteinase-3

Inflammatory diseases such as acute lung injury and ischaemic tissue injury are caused by the adhesion of a type of white blood cell--polymorphonuclear neutrophils--to the lining of the circulatory system or vascular endothelium and unchecked neutrophil transmigration. Nanoparticle-mediated targeting of activated neutrophils on vascular endothelial cells at the site of injury may be a useful means of directly inactivating neutrophil transmigration and hence mitigating vascular inflammation. Here, we report a method employing drug-loaded albumin nanoparticles, which efficiently deliver drugs into neutrophils adherent to the surface of the inflamed endothelium. Using intravital microscopy of tumour necrosis factor-α-challenged mouse cremaster post-capillary venules, we demonstrate that fluorescently tagged albumin nanoparticles are largely internalized by neutrophils adherent to the activated endothelium via cell surface Fcɣ receptors. Administration of albumin nanoparticles loaded with the spleen tyrosine kinase inhibitor, piceatannol, which blocks 'outside-in' β2 integrin signalling in leukocytes, detached the adherent neutrophils and elicited their release into the circulation. Thus, internalization of drug-loaded albumin nanoparticles into neutrophils inactivates the pro-inflammatory function of activated neutrophils, thereby offering a promising approach for treating inflammatory diseases resulting from inappropriate neutrophil sequestration and activation.

Topics: Animals; Cattle; Cell Adhesion; Drug Carriers; Endothelium, Vascular; Inflammation; Mice; Nanoparticles; Neutrophils; Protein-Tyrosine Kinases; Receptors, IgG; Serum Albumin, Bovine; Stilbenes

Patients with Duchenne muscular dystrophy (DMD) have reduced muscle function due to chronic muscle damage, inflammation, oxidative stress, and reduced oxidative capacity. Resveratrol reduces inflammation and oxidative stress, and increases oxidative capacity in other disease models. The purpose of this study was to determine the effects of resveratrol on muscle function, muscle pathology, and oxidative capacity in young mdx mice. For this, 4- to 5-week-old male mdx mice were randomized into control or resveratrol-treated groups and given resveratrol (100 mg/kg body mass) or an equal volume of water by gavage every other day for 8 weeks. Muscle function was assessed pre- and post-treatment. Central nucleation, total immune cell infiltrate, oxidative stress, and oxidative capacity were measured post-treatment. Resveratrol mediated substantial improvements in rotarod performance and in-situ peak tension by 53% and 17%, respectively, and slight improvements in central nucleation and oxidative stress. Resveratrol did not affect total immune cell infiltrate at 12 weeks of age, and had no effect on oxidative capacity. Resveratrol improves muscle function in mdx mice despite small changes in muscle pathology. The likely mechanism is a resveratrol-mediated reduction in immune cell infiltrate at the early stages of this disease, as previously reported by our laboratory.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Inflammation; Male; Mice, Inbred mdx; Muscle, Skeletal; Myocardium; Organ Size; Oxidative Stress; Random Allocation; Resveratrol; Spleen; Stilbenes; Utrophin

In RA, synoviocytes cause increased oxidative stress, leading to mitochondrial alterations that may participate in the pathogenesis of RA. Here we investigated whether mitochondrial dysfunction induces inflammatory responses in cultured normal human synoviocytes, a hallmark of RA.. Mitochondrial dysfunction was induced with the inhibitor oligomycin. The effects of mitochondrial dysfunction on cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and IL-8 expression; cellular and mitochondrial reactive oxygen species (ROS) production; nuclear factor-κB (NF-κB) activation and p65 translocation were studied. ROS scavengers (N-acetylcysteine and mitoTEMPO) and an NF-κB inhibitor (BAY-117085) were used to investigate the pathways involved. The natural anti-inflammatory antioxidant resveratrol was also tested.. Mitochondrial dysfunction per se significantly stimulated mitochondrial ROS production as well as low-grade expressions of COX-2, PGE2 and IL-8. Interestingly, mitochondrial dysfunction induced by pretreatment of synoviocytes with oligomycin synergized with IL-1β to increase the expression of these inflammatory mediators. The inflammatory effects of mitochondrial damage appeared to be dependent on ROS production and NF-κB activation since the inflammatory response was counteracted by both N-acetylcysteine and mitoTEMPO and it was also reduced by BAY-117085. Antimycin A and paraquat (inhibitors of mitochondrial function) also induced inflammatory responses. Furthermore, resveratrol significantly reduced the inflammatory response by decreasing ROS production and NF-κB activation.. These data suggest that mitochondrial dysfunction could induce an inflammatory response in normal human synoviocytes and sensitize these cells, causing a significant amplification of the inflammatory response induced by IL-1β. Resveratrol may represent a promising strategy in controlling the synovial inflammatory response.

Topics: Aged; Arthritis, Rheumatoid; Cells, Cultured; Cyclooxygenase 2; Dinoprostone; Enzyme Inhibitors; Humans; Inflammation; Interleukin-1beta; Interleukin-8; Middle Aged; Mitochondria; NF-kappa B; Oligomycins; Oxidative Stress; Reactive Oxygen Species; Resveratrol; Stilbenes; Synovial Membrane

Dendritic cells (DC) are promising targets for inducing tolerance in inflammatory conditions. Thus, this study aims to investigate the effects of the natural anti-inflammatory molecule resveratrol on human DC at phenotypic and functional levels, including their capacity to recruit mesenchymal stem/stromal cells (MSC). Primary human monocyte-derived DC and bone marrow MSC were used. DC immunophenotyping revealed that small doses of resveratrol (10 µM) reduce cell activation in response to tumor necrosis factor (TNF)-α, significantly decreasing surface expression of CD83 and CD86. Functionally, IL-12/IL-23 secretion induced by TNF-α was significantly reduced by resveratrol, while IL-10 levels increased. Resveratrol also inhibited T cell proliferation, in response to TNF-α-stimulated DC. The underlying mechanism was investigated by Western blot and imaging flow cytometry (ImageStreamX), and likely involves impairment of nuclear translocation of the p65 NF-κB subunit. Importantly, results obtained demonstrate that DC are able to recruit MSC through extracellular matrix components, and that TNF-α impairs DC-mediated recruitment. Matrix metalloproteinases (MMP) produced by both cell populations were visualized by gelatin zymography. Finally, time-lapse microscopy analysis revealed a significant decrease on DC and MSC motility in co-cultures, indicating cell interaction, and TNF-α further decreased MSC motility, while resveratrol recovered it. Thus, the current study points out the potential of resveratrol as a natural anti-TNF-α drug, capable of modulating DC phenotype and function, as well as DC-mediated MSC recruitment.

Topics: Cell Death; Cell Differentiation; Cell Movement; Cell Nucleus; Cell Proliferation; Coculture Techniques; Cytokines; Dendritic Cells; Humans; Inflammation; Mesenchymal Stem Cells; NF-kappa B; Phenotype; Protein Transport; Resveratrol; Signal Transduction; Stilbenes; Tumor Necrosis Factor-alpha

Topics: Animals; Drug Carriers; Endothelium, Vascular; Inflammation; Nanoparticles; Neutrophils; Serum Albumin, Bovine; Stilbenes

The role of resveratrol (Res) in inflammation induced by ischemia/reperfusion is not well understood. The aim of the present study was to investigate whether Res modulates neutrophil accumulation and tumor necrosis factor-α (TNF-α) induction in an ischemia/reperfusion-injured rat heart model. The rats were randomly exposed to sham surgery, myocardial ischemia/reperfusion (MI/R) alone, MI/R + Res, MI/R + Res + L-NG-nitroarginine methyl ester (L-NAME) and MI/R + Res + methylene blue (MB). The results demonstrated that compared with MI/R, Res reduced the myocardial infarct area, myocardial myeloperoxidase levels, serum creatinine kinase and lactate dehydrogenase levels, and serum and myocardial TNF-α production. All the effects of Res demonstrated were inhibited by L-NAME (a nitric oxide (NO) synthase inhibitor) and MB [a cyclic guanosine monophosphate (cGMP) inhibitor]. Thus, Res produces cardioprotective and anti-inflammatory effects. These effects may be associated with an increase in NO production, the inhibition of neutrophil accumulation, TNF-α induction and cGMP signaling pathways in myocardium subjected to MI/R.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Creatine Kinase; Disease Models, Animal; Inflammation; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Neutrophil Infiltration; Rats; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

Antioxidants possess significant therapeutic potential for the treatment of inflammatory disorders. One such disorder is periodontitis characterised by an antimicrobial immune response, inflammation, and irreversible changes to the supporting structures of the teeth. Recognition of conserved pathogen-associated molecular patterns is a crucial component of innate immunity to Gram-negative bacteria such as Escherichia coli, as well as the periodontal pathogen Aggregatibacter actinomycetemcomitans. In this study, we investigated the antioxidants Phloretin, Silymarin, Hesperetin, and Resveratrol to ascertain whether they altered the production of inflammatory mediators by innately-activated leukocytes. Peripheral blood mononuclear cells were stimulated with lipopolysaccharide purified from Aggregatibacter actinomycetemcomitans, and the production of cytokines, chemokines, and differentiation factors was assayed by enzyme-linked immunosorbent assay, cytometric bead array, and RT-PCR. Significant inhibition of these factors was achieved upon treatment with Phloretin, Silymarin, Hesperetin, and Resveratrol. These data further characterise the potent anti-inflammatory properties of antioxidants. Their ability to inhibit the production of inflammatory cytokines, chemokines, and differentiation factors by a heterogeneous population of leukocytes has clear implications for their therapeutic potential in vivo.

Topics: Aggregatibacter actinomycetemcomitans; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cell Differentiation; Cells, Cultured; Cytokines; Escherichia coli; Hesperidin; Humans; I-kappa B Proteins; Inflammation; Leukocytes; Leukocytes, Mononuclear; Lipopolysaccharides; Monocytes; Neutrophils; NF-KappaB Inhibitor alpha; Phloretin; Resveratrol; RNA, Messenger; Silymarin; Stilbenes

Resveratrol has beneficial effects on aging, inflammation and metabolism, which are thought to result from activation of the lysine deacetylase, sirtuin 1 (SIRT1), the cAMP pathway, or AMP-activated protein kinase. In this study, we report that resveratrol acts as a pathway-selective estrogen receptor-α (ERα) ligand to modulate the inflammatory response but not cell proliferation. A crystal structure of the ERα ligand-binding domain (LBD) as a complex with resveratrol revealed a unique perturbation of the coactivator-binding surface, consistent with an altered coregulator recruitment profile. Gene expression analyses revealed significant overlap of TNFα genes modulated by resveratrol and estradiol. Furthermore, the ability of resveratrol to suppress interleukin-6 transcription was shown to require ERα and several ERα coregulators, suggesting that ERα functions as a primary conduit for resveratrol activity.DOI: http://dx.doi.org/10.7554/eLife.02057.001.

Topics: Adenylate Kinase; Cyclic AMP; Estrogen Receptor alpha; Female; Humans; Inflammation; Interleukin-6; Ligands; MCF-7 Cells; Promoter Regions, Genetic; Protein Conformation; Resveratrol; Signal Transduction; Stilbenes; Tumor Necrosis Factor-alpha

Resveratrol and curcumin are natural antioxidants found in the human diet that have been used in the prevention and treatment of different diseases associated with oxidative stress. Aiming to improve the antioxidant effects of resveratrol and curcumin, lipid-core nanocapsules containing the combination of both polyphenols were developed. Physicochemical characteristics were evaluated and compared to the formulations containing each polyphenol individually. Co-encapsulation did not influence nanotechnological characteristics, and all formulations presented mean diameter around 200 nm, low polydispersity index, and encapsulation efficiency close to 100%. Nanoencapsulation increases the photostability of resveratrol and curcumin, and co-encapsulation improves resveratrol photostability. The in vitro antioxidant activity of polyphenols against HO radicals was enhanced by nanoencapsulation, and a better effect was observed after their co-nanoencapsulation. Also, nanocapsules exhibited controlled release profile, for both polyphenols. The results showed that the strategy to co-encapsulate resveratrol and curcumin is a promising approach to improve the performance of medicines used to prevent and treat diseases associated with oxidative stress.

Topics: Antioxidants; Chromatography, High Pressure Liquid; Curcumin; Drug Delivery Systems; Free Radicals; Humans; Hydrogen-Ion Concentration; Inflammation; Lipids; Microscopy, Electron, Transmission; Nanocapsules; Nanoparticles; Nanotechnology; Oxidative Stress; Particle Size; Polyphenols; Resveratrol; Stilbenes

Resveratrol (Res) is a polyphenol anti-inflammatory agent. We have studied the link between the anti-inflammatory effects of Res and the high mobility group box 1(HMGB1) signaling pathway.. Murine macrophage-like RAW264.7 cells (RAW264.7 cells) were either untreated (control) or treated with Res, LPS, or LPS + Res. Levels of IL-6, NO, and TNF-α were measured by ELISA and colorimetric assays. Expression of HMGB1 was detected by qRT-PCR, western blot, and immunofluorescence assays. Protein and mRNA expression levels of TLR4 were also examined.. Res significantly reduced the levels of IL-6, NO, and TNF-α in RAW264.7 cells exposed to LPS. Expression levels of HMGB1 (mRNA and protein) and of TLR4 in the LPS + Res-treated cells were lower than in cells treated with LPS alone.. Res can block the inflammatory effects induced by LPS in RAW264.7 cells. Down-regulation of HMGB expression may be one of the mechanisms of action of Res. Res may also influence TLR4 expression in the HMGB1-TLR4 signaling pathway.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Dose-Response Relationship, Drug; HMGB1 Protein; Inflammation; Lipopolysaccharides; Mice; Molecular Structure; Resveratrol; RNA, Messenger; Stilbenes; Structure-Activity Relationship; Toll-Like Receptor 4

High-fat diet (HFD)-induced obesity is often associated with immune dysfunction. Resveratrol (trans-3,5,4'-trihydroxystilbene), which has well-founded immunity-related beneficial properties, was used to elucidate the regulatory effect on glucose metabolism and T-lymphocyte subsets in the development of HFD-induced obesity. Resveratrol, being associated with decreases of plasma leptin and plasma lipids and the release of oxidative stress, significantly decreased the body weight and fat masses in HF mice after 26 weeks of feeding. Furthermore, resveratrol decreased the fasting blood glucose and fasting plasma insulin and increased the CD3(+)CD4(+)/CD3(+)CD8(+) subsets percentages and the regulatory T cells (Tregs) production after 13 and 26 weeks of feeding. The results indicate that resveratrol, as an effective supplement for HFD, maintained glucose homeostasis by activating the PI3K and SIRT1 signaling pathways. Moreover, resveratrol activated the Nrf2 signaling pathway-mediated antioxidant enzyme expression to alleviate inflammation by protecting against oxidative damage and T-lymphocyte subset-related chronic inflammatory response in the development of HFD-induced obesity.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Blood Glucose; Body Weight; Diet, High-Fat; Fasting; Female; Inflammation; Insulin; Leptin; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Obesity; Oxidative Stress; Phosphatidylinositol 3-Kinases; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; T-Lymphocyte Subsets

Brain damage or exposure to inflammatory agents provokes the activation of microglia and secretion of pro-inflammatory and neurotoxic mediators responsible for neuronal loss. Several lines of evidence show that resveratrol, a natural non-flavonoid polyphenol, may exert a neuroprotective action in neurodegenerative diseases. Suppressor of cytokine signaling (SOCS) proteins are a family of eight members expressed by immune cells and the central nervous system (CNS) cells, that regulate immune processes within the CNS, including microglia activation. We demonstrate that resveratrol had anti-inflammatory effects in murine N13 microglial cells stimulated with lipopolysaccharide (LPS), through up-regulating SOCS-1 expression. Interestingly, in SOCS-1-silenced cells resveratrol failed to play a protective role after LPS treatment. Our data demonstrate that resveratrol can impair microglia activation by activating a SOCS-1 mediated signaling pathway.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Cell Survival; Inflammation; Lipopolysaccharides; Mice; Microglia; Nitric Oxide; Reactive Oxygen Species; Resveratrol; RNA, Small Interfering; Signal Transduction; Stilbenes; Superoxides; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins

Central arterial wall stiffening, driven by a chronic inflammatory milieu, accompanies arterial diseases, the leading cause of cardiovascular (CV) morbidity and mortality in Western society. An increase in central arterial wall stiffening, measured as an increase in aortic pulse wave velocity (PWV), is a major risk factor for clinical CV disease events. However, no specific therapies to reduce PWV are presently available. In rhesus monkeys, a 2 year diet high in fat and sucrose (HFS) increases not only body weight and cholesterol, but also induces prominent central arterial wall stiffening and increases PWV and inflammation. The observed loss of endothelial cell integrity, lipid and macrophage infiltration, and calcification of the arterial wall were driven by genomic and proteomic signatures of oxidative stress and inflammation. Resveratrol prevented the HFS-induced arterial wall inflammation and the accompanying increase in PWV. Dietary resveratrol may hold promise as a therapy to ameliorate increases in PWV.

Topics: Aldehydes; Animals; Aorta; Caspase 3; Cell Adhesion; Cells, Cultured; Diet, High-Fat; Endothelial Cells; Humans; Inflammation; Monocytes; Primates; Pulse Wave Analysis; Resveratrol; Stilbenes; Sucrose; Transcription, Genetic

the proinflammatory M1 subset and the anti-inflammatory M2 one. 7-oxo-cholesterol, the most abundant cholesterol autoxidation product within atherosclerotic plaque, is able to skew the M1/M2 balance towards a proinflammatory profile. In the present study, we explored the ability of the polyphenolic compound resveratrol to counteract the 7-oxo-cholesterol-triggered proinflammatory signaling in macrophages. Resveratrol-pretreated human monocyte-derived M1 and M2 macrophages were challenged with 7-oxo-cholesterol and analyzed for phenotype and endocytic ability by flow cytometry, for metalloproteinase- (MMP-) 2 and MMP-9 by gelatin zymography, and for cytokine, chemokine, and growth factor secretome by a multiplex immunoassay. We also investigated the NF-κB signaling pathway. In the M1 subset, resveratrol prevented the downregulation of CD16 and the upregulation of MMP-2 in response to 7-oxo-cholesterol, whereas in M2 macrophages it prevented the upregulation of CD14, MMP-2, and MMP-9 and the downregulation of endocytosis. Resveratrol prevented the upregulation of several proinflammatory and proangiogenic molecules in both subsets. We identified modulation of NF-κB as a potential mechanism implicated in 7-oxo-cholesterol and resveratrol effects. Our results strengthen previous findings on the immunomodulatory ability of resveratrol and highlight its role as potential therapeutic or preventive compound, to counteract the proatherogenic oxysterol signaling within atherosclerotic plaque.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Atherosclerosis; Cells, Cultured; Chemokines; Cytokines; Down-Regulation; Endocytosis; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Ketocholesterols; Lipopolysaccharide Receptors; Macrophages; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Monocytes; NF-kappa B; Receptors, IgG; Resveratrol; Stilbenes; Up-Regulation

We hypothesized that a high-protein diet and/or resveratrol supplementation will improve acute inflammatory responses in rats after receiving experimental abdominal radiation treatment (ART). Based on our previous study, the period of 10 days after ART was used as an acute inflammation model. Rats were exposed to a radiation dose of 17.5 Gy and were supplied with a control (C), 30% high-protein diet (HP), resveratrol supplementation (RES), or HP with RES diet ([HP+RES]). At day 10 after ART, we measured profiles of lipids, proteins, and immune cells in blood. The levels of clusters of differentiating 4(+) (CD4(+)) cells and regulatory T cells, serum proinflammatory cytokines, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine were also measured. ART caused significant disturbances of lipid profiles by increasing triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C), and decreasing high-density lipoprotein cholesterol. The proinflammatroy cytokine levels were also increased by ART. All the experimental diets (HP, RES, and [HP+RES]) significantly decreased levels of TG, monocytes, proinflammatory cytokines, and 8-OHdG, whereas the platelet counts were increased. In addition, the HP and [HP+RES] diets decreased the concentrations of plasma LDL-C and total cholesterol. Also, the HP and RES diets decreased regulatory T cells compared with those of the control diet in ART group. Further, the HP diet led to a significant recovery of white blood cell counts, as well as increased percentages of lymphocyte and decreased percentages of neutrophils. In summary, RES appeared to be significantly effective in minimizing radiation-induced damage to lipid metabolism and immune responses. Our study also demonstrated the importance of dietary protein intake in recovering from acute inflammation by radiation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Deoxyguanosine; Diet; Dietary Proteins; Dietary Supplements; Female; Immune System; Inflammation; Leukocyte Count; Lipid Metabolism; Lipids; Neoplasms; Phytotherapy; Plant Extracts; Platelet Count; Radiation Injuries, Experimental; Rats, Wistar; Resveratrol; Stilbenes

The development of choroidal neovascularization (CNV) is a critical step in the pathogenesis of age-related macular degeneration (AMD), a vision-threatening disease. In this study, we used a mouse model of AMD to study the protective effects of resveratrol (RSV) supplementation against CNV as well as the underlying molecular mechanisms. Mice were orally pretreated with RSV daily for 5 days. On the fifth day, the mice underwent laser photocoagulation to induce CNV. One week after laser treatment, CNV volume was significantly lower in the RSV-treated mice compared with vehicle-treated animals. In addition, RSV treatment significantly inhibited macrophage infiltration into the retinal pigment epithelium (RPE)-choroid and suppressed the expression of inflammatory and angiogenic molecules, including vascular endothelial growth factor, monocyte chemotactic protein-1 and intercellular adhesion molecule-1. Importantly, RSV prevented the CNV-induced decrease in activated AMP-activated protein kinase and increase in activated nuclear factor-κB in the RPE-choroid complex. The regulatory effects of RSV on these molecules were confirmed in RPE, microvascular endothelial and macrophage cell lines. Inhibition of macrophage infiltration by RSV was confirmed by in vitro scratch and migration assays. RSV suppressed CNV development, reducing the levels of multiple cytokines secreted from several cell types and inhibiting macrophage migration. The direct effects of RSV on each cell type were confirmed in vitro. Although further studies are needed, RSV could potentially be applied in the clinic to prevent CNV development in AMD.

Topics: AMP-Activated Protein Kinases; Animals; Cell Movement; Choroidal Neovascularization; Inflammation; Macrophages; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Real-Time Polymerase Chain Reaction; Resveratrol; Retinal Pigment Epithelium; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes

Oxidative stress is a key factor regulating the systemic pathophysiological effects associated with periodontitis. Resveratrol is a phytochemical with antioxidant and anti-inflammatory properties that can reduce oxidative stress and inflammation. We hypothesized that resveratrol may prevent the progression of periodontitis and reduce systemic oxidative stress through the activation of the sirtuin 1 (Sirt1)/AMP-activated protein kinase (AMPK) and the nuclear factor E2-related factor 2 (Nrf2)/antioxidant defense pathways. Three groups of male Wistar rats (periodontitis treated with melinjo resveratrol, periodontitis without resveratrol, and control rats with no periodontitis or resveratrol treatment) were examined. A ligature was placed around the maxillary molars for 3 weeks to induce periodontitis, and the rats were then given drinking water with or without melinjo resveratrol. In rats with periodontitis, ligature placement induced alveolar bone resorption, quantified using three-dimensional images taken by micro-CT, and increased proinflammatory cytokine levels in gingival tissue. Melinjo resveratrol intake relieved alveolar bone resorption and activated the Sirt1/AMPK and the Nrf2/antioxidant defense pathways in inflamed gingival tissues. Further, melinjo resveratrol improved the systemic levels of 8-hydroxydeoxyguanosine, dityrosine, nitric oxide metabolism, nitrotyrosine, and proinflammatory cytokines. We conclude that oral administration of melinjo resveratrol may prevent the progression of ligature-induced periodontitis and improve systemic oxidative and nitrosative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Antioxidants; Bone Resorption; Cytokines; Deoxyguanosine; Disease Models, Animal; Gingiva; Inflammation; Male; NF-E2-Related Factor 2; Nitric Oxide; Oxidative Stress; Periodontitis; Random Allocation; Rats; Rats, Wistar; Resveratrol; Sirtuin 1; Stilbenes; Tyrosine

The present study was aimed at elucidating the molecular mechanisms of anti-inflammatory activity of piceatannol (trans-3,4,3',5'-tetrahydroxystilbene) in mouse skin in vivo.. Female HR-1 hairless mice were topically treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) with or without piceatannol pretreatment. Epidermal protein expression was assessed by Western blot analysis. The cyclooxygenase-2 (COX-2) expression was detected by immunohistochemistry. The DNA binding of nuclear factor-kappaB (NF-κB) and activator protein-1 (AP-1) was examined by the electrophoretic mobility gel shift assay. The catalytic activity of IκBα kinase-β (IKKβ) was measured by in vitro kinase assay.. Pretreatment with piceatannol attenuated TPA-induced expression of COX-2 and inducible nitric oxide synthase (iNOS) in mouse skin. Piceatannol diminished nuclear translocation and the DNA binding of NF-κB through the blockade of phosphorylation and subsequent degradation of IκBα. Piceatannol attenuated the catalytic activity of IKKβ and inhibited the phosphorylation of mitogen-activated protein (MAP) kinases in TPA-treated mouse skin. In addition, piceatannol decreased TPA-induced expression of c-Fos and the DNA binding of AP-1.. Piceatannol inhibits TPA-induced COX-2 and iNOS expression by blocking the activation of NF-κB and AP-1 via suppression of the IKKβ activity and phosphorylation of MAP kinases, which provides a mechanistic basis of its anti-inflammatory effects in mouse skin.

Topics: Animals; Catalysis; Catalytic Domain; Cyclooxygenase 2; Female; I-kappa B Kinase; Immunohistochemistry; Inflammation; Mice; NF-kappa B; Nitric Oxide Synthase Type II; Phosphorylation; Protein Binding; Proto-Oncogene Proteins c-fos; Skin; Stilbenes; Tetradecanoylphorbol Acetate; Transcription Factor AP-1

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease characterized by the production of autoantibodies. To date, no therapy has been found to satisfactorily treat SLE. SIRT1 deficiency results in the development of an autoimmune syndrome in mice, including a high titer of anti-nuclear antibody in serum, immunoglobulin deposition in the kidney, and immune complex glomerulonephritis. Resveratrol is an activator of SIRT1 and possesses anti-inflammation and immune-regulatory properties.. To evaluate the preventative effects of resveratrol on a pristane-induced lupus animal model and assess its putative immune modulation effects.. BALB/c mice received a single intraperitoneal injection of 0.5 ml of pristane on day 1 and then various doses of resveratrol were given to the mice daily starting on day 2 and continuing for seven months. The autoantibodies in serum and supernatants were measured. Single cells isolated from spleen, isolated CD4+ T cells, and CD19+ B cells were cultured with or without resveratrol in vitro and assessed by flow cytometry.. Resveratrol attenuated proteinuria, immunoglobuin depositon in kidney, and glomerulonephritis as well as IgG1 and IgG2a in serum in pristane-induced lupus mice. Resveratrol also suppressed CD69 and CD71 expression on CD4+ T cells as well as CD4+ T cell proliferation, induced CD4+ T cell apoptosis, and decreased CD4 IFNγ+ Th1 cells and the ratio of Th1/Th2 cells in vitro. In vitro antibody production and proliferation of B cells were also inhibited.. Resveratrol possesses protective effects in pristane-induced lupus mice and may represent a novel approach for the management of SLE.

Topics: Animals; Antigens, CD; Antigens, CD19; Antigens, Differentiation, T-Lymphocyte; Apoptosis; B-Lymphocytes; CD4-Positive T-Lymphocytes; Gene Expression Regulation; Humans; Inflammation; Lectins, C-Type; Lupus Erythematosus, Systemic; Mice; Receptors, Transferrin; Resveratrol; Sirtuin 1; Stilbenes; Terpenes

Resveratrol (RESV) is a plant polyphenol, which is thought to have beneficial metabolic effects in laboratory animals as well as in humans. Following oral administration, RESV is immediately catabolized, resulting in low bioavailability. This study compared RESV metabolites and their tissue distribution after oral uptake and skin absorption. Metabolomic analysis of various mouse tissues revealed that RESV can be absorbed and metabolized through skin. We detected sulfated and glucuronidated RESV metabolites, as well as dihydroresveratrol. These metabolites are thought to have lower pharmacological activity than RESV. Similar quantities of most RESV metabolites were observed 4 h after oral or skin administration, except that glucuronidated RESV metabolites were more abundant in skin after topical RESV application than after oral administration. This result is consistent with our finding of glucuronidated RESV metabolites in cultured skin cells. RESV applied to mouse ears significantly suppressed inflammation in the TPA inflammation model. The skin absorption route could be a complementary, potent way to achieve therapeutic effects with RESV.

Topics: Administration, Cutaneous; Animals; Biological Availability; Cells, Cultured; Female; Glucuronides; Humans; Inflammation; Male; Mice; Resveratrol; Skin; Skin Absorption; Stilbenes

Anti-inflammatory and anti-apoptotic effects of polydatin (PD) have been demonstrated in our previous studies. Recently, we have found that PD treatment can ameliorate burn-induced acute lung injury (ALI). In the present study, we hypothesized that PD may provide protective effect against LPS-induced ALI through reducing inflammation and apoptosis. Rats were respectively pretreated with PD at doses of 15, 30 and 45 mg/kg weight, followed by intratracheal administration of lipopolysaccharide (LPS). LPS-challenged rats exhibited significant lung injury characterized by the deterioration of histopathology, pulmonary microvascular hyperpermeability, wet-to-dry weight ratio, and oxygenation index, which was attenuated by PD (30 and 45 mg/kg) treatment. Moreover, PD (30 and 45 mg/kg) treatment inhibited LPS-induced inflammatory response, as evidenced by the downregulation of lung myeloperoxidase activity, total cells and PMNs in bronchoalveolar lavage fluid, and the systemic levels of the pro-inflammatory cytokines. Furthermore, PD (30 and 45 mg/kg) treatment remarkably improved LPS-induced increase in TUNEL (deoxynucleotidyl transferase dUTP nick end labeling) staining-positive cells, caspase 3 activity, Bax over-expression and Bcl-2 down-expression. In conclusion, these results demonstrate that PD (30 and 45 mg/kg) treatment attenuates LPS-induced ALI through reducing lung inflammation and apoptosis.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Apoptosis; Blotting, Western; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Glucosides; In Situ Nick-End Labeling; Inflammation; Lipopolysaccharides; Male; Rats; Rats, Sprague-Dawley; Stilbenes

A DNA oligo-microarray enriched in genes and involved in inflammatory and immune responses was used to evaluate the effects of resveratrol on gene expression in turbot head kidney leucocytes. Leucocytes were cultured for 3, 6 and 24 h, in the presence or absence of resveratrol, or were stimulated with the membrane fraction of the parasite Philasterides dicentrarchi or with the membrane plus resveratrol. Gene expression changed considerably in control cells, and several of the regulated genes were related to inflammatory and immune responses and to the cytoskeleton. Similar changes in gene expression occurred in control cells and in cells stimulated with P. dicentrarchi membrane fraction. Treatment with resveratrol induced changes in the expression (mostly down-regulation) of several genes involved in immune responses and inflammation. Thus, the down-regulation of the transcription factor PU.1, pentraxin-multidomain protein, heme oxygenase 1, S100 calcium-binding protein A-16 (S100A16) and the signal transducer and activator of transcription 4 was observed after all three incubation times. The down-regulation of the suppressor of cytokine signalling 3a, LPS-induced tumour necrosis alpha, hepcidin, metallothionein, TLR8 and the calcium dependent lectin A was observed after 3 and 6 h. Resveratrol also decreased the expression of CCL20, IL-8, apolipoprotein E and glutathione S-transferase after incubation for 6 and 24 h, and of TNF-α after incubation for 3 and 24 h. Resveratrol also induced strong regulation of several cytoskeleton-related genes. The use of the turbot oligo-microarray enabled us to discover genes whose expression was not previously suspected of being modulated by this polyphenol.

Topics: Animals; Antigens, Protozoan; Cells, Cultured; Ciliophora; Flatfishes; Gene Expression Regulation; Head Kidney; Heme Oxygenase-1; Immunity; Inflammation; Inflammation Mediators; Leukocytes; Microarray Analysis; Proto-Oncogene Proteins; Resveratrol; S100 Proteins; STAT4 Transcription Factor; Stilbenes; Trans-Activators

Hypoxia modulates the production of proteins involved in e.g. inflammation, angiogenesis and glucose utilization and hypoxia may therefore be an important factor underlying adipose tissue dysfunction in obesity. Resveratrol (RSV) is a natural polyphenolic compound and has been shown to have powerful anti-inflammatory effects and beneficial effects on several obesity-related complications. Thus, in the present study we investigated whether RSV has effects on hypoxic markers (GLUT-1, VEGF), hypoxia-induced key markers of inflammation (IL8, IL6), and leptin in human adipose tissue in vitro. Hypoxia was induced by incubating human adipose tissue fragments with 1% O2 for 24h as compared to 21% O2 The gene expressions were investigated by RT-PCR and protein release by Elisa. Hypoxia increases the expression of glucose transporter-1 (GLUT-1) (19-fold, p<0.001), vascular endothelial growth factor (VEGF) (10-fold, p<0.05), interleukin-8 (IL8) (8-fold, p<0.05), interleukin-6 (IL6) (5-fold, p<0.05) and leptin (9-fold). The protein levels of VEGF released to the medium was increased (8-fold, p<0.01) by hypoxia. RSV dose-dependently inhibited several of these hypoxia-induced expressions and at a concentration of 50 μM RSV almost completely inhibited the hypoxic responses at the above mentioned gene expression levels (p<0.05-p<0.001) and significantly attenuated the hypoxia-induced protein releases by 50-60%. These results demonstrate that hypoxia induces extensive changes in human adipose tissue in the expression and release of inflammation and angiogenesis-related adipokines. In addition the inhibition of hypoxia-mediated inflammation and angiogenesis might represent a novel mechanism of RSV in preventing obesity-related pathologies.

Topics: Adipose Tissue; Adult; Angiogenesis Inhibitors; Anti-Inflammatory Agents; Female; Glucose Transporter Type 1; Humans; Hypoxia; In Vitro Techniques; Inflammation; Interleukin-6; Interleukin-8; Leptin; Neovascularization, Physiologic; Resveratrol; RNA, Messenger; Stilbenes; Vascular Endothelial Growth Factor A

Resveratrol is a phytoalexin abundantly found in red grape skin and is effective in antitumor and antiinflammation associated with immune responses. This study investigated whether resveratrol suppressed immunoglobulin (Ig)E-mediated allergic responses and passive cutaneous anaphylaxis (PCA) in rat RBL-2H3 mast cells and in BALB/c mice. The release of β-hexosaminidase and histamine was enhanced in mast cells sensitized with anti-dinitrophenyl (DNP)-IgE and subsequently stimulated by DNP-human serum albumin (HSA), indicative of mast cell degranulation. When mast cells were pretreated with nontoxic resveratrol at 1-25 μmol/L, such induction was dose dependently diminished. Spleen tyrosine kinase (Syk) and phospholipase Cγ (PLCγ) of sensitized mast cells were activated by stimulation with DNP-HSA antigen, which was dampened by ≥5 μmol/L resveratrol. The phosphorylation of protein kinase C (PKC)μ and PKCθ was attenuated by administering resveratrol to DNP-HSA-exposed mast cells, whereas quiescent PKCζ/λ in sensitized cells was dose-dependently activated by resveratrol. Male BALB/c mice were sensitized for 24 h with DNP-IgE and orally administered with resveratrol 1 h before the DNP-HSA challenge. The histamine concentration was enhanced in sensitized mice challenged to DNP-HSA, which was reversed by administration of 10 mg/kg resveratrol. Additionally, it encumbered the tissue activation of Syk, PLCγ, and PKCμ in antigen-exposed mice. Resveratrol decreased IgE-mediated PCA and alleviated allergic edema of mouse ear and dorsal skin. Mast cell degranulation and allergic inflammation, accompanying the induction of monocyte chemotactic protein-1 and macrophage inflammatory protein-2, were inhibited by supplementing resveratrol to antigen-challenged mice. Resveratrol inhibited mast cell-derived, immediate-type allergic reactions, and these responses of resveratrol suggest possible therapeutic strategies in preventing allergic inflammatory diseases.

Topics: Anaphylaxis; Animals; Basophils; beta-N-Acetylhexosaminidases; CD24 Antigen; Chemokine CCL2; Chemokine CXCL2; Dietary Supplements; Dinitrophenols; Dose-Response Relationship, Drug; Edema; Histamine; Histamine Release; Immunoglobulin E; Inflammation; Intracellular Signaling Peptides and Proteins; Male; Mast Cells; Mice; Mice, Inbred BALB C; Passive Cutaneous Anaphylaxis; Phospholipase C gamma; Phosphorylation; Phytotherapy; Plant Extracts; Protein-Tyrosine Kinases; Rats; Resveratrol; Serum Albumin; Skin; Stilbenes; Syk Kinase; Vitis

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that can cause severe pulmonary infection in immunocompromized individuals. During the infectious process, P. aeruginosa provokes a potent inflammatory response and induces the release of reactive oxygen species (ROS). Cells undergo oxidative stress when cellular antioxidants are unable to effectively scavenge and detoxify ROS, resulting in lung damage. Resveratrol (3,5,4'-trihydroxystilbene) is a natural polyphenolic compound with recognized antioxidant effects. We hypothesized that owing to its antioxidant activities, resveratrol can attenuate an inflammatory response in P. aeruginosa-infected cells. Lung epithelial A549 cells were pre-treated with 100 μmol/L of resveratrol for 5 h, followed by infection with P. aeruginosa. Intracellular ROS generation was used as an indicator of P. aeruginosa-induced oxidative stress, and cell surface expression of Fas receptor and activation of caspases-3 and -7 as indicators of apoptosis. We also measured the surface expression of intercellular adhesion molecule (ICAM)-1 and enzymes related to inflammation and redox signaling. Resveratrol significantly reduced ROS generation, ICAM-1, and human beta-defensin-2 expression, as well as the markers of apoptosis in A549 cells infected with P. aeruginosa, and up-regulated glutathione peroxidase, suggesting its potential therapeutic role in protecting the lungs against the deleterious effects of P. aeruginosa infection.

Topics: Antioxidants; Cell Line; Down-Regulation; Epithelial Cells; Humans; Inflammation; Lung; Pseudomonas aeruginosa; Pseudomonas Infections; Reactive Oxygen Species; Respiratory Mucosa; Resveratrol; Stilbenes

Treatment of experimental autoimmune encephalomyelitis (EAE) with resveratrol, an activator of sirtuin 1 (SIRT1), reduces disease severity. This suggested that activators of SIRT1, a highly conserved NAD-dependent protein deacetylase, might have immune-modulating or neuroprotective therapeutic effects in EAE. Previously, we showed that SIRT1 expression increases in EAE, suggesting that it is an adaptive response. In this study, we investigated the potential function of SIRT1 in regulating EAE using SIRT1-overexpressing mice. The current studies examine potential neuroprotective and immunomodulatory effects of SIRT1 overexpression in chronic EAE induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35-55. SIRT1 suppressed EAE clinical symptoms compared with wild-type EAE mice and prevented or altered the phenotype of inflammation in spinal cords; as a result, demyelination and axonal injury were reduced. Significant neuroprotective effects were observed, with fewer apoptotic cells found in the spinal cords of SIRT1-overexpressing EAE mice associated with increased brain-derived neurotrophic factor and NAD levels. Earlier, we showed that brain-derived neurotrophic factor and NAD play crucial neuroprotective roles in EAE. These results suggest that SIRT1 reduces neuronal loss in this chronic demyelinating disease model and that this is associated with a reduction in inflammation.

Topics: Animals; Apoptosis; Axons; Brain-Derived Neurotrophic Factor; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Female; Inflammation; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; NAD; Neurons; Neuroprotective Agents; Resveratrol; Sirtuin 1; Spinal Cord; Stilbenes

The development of acute lung injury (ALI) during sepsis almost doubles the mortality rate of patients. The efficacy of current treatment strategies is low as treatment is usually initiated following the onset of symptoms. Inflammation is one of the main mechanisms of autoimmune disorders and is a common feature of sepsis. The suppression of inflammation is therefore an important mechanism for the treatment of sepsis. Sirtuin 1 (Sirt1) has been demonstrated to play a role in the regulation of inflammation. Resveratrol, a potent Sirt1 activator, exhibits anti‑inflammatory properties. However, the role of resveratrol for the treatment of ALI during sepsis is not fully understood. In the present study, the anti‑inflammatory role of Sirt1 in the lipopolysaccharide (LPS)‑induced TC‑1 cell line and its therapeutic role in ALI was investigated in a mouse model of sepsis. The upregulation of matrix metalloproteinase-9, interleukin (IL)‑1β, IL‑6 and inducible nitric oxide synthase was induced by LPS in the mouse model of sepsis and the TC‑1 cell line, and resveratrol suppressed the overexpression of these proinflammatory molecules in a dose‑dependent manner. Resveratrol decreased pulmonary edema in the mouse model of sepsis induced by LPS. In addition, resveratrol improved lung function and reduced pathological alterations in the mouse model of sepsis. Knockdown of Sirt1 by RNA interference resulted in an increased susceptibility of TC‑1 cells to LPS stimulation and diminished the anti‑inflammatory effect of resveratrol. These results demonstrated that resveratrol inhibits LPS‑induced ALI and inflammation via Sirt1, and indicated that Sirt1 is an efficient target for the regulation of LPS‑induced ALI and inflammation. The present study provides insights into the treatment of ALI during sepsis.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Disease Models, Animal; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Male; Matrix Metalloproteinase 9; Mice; Nitric Oxide Synthase Type II; Resveratrol; RNA Interference; RNA, Small Interfering; Sepsis; Sirtuin 1; Stilbenes; Up-Regulation

Increased plasminogen activator inhibitor-1 (PAI-1) levels are associated with a number of pathophysiological complications; among them is obesity. Resveratrol was proposed to improve obesity-related health problems, but the effect of resveratrol on PAI-1 gene expression in obesity is not completely understood. In this study, we used SGBS adipocytes and a model of human adipose tissue inflammation to examine the effects of resveratrol on the production of PAI-1. Treatment of SGBS adipocytes with resveratrol reduced PAI-1 mRNA and protein in a time- and concentration-dependent manner. Further experiments showed that obesity-associated inflammatory conditions lead to the upregulation of PAI-1 gene expression which was antagonized by resveratrol. Although signaling via PI3K, Sirt1, AMPK, ROS, and Nrf2 appeared to play a significant role in the modulation of PAI-1 gene expression under noninflammatory conditions, those signaling components were not involved in mediating the resveratrol effects on PAI-1 production under inflammatory conditions. Instead, we demonstrate that the resveratrol effects on PAI-1 induction under inflammatory conditions were mediated via inhibition of the NF κ B pathway. Together, resveratrol can act as NF κ B inhibitor in adipocytes and thus the subsequently reduced PAI-1 expression in inflamed adipose tissue might provide a new insight towards novel treatment options of obesity.

Topics: Adipocytes; Adipose Tissue; AMP-Activated Protein Kinases; Animals; Arrhythmias, Cardiac; Culture Media, Conditioned; DNA; Down-Regulation; Female; Gene Expression Regulation; Genetic Diseases, X-Linked; Gigantism; Heart Defects, Congenital; Humans; Inflammation; Intellectual Disability; Mice; Models, Biological; NF-E2-Related Factor 2; NF-kappa B; Phosphatidylinositol 3-Kinases; Plasminogen Activator Inhibitor 1; Protein Binding; Reactive Oxygen Species; Resveratrol; RNA, Messenger; Sirtuin 1; Stilbenes; Time Factors; Up-Regulation

IL-1β, a pro-inflammatory cytokine, has been shown to contribute to radiation injury. Sirt1, an NAD+-dependent class III protein deacetylase, plays an important role in the regulation of the proinflammatory cytokines involved in inflammation-associated diseases. The relationship between Sirt1 and IL-1β, however, has remained elusive. The present study was designed to explore the potential effect of Sirt1 on IL-1β expression induced by radiation and to provide a new target for the development of radiation protection drugs. Our results showed that radiation significantly increased IL-1β mRNA and protein expression and that pretreatment with resveratrol, a Sirt1 activator, inhibited the radiation-induced IL-1β expression in a concentration-dependent manner, whereas the knockdown or inhibition of Sirt1 by nicotinamide significantly enhanced radiation-induced IL-1β expression. This effect can likely be attributed to Sirt1-mediated inhibition of NLRP-3 inflammasome activation because Sirt1 inhibits the transactivation potential of NF-κb by deacetylation, which then suppresses NLRP3 transcription. Taken together, the results demonstrate that Sirt1 exerts anti-inflammatory effects by regulating NLRP3 expression partially through the NF-κb pathway in mesenchymal stem cells. More importantly, our findings suggest that resveratrol is an effective agent in protecting against radiation injury, and we provide a theoretical basis for developing a drug to protect against radiation injury by targeting Sirt1.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Carrier Proteins; Cells, Cultured; Humans; Inflammation; Interleukin-1beta; Mesenchymal Stem Cells; NF-kappa B; Niacinamide; NLR Family, Pyrin Domain-Containing 3 Protein; Radiation, Ionizing; Resveratrol; RNA Interference; RNA, Messenger; RNA, Small Interfering; Sirtuin 1; Stilbenes; Up-Regulation

Age-related metabolic diseases are often associated with low-grade inflammation. The aim of the present study was to investigate the role of the transcriptional co-activator PGC-1α in the potential beneficial effects of exercise training and/or resveratrol in the prevention of age-associated low-grade inflammation. To address this, a long-term voluntary exercise training and resveratrol supplementation study was conducted.. Three month old whole body PGC-1α KO and WT mice were randomly assigned to four groups: untrained chow-fed, untrained chow-fed supplemented with resveratrol, chow-fed voluntarily exercise trained and chow-fed supplemented with resveratrol and voluntarily exercise trained. The intervention lasted 12 months and three month old untrained chow-fed mice served as young controls.. Voluntary exercise training prevented an age-associated increase (p<0.05) in systemic IL-6 and adiposity in WT mice. PGC-1α expression was required for a training-induced prevention of an age-associated increase (p<0.05) in skeletal muscle TNFα protein. Independently of PGC-1α, both exercise training and resveratrol prevented an age-associated increase (p<0.05) in skeletal muscle protein carbonylation.. The present findings highlight that exercise training is a more effective intervention than resveratrol supplementation in reducing age-associated inflammation and that PGC-1α in part is required for the exercise training-induced anti-inflammatory effects.

Topics: Aging; Animals; Antioxidants; Female; Inflammation; Interleukin-6; Mice; Mice, Knockout; Muscle, Skeletal; Nitric Oxide Synthase Type II; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Physical Conditioning, Animal; Protein Carbonylation; Resveratrol; RNA, Messenger; Stilbenes; Transcription Factors; Tumor Necrosis Factor-alpha

Chronic inflammation induced by amyloid-beta (Aβ) plays a key role in the development of age-related macular degeneration (AMD), and matrix metalloproteinase-9 (MMP-9), interleukin (IL)-6, and IL-8 may be associated with chronic inflammation in AMD. Sirtuin 1 (SIRT1) regulates inflammation via inhibition of nuclear factor-kappa B (NF-κB) signaling, and resveratrol has been reported to prevent Aβ-induced retinal degeneration; therefore, we investigated whether this action was mediated via activation of SIRT1 signaling. Human adult retinal pigment epithelial (RPE) cells were exposed to Aβ, and overactivation and knockdown of SIRT1 were performed to investigate whether SIRT1 is required for abrogating Aβ-induced inflammation. We found that Aβ-induced RPE barrier disruption and expression of IL-6, IL-8, and MMP-9 were abrogated by the SIRT1 activator SRT1720, whereas alterations induced by Aβ in SIRT1-silenced RPE cells were not attenuated by SRT1720. In addition, SRT1720 inhibited Aβ-mediated NF-κB activation and decrease of the NF-κB inhibitor, IκBα. Our findings suggest a protective role for SIRT1 signaling in Aβ-dependent retinal degeneration and inflammation in AMD.

Topics: Adult; Amyloid beta-Peptides; Antioxidants; Blood-Retinal Barrier; Cell Survival; Enzyme Assays; Gene Silencing; Heterocyclic Compounds, 4 or More Rings; Humans; Inflammation; Interleukin-6; Interleukin-8; Macular Degeneration; Matrix Metalloproteinase 9; NF-kappa B; Primary Cell Culture; Real-Time Polymerase Chain Reaction; Resveratrol; Retinal Pigment Epithelium; RNA Interference; Signal Transduction; Sirtuin 1; Stilbenes

Obesity is associated with a chronic, low-grade, systemic inflammation that may contribute to the development of insulin resistance and type 2 diabetes. Resveratrol, a natural compound with anti-inflammatory properties, is shown to improve glucose tolerance and insulin sensitivity in obese mice and humans. Here, we tested the effect of a 2-year resveratrol administration on proinflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Resveratrol supplementation (80 and 480 mg/day for the first and second year, respectively) decreased adipocyte size, increased sirtuin 1 expression, decreased NF-κB activation, and improved insulin sensitivity in visceral, but not subcutaneous, WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS ± resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys.

Topics: Adipocytes; Adipose Tissue, White; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbohydrates; Cell Line; Diet, High-Fat; Inflammation; Insulin; Macaca mulatta; Male; Mice; NF-kappa B; Obesity; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Transcriptome; Viscera

Inflammation participates centrally in all stages of atherosclerosis (AS), which begins with inflammatory changes in the endothelium, characterized by expression of the adhesion molecules. Resveratrol (RSV) is a naturally occurring phytoalexin that can attenuate endothelial inflammation; however, the exact mechanisms have not been thoroughly elucidated. Autophagy refers to the normal process of cell degradation of proteins and organelles, and is protective against certain inflammatory injuries. Thus, we intended to determine the role of autophagy in the antiinflammatory effects of RSV in human umbilical vein endothelial cells (HUVECs). We found that RSV pretreatment reduced tumor necrosis factor ? (TNF/TNF?)-induced inflammation and increased MAP1LC3B2 (microtubule-associated protein 1 light chain 3 ? 2) expression and SQSTM1/p62 (sequestosome 1) degradation in a concentration-dependent manner. A bafilomycin A 1 (BafA1) challenge resulted in further accumulation of MAP1LC3B2 in HUVECs. Furthermore, autophagy inhibitors 3-methyladenine (3-MA), chloroquine as well as ATG5 and BECN1 siRNA significantly attenuated RSV-induced autophagy, which, subsequently, suppressed the downregulation of RSV-induced inflammatory factors expression. RSV also increased cAMP (cyclic adenosine monophosphate) content, the expression of PRKA (protein kinase A) and SIRT1 (sirtuin 1), as well as the activity of AMPK (AMP-activated protein kinase). RSV-induced autophagy in HUVECs was abolished in the presence of inhibitors of ADCY (adenylyl cyclase, KH7), PRKA (H-89), AMPK (compound C), or SIRT1 (nicotinamide and EX-527), as well as ADCY, PRKA, AMPK, and SIRT1 siRNA transfection, indicating that the effects of RSV on autophagy induction were dependent on cAMP, PRKA, AMPK and SIRT1. In conclusion, RSV attenuates endothelial inflammation by inducing autophagy, and the autophagy in part was mediated through the activation of the cAMP-PRKA-AMPK-SIRT1 signaling pathway.

Topics: Adenine; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Autophagy; Carbazoles; Cyclic AMP; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Isoquinolines; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Sulfonamides; Tumor Necrosis Factor-alpha; Vasculitis

Consumption of a high-fat diet (HFD) is correlated with increased oxidative stress and chronic inflammation in many organs. Regulatory T cells (Tregs) are essential negative regulators of inflammation. We hypothesized that resveratrol (trans-3,5,4'-trihydroxystilbene) could protect against HFD-induced oxidative stress and inflammation. Therefore, we examined the effect of resveratrol on oxidative stress and the relevant peripheral immune-regulating mechanisms in HFD-induced obese (DIO) and diet-resistant mice. C57BL/6 mice were fed a normal diet and an HFD for 13 weeks. Then the experimental group was subdivided into DIO and diet-resistant groups according to their body weights, which were further supplemented with 0.03% resveratrol and 0.06% resveratrol, respectively, for an additional 13 weeks. Resveratrol prevented the accumulation of chronic oxidative stress and suppression of Tregs production in HFD mice, modulated changes of cytokines in the plasma and spleen, and decreased expressions of inflammatory mediators compared with those of the DIO group. Our results indicate that resveratrol, as a feasible effective supplement for HFD, can relieve oxidative stress, inhibit inflammatory genes expression, and increase Tregs number via aryl hydrocarbon receptor activation inhibited by HFD, especially in DIO mice.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Cytokines; Diet, High-Fat; Dietary Fats; Dietary Supplements; Inflammation; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; Obesity; Oxidative Stress; Phytotherapy; Plant Extracts; Receptors, Aryl Hydrocarbon; Resveratrol; Spleen; Stilbenes; T-Lymphocytes, Regulatory

Resveratrol, a natural polyphenolic compound, has attracted considerable interest for its anti-inflammatory and neuroprotective properties. However, the biological effects of resveratrol appear strongly limited because it is photosensitive, easily oxidized, and has unfavorable pharmacokinetics. The present study aimed to elucidate the effect of resveratrol on Abeta-triggered neuroinflammation by comparing the effects of free resveratrol (RSV) treatment with those of treatment with resveratrol-loaded lipid-core nanocapsules (RSV-LNC). Organotypic hippocampal cultures were stimulated by Abeta1-42 with or without different concentrations of RSV or RSV-LNC. We found that Abeta triggered a harmful neuroinflammation process in organotypic hippocampal cultures. Pre- and co-treatments with RSV-LNC were able to protect cultures against ROS formation and cell death induced by Abeta, possibly through sustained blocking of TNF-alpha, IL-1beta, and IL-6 release. Furthermore, RSV-LNC was able to increase IL-10 release even in the presence of Abeta and prevent or decrease both glial and JNK activation. On the other hand, both pre- and co-treatment with RSV exhibited a lower ability to prevent or decrease neuroinflammation, ROS formation, and cell death, and failed to increase IL-10 release. Our findings suggest that modulation of neuroinflammation through a combination of resveratrol and a lipid-core nanocapsule-based delivery system might represent a promising approach for preventing or delaying the neurodegenerative process triggered by Abeta. The results open new vistas to the interplay between inflammation and amyloid pathology.

Topics: Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Cells, Cultured; Drug Synergism; Encephalitis; Hippocampus; Inflammation; Lipids; Male; Nanocapsules; Neurons; Rats; Rats, Wistar; Reactive Oxygen Species; Resveratrol; Stilbenes

Neuroinflammation is closely implicated in the pathogenesis of neurological diseases. The hallmark of neuroinflammation is the microglia activation. Upon activation, microglia are capable of producing various proinflammatory factors and the accumulation of these factors contribute to the neuronal damage. Therefore, inhibition of microglia-mediated neuroinflammation might hold potential therapy for neurological disorders. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG), an active component extracted from Polygonum multiflorum, is reported to be beneficial for human health with a great number of pharmacological properties including antioxidant, free radical-scavenging, anti-inflammation, antilipemia, and cardioprotective effects. Recently, TSG-mediated neuroprotective effects have been well demonstrated. However, the neuroprotective actions of TSG on microglia-induced neuroinflammation are not known. In the present study, microglia BV2 cell lines were applied to investigate the anti-neuroinflammatory effects of TSG. Results showed that TSG reduced LPS-induced microglia-derived release of proinflammatory factors such as TNFα, IL-1β, and NO. Moreover, TSG attenuated LPS-induced NADPH oxidase activation and subsequent reactive oxygen species (ROS) production. Further studies indicated that TSG inhibited LPS-induced NF-κB signaling pathway activation. Together, TSG exerted neuroprotection against microglia-mediated neuroinflammation, suggesting that TSG might present a promising benefit for neurological disorders treatment.

Topics: Animals; Cell Line; Enzyme Activation; Glucosides; Humans; Inflammation; Lipopolysaccharides; Mice; Microglia; NADPH Oxidases; Neurons; Neuroprotective Agents; NF-kappa B; Reactive Oxygen Species; Signal Transduction; Stilbenes

Neuroinflammation is closely associated with the pathogenesis of neurological disorders. The hallmark of neuroinflammation is considered to be microglial activation. Therefore, inhibition of microglial activation might hold a promising therapy for neurological disorders. Resveratrol, a natural non-flavonoid polyphenol found in grapes and red wine, has been recognized as a bioactive agent with potential benefit for health. Several lines of evidence show that resveratrol could exert neuroprotection against ischemia, seizure, and neurodegenerative diseases. However, the mechanisms underlying its beneficial neuroprotective effects are poorly defined. Here, by using rat primary cortical neuron-glia cultures, results showed that resveratrol attenuated lipopolysaccharide (LPS)-induced cortical neurotoxicity. Further studies revealed that microglia were responsible for resveratrol-mediated neuroprotection. Resveratrol significantly inhibited LPS-induced microglial activation and subsequent production of multiple pro-inflammatory and cytotoxic factors such as tumor necrosis factor-α, nitric oxide, and interleukin-1β. Collectively, resveratrol produced neuroprotection against microglia-induced neurotoxicity. Thus, resveratrol might represent a potential benefit for the treatment of inflammation-related neurological disorders.

Topics: Animals; Cells, Cultured; Embryo, Mammalian; Female; Inflammation; Interleukin-1beta; Lipopolysaccharides; Microglia; Neurons; Neuroprotective Agents; Nitric Oxide; Rats; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

We evaluated the effect of resveratrol on the senescence-associated secretory phenotype (SASP) and on adhesion-related processes in cultured human MRC5 fibroblasts. Presenescent cultures were chronically treated with or without 5 µM resveratrol. The development of SASP in MRC5 fibroblasts approaching senescence was significantly attenuated by resveratrol treatment, which reduced both gene expression and release of proinflammatory cytokines. Although to a lesser extent, 1 µM resveratrol proved to be effective on cytokine gene expression. Cell spreading capacity and plating efficiency were strikingly increased and accompanied by recovery of type I collagen expression to presenescent levels. As p16(INK4a) protein expression was not significantly modified, and based on our previous data, we propose that resveratrol does not affect fibroblast replicative senescence, but improves tissue maintenance and repair during normal cellular aging. Considering these low concentrations proved effective in vitro, translation of these data to human research on inflammation-related pathologies can be envisaged.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cell Adhesion; Cell Division; Cells, Cultured; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p16; Cytokines; Fibroblasts; Gene Expression; Humans; Inflammation; Resveratrol; Stilbenes

It is well known that human keratinocytes produce the anti-microbial peptide β-defensin 2. Its production is enhanced by pathogenic microorganisms or other environmental stressors. In this study, we evaluated the effect of resveratrol, a polyphenol found in several dietary source as grape seed, and its natural precursor, polydatin on heat-stressed human keratinocytes. By reverse transcription-polymerase chain reaction and enzyme-linked immunoadsorbent assay, we demonstrated that resveratrol used in combination with polydatin was able to modulate interleukin (IL)-6, IL-8 and tumor necrosis factor-alpha gene expression. In addition, our data show that resveratrol and polydatin increased the heat shock protein (Hsp)70B' gene expression, a Hsp that plays an important role in the cytoprotection and repair of cells and tissues. Worthy of note, polydatin used alone or in combination with resveratrol, increased the release of human β-defensin 2. These results highlighted the ability of polydatin and resveratrol to reinforce cytoprotective response in stress conditions and suggest their use in cosmetic or pharmaceutical preparations.

Topics: beta-Defensins; Cell Line; Cytoprotection; Enzyme-Linked Immunosorbent Assay; Gene Expression; Glucosides; Heat-Shock Response; HSP70 Heat-Shock Proteins; Humans; Inflammation; Interleukin-6; Interleukin-8; Keratinocytes; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes; Tumor Necrosis Factor-alpha

A series of studies have recently demonstrated that the oxidative stress, nuclear factor-kappa B (NF-κB) activation and the subsequent coordinated inflammatory responses played an important role in the pathogenesis of urate nephropathy (UN). Polydatin has been suggested to have the properties of anti-oxidative, anti-inflammatory and nephroprotective effects. However, the possible protective and beneficial effects of polydatin on UN are not fully elucidated. Therefore, we investigated the potential beneficial effects and possible mechanisms of polydatin on UN. In this study, polydatin showed inhibitory activities on xanthine oxidase to repress the level of serum uric acid in vivo and in vitro. Further investigations revealed that polydatin displayed little toxic effects and significantly ameliorated the renal function in fructose-induced UN mice. The nephroprotective activities of polydatin was not only due to the effects on remarkably attenuating the oxidative stress induced by uric acid, but also on markedly suppressing the oxidative stress-related inflammatory cascade, including decreasing the expressions of NF-κB p65, COX-2 and iNOS proteins and inhibiting the productions of TNF-α, PGE(2) and IL-1β. These findings elucidated that polydatin exhibited prominent nephroprotective activities and low toxic effects.

Topics: Animals; Blood Chemical Analysis; Body Weight; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Drugs, Chinese Herbal; Fructose; Glucosides; Inflammation; Interleukin-1beta; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred Strains; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Protective Agents; Stilbenes; Tumor Necrosis Factor-alpha; Uric Acid; Xanthine Oxidase

2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) extracted from Polygonum multiflorum (a traditional Chinese medicinal herb) has been proved to exhibit significant anti-atherosclerotic activity. In this study, we firstly used proteomic analyses to investigate the molecular events occurring in the atherosclerotic rats after TSG treatment. Aortic samples were collected from the atherosclerotic rat group and the TSG-treated group, and its proteome was analyzed by two-dimensional gel electrophoresis (2-DE). Proteins showing significant changes in expression were identified and analyzed by matrix-assisted desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). As a result, 21 protein spots were found with significant differential expression after the treatment with TSG. A total of 18 spots were identified by database searching, and 17 spots matched with known proteins. Among these proteins (11 proteins up-regulated and six proteins down-regulated), five proteins were mainly involved in inflammation, cholesterol transport, cell apoptosis and adhesion. TSG treatment enhanced the expression of HSP 70, lipocortin 1 and Apo A-I, and inhibited the expression of calreticulin, vimentin. Furthermore, we randomly selected four proteins and confirmed the results of proteomic analysis by RT-PCR and western blotting. In conclusion, TSG treatment suppresses atherosclerosis by altering the expression of different proteins. Calreticulin, vimentin, HSP 70, lipocortin 1, and Apo A-I, are key proteins that may be novel molecular targets responsible for atherogenesis suppression induced by TSG treatment.

Topics: Animals; Annexin A1; Aorta; Apolipoprotein A-I; Apoptosis; Atherosclerosis; Calreticulin; Cell Adhesion; Cholesterol; Down-Regulation; Gene Expression Regulation; Glucosides; HSP70 Heat-Shock Proteins; Inflammation; Male; Proteome; Proteomics; Rats; Rats, Sprague-Dawley; Stilbenes; Up-Regulation; Vimentin

Resveratrol is indicated to be involved in neuroprotection and anti-inflammation in epileptic rats. The molecular mechanism is still not fully understood. In this study, we investigated the role of resveratrol in nuclear factor-kappa B associated inflammatory responses induced by status epilepticus. Our data showed that seizures activated mammalian target of rapamycin (mTOR), increased the activity of nuclear factor-kappa B and promoted the expressions of inflammatory molecules including inducible nitric oxide synthase, cyclooxygenase-2 and interleukin-1β. Futhermore, resveratrol significantly inhibited the activation of nuclear factor-kappa B and the production of proinflammatory molecules via mTOR pathway. Additionally, we also proved that the inhibition of mTOR signal by resveratrol was mostly attributed to AMP-activated kinase (AMPK) activation. Altogether, our results suggest that resveratrol suppresses inflammatory responses induced by seizures partially via AMPK/mTOR pathway.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Hippocampus; Inflammation; Male; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Status Epilepticus; Stilbenes; TOR Serine-Threonine Kinases

Resveratrol is a major constituent of traditional Asian medicinal herbs and red wine and is suggested to be a potential antiatherosclerotic drug due to its proposed hypolipidemic, anti-inflammatory and antioxidative properties. The aim of this study was to evaluate whether resveratrol protects against atherosclerosis development in APOE*3-Leiden.CETP (E3L.CETP) mice and adds to the antiatherogenic effect of mild statin treatment, currently the most widely used antiatherogenic therapy. E3L.CETP mice were fed a cholesterol-rich diet without (control) or with resveratrol (0.01% w/w), atorvastatin (0.0027% w/w) or both for 14 weeks. During the study plasma lipid, inflammatory and oxidative stress parameters were determined. Resveratrol reduced atherosclerotic lesion area (-52%) in the aortic root, comparable to atorvastatin (-40%) and the combination of both drugs (-47%). The collagen/macrophage ratio in the atherosclerotic lesion, a marker of plaque stability, was increased by resveratrol (+108%), atorvastatin (+124%) and the combination (+154%). Resveratrol decreased plasma cholesterol levels (-19%) comparable to atorvastatin (-19%) and the combination (-22%), which was completely confined to (very)low-density lipoprotein cholesterol levels in all groups. Post hoc analyses showed that the antiatherogenic effect of atorvastatin could be explained by cholesterol lowering, while the antiatherosclerotic effect of resveratrol could be attributed to factors additional to cholesterol lowering. Markers of inflammation and oxidative stress were not different, but resveratrol improved macrophage function. We conclude that resveratrol potently reduces atherosclerosis development and induces a more stable lesion phenotype in E3L.CETP mice. However, under the experimental conditions tested, resveratrol does not add to the antiatherogenic effect of atorvastatin.

Topics: Animals; Atherosclerosis; Atorvastatin; Biomarkers; Cholesterol, Dietary; Cholesterol, LDL; Drug Synergism; Female; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Mice; Mice, Transgenic; Oxidative Stress; Pyrroles; Resveratrol; Stilbenes

Resveratrol (RSV) has various metabolic effects, especially with relatively high-dose therapy. However, the ability of RSV to modulate insulin signaling has not been completely evaluated. Here, we determined whether RSV alters insulin signaling in insulin-responsive cells and tissues. The effects of RSV on insulin signaling in 3T3-L1 adipocytes under both insulin-sensitive and insulin-resistant states and in insulin-sensitive tissues of high fat-fed diet-induced obese (DIO) mice were investigated. Insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation (Y612) was suppressed in RSV-treated adipocytes compared with untreated adipocytes, as was the insulin-stimulated Akt phosphorylation (Ser473). However, under an insulin-resistant condition that was made by incubating 3T3-L1 adipocytes in the conditioned medium from lipopolysaccharide-stimulated LAW264.7 cells, RSV reduced inducible nitric oxide synthase expression and IκBα protein degradation and improved insulin-stimulated Akt phosphorylation (Ser473). In DIO mice, relatively low-dose RSV (30 mg/kg daily for 2 weeks) therapy lowered fasting blood glucose level and serum insulin, increased hepatic glycogen content, and ameliorated fatty liver without change in body weight. The insulin-stimulated Akt phosphorylation was decreased in the liver and white adipose tissue of DIO mice, but it was completely normalized by RSV treatment. However, in the skeletal muscle of DIO mice, insulin signaling was not improved by RSV treatment, whereas the phosphorylation of adenosine monophosphate-activated protein kinase α (Thr172) was improved by it. Our results show that RSV enhances insulin action only under insulin-resistant conditions and suggest that the effect of RSV may depend on the type of tissue being targeted and its metabolic status.

Topics: 3T3-L1 Cells; Adipocytes; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Blotting, Western; Cells, Cultured; Culture Media, Conditioned; Dietary Fats; Inflammation; Insulin; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Phosphorylation; Real-Time Polymerase Chain Reaction; Resveratrol; Signal Transduction; Stilbenes

Inflammation and oxidative stress play an important role in cerebral ischemic pathogenesis. Polydatin has been proved to elicit numerous biological effects through its anti-inflammatory and anti-oxidant properties. However, little is known regard to the mechanism of polydatin's neuroprotection in ischemic stroke. We therefore investigated the potential neuroprotective effects of polydatin and explored the underlying mechanisms. Male, Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (pMCAO). Experiment 1 was used to evaluate the expression of glioma-associated oncogene homolog1 (Gli1), Patched-1 (Ptch1) and Superoxide dismutase 1 (SOD1) after pMCAO, six time points were included. Experiment 2 was used to detect polydatin's neuroprotection after pMCAO. Neurological deficit, brain water content and infarct size were measured at 24h and 72 h after pMCAO. Immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR), Western Blotting, activity assay and confocal microscope were used to analyse the expression of Gli1, Ptch1, SOD1 and nuclear factor-kappa B (NF-κB). Experiment 3 was used to detect polydatin's influence on blood-brain barrier (BBB). Compared with Sham group, the expression of Gli1, Ptch1 and SOD1 were up-regulated shortly after pMCAO (P<0.05). Compared with Vehicle group, high dose of polydatin (50mg/kg) up-regulated Gli1, Ptch1, SOD1 and down-regulated NF-κB, and reduced infarct volume, brain water content and behavioral deficits (P<0.05). Meanwhile, BBB permeability was also ameliorated. The results indicated that polydatin protected the brain from damage caused by pMCAO, and this effect may be through up-regulating the expression of Gli1, Ptch1 and SOD1 and down-regulating the expression of NF-κB, and ameliorating BBB permeability.

Topics: Animals; Blood-Brain Barrier; Brain; Claudin-5; Claudins; Glucosides; Infarction, Middle Cerebral Artery; Inflammation; Kruppel-Like Transcription Factors; Male; Molecular Structure; Neuroprotective Agents; Neuropsychological Tests; NF-kappa B; Oxidative Stress; Patched Receptors; Patched-1 Receptor; Permeability; Random Allocation; Rats; Receptors, Cell Surface; Stilbenes; Superoxide Dismutase; Superoxide Dismutase-1; Zinc Finger Protein GLI1

We investigated the contribution of cytochrome P-450 1B1 (CYP1B1) to renal dysfunction and organ damage associated with ANG II-induced hypertension in rats. ANG II (300 ng·kg(-1)·min(-1)) or vehicle were infused for 2 wk, with daily injections of a selective CYP1B1 inhibitor, 2,4,3',5'-tetramethoxystilbene (TMS; 300 μg/kg ip), or its vehicle. ANG II increased blood pressure and renal CYP1B1 activity that were prevented by TMS. ANG II also increased water intake and urine output, decreased glomerular filtration rate, increased urinary Na(+) and K(+) excretion, and caused proteinuria, all of which were prevented by TMS. ANG II infusion caused hypertrophy, endothelial dysfunction, and increased reactivity of renal and interlobar arteries to vasoconstrictor agents and renal vascular resistance and interstitial fibrosis as indicated by accumulation of α-smooth muscle actin, fibronectin, and collagen, and inflammation as indicated by increased infiltration of CD-3(+) cells; these effects were inhibited by TMS. ANG II infusion also increased production of reactive oxygen species (ROS) and activities of NADPH oxidase, ERK1/2, p38 MAPK, and c-Src that were prevented by TMS. TMS alone had no effect on any of the above parameters. These data suggest that CYP1B1 contributes to the renal pathophysiological changes associated with ANG II-induced hypertension, most likely via increased ROS production and activation of ERK1/2, p38 MAPK, and c-Src and that CYP1B1 could serve as a novel target for treating renal disease associated with hypertension.

Topics: Angiotensin II; Animals; Aryl Hydrocarbon Hydroxylases; Blood Pressure; Cytochrome P-450 CYP1B1; Endothelium, Vascular; Hemodynamics; Hypertension, Renal; Inflammation; Kidney; Male; NADPH Oxidases; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Stilbenes

The natural phytoestrogen resveratrol (RSV) may have therapeutic potential for arthritic conditions. RSV is chondroprotective for articular cartilage in rabbit models for arthritis, but its biological effects on human articular cartilage and chondrosarcoma cells are unknown. Effects of RSV on human articular cartilage homeostasis were studied by assessing production of matrix-degrading enzymes (MMP-13, ADAMTS4, and ADAMTS5), as well as proteoglycan production and synthesis. The counteractions of RSV against catabolic factors (e.g., FGF-2 or IL-1β) were examined by in vitro and ex vivo using monolayer, three-dimensional alginate beads and cartilage explants cultures, respectively. RSV improves cell viability of articular chondrocytes and effectively antagonizes cartilage-degrading protease production that was initiated by catabolic and/or anti-anabolic cytokines in human articular chondrocytes. RSV significantly also enhances BMP7-promoted proteoglycan synthesis as assessed by (35) S-sulfate incorporation. Protein-DNA interaction arrays suggest that RSV inhibits the activation of transcription factors involved in inflammation and cartilage catabolic signaling pathways, including direct downstream regulators of MAPK (e.g., AP-1, PEA3) and NFκB. RSV selectively compromises survival of human chondrosarcoma cells, but not primary articular chondrocytes, revealing cell-specific activity of RSV on non-tumorigenic versus tumor-derived cells. We propose that RSV exerts its chondroprotective functions, in part, by deactivating p53-induced apoptosis in human primary chondrocytes, but not human chondrosarcoma. Our findings suggest that RSV has potential as a unique biologic treatment for both prevention and treatment of cartilage degenerative diseases.

Topics: Apoptosis; Bone Morphogenetic Protein 7; Bone Neoplasms; Cartilage, Articular; Cell Line, Tumor; Chondrocytes; Chondrosarcoma; Cytokines; DNA-Binding Proteins; Extracellular Signal-Regulated MAP Kinases; Humans; Inflammation; Interleukin-1beta; Metabolism; Oncogene Protein v-akt; Peptide Hydrolases; Plants; Polyphenols; Proteasome Endopeptidase Complex; Proteins; Resveratrol; Signal Transduction; Stilbenes; Transcription Factors

HIV-1 Tat protein has been shown to play multiple roles in the pathogenesis of AIDS; however, there is no information currently available on its effects on adipose tissue alterations. We have studied the effects of Tat on SGBS adipocytes to gain insight on its role on the development of lipodystrophy.. SGBS preadipocytes were exposed to Tat during and after differentiation. Acquisition of adipocyte morphology, expression of gene markers of adipogenesis and inflammation, release of adipokines and cytokines to the medium, and glucose uptake were measured. The action of Tat on tumour necrosis factor (TNF)-α-regulated messenger RNA expression was determined in differentiated adipocytes. The capacity of rosiglitazone, resveratrol and parthenolide to influence the action of Tat was also assessed.. Tat treatment reduced the number of SGBS preadipocytes that acquired adipocyte morphology. It also led to repression of adipogenic gene expression and induced the coordinate expression and release of proinflammatory cytokines in human adipose cells. Moreover, combined treatment with Tat and TNF-α produced an additive effect on the repression of adipocyte genes. The observed effects of Tat on gene transcription in adipocytes were due, in part, to TNF-α that was secreted as a consequence of intracellular exposure to Tat.. Tat impairs adipogenesis in human SGBS preadipocytes and increases the expression and release of proinflammatory cytokines. Positive crosstalk between Tat and TNF-α contributes to the anti-adipogenic and proinflammatory effects. HIV-1 Tat protein may play a role in the adipose tissue alterations that ultimately lead to lipoatrophy and systemic metabolic disturbances observed in HIV-1-infected patients.

Topics: Adipocytes; Adipogenesis; Cytokines; Gene Expression Regulation; HIV Infections; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Inflammation; Resveratrol; Rosiglitazone; Sesquiterpenes; Stilbenes; tat Gene Products, Human Immunodeficiency Virus; Thiazolidinediones; Tumor Necrosis Factor-alpha

Obesity-induced diabetes is associated with chronic inflammation and is considered a risk factor for neurodegeneration. We tested the hypothesis that an AMP-activated protein kinase activator, resveratrol (RES), which is known to exert potent anti-inflammatory effects, would attenuate peripheral and central inflammation and improve memory deficit in mice fed a high-fat diet (HFD). C57BL/6J mice were fed an HFD or an HFD supplemented with RES for 20 weeks. Metabolic parameters in serum were evaluated, and Western blot analysis and immunohistochemistry in peripheral organs and brain were completed. We used the Morris water maze test to study the role of RES on memory function in HFD-treated mice. RES treatment reduced hepatic steatosis, macrophage infiltration, and insulin resistance in HFD-fed mice. In the hippocampus of HFD-fed mice, the protein levels of tumor necrosis factor-α and Iba-1 expression were reduced by RES treatment. Choline acetyltransferase was increased, and the phosphorylation of tau was decreased in the hippocampus of HFD-fed mice upon RES treatment. In particular, we found that RES significantly improved memory deficit in HFD-fed mice. These findings indicate that RES reverses obesity-related peripheral and central inflammation and metabolic derangements and improves memory deficit in HFD-fed diabetic mice.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents, Non-Steroidal; Diet, High-Fat; Fatty Liver; Glucose Tolerance Test; Inflammation; Insulin Resistance; Male; Maze Learning; Memory Disorders; Mice; Obesity; Resveratrol; Stilbenes

Resveratrol have been known to possess many pharmacological properties including antioxidant, cardioprotective and anticancer effects. Although current studies indicate that resveratrol produces neuroprotection against neurological disorders, the precise mechanisms for its beneficial effects are still not fully understood. We investigate the effect of anti-inflammatory and mechamisms of resveratrol by using lipopolysaccharide (LPS)-stimulated murine microglial BV-2 cells.. BV-2 cells were treated with resveratrol (25, 50, and 100 µM) and/or LPS (1 µg/ml). Nitric oxide (NO) and prostaglandin E2 (PGE2) were measured by Griess reagent and ELISA. The mRNA and protein levels of proinflammatory proteins and cytokines were analysed by RT-PCR and double immunofluorescence labeling, respectively. Phosphorylation levels of PTEN (phosphatase and tensin homolog deleted on chromosome 10), Akt, mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs) cascades, inhibitor κB-α (IκB-α) and cyclic AMP-responsive element-binding protein (CREB) were measured by western blot. Resveratrol significantly attenuated the LPS-induced expression of NO, PGE2, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and nuclear factor-κB (NF-κB) in BV-2 cells. Resveratrol increased PTEN, Akt and mTOR phosphorylation in a dose-dependent manner or a time-dependent manner. Rapamycin (10 nM), a specific mTOR inhibitor, blocked the effects of resveratrol on LPS-induced microglial activation. In addition, mTOR inhibition partially abolished the inhibitory effect of resveratrol on the phosphorylation of IκB-α, CREB, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK).. This study indicates that resveratrol inhibited LPS-induced proinflammatory enzymes and proinflammatory cytokines via down-regulation phosphorylation of NF-κB, CREB and MAPKs family in a mTOR-dependent manner. These findings reveal, in part, the molecular basis underlying the anti-inflammatory properties of resveratrol.

Topics: Animals; Cell Survival; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; Cyclooxygenase 2; Cytoprotection; Dinoprostone; Gene Expression Regulation; I-kappa B Proteins; Inflammation; Interleukin-1beta; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Microglia; NF-kappa B; NF-KappaB Inhibitor alpha; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphorylation; Proto-Oncogene Proteins c-akt; Resveratrol; RNA, Messenger; Signal Transduction; Sirolimus; Stilbenes; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha

Mutation of tumor suppressor gene, adenomatous polyposis coli (APC), is the primary molecular event in the development of most intestinal carcinomas. Animal model with APC gene mutation is an effective tool for study of preventive approaches against intestinal carcinomas. We aimed to evaluate the effect of Riccardin D, a macrocyclic bisbibenzyl compound, as a chemopreventive agent against intestinal adenoma formation in APC(Min/+) mice.. APC(Min/+) mice were given Riccardin D by p.o. gavage for 7 weeks. Mice were sacrificed, and the number, size and histopathology of intestinal polyps were examined under a microscope. We performed immunohistochemical staining, western blotting, reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) in intestinal polyps to investigate the mechanism of chemopreventive effect of Riccardin D.. Riccardin D treatment resulted in a significant inhibition of intestinal adenoma formation, showing a reduction of polyp number by 41.7%, 31.1% and 44.4%, respectively, in proximal, middle and distal portions of small intestine. The activity of Riccardin D against polyp formation was more profound in colon, wherein Riccardin D decreased polyp number by 79.3%. Size distribution analysis revealed a significant reduction in large-size polyps (2-3 mm) by 40.0%, 42.5% and 33.3%, respectively, in proximal, middle and distal portions of small intestine, and 77.8% in colon. Histopathological analysis of the intestinal polyps revealed mostly hyperplastic morphology without obvious dysplasia in Riccardin D-treated mice. Molecular analyses of the polyps suggested that the inhibitory effect of Riccardin D on intestinal adenoma formation was associated with its abilities of reduction in cell proliferation, induction of apoptosis, antiangiogenesis, inhibition of the Wnt signaling pathway and suppression of inflammatory mediators in polyps.. Our results suggested that Riccardin D exerts its chemopreventive effect against intestinal adenoma formation through multiple mechanisms including anti-proliferative, apoptotic, anti-angiogenic and anti-inflammatory activity.

Topics: Adenoma; Adenomatous Polyposis Coli Protein; Animals; Apoptosis; beta Catenin; Biological Products; Caspases; Cell Proliferation; Colon; Cyclin D1; Cyclooxygenase 2; Hepatophyta; Inflammation; Intestinal Neoplasms; Intestinal Polyps; Intestine, Small; Mice; Neovascularization, Pathologic; NF-kappa B; Phenyl Ethers; Precancerous Conditions; Signal Transduction; Stilbenes

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an antioxidant-activated transcription factor that recently emerged as a critical regulator of cellular defense against oxidative and inflammatory lesions. Resveratrol (Res) is a natural phytoalexin that exhibits multiple therapeutic potentials, including antioxidative and anti-inflammatory effects in animals. Paraquat (PQ) is the second most widely used herbicide worldwide, but it selectively accumulates in human lungs to cause oxidative injury and fibrosis with high mortality. Here, we analyzed the molecular mechanism of the fibrogenic response to PQ and its inhibition by Res and Nrf2. PQ dose-dependently caused toxicity in normal human bronchial epithelial cells (BEAS-2B), resulting in mitochondrial damage, oxidative stress, and cell death. Res at 10 μM markedly inhibited PQ toxicity. PQ at 10 μM stimulated production of inflammatory and profibrogenic factors (tumor necrosis factor α, interleukin 6, and transforming growth factor β1) and induced the transformation of normal human lung fibroblasts (WI38-VA13) to myofibroblasts; both effects were inhibited by Res. Res strongly activated the Nrf2 signaling pathway and induced antioxidant response element-dependent cytoprotective genes. On the other hand, knockout or knockdown of Nrf2 markedly increased PQ-induced cytotoxicity, cytokine production, and myofibroblast transformation and abolished protection by Res. The findings demonstrate that Res attenuates PQ-induced reactive oxygen species production, inflammation, and fibrotic reactions by activating Nrf2 signaling. The study reveals a new pathway for molecular intervention against pulmonary oxidative injury and fibrosis.

Topics: Animals; Antioxidants; Apoptosis; Cell Death; Cells, Cultured; Cytoprotection; Epithelial Cells; Fibroblasts; Humans; Inflammation; Interleukin-6; Mice; Mice, Knockout; Mitochondria; Myofibroblasts; NF-E2-Related Factor 2; Oxidative Stress; Paraquat; Reactive Oxygen Species; Response Elements; Resveratrol; Signal Transduction; Stilbenes; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Proliferation of pulmonary artery smooth muscle cells (PASMC) is an important contributor to the progress of pulmonary arterial hypertension (PAH). Anti-inflammatory therapies may have therapeutic applicability for PAH. Resveratrol (RES) has prominent anti-inflammatory effects in vitro, but in vivo its beneficial effects are limited by short systemic half life and poor lipotrophy. A derivative of RES, trimethoxystilbene (TMS), has higher lipotropy and extended half life compared with RES, and can potentially overcome the limitations of RES. In the present study, we studied the effects of TMS and RES on proliferation and apoptosis of PASMC stimulated with Tumor Necrosis Factor-α. The effects on PASMC proliferation were quantified by MTT, while apoptosis was assessed by flow cytometry (Annexin V/propidium iodide assay). We observed strong inhibitory effects of TMS on the growth of PASMC, and these effects were 20 times more potent than those of RES. We further documented induction of apoptosis in PASMC treated with TMS, again, to a higher degree than with RES. In conclusion, TMS is more potent than RES in the inhibition of proliferation and induction of apoptosis of PASMC, demonstrating its potentially beneficial role for treating PAH.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cell Proliferation; Cell Survival; Cells, Cultured; Flow Cytometry; Humans; Hypertension; Inflammation; Male; Myocytes, Smooth Muscle; Pulmonary Artery; Rats; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

In the present study, we examined the effects and mechanisms of the Chinese herb resveratrol on attenuation of morphine tolerance in rats.. Male Wistar rats were implanted with 2 intrathecal catheters; one catheter was connected to a mini-osmotic pump, used for either morphine (15 μg/h) or saline (1 μL/h) infusion for 5 days. On day 5, resveratrol (7.5, 15, 30, or 60 μg), dimethyl sulfoxide (5 μL), or saline (5 μL) was injected via the other catheter immediately after the discontinued morphine infusion. Three hours later, intrathecal morphine (15 μg in 5 μL saline) was given. All rats received the nociceptive tail-flick test every 30 minutes for 120 minutes after the morphine challenge.. Long-term morphine infusion induced antinociceptive tolerance and up-regulated N-methyl-D-aspartate receptor (NMDAR) subunit NR1 and NR2B expression in the synaptosome fraction of the tolerant spinal cord dorsal horn. Resveratrol pretreatment provided a significant antinociceptive effect of morphine in morphine-tolerant rats, and it was associated with reversal of the up-regulated NR1 and NR2B subunits in the synaptosome fraction of morphine-tolerant rat spinal cords. NR1/NR2B-specific antagonist ifenprodil treatment produced a similar effect as that of resveratrol. Furthermore, an increase of postsynaptic density-95/NR1/NR2B complex immunoprecipitation in morphine-tolerant rat spinal cord was also inhibited by resveratrol pretreatment. Moreover, chronic morphine infusion activated glial cells with an increase of proinflammatory cytokine tumor necrosis factor-α, interleukin-1β, and interleukin-6 mRNA expression in morphine-tolerant rat spinal cords and these effects were suppressed by resveratrol pretreatment before the morphine challenge.. Resveratrol attenuates morphine tolerance by inhibiting neuroinflammation and down-regulating NMDAR NR1 and NR2B subunit expression. Resveratrol regulates the NMDAR expression, which might be involved in a loss of scaffolding postsynaptic density-95 protein.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Down-Regulation; Gene Expression Regulation; Inflammation; Male; Morphine; Pain Measurement; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Resveratrol; Stilbenes

Restenosis is a critical complication of angioplasty and stenting. Restenosis is multifactorial, involving endothelial injury, inflammation, platelet activation, and vascular smooth muscle cell (VSMC) proliferation. Thus, dietary strategies to prevent restenosis likely require the use of more than one agent. Resveratrol (R) and quercetin (Q) are polyphenols that are known to exhibit vascular protective effects. We tested whether R and Q administered in the diet interact to inhibit vessel stenosis in mice with a carotid injury. B6.129 mice were administered a high-fat diet containing 21% fat and 0.2% cholesterol along with R (25 mg/kg), Q (10 mg/kg), or R + Q for 2 wk. A carotid injury was induced and the mice were again administered the enriched diet for 2 wk. Compared with the controls, R significantly decreased stenosis, assessed as an intima:media ratio, by 76%. Although Q treatment alone exhibited no effect, it potentiated the effect of R in that treatment with R + Q significantly decreased the intima:media ratio by 94%. Moreover, this effect was greater than that of R treatment alone (P < 0.05). Although treatments with R, Q, and R + Q significantly affected platelet activation and endothelial function, the responses observed for R + Q were less than additive. Specifically, the effects of R + Q were less than the sum of effects for treatments with R and Q alone. In contrast, treatment with R + Q exhibited more-than-additive effects on inflammatory markers and significant interactions between R and Q were observed. The presence of synergy between R and Q was thus tested in cultures of VSMC and macrophages. Isobolographic analysis revealed that 2:1 molar ratios of R:Q exhibited synergistic inhibition of VSMC proliferation and macrophage chemotaxis. In conclusion, in combination, R and Q can interact to reduce the extent of restenosis, perhaps due to their synergistic inhibition of VSMC proliferation and inflammation.

Topics: Animals; Antioxidants; Carotid Artery Injuries; Cell Proliferation; Chemotaxis; Drug Interactions; Endothelial Cells; Endothelium, Vascular; Female; Hyperplasia; Inflammation; Mice; Monocytes; Neointima; Quercetin; Resveratrol; Stilbenes; Thromboxane B2

We reported previously that pterostilbene, a natural analogue of resveratrol from blueberries, strongly suppressed lipopolysaccharide-induced up-expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in murine macrophages. In this study, we further investigated pterostilbene's molecular mechanism of action and its anti-tumor properties. Pretreatment with pterostilbene has resulted in the reduction of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced nuclear translocation of the nuclear factor-κB (NFκB) subunits. Pterostilbene also reduced TPA-induced phosphorylation of IκBα and p65 and caused subsequent degradation of IκBα. Moreover, pterostilbene markedly suppressed TPA-induced activation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK)1/2, phosphatidylinositol 3-kinase (PI3K) and Akt, which are upstream of NFκB and activator protein 1 (AP-1). Furthermore, pterostilbene significantly inhibited 7,12-dimethylbenz[a]anthracene (DMBA)/TPA-induced skin tumor formation measured by the tumor multiplicity of papillomas at 20 weeks. The presented data has, for the first time, revealed that pterostilbene is an effective anti-tumor agent that functions by downregulating inflammatory iNOS and COX-2 gene expression in mouse skin. It is suggested that pterostilbene is a novel functional agent capable of preventing inflammation-associated tumorigenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents, Phytogenic; Cell Proliferation; Cyclooxygenase 2; Down-Regulation; Female; Inflammation; Mice; Mice, Inbred ICR; NF-kappa B; Nitric Oxide Synthase Type II; Protein Kinase Inhibitors; Resveratrol; Skin; Skin Neoplasms; Stilbenes; Tetradecanoylphorbol Acetate

Despite increased risk of a recurrent stroke following a minor stroke, information is minimal regarding the interaction between injurious mild cerebral ischemic episodes and the possible treatments which might be effective. The aim of the current study was to investigate recurrent ischemic stroke and whether resveratrol, a nutritive polyphenol with promising cardio- and neuro- protective properties, could ameliorate the associated brain damage. Experiments in adult rats demonstrated that a mild ischemic stroke followed by a second mild cerebral ischemia exacerbated brain damage, and, daily oral resveratrol treatment after the first ischemic insult reduced ischemic cell death with the recurrent insult (P<0.002). Further investigation demonstrated reduction of both inflammatory changes and markers of oxidative stress in resveratrol treated animals. The protection observed with resveratrol treatment could not be explained by systemic effects of resveratrol treatment including effects either on blood pressure or body temperature measured telemetrically. Investigation of resveratrol effects on the blood-brain barrier in vivo demonstrated that resveratrol treatment reduced blood-brain barrier disruption and edema following recurrent stroke without affecting regional cerebral blood flow. Investigation of the mechanism in primary cell culture studies demonstrated that resveratrol treatment significantly protected endothelial cells against an in vitro 'ischemia' resulting in improved viability against oxygen and glucose deprivation (39.6 ± 6.6% and 81.3 ± 9.5% in vehicle and resveratrol treated cells, respectively). An inhibition of nitric oxide synthesis did not prevent the improved cell viability following oxygen glucose deprivation but SIRT-1 inhibition with sirtinol partially blocked the protection (P<0.001) suggesting endothelial protection is to some extent SIRT-1 dependent. Collectively, the results support that oral resveratrol treatment provides a low risk strategy to protect the brain from enhanced damage produced by recurrent stroke which is mediated in part by a protective effect of resveratrol on the endothelium of the cerebrovasculature.

Topics: Administration, Oral; Animals; Biomarkers; Blood Gas Analysis; Blood Pressure; Blood-Brain Barrier; Body Temperature; Brain; Cell Death; Cell Hypoxia; Cerebrovascular Circulation; Endothelial Cells; Endothelium, Vascular; Glucose; Heart Rate; Inflammation; Liver; Nitrosation; Oxidation-Reduction; Oxygen; Rats; Recurrence; Resveratrol; Stilbenes; Stress, Physiological; Stroke; Treatment Outcome

Thymic involution and shrinkage of secondary lymphoid organs are leading causes of the deterioration of the T-cell compartment with age. Inflamm-aging, a sustained inflammatory status, has been associated with chronic diseases and shortened longevity. This is the first study to investigate the effect of treating aging hybrid mice with long-term, low-dose resveratrol (RSV) in drinking water by assessing multiple immunological markers and profiles in the immune system. We found that hybrid mice exhibited marked age-related changes in the CD3+CD4+, C3+CD8+, CD4+CD25+, CD4M and CD8M surface markers. RSV reversed surface phenotypes of old mice to that of young mice by maintaining the CD4+ and CD8+ population in splenocytes as well as reducing CD8+CD44+ (CD8M) cells in the aged. RSV also enhanced the CD4+CD25+ population in old mice. Interestingly, pro-inflammatory status in young mice was transiently elevated by RSV but it consequently mitigated the age-dependent increased pro-inflammatory cytokine profile while preserving the anti-inflammatory cytokine condition in the old mice. Age-dependent increase in 8OHdG, an oxidative DNA damage marker was ameliorated by RSV. Immunological-focused microarray gene expression analysis showed that only the CD72 gene was significantly downregulated in the 12-month RSV-treated mice compared to age-matched controls. Our study indicates that RSV even at low physiological relevant levels is able to affect the immune system without causing marked gene expression changes.

Topics: Aging; Animals; Antigens, Surface; Antioxidants; Cell Count; Cytokines; DNA Damage; Inflammation; Mice; Mice, Inbred Strains; Models, Animal; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Resveratrol; Spleen; Stilbenes; T-Lymphocyte Subsets

Werner syndrome is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many features of Werner syndrome, including a pro-oxidant status and a shorter mean life span. Here, we show that resveratrol supplementation improved the hyperglycemia and the insulin resistance phenotype in these Wrn mutant mice. In addition, resveratrol reversed liver steatosis, lipid peroxidaton, and the defenestration phenotypes observed in such mice. Resveratrol, however, did not improve the hypertriglyceridemia, inflammatory stress, nor extend the mean life span of these mutant mice. Microarray and biologic pathway enrichment analyses on liver tissues revealed that resveratrol mainly decreased lipidogenesis and increased genes involved in the insulin signaling pathway and the glutathione metabolism in Wrn mutant mice. Finally, resveratrol-treated mutant mice exhibited an increase in the frequency of lymphoma and of several solid tumors. These results indicate that resveratrol supplementation might exert at least metabolic benefits for Werner syndrome patients.

Topics: Animals; Anticarcinogenic Agents; Disease Models, Animal; Fatty Liver; Hyperglycemia; Hypertriglyceridemia; Inflammation; Insulin Resistance; Mice; Mice, Inbred C57BL; Resveratrol; Stilbenes; Werner Syndrome

Hypercatabolic syndrome is a biochemical state characterized by a imbalance between catabolism and anabolism in favor of catabolism. Diabetes is an example of hypercatabolic syndrome with presence of decreased insulin level or impaired insulin signaling besides increased inflammatory cytokines. One of the significant outcomes of this state is accelerated protein degradation and muscle wasting. Increased ubiquitin-proteasomal system activity is the major responsible for the muscle wasting. Increase in expression and activities of proteasomal proteins in diabetes had been determined. NF-κB transcription factor mediated inflammation and oxidative stress accompanies proteasomal activity increase. Oxidative stress continuously produces substrate for proteasomes by causing protein oxidation. An intervention that inhibits proteasomal activity, suppressing inflammation and oxidative stress may form a solution in order to prevent muscle wasting. Therefore, I am considering that the combined use of bortezomib, a proteasome inhibitor and an anti-inflammatory with resveratrol, an antioxidant and anti-inflammatory, could prevent diabetes induced muscle wasting. This combination may be a novel therapeutic approach for muscle wasting.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Boronic Acids; Bortezomib; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Humans; Inflammation; Models, Biological; Muscular Atrophy; Protease Inhibitors; Proteasome Endopeptidase Complex; Pyrazines; Rats; Resveratrol; Stilbenes

High-fat, high-carbohydrate (HFHC) meals are known to induce oxidative and inflammatory stress, an increase in plasma endotoxin concentrations, and an increase in the expression of suppressor of cytokine signaling-3 (SOCS-3).. The intake of a nutritional supplement containing resveratrol and muscadine grape polyphenols reduces HFHC meal-induced oxidative and inflammatory stress and stimulates the activity of the antioxidant transcription factor, NF-E2-related factor-2 (Nrf-2), and its downstream targets.. Ten normal, healthy subjects were given a 930-kcal HFHC meal either with placebo or with the supplement. Indices of oxidative stress, inflammation, Nrf-2 binding activity, the concentrations of endotoxin (lipopolysaccharide) and lipoprotein binding protein (LBP), and the expression of toll-like receptor 4 (TLR-4), CD14, IL-1β, TNFα, SOCS-3, Keap-1, NAD(P)H:quinone oxidoreductase-1 (NQO-1), and GST-P1 were measured.. The intake of the supplement suppressed the meal-induced elevations of plasma endotoxin and LBP concentrations, the expression of p47(phox), TLR-4, CD14, SOCS-3, IL-1β, and Keap-1, while enhancing Nrf-2 binding activity and the expression of NQO-1 and GST-P1 genes.. A supplement containing resveratrol and muscadine polyphenols suppresses the increase in oxidative stress, lipopolysaccharide and LBP concentrations, and expression of TLR-4, CD14, IL-1β and SOCS-3 in mononuclear cells after an HFHC meal. It also stimulates specific Nrf-2 activity and induces the expression of the related antioxidant genes, NQO-1 and GST-P1. These results demonstrate the acute antioxidant and antiinflammatory effects of resveratrol and polyphenolic compounds in humans in the postprandial state.

Topics: Adult; Antioxidants; Blotting, Western; Cytokines; Dietary Carbohydrates; Dietary Fats; DNA; Fallopia japonica; Female; Flavonoids; Humans; Inflammation; Lipopolysaccharide Receptors; Lipopolysaccharides; Male; NF-E2-Related Factor 2; Oxidative Stress; Phenols; Plant Extracts; Polyphenols; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Toll-Like Receptor 4; Vitis

Topics: Animals; Cell Line, Tumor; Colorectal Neoplasms; Cytokines; Gene Expression Regulation; Humans; Inflammation; Inflammation Mediators; MicroRNAs; Models, Biological; Neoplasm Proteins; Prostaglandins; Proto-Oncogene Proteins c-jun; Reactive Oxygen Species; Resveratrol; RNA, Neoplasm; Stilbenes

The high mortality index due to sepsis and the lack of an effective treatment requires the search for new compounds that can serve as therapy for this disease. Resveratrol, a well-known anti-inflammatory natural compound, might be a good candidate for the treatment of sepsis. The aim of this work was to study the effects of oral administration of resveratrol, before and after sepsis initiation, on inflammation markers in a murine model of endotoxin-induced sepsis.. Sprague-Dawley male rats were treated with resveratrol the 3 days prior to LPS administration and 45 min later. Hematological parameters, TNF-α, IL-1β and CINC-1, FRAP and TBARS levels were determined. Resveratrol and resveratrol-derived metabolites profile in plasma was compared after oral and intraperitoneal administration.. Oral treatment with resveratrol had no apparent systemic protective effects. However, resveratrol reduced the levels of lipid peroxidation in the small intestine and colon. Importantly, the administration of LPS caused a decrease in resveratrol absorption. When resveratrol bioavailability after i.p. administration was compared to that observed after oral administration, a different profile of resveratrol metabolites was found in plasma.. These results highlight the importance of studying the bioavailability of the assayed compounds in the experimental models used to be able to choose the best route of administration depending on the target organ and to determine which compounds or derived metabolites are effective treating the studied disease.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antioxidants; Chromatography, Liquid; Endotoxins; Inflammation; Interleukin-1beta; Lipid Peroxidation; Lipopolysaccharides; Male; Rats; Rats, Sprague-Dawley; Resveratrol; Sepsis; Stilbenes; Tandem Mass Spectrometry; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

Human prenatal ethanol exposure that occurs during a period of increased synaptogenesis known as the 'brain growth spurt' has been associated with significant impairments in attention, learning and memory. Recent studies have shown that administration of ethanol to infant rats during the synaptogenesis period (first 2 weeks after birth) triggers extensive apoptotic neurodegeneration throughout many regions of the developing brain and results in cognitive dysfunctions as the animal matures. The present study was designed with an aim to investigate the effect of resveratrol, a polyphenolic phytoalexin (trans-3,5,4-trihydroxy stilbene) present in red wine on alcohol-induced cognitive deficits and neuronal apoptosis in rat pups postnatally exposed to ethanol. Pups were administered ethanol (5 g/kg, 12% v/v) by intragastric intubation on postnatal days 7, 8, and 9. Ethanol-exposed pups showed impaired memory performance in both Morris water maze elevated plus maze task recorded by using computer tracking with EthoVision software. Behavioral deficit in ethanol-exposed pups was associated with enhanced acetylcholinesterase activity, increased oxidative-nitrosative stress, cytokine (TNF-α, IL-1β and TGF-β), nuclear factor kappa beta and caspase 3 levels in both cerebral cortex and hippocampus. Chronic treatment with resveratrol (10 and 20 mg/kg) significantly attenuated all the behavioral, biochemical and molecular changes in different brain regions of ethanol administered pups. The major finding of the study is that resveratrol blocks activation of nuclear factor kappa beta pathway and apoptotic signaling and prevents cognitive deficits in rats postnatally exposed to ethanol.

Topics: Acetylcholinesterase; Animals; Animals, Newborn; Antioxidants; Brain Damage, Chronic; Caspase 3; Cell Death; Central Nervous System Depressants; Cognition Disorders; Ethanol; Inflammation; Lipid Peroxidation; Male; Maze Learning; Memory; Nerve Degeneration; Neuroprotective Agents; NF-kappa B; Rats; Rats, Wistar; Resveratrol; Signal Transduction; Stilbenes; Superoxide Dismutase

Resveratrol is a natural polyphenolic stilbene derivative found in a variety of edible fruits, including nuts, berries, and grape skin. Although resveratrol has been suggested to improve thermogenesis in the brown adipose tissues of obese animals, there have been no reports on the anti-adipogenic and anti-inflammatory effects of resveratrol in the white adipose tissues of obese animals. The primary aim of this study was to investigate whether resveratrol attenuates high-fat diet (HFD)-induced adipogenesis and inflammation in the epididymal fat tissues of mice and to explore the underlying mechanisms involved in this attenuation. In comparison with HFD-fed mice, mice fed with a 0.4% resveratrol-supplemented diet (RSD) showed significantly lower body weight gain (-48%), visceral fat-pad weights (-58%), and plasma levels of triglyceride, FFA, total cholesterol, glucose, tumor necrosis factor (TNF) α, and monocyte chemoattractant protein-1 (MCP1). Resveratrol significantly reversed the HFD-induced up-regulation of galanin-mediated signaling molecules (GalR1/2, PKCδ, Cyc-D, E2F1, and p-ERK) and key adipogenic genes (PPARγ2, C/EBPα, SREBP-1c, FAS, LPL, aP2, and leptin) in the epididymal adipose tissues of mice. Furthermore, resveratrol significantly attenuated the HFD-induced up-regulation of pro-inflammatory cytokines (TNFα, IFNα, IFNβ, and IL-6) and their upstream signaling molecules (TLR2/4, MyD88, Tirap, TRIF, TRAF6, IRF5, p-IRF3, and NF-κB) in the adipose tissues of mice. The results of this study suggest that resveratrol inhibits visceral adipogenesis by suppressing the galanin-mediated adipogenesis signaling cascade. It may also attenuate cytokine production in the adipose tissue by repressing the TLR2- and TLR4-mediated pro-inflammatory signaling cascades in HFD-fed mice.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Base Sequence; DNA Primers; Down-Regulation; Inflammation; Male; Mice; Mice, Inbred C57BL; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes

We sought to examine the effect of resveratrol (3,4',5-trihydroxy-trans-stilbene), a plant-derived polyphenolic compound, on the development of abdominal aortic aneurysm (AAA).. AAA was induced in mice by periaortic application of CaCl(2). NaCl (0.9%)-applied mice were used as a sham group. Mice were treated with intraperitoneal injection of PBS (Sham/CON, AAA/CON, n=30 for each) or resveratrol (100 mg/kg/day) (AAA/RSVT, n=30). Six weeks after the operation, aortic tissue was excised for further examinations.. Aortic diameter was enlarged in AAA/CON compared with Sham/CON. Resveratrol treatment reduced the aneurysm size and inflammatory cell infiltration in the aortic wall compared with AAA/CON. Elastica Van Gieson staining showed destruction of the wavy morphology of the elastic lamellae in AAA/CON, while it was preserved in AAA/RSVT. The increased mRNA expression of monocyte chemotactic protein-1, tumor necrosis factor-α, intercellular adhesion molecule-1, CD68, vascular endothelial growth factor-A, p47, glutathione peroxidase (GPX)1 and GPX3 were attenuated by resveratrol treatment (all p<0.05). Administration of resveratrol decreased protein expression of phospho-p65 in AAA. The increased 8-hydroxy-2'-deoxyguanosine-positive cell count and 4-hydroxy-2-nonenal-positive cell count in AAA were also reduced by resveratrol treatment. Zymographic activity of matrix metalloproteinase (MMP)-9 and MMP-2 was lower in AAA/RSVT compared with AAA/CON (both p<0.05). Compared with AAA/CON, Mac-2(+) macrophages and CD31(+) vessels in the aortic wall were decreased in AAA/RSVT (both p<0.05).. Treatment with resveratrol in mice prevented the development of CaCl(2)-induced AAA, in association with reduced inflammation, oxidative stress, neoangiogenesis, and extracellular matrix disruption. These findings suggest therapeutic potential of resveratrol for AAA.

Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Antioxidants; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Calcium Chloride; Disease Models, Animal; Extracellular Matrix; Inflammation; Inflammation Mediators; Macrophages; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Oxidative Stress; Phosphorylation; Reactive Oxygen Species; Resveratrol; Stilbenes; Transcription Factor RelA

Implantation and growth of metastatic cancer cells at distant organs is promoted by inflammation-dependent mechanisms. A hepatic melanoma metastasis model where a majority of metastases are generated via interleukin-18-dependent mechanisms was used to test whether anti-inflammatory properties of resveratrol can interfere with mechanisms of metastasis.. Two experimental treatment schedules were used: 1) Mice received one daily oral dose of 1 mg/kg resveratrol after cancer cell injection and the metastasis number and volume were determined on day 12. 2) Mice received one daily oral dose of 1 mg/kg resveratrol along the 5 days prior to the injection of cancer cells and both interleukin-18 (IL-18) concentration in the hepatic blood and microvascular retention of luciferase-transfected B16M cells were determined on the 18th hour. In vitro, primary cultured hepatic sinusoidal endothelial cells were treated with B16M-conditioned medium to mimic their in vivo activation by tumor-derived factors and the effect of resveratrol on IL-18 secretion, on vascular cell adhesion molecule-1 (VCAM-1) expression and on tumor cell adhesion were studied. The effect of resveratrol on melanoma cell activation by IL-18 was also studied.. Resveratrol remarkably inhibited hepatic retention and metastatic growth of melanoma cells by 50% and 75%, respectively. The mechanism involved IL-18 blockade at three levels: First, resveratrol prevented IL-18 augmentation in the blood of melanoma cell-infiltrated livers. Second, resveratrol inhibited IL-18-dependent expression of VCAM-1 by tumor-activated hepatic sinusoidal endothelium, preventing melanoma cell adhesion to the microvasculature. Third, resveratrol inhibited adhesion- and proliferation-stimulating effects of IL-18 on metastatic melanoma cells through hydrogen peroxide-dependent nuclear factor-kappaB translocation blockade on these cells.. These results demonstrate multiple sites for therapeutic intervention using resveratrol within the prometastatic microenvironment generated by tumor-induced hepatic IL-18, and suggest a remarkable effect of resveratrol in the prevention of inflammation-dependent melanoma metastasis in the liver.

Topics: Animals; Cell Adhesion; Cell Proliferation; Endothelium; Inflammation; Interleukin-18; Liver; Liver Neoplasms; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Microvessels; Models, Biological; Neoplasm Transplantation; Resveratrol; Stilbenes; Tumor Microenvironment; Vascular Cell Adhesion Molecule-1

Orthodontic force causes gradual compression of the periodontal ligament tissues, which leads to local hypoxia in the compression side of the tissues. In this study, we investigated whether antioxidants exert a regulatory effect on two factors: the expression of pro-inflammatory cytokines in human periodontal ligament fibroblasts (PDLFs) that were exposed to mechanical compression and hypoxia and the rate of orthodontic tooth movement in rats. Exposure of PDLFs to mechanical compression (0.5-3.0 g/cm(2)) or hypoxic conditions increased the production of intracellular reactive oxygen species. Hypoxic treatment for 24 h increased the mRNA levels of IL-1β, IL-6 and IL-8 as well as vascular endothelial growth factor (VEGF) in PDLFs. Resveratrol (10 nM) or N-acetylcysteine (NAC, 20 mM) diminished the transcriptional activity of hypoxiainducible factor-1 and hypoxia-induced expression of VEGF. Combined treatment with mechanical compression and hypoxia significantly increased the expression levels of IL-1β, IL-6, IL-8, TNF-α and VEGF in PDLFs. These levels were suppressed by NAC and resveratrol. The maxillary first molars of rats were moved mesially for seven days using an orthodontic appliance. NAC decreased the amount of orthodontic tooth movement compared to the vehicle-treated group. The results from immunohistochemical staining demonstrated that NAC suppressed the expression of IL-1β and TNF-α in the periodontal ligament tissues compared to the vehicle-treated group. These results suggest that antioxidants have the potential to negatively regulate the rate of orthodontic tooth movement through the down-regulation of pro-inflammatory cytokines in the compression sides of periodontal ligament tissues.

Topics: Acetylcysteine; Animals; Antioxidants; Cells, Cultured; Fibroblasts; Humans; Hypoxia; Inflammation; Inflammation Mediators; Interleukin-1beta; Male; Molar; Periodontal Ligament; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Stress, Mechanical; Tooth Mobility; Tumor Necrosis Factor-alpha; Up-Regulation

Resveratrol has been purported to modify risk factors for obesity and cardiovascular disease. We sought to examine the effects of resveratrol in a porcine model of metabolic syndrome and chronic myocardial ischemia. Yorkshire swine were fed either a normal diet (control), a high cholesterol diet (HCD), or a high cholesterol diet with supplemental resveratrol (HCD-R; 100mg/kg/day) for 11 weeks. After 4 weeks of diet modification a baseline cardiovascular MRI was performed and an ameroid constrictor was placed on the left circumflex coronary artery of each animal to induce chronic myocardial ischemia. At 7 weeks, a second cardiovascular MRI was performed and swine were sacrificed and myocardial tissue harvested. Resveratrol supplementation resulted in lower body mass indices, serum cholesterol, and C-reactive protein levels, improved glucose tolerance and endothelial function, and favorably augmented signaling pathways associated with myocardial metabolism. Interestingly, serum tumor necrosis factor-α levels were not influenced by resveratrol treatment. Immunoblotting for markers of metabolism demonstrated that insulin receptor substrate-1, glucose transporters 1 and 4, and phospho-AMPK were increased in the HCD-R group. Peroxisome proliferator-activated receptor γ and retinol binding protein 4 were downregulated in the HCD-R group as compared to the HCD group. Myocardial perfusion and function at rest as assessed with magnetic resonance imaging were not different between groups. By favorably influencing risk factors, resveratrol may decrease the burden of chronic metabolic disease and improve cardiovascular health.

Topics: Animals; Biomarkers; Cholesterol; Coronary Artery Disease; Diet; Dietary Supplements; Fatty Acids, Nonesterified; Gene Expression Regulation; Glucose Tolerance Test; Glucose Transporter Type 4; Heart; Inflammation; Insulin; Magnetic Resonance Imaging; Metabolic Syndrome; Microvessels; Muscle Cells; Myocardial Ischemia; Oxidation-Reduction; Protein Transport; Resveratrol; Risk Factors; Stilbenes; Swine

Resveratrol, a stilbene type compound identified in wine and fruit juice, has been found to exhibit various pharmacological activities such as anti-oxidative, anti-cancerous, anti-inflammatory and anti-aging effects. Although numerous papers have explored the pharmacology of resveratrol in one particular cellular action, how this compound can have multiple effects simultaneously has not been fully addressed. In this study, therefore, we explored its broad-spectrum inhibitory mechanism using lipopolysaccharide (LPS)-mediated inflammatory responses and reporter gene assays involving overexpression of toll like receptor (TLR) adaptor molecules. Co-transfection of adaptor molecules such as (1) myeloid differentiation primary response gene 88 (MyD88), (2) Toll/4ll-1 Receptor-domain-containing adapter-inducing interferon-beta (TRIF), (3) TRIF-related adaptor molecule (TRAM), or (4) TANK-binding kinase (TBK) 1 strongly enhanced luciferase activity mediated by transcription factors including nuclear factor (NF)-KB, activator protein (AP)-1, and interferon regulatory factor (IRF)-3. Of the adaptor proteins, TRIF and TBK1 but not MyD88 and IKK enhanced luciferase activity mediated by these transcription factors. Resveratrol dose-dependently suppressed LPS-induced NO production in macrophages. It also blocked the increases in levels of mRNA for IFN-1, tumor necrosis factor (TNF)-alpha, and inducible nitric oxide synthase (iNOS) that were induced by LPS. Resveratrol diminished the translocation or activation of IRF-3 at 90min, c-Jun, a subunit of AP-1, and STAT-1 at 120 min, and p50, a subunit of NF-KB, at 60 and 90 min. Resveratrol strongly suppressed the up-regulation of luciferase activity induced by these adaptor molecules with IC50 values of 5 to 65 microM. In particular, higher inhibitory effects of resveratrol were when TRIF or TBK1 were overexpressed following cotransfection of luciferase constructs with IRF-3 binding sequences. Taken together, our data suggest that the suppression of TRIF and TBK1, which mediates transcriptional activation of NF-kappaB, AP-1, and IRF-3, contributes to resveratrol's broad-spectrum inhibitory activity, and that this compound can be further developed as a lead anti-inflammatory compound.

Topics: Adaptor Proteins, Vesicular Transport; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Cell Nucleus; Cells, Cultured; Coloring Agents; Genes, Reporter; Inflammation; Interferon Regulatory Factor-3; Lipopolysaccharides; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Plasmids; Protein Serine-Threonine Kinases; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Stilbenes; Tetrazolium Salts; Thiazoles

Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo.

Topics: Animals; Blood Glucose; Dietary Fats; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Inflammation; Intestines; Male; Metagenome; Mice; Mice, Inbred C57BL; Receptors, Glucagon; Resveratrol; Stilbenes; Time Factors

Long-term spaceflight induces hypokinesia and hypodynamia, which, along microgravity per se, result in a number of significant physiological alterations, such as muscle atrophy, force reduction, insulin resistance, substrate use shift from fats to carbohydrates, and bone loss. Each of these adaptations could turn to serious health deterioration during the long-term spaceflight needed for planetary exploration. We hypothesized that resveratrol (RES), a natural polyphenol, could be used as a nutritional countermeasure to prevent muscle metabolic and bone adaptations to 15 d of rat hindlimb unloading. RES treatment maintained a net protein balance, soleus muscle mass, and soleus muscle maximal force contraction. RES also fully maintained soleus mitochondrial capacity to oxidize palmitoyl-carnitine and reversed the decrease of the glutathione vs. glutathione disulfide ratio, a biomarker of oxidative stress. At the molecular level, the protein content of Sirt-1 and COXIV in soleus muscle was also preserved. RES further protected whole-body insulin sensitivity and lipid trafficking and oxidation, and this was likely associated with the maintained expression of FAT/CD36, CPT-1, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in muscle. Finally, chronic RES supplementation maintained the bone mineral density and strength of the femur. For the first time, we report a simple countermeasure that prevents the deleterious adaptations of the major physiological functions affected by mechanical unloading. RES could thus be envisaged as a nutritional countermeasure for spaceflight but remains to be tested in humans.

Topics: Adipose Tissue; Animals; Biological Availability; Biomarkers; Body Temperature Regulation; Bone Density; Enzyme Inhibitors; Glucose Tolerance Test; Hindlimb Suspension; Inflammation; Insulin Resistance; Male; Muscle, Skeletal; Muscular Atrophy; Physical Conditioning, Animal; Rats; Rats, Wistar; Resveratrol; Stilbenes

Respiratory syncytial virus (RSV) is the most important cause of severe, lower respiratory tract infections in infants, and RSV infections have been associated with chronic wheezing and asthma during childhood. However, the mechanism of RSV-induced airway inflammation and airway hyperresponsiveness (AHR) is poorly understood. Furthermore, there are presently neither effective vaccines nor drugs available for the prevention or treatment of RSV infections. In this study, we investigated the effect of the plant extract resveratrol as a means of preventing airway inflammation and attenuating RSV-induced AHR. Our data showed that resveratrol reduced RSV lung titers and the number of infiltrating lymphocytes present in bronchoalveolar lavage fluid (BALF) and reduced inflammation. Furthermore, resveratrol attenuated airway responses to methacholine following RSV infection and significantly decreased gamma interferon (IFN-γ) levels in BALF of RSV-infected mice. Data presented in this report demonstrated that resveratrol controlled Toll-like receptor 3 (TLR3) expression, inhibited the TRIF signaling pathway, and induced M2 receptor expression following RSV infection. These data support a role for the use of resveratrol as a means of reducing IFN-γ levels associated with RSV-mediated airway inflammation and AHR, which may be mediated via TLR3 signaling.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bronchoalveolar Lavage Fluid; Female; Gene Expression Profiling; Inflammation; Interferon-gamma; Lung; Mice; Mice, Inbred BALB C; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Resveratrol; Signal Transduction; Stilbenes; Toll-Like Receptor 3; Viral Load

This study describes the development and evaluation of novel polymer films that provide controlled release of two vascular-protective polyphenols for endovascular devices. Resveratrol (RESV) and quercetin (QUER) have antimigratory and antiproliferative actions on vascular smooth muscle cells (VSMCs), inhibit both platelet and inflammatory cell activation, and promote endothelial cell function. Our aim is to develop and characterize coatings that release these drugs within a therapeutic range. The most synergistic drug combination, as determined by isobolographic analysis, was incorporated into an arborescent poly(styrene-isobutylene-styrene) tri-block polymer (arbIBS) and applied to stainless steel coupons using an electrospray process. Physical characterization of the resulting coating revealed a film featuring micro-scale architecture consisting of drug-containing domains. To determine drug-mediated effects, vascular cells were exposed to coatings incorporating several loadings of RESV and QUER. Results from this study indicate that arbIBS exhibits no cytotoxicity, and that the films release RESV and QUER at therapeutic levels, dose-dependently inhibiting macrophage activation, VSMC proliferation, and platelet stimulation. We conclude that RESV and QUER released from arbIBS interfere with key processes responsible for in-stent stenosis, suggesting that RESV and QUER may have utility as therapeutics in a novel coating for device-based interventions.

Topics: Antioxidants; Blood Platelets; Cell Proliferation; Diffusion; Drug Synergism; Drug-Eluting Stents; Humans; Inflammation; Kinetics; Macrophages; Muscle, Smooth, Vascular; Nanocomposites; Platelet Activation; Polymers; Quercetin; Resveratrol; Stents; Stilbenes; Vasodilator Agents

Resveratrol, a polyphenol compound with anti-inflammatory properties, has been previously evaluated for its beneficial effects in several ulcerative colitis models. However, the current study elucidates the effect of resveratrol on adhesion molecules, as well as its antioxidant efficacy in a trinitrobenzene sulfonic acid (TNBS)-induced ulcerative-colitis model. Colitis was induced by rectal instillation of TNBS, followed by daily per os administration of either sulphasalazine (300 mg/kg) or resveratrol (2 and 10 mg/kg) for 7 days. Administration of resveratrol decreased the ulcerative area and colon mass index; these effects were further supported by the reduction in colon inflammation grades, as well as histolopathological changes, and reflected by the stalling of body mass loss. The anti-inflammatory effects of resveratrol were indicated by lowered myeloperoxidase activity, and by suppressing ICAM-1 and VCAM-1 levels in the colon and serum. In addition, it restored a reduced colonic nitric oxide level and reinstated its redox balance, as evidenced by the suppression of lipid peroxides and prevention of glutathione depletion. The anti-ulcerative effect of the higher dose of resveratrol was comparable with those of sulphasalazine. The study confirms the anti-ulcerative effect of resveratrol in TNBS-induced experimental colitis via reduction of neutrophil infiltration, inhibition of adhesive molecules, and restoration of the nitric oxide level, as well as the redox status.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cell Adhesion Molecules; Colitis, Ulcerative; Colon; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Glutathione; Inflammation; Intercellular Adhesion Molecule-1; Lipid Peroxidation; Male; Peroxidase; Rats; Rats, Wistar; Resveratrol; Stilbenes; Sulfasalazine; Trinitrobenzenesulfonic Acid; Vascular Cell Adhesion Molecule-1

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. The purpose of the present study was to elucidate the roles of AMPK in the pathogenesis of diabetic retinopathy using the known AMPK activators resveratrol and AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) in a mouse model.. C57BL/6 mice with streptozotocin-induced diabetes were treated with resveratrol orally at 50 mg/kg for 7 days or with AICAR intraperitoneally at 100 mg/kg 24 hours before death. Retinal protein levels of phosphorylated and total AMPK, phosphorylated nuclear factor (NF)-κB p65, intercellular adhesion molecule (ICAM)-1, and vascular endothelial growth factor (VEGF) were evaluated by Western blot analysis or enzyme-linked immunosorbent assay. Retinal activity of sirtuin (SIRT)1 was measured by deacetylase fluorometric assay. Leukocyte adhesion to the retinal vasculature was examined with a concanavalin A lectin perfusion-labeling technique.. Induction of diabetes in mice led to retinal AMPK dephosphorylation, which was significantly reversed by either resveratrol or AICAR. Either resveratrol or AICAR significantly reversed SIRT1 deactivation and NF-κB phosphorylation, both of which were induced in the diabetic retina. Administration of resveratrol to diabetic mice significantly reduced diabetes-induced retinal leukocyte adhesion, together with retinal expression of ICAM-1 and VEGF.. The present findings reveal that diabetes-induced retinal inflammation stems from downregulation of the AMPK pathway, leading subsequently to SIRT1 deactivation and NF-κB activation. The data also suggest the potential use of the AMPK activator resveratrol as a therapeutic agent for diabetic retinopathy.

Topics: Administration, Oral; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Blotting, Western; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Inflammation; Injections, Intraperitoneal; Intercellular Adhesion Molecule-1; Mice; Mice, Inbred C57BL; Phosphorylation; Resveratrol; Retinitis; Ribonucleotides; Sirtuin 1; Stilbenes; Transcription Factor RelA; Vascular Endothelial Growth Factor A

Inflammation is one of main mechanisms of autoimmune disorders and a common feature of most diseases. Appropriate suppression of inflammation is a key resolution to treat the diseases. Sirtuin1 (Sirt1) has been shown to play a role in regulation of inflammation. Resveratrol, a potent Sirt1 activator, has anti-inflammation property. However, the detailed mechanism is not fully understood. In this study, we investigated the anti-inflammation role of Sirt1 in NIH/3T3 fibroblast cell line. Upregulation of matrix metalloproteinases 9 (MMP-9), interleukin-1beta (IL-1β), IL-6 and inducible nitric oxide synthase (iNOS) were induced by tumor necrosis factor alpha (TNF-α) in 3T3 cells and resveratrol suppressed overexpression of these pro-inflammatory molecules in a dose-dependent manner. Knockdown of Sirt1 by RNA interference caused 3T3 cells susceptible to TNF-α stimulation and diminished anti-inflammatory effect of resveratrol. We also explored potential anti-inflammatory mechanisms of resveratrol. Resveratrol reduced NF-κB subunit RelA/p65 acetylation, which is notably Sirt1 dependent. Resveratrol also attenuated phosphorylation of mammalian target of rapamycin (mTOR) and S6 ribosomal protein (S6RP) while ameliorating inflammation. Our data demonstrate that resveratrol inhibits TNF-α-induced inflammation via Sirt1. It suggests that Sirt1 is an efficient target for regulation of inflammation. This study provides insight on treatment of inflammation-related diseases.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Blotting, Western; Cell Line; Cell Proliferation; Fibroblasts; Inflammation; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Matrix Metalloproteinase 9; Mice; NF-kappa B; Nitric Oxide Synthase Type II; Real-Time Polymerase Chain Reaction; Resveratrol; RNA, Messenger; RNA, Small Interfering; Sirtuin 1; Stilbenes; TOR Serine-Threonine Kinases; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Liver injuries can trigger a cascade of inflammatory responses and as a result, initiate the process of hepatic regeneration and fibrogenesis. Resveratrol (RSV) has multiple health-promoting benefits. This study evaluated the potential protective effects and mechanism of RSV as related to cholestatic liver injury. RSV was given (4 mg/kg/day, i.p.) for either 3 days or 7 days after bile duct ligation (BDL) injury. RSV significantly reduced serum ALT, AST but not T-bil on Day 3. At this early stage of injury, RSV significantly reduced TNF-α and IL-6 mRNA and decreased the number of Kupffer cells (CD68(+) ) recruited in the injured liver. RSV decreased hepatic fibrosis and reduced collagen Iα1 and TIMP-1 mRNA on Day 7. At the later stages of injury, RSV increased the number of Ki67(+) hepatocytes indicating that RSV promoted hepatocyte proliferation. Additionally, it resulted in decreased expression of 4-hydroxynonenal and increased expression of the hepatocyte growth factor protein and mRNA in the RSV-treated BDL group. Meanwhile, RSV reduced the mortality rate of BDL mice. In conclusion, RSV attenuated inflammation and reduced Kupffer cells activation. RSV decreased fibrosis and promoted hepatocyte regeneration, which increased the survival of BDL mice. RSV was beneficial for the treatment of cholestatic liver injury.

Topics: Aldehydes; Animals; Bile Ducts; Cell Proliferation; Cholestasis; Collagen Type I; Hepatocytes; Inflammation; Interleukin-6; Kupffer Cells; Ligation; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Resveratrol; RNA, Messenger; Stilbenes; Tissue Inhibitor of Metalloproteinase-1; Tumor Necrosis Factor-alpha

To study the anti-inflammatory effect of resveratrol in primary cortical astrocyte cultures stimulated by lipopolysaccharide (LPS) and explore the underlying mechanism of this protective effect.. The astrocytes were cultured in the presence of resveratrol at different concentrations for 12 h followed by stimulation with lipopolysaccharide (LPS) for another 24 h. Lactate dehydrogenas (LDH) leakage volumes were detected, the cytotoxicity of resveratrol was examined using cell counting kit-8 (CCK-8), the release of NO was measured by Griess reaction, and the expression levels of TNF-α and iNOS were measured using ELISA and Western blotting respectively.. The purity of the astrocytes cultured in vitro was (95.49∓1.86)%. LPS treatment increased LDH leakage and reduced the survival rate of the astrocytes, resulting also in significantly increased NO and TNF-α release and iNOS protein expressions. Within the concentration range of 5-50 µmol/L, resveratrol effectively improved the survival rate of the astrocytes and decreased LDH leakage with a dose-response relationship. Only 25 and 50 µmol/L resveratrol produced obvious inhibitory effect on NO and TNF-α release and iNOS expression, while 5 µmol/L resveratrol had no such effects.. High concentration of resveratrol can inhibit the release of inflammatory mediators and improve the inflammation injury induced by LPS in astrocytes, the mechanism of which may involve the inhibition of iNOS/NO expression pathway.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Astrocytes; Cerebral Cortex; Inflammation; Lipopolysaccharides; Nitric Oxide; Nitric Oxide Synthase Type II; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

This study examined the analgesic and anti-inflammatory actions of cis-mulberroside A isolated from Ramulus mori in several models of inflammatory pain in mice. Cis-mulberroside A (25 and 50mg/kg) given by p.o. route 30 min before challenge produced a dose-dependent inhibition of the acetic acid-induced pain and Evans blue leakage in mice. In addition, this compound exhibited significant systemic anti-inflammatory activity in carrageenan-induced mouse paw edema in a concentration-related manner (33.1-68.5% inhibition), and similar results were achieved in formalin test. Suppressive effects of cis-mulberroside A on the production of NO and expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-stimulated macrophages were also assessed. Collectively, cis-mulberroside A showed high analgesic and anti-inflammatory activities. The above results will be the supporting evidence for the potential anti-rheumatoid activity of R.mori in Chinese traditional medicine.

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Cell Line; Disaccharides; Dose-Response Relationship, Drug; Edema; Evans Blue; Formaldehyde; Inflammation; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred ICR; Moraceae; Nitric Oxide; Nitric Oxide Synthase Type II; Pain; Phytotherapy; Plant Extracts; Plant Stems; Stilbenes

Resveratrol is a potent inhibitor of inflammation and has anti-diabetic potentiality, however whether its anti-inflammatory potency contributes to the amelioration of diabetes or insulin resistance remains to be determined. This study aims at evaluating the effects of resveratrol on inflammation-related adipokines expression and insulin sensitivity in adipocytes. We stimulated RAW264.7 cells with LPS and collected the supernatant as a conditioned medium (CM) for the culture of adipocytes. Resveratrol, at concentrations ranging from 0.1 to 10 muM, effectively inhibited lipopolysaccharide (LPS)-induced TNF-alpha and IL-6 production with the downregulation of relative genes expression in macrophages. Exposing differentiated 3T3-L1 cells to RAW264.7 CM resulted in gene over-expressions of TNF-alpha, IL-6 and resistin, however, mRNA expression of adiponectin and PPARgamma were down-regulated. Pretreatment of CM from resveratrol-treated macrophages reduced the elevated levels of TNF-alpha and IL-6, and significantly reversed inflammation-related changes in adipokine gene expression in 3T3-L1 adipocytes. Resveratrol suppressed extracellular receptor-activated kinase (ERK) and transcription factor-kappaB (NF-kappaB) activation by reducing the phosphorylation of ERK1/2 and NF-kappaB p65; moreover, it modulated insulin signaling transduction by modification of Ser/Thr phosphorylation of insulin receptor substrate-1 (IRS-1) and downstream AKT (T308), and thereby improved insulin sensitivity in adiposities. These results demonstrated that resveratrol modulated adipokines expression and improved insulin sensitivity which relative to inhibition of inflammatory-like response in adipocytes.

Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Animals; Anti-Inflammatory Agents; Culture Media, Conditioned; Gene Expression Regulation; Glucose; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Lipopolysaccharides; Macrophages; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Phosphorylation; Resveratrol; RNA, Messenger; Signal Transduction; Stilbenes; Tumor Necrosis Factor-alpha

Resveratrol is a naturally occurring polyphenol that exhibits pleiotropic health beneficial effects, including anti-inflammatory, cardio-protective, and cancer-protective activities. It is recognized as one of the more promising natural molecules in the prevention and treatment of chronic inflammatory and autoimmune disorders. Ulcerative colitis is an idiopathic, chronic inflammatory disease of the colon associated with a high colon cancer risk. Here, we used a dextran sulfate sodium (DSS) mouse model of colitis, which resembles human ulcerative colitis pathology. Resveratrol mixed in food ameliorates DSS-induced colitis in mice in a dose-dependent manner. Resveratrol significantly improves inflammation score, downregulates the percentage of neutrophils in the mesenteric lymph nodes and lamina propria, and modulates CD3(+) T cells that express tumor necrosis factor-alpha and IFN-gamma. Markers of inflammation and inflammatory stress (p53 and p53-phospho-Ser(15)) are also downregulated by resveratrol. Because chronic colitis drives colon cancer risk, we carried out experiments to determine the chemopreventive properties of resveratrol. Tumor incidence is reduced from 80% in mice treated with azoxymethane (AOM) + DSS to 20% in mice treated with AOM + DSS + resveratrol (300 ppm). Tumor multiplicity also decreased with resveratrol treatment. AOM + DSS-treated mice had 2.4 +/- 0.7 tumors per animal compared with AOM + DSS + 300 ppm resveratrol, which had 0.2 +/- 0.13 tumors per animal. The current study indicates that resveratrol is a useful, nontoxic complementary and alternative strategy to abate colitis and potentially colon cancer associated with colitis.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinogens; Cell Separation; Colitis; Colonic Neoplasms; Female; Flow Cytometry; Immunohistochemistry; Inflammation; Male; Mice; Mice, Inbred C57BL; Precancerous Conditions; Resveratrol; Stilbenes; T-Lymphocytes

Oxysterols are assumed to play important roles in age-related macular degeneration, a major cause of blindness. So we characterized the cytotoxic, oxidative, inflammatory, and angiogenic activities of oxysterols (7β-hydroxycholesterol (7β-OH), 7-ketocholesterol (7KC), 25-hydroxycholesterol (25-OH)) in human retinal ARPE-19 cells, and evaluated the protective effects of resveratrol (Rsv: 1 μM), a polyphenol from red wine.. ARPE-19 cells were treated with 7β-OH, 7KC, or 25-OH (5-40 μg/mL; 24-48 h) without or with Rsv. Cell viability was determined using trypan blue and the MTT assay. Cell death was characterized by electron microscopy and in situ detection of activated caspases with fluorochrome-labeled inhibitors of caspases. Reactive oxygen species (ROS) production was measured with hydroethidine. ELISA methods and a cytometric bead assay were used to quantify cytokines involved in inflammation (IL-8, IL-1β, IL-6, IL-10, IL-12p70, TNF-α, MCP-1) and VEGF.. 7β-OH and 7KC triggered a caspase-independent cell death process associated with the presence of multilamellar cytoplasmic structures evocating phospholipidosis, increased ROS production, and IL-8 secretion. 7β-OH enhanced VEGF secretion. No cytotoxic effects were identified with 25-OH, which highly stimulated ROS production, MCP-1, and VEGF secretion. With oxysterols, no IL-10, TNF-α, and IL-12p70 secretion were detected. 25-OH induced IL-8 secretion through the MEK/ERK½ signaling pathway, and Rsv showed cytoprotective activities and inhibited VEGF secretion.. 7β-OH, 7KC, and 25-OH have cytotoxic, oxidative, inflammatory, and/or angiogenic activities on ARPE-19 cells. As Rsv has some protective effects against oxysterol-induced cell death and VEGF secretion it could be valuable in ARMD treatment.

Topics: Antioxidants; Cell Death; Cell Line; Cell Survival; Cholesterol; Cytokines; Cytoprotection; Humans; Inflammation; Phospholipids; Reactive Oxygen Species; Resveratrol; Retina; Stilbenes; Vascular Endothelial Growth Factor A; Wine

Resveratrol, present in grapes and red wine, has been found to prevent diethylnitrosamine (DENA)-initiated rat liver tumorigenesis, though the chemopreventive mechanisms are not completely elucidated. The current study was designed to explore whether the antiinflammatory properties of resveratrol play a role in its antihepatocarcinogenic action.. Liver samples were harvested from a 20-week chemopreventive study in which resveratrol (50, 100 and 300 mg/kg) was shown to inhibit DENA-induced hepatocyte nodules in Sprague-Dawley rats in a dose-responsive manner. Hepatic preneoplastic and inflammatory markers, namely heat shock protein (HSP70), cyclooxygenase-2 (COX-2) and nuclear factor-kappaB (NF-kappaB), were studied using immunohistochemical as well as Western blot techniques.. Resveratrol dose-dependently suppressed DENA-induced increased expressions of hepatic HSP70 and COX-2. Resveratrol also attenuated the DENA-mediated translocation of NF-kappaB p65 from the cytosol to the nucleus with stabilization of inhibitory kappaB.. The present findings indicate that resveratrol exerts chemoprevention of hepatocarcinogenesis possibly through antiinflammatory effects during DENA-evoked rat liver carcinogenesis by suppressing elevated levels of HSP70, COX-2 as well as NF-kappaB. These beneficial effects combined with an excellent safety profile encourage the development of resveratrol for chemoprevention and intervention of human HCC that remains a devastating disease.

Topics: Animals; Anticarcinogenic Agents; Chemoprevention; Cyclooxygenase 2; Diethylnitrosamine; Female; HSP70 Heat-Shock Proteins; Humans; Inflammation; Liver; Liver Neoplasms; NF-kappa B; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Hepatocellular carcinoma (HCC), one of the most frequent and deadliest cancers, has been increasing considerably in the United States. In the absence of a proven effective therapy for HCC, novel chemopreventive strategies are urgently needed to lower the current morbidity and mortality of HCC. Recently, we have reported that resveratrol, a compound present in grapes and red wine, significantly prevents diethylnitrosamine (DENA)-induced liver tumorigenesis in rats, although the mechanism of action is not completely understood. In the present study, we have examined the underlying mechanisms of resveratrol chemoprevention of hepatocarcinogenesis by investigating the effects of resveratrol on oxidative damage and inflammatory markers during DENA-initiated rat liver carcinogenesis. There was a significant increase in hepatic lipid peroxidation and protein oxidation in carcinogen control animals compared with their normal counterparts at the end of the study (20 weeks). Elevated expressions of inducible nitric oxide synthase and 3-nitrotyrosine were noticed in the livers of the same animals. Dietary resveratrol (50-300 mg/kg) administered throughout the study reversed all the aforementioned markers in a dose-responsive fashion in rats challenged with DENA. Resveratrol also elevated the protein and mRNA expression of hepatic nuclear factor E2-related factor 2 (Nrf2). Results of the present investigation provide evidence that attenuation of oxidative stress and suppression of inflammatory response mediated by Nrf2 could be implicated, at least in part, in the chemopreventive effects of this dietary agent against chemically induced hepatic tumorigenesis in rats. The outcome of this study may benefit the development of resveratrol in the prevention and intervention of human HCC.

Topics: Animals; Antioxidants; Carcinogens; Chemical and Drug Induced Liver Injury; Diethylnitrosamine; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Induction; Female; Hyperplasia; Inflammation; Lipid Peroxidation; Liver; Liver Neoplasms, Experimental; NF-E2-Related Factor 2; Nitric Oxide Synthase Type II; Oxidative Stress; Phenobarbital; Precancerous Conditions; Rats; Rats, Sprague-Dawley; Resveratrol; RNA, Messenger; Stilbenes; Tyrosine

Human obesity is closely associated with a state of chronic low-grade inflammation, which also involves the adipose tissue with enhanced production of bioactive substances (adipokines). Calorie restriction (CR) reduces adipocytokine production and improves metabolic profile in rodents. Some of these effects are mediated through activation of the sirtuin 1 (Sirt1) enzyme, and in this study, we investigate whether the natural phytoalexin, resveratrol (RSV), which is a potent Sirt1 activator, has anti-inflammatory effects in human adipose tissue explants.. The effect of RSV on interleukin 1β (IL1β)-induced change of adipokine mRNA gene expression and secretion were measured in human adipose tissue explants.. Exposure of human adipose tissue in vitro to IL1β for 24 h increased secretion of the proinflammatory adipokines IL6, IL8 and monocyte chemoattractant protein 1 (MCP-1) 3-7.7-fold (P<0.05) and increased IL6, IL8, MCP-1, IL1β and PAI-1 mRNA expression 1.3-7.2-fold (P<0.05) accordingly. Concomitant incubations with RSV reversed the IL1β-stimulated secretion (16-36%) and gene expression (25-48%) of these adipokines. IL1β reduced adiponectin mRNA expression (40%), a decrement that was reversed by RSV treatment. Similar effects were observed in differentiated human preadipocytes in primary culture, indicating that human adipocytes are a potential target for RSV effects. Finally, the effects were neutralized by sirtinol, a Sirt1 inhibitor.. This study is the first to show anti-inflammatory effects of RSV on adipokine expression and secretion in human adipose tissue in vitro through the SIRT1 pathway. Thus, RSV is hypothesized to possess beneficial effects and might improve the metabolic profile in human obesity.

Topics: Adipocytes; Adipose Tissue; Adult; Anti-Inflammatory Agents, Non-Steroidal; Female; Gene Expression; Humans; Inflammation; Male; Obesity; Resveratrol; RNA, Messenger; Stilbenes

Inflammatory responses in the CNS mediated by activated glial cells play an important role in host-defense but are also involved in the development of neurodegenerative diseases. Resveratrol is a natural polyphenolic compound that has cardioprotective, anticancer and anti-inflammatory properties. We investigated the capacity of resveratrol to protect microglia and astrocyte from inflammatory insults and explored mechanisms underlying different inhibitory effects of resveratrol on microglia and astrocytes.. A murine microglia cell line (N9), primary microglia, or astrocytes were stimulated by LPS with or without different concentrations of resveratrol. The expression and release of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, MCP-1) and iNOS/NO by the cells were measured by PCR/real-time PCR and ELISA, respectively. The phosphorylation of the MAP kinase superfamily was analyzed by western blotting, and activation of NF-kappaB and AP-1 was measured by luciferase reporter assay and/or electrophoretic mobility shift assay.. We found that LPS stimulated the expression of TNF-alpha, IL-1beta, IL-6, MCP-1 and iNOS in murine microglia and astrocytes in which MAP kinases, NF-kappaB and AP-1 were differentially involved. Resveratrol inhibited LPS-induced expression and release of TNF-alpha, IL-6, MCP-1, and iNOS/NO in both cell types with more potency in microglia, and inhibited LPS-induced expression of IL-1beta in microglia but not astrocytes. Resveratrol had no effect on LPS-stimulated phosphorylation of ERK1/2 and p38 in microglia and astrocytes, but slightly inhibited LPS-stimulated phosphorylation of JNK in astrocytes. Resveratrol inhibited LPS-induced NF-kappaB activation in both cell types, but inhibited AP-1 activation only in microglia.. These results suggest that murine microglia and astrocytes produce proinflammatory cytokines and NO in response to LPS in a similar pattern with some differences in signaling molecules involved, and further suggest that resveratrol exerts anti-inflammatory effects in microglia and astrocytes by inhibiting different proinflammatory cytokines and key signaling molecules.

Topics: Analysis of Variance; Animals; Astrocytes; Blotting, Western; Cell Line; Cells, Cultured; Cytokines; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Inflammation; Lipopolysaccharides; Mice; Microglia; Mitogen-Activated Protein Kinases; Nitric Oxide Synthase Type II; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stilbenes

Quercetin and trans-resveratrol (trans-RSV) are plant polyphenols reported to reduce inflammation or insulin resistance associated with obesity. Recently, we showed that grape powder extract, which contains quercetin and trans-RSV, attenuates markers of inflammation in human adipocytes and macrophages and insulin resistance in human adipocytes. However, we do not know how quercetin and trans-RSV individually affected these outcomes.. The aim of this study was to examine the extent to which quercetin and trans-RSV prevented inflammation or insulin resistance in primary cultures of human adipocytes treated with tumor necrosis factor-α (TNF-α)-an inflammatory cytokine elevated in the plasma and adipose tissue of obese, diabetic individuals.. Cultures of human adipocytes were pretreated with quercetin and trans-RSV followed by treatment with TNF-α. Subsequently, gene and protein markers of inflammation and insulin resistance were measured.. Quercetin, and to a lesser extent trans-RSV, attenuated the TNF-α-induced expression of inflammatory genes such as interleukin (IL)-6, IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) and the secretion of IL-6, IL-8, and MCP-1. Quercetin attenuated TNF-α-mediated phosphorylation of extracellular signal-related kinase and c-Jun-NH₂ terminal kinase, whereas trans-RSV attenuated only c-Jun-NH₂ terminal kinase phosphorylation. Quercetin and trans-RSV attenuated TNF-α-mediated phosphorylation of c-Jun and degradation of inhibitory κB protein. Quercetin, but not trans-RSV, decreased TNF-α-induced nuclear factor-κB transcriptional activity. Quercetin and trans-RSV attenuated the TNF-α-mediated suppression of peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ target genes and of PPARγ protein concentrations and transcriptional activity. Quercetin prevented the TNF-α-mediated serine phosphorylation of insulin receptor substrate-1 and protein tyrosine phosphatase-1B gene expression and the suppression of insulin-stimulated glucose uptake, whereas trans-RSV prevented only the TNF-α-mediated serine phosphorylation of insulin receptor substrate-1.. These data suggest that quercetin is equally or more effective than trans-RSV in attenuating TNF-α-mediated inflammation and insulin resistance in primary human adipocytes.

Topics: Adipocytes; Adult; Anti-Inflammatory Agents; Female; Gene Expression; Glucose; Humans; Inflammation; Insulin; Insulin Resistance; Middle Aged; Phosphorylation; Phytotherapy; Plant Extracts; PPAR gamma; Quercetin; Resveratrol; Signal Transduction; Stilbenes; Transcription, Genetic; Tumor Necrosis Factor-alpha; Vitis; Young Adult

Ferrochelatase catalyzes the insertion of ferrous iron into protoporphyrin IX to form heme. The severe metal ion substrate inhibition observed during in vitro studies of the purified enzyme is almost completely eliminated by mutation of an active site histidine residue (His-287, murine ferrochelatase numbering) to leucine and reduced over 2 orders of magnitude by mutation of a nearby conserved phenylalanine residue (Phe-283) to leucine. Elimination of substrate inhibition had no effect on the apparent V(max) for Ni(2+), but the apparent K(m) was increased 100-fold, indicating that the integrity of the inhibitory binding site is important for the enzyme to turn over substrates rapidly at low micromolar metal ion concentrations. The inhibitory site was observed to have a pK(a) value of 8.0, and this value was reduced to 7.5 by the F283L mutation and to 7.4 in a naturally occurring positional variant observed in most bacterial ferrochelatases, murine ferrochelatase H287C. A H287N variant was also found to be substrate-inhibited, but unlike the H287C variant, pH dependence of substrate inhibition was largely eliminated. The data indicate that the inhibitory metal ion-binding site is composed of multiple residues but primarily defined by His-287 and Phe-283 and is crucial for optimal activity at low metal ion concentrations. It is proposed that this binding site may be important for ferrous iron acquisition and desolvation in vivo.

Topics: Animals; Binding Sites; Buffers; Ferrochelatase; Humans; Hydrogen-Ion Concentration; Inflammation; Ions; Kinetics; Liver; Metals; Mice; Models, Molecular; Mutation; Protein Binding; Protoporphyrins; Resveratrol; Stilbenes

The health beneficial effects of Resveratrol, Curcumin and Simvastatin have been demonstrated in various experimental models of inflammation. We investigated the potential anti-inflammatory and immunomodulatory mechanisms of the above mentioned compounds in a murine model of hyper-acute Th1-type ileitis following peroral infection with Toxoplasma gondii.. Here we show that after peroral administration of Resveratrol, Curcumin or Simvastatin, mice were protected from ileitis development and survived the acute phase of inflammation whereas all Placebo treated controls died. In particular, Resveratrol treatment resulted in longer-term survival. Resveratrol, Curcumin or Simvastatin treated animals displayed significantly increased numbers of regulatory T cells and augmented intestinal epithelial cell proliferation/regeneration in the ileum mucosa compared to placebo control animals. In contrast, mucosal T lymphocyte and neutrophilic granulocyte numbers in treated mice were reduced. In addition, levels of the anti-inflammatory cytokine IL-10 in ileum, mesenteric lymph nodes and spleen were increased whereas pro-inflammatory cytokine expression (IL-23p19, IFN-γ, TNF-α, IL-6, MCP-1) was found to be significantly lower in the ileum of treated animals as compared to Placebo controls. Furthermore, treated animals displayed not only fewer pro-inflammatory enterobacteria and enterococci but also higher anti-inflammatory lactobacilli and bifidobacteria loads. Most importantly, treatment with all three compounds preserved intestinal barrier functions as indicated by reduced bacterial translocation rates into spleen, liver, kidney and blood.. Oral treatment with Resveratrol, Curcumin or Simvastatin ameliorates acute small intestinal inflammation by down-regulating Th1-type immune responses and prevents bacterial translocation by maintaining gut barrier function. These findings provide novel and potential prophylaxis and treatment options of patients with inflammatory bowel diseases.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Disease Models, Animal; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ileitis; Inflammation; Intestine, Small; Mice; Mice, Inbred C57BL; Resveratrol; Simvastatin; Stilbenes; Th1 Cells; Toxoplasma

The aim of the present study is to investigate the effects of Vam3 which is one of the dihydroxystilbene compounds on expressions of ICAM-1 in the lungs of OVA-induced asthmatic mice and the mechanisms of anti-airway inflammation. Balb/c mice were challenged with OVA inhalation. Lung tissues were stained with Mayer's hematoxylin and eosin for histopathologic examination. The expression of ICAM-1 in the lungs of mice was analyzed by Western blotting and immunohistochemistry method. The NF-kappaB activities were detected by NF-kappaB-luc reporter genetic transient transfection method. The activities of MMP-9 induced by LPS, TNF-alpha and PMA in THP-1 cells were determined by gelatin zymography method. The results showed that Vam3 could inhibit the expression of ICAM-1 in the OVA-induced mouse model. In addition, Vam3 could significantly suppress the activities of NF-kappaB in A549 cells and MMP-9 in THP-1 cells induced by LPS, TNF-alpha and PMA. These results suggested that Vam3 could alleviate the asthmatic inflammation by decreasing ICAM-1 expression in asthmatic mice, down regulating NF-kappaB and MMP-9 activities. Compound Vam3 showed inhibitory effects on inflammatory signal pathways involved in asthma.

Topics: Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Benzofurans; Cell Line, Tumor; Humans; Inflammation; Intercellular Adhesion Molecule-1; Leukemia, Myeloid; Lung; Lung Neoplasms; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; NF-kappa B; Ovalbumin; Stilbenes

Elevated intraocular pressure (IOP) constitutes the best characterized risk for primary open-angle glaucoma (POAG). Elevated IOP is believed to result from an increase in aqueous humor outflow resistance at the level of the trabecular meshwork (TM)/Schlemm's canal. Malfunction of the TM in POAG is associated with the expression of markers for inflammation, cellular senescence, oxidative damage, and decreased cellularity. Current POAG treatments rely on lowering IOP, but there is no therapeutic approach available to delay the loss of function of the TM in POAG patients. We evaluated the effects of chronic administration of the dietary supplement resveratrol on the expression of markers for inflammation, oxidative damage, and cellular senescence in primary TM cells subjected to chronic oxidative stress (40% O2). Resveratrol treatment effectively prevented increased production of intracellular reactive oxygen species (iROS) and inflammatory markers (IL1alpha, IL6, IL8, and ELAM-1), and reduced expression of the senescence markers sa-beta-gal, lipofuscin, and accumulation of carbonylated proteins. Furthermore, resveratrol exerted antiapoptotic effects that were not associated with a decrease in cell proliferation. These results suggest that resveratrol could potentially have a role in preventing the TM tissue abnormalities observed in POAG.

Topics: Animals; Apoptosis; Biomarkers; Dose-Response Relationship, Drug; Glaucoma; Hydrogen Peroxide; Inflammation; Oxidative Stress; Oxygen; Reactive Oxygen Species; Resveratrol; Stilbenes; Swine; Trabecular Meshwork

Hexosamine biosynthetic pathway (HBP) accounts for some cardiovascular adverse effects of hyperglycemia. We investigated whether the HBP inhibitor azaserine protects against hyperglycemia-induced endothelial damage dependently of HBP. Human endothelial cells isolated from umbilical veins were exposed either to a high (30.5 mmol/l) or low concentration of glucose (5.5 mmol/l) for 4 days, followed by a stimulation with TNF-alpha (1 ng/ml, 24 h). The blockade of the rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase inhibited HBP flux and oxidative stress (generation of superoxide and peroxynitrite) under the hyperglycemic condition and prevented the synergistic stimulation of VCAM-1 and ICAM-1 expression by hyperglycemia and TNF-alpha. In the cells cultured under a low-glucose condition when no increased HBP flux occurred, azaserine enhanced the manganese-superoxide dismutase (MnSOD) protein level and also inhibited the oxidative stress and the expression of VCAM-1 and ICAM-1 in response to TNF-alpha. Moreover, the polyphenol resveratrol inhibited the oxidative stress and adhesion molecule expression and did not decrease the HBP flux under the hyperglycemia condition. In addition, in isolated rat aortas exposed to hyperglycemic buffer for 5 h when no significant HBP flux occurred, azaserine upregulated the MnSOD protein level and prevented decreased endothelium-dependent relaxations to acetylcholine. In conclusion, hyperglycemia independently increases oxidative stress and HBP flux, amplifies endothelial inflammation, and impairs endothelial function mainly through oxidative stress and not the HBP pathway. Azaserine protects against hyperglycemic endothelial damage through its antioxidant effect independently of inhibiting HBP pathway.

Topics: Acetylcholine; Animals; Anti-Inflammatory Agents; Antioxidants; Azaserine; Cells, Cultured; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; Glucose; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); Hexosamines; Humans; Hyperglycemia; Inflammation; Intercellular Adhesion Molecule-1; Male; Oxidative Stress; Rats; Rats, Inbred WKY; Resveratrol; Stilbenes; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vasodilation; Vasodilator Agents

Resveratrol is known as one of the antioxidant polyphenols contained in red wine and grape skin. The purpose of the present study was to investigate the role of resveratrol in ocular inflammation in endotoxin-induced uveitis (EIU).. EIU was induced in male C57/B6 mice at the age of 6 weeks by a single intraperitoneal injection of lipopolysaccharide (LPS). Animals had received oral supplementation of resveratrol at the doses of 5, 50, 100, or 200 mg/kg for 5 days until LPS injection. Twenty-four hours after LPS administration, leukocyte adhesion to the retinal vasculature was examined with a concanavalin A lectin perfusion-labeling technique. Retinal and retinal pigment epithelium (RPE)-choroidal levels of intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nuclear translocation of nuclear factor (NF)-kappaB p65 were evaluated by enzyme-linked immunosorbent assay. Retinal and RPE-choroidal activities of silent information regulator two ortholog (SIRT) 1 were measured by deacetylase fluorometric assay.. Resveratrol pretreatment led to significant and dose-dependent suppression of leukocyte adhesion to retinal vessels of EIU mice compared with vehicle application. Protein levels of MCP-1 and ICAM-1 in the retina and the RPE-choroid of EIU animals were significantly reduced by resveratrol administration. Importantly, resveratrol-treated animals showed significant decline of retinal 8-OHdG generation and nuclear NF-kappaB P65 translocation, both of which were upregulated after EIU induction. RPE-choroidal SIRT1 activity, reduced in EIU animals, was significantly augmented by treatment with resveratrol.. Resveratrol prevented EIU-associated cellular and molecular inflammatory responses by inhibiting oxidative damage and redox-sensitive NF-kappaB activation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Animals; Antioxidants; Blotting, Western; Chemokine CCL2; Deoxyguanosine; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Fluorescent Antibody Technique, Indirect; Inflammation; Injections, Intraperitoneal; Intercellular Adhesion Molecule-1; Leukocytes; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Oxidative Stress; Resveratrol; Retina; Retinal Pigment Epithelium; Retinal Vessels; Sirtuin 1; Sirtuins; Stilbenes; Transcription Factor RelA; Uveitis

The anti-inflammatory activity of the phytoalexin resveratrol (RSV) was evaluated in C5 anaphylatoxin (C5a)-stimulated primary neutrophils and in a mouse model of acute peritonitis. Pretreatment of human and mouse neutrophils with RSV significantly blocked oxidative burst, leukocyte migration, degranulation, and inflammatory cytokine production. The anti-inflammatory activity of RSV was a function of inhibition of sphingosine kinase (SphK) activity (IC(50) approximately 20 microM) within 5 min of exposure, its membrane localization, and SphK1-mediated Ca(2+) release. As an experimental control, the SphK1 pharmacological inhibitor N,N-dimethyl sphingosine (DMS) was used to compare the inhibitory effect of RSV. We also provide evidence that the SphK inhibitory effect of RSV was mediated via its ability to block phospholipase D (PLD) activity and membrane recruitment. Furthermore, RSV blocked ERK1/2 phosphorylation, which functioned independently of SphK1 in this study. To provide in vivo relevance to these data, C5a-induced model of acute peritonitis was established, and the effects of prior injection of RSV were investigated. Indeed, prior injection of RSV virtually completely attenuated the effects of C5a on vascular permeability, neutrophil migration, release of interleukin 1beta, tumor necrosis factor alpha, interleukin 6, and the chemokine MIP-1alpha. Taken together, these data demonstrate strong anti-inflammatory activity of RSV in vitro and in vivo and highlight SphK1 as a potential target of this remarkable phytoalexin. These data could have tremendous implications for the clinical use of RSV in inflammatory pathologies.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Transport, Active; Cell Degranulation; Cell Membrane; Chemokines; Chemotaxis, Leukocyte; Complement C5a; Cytokines; Disease Models, Animal; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Humans; In Vitro Techniques; Inflammation; Male; Mice; Mice, Inbred BALB C; Neutrophils; NF-kappa B; Peritonitis; Phospholipase D; Phosphotransferases (Alcohol Group Acceptor); Respiratory Burst; Resveratrol; Stilbenes

Endothelial dysfunction, oxidative stress and inflammation are associated with vascular aging and promote the development of cardiovascular disease. Caloric restriction (CR) mitigates conditions associated with aging, but its effects on vascular dysfunction during aging remain poorly defined. To determine whether CR exerts vasoprotective effects in aging, aortas of ad libitum (AL) fed young and aged and CR-aged F344 rats were compared. Aging in AL-rats was associated with impaired acetylcholine-induced relaxation, vascular oxidative stress and increased NF-kappaB activity. Lifelong CR significantly improved endothelial function, attenuated vascular ROS production, inhibited NF-kappaB activity and down-regulated inflammatory genes. To elucidate the role of circulating factors in mediation of the vasoprotective effects of CR, we determined whether sera obtained from CR animals can confer anti-oxidant and anti-inflammatory effects in cultured coronary arterial endothelial cells (CAECs), mimicking the effects of CR. In CAECs cultured in the presence of AL serum TNFalpha elicited oxidative stress, NF-kappaB activation and inflammatory gene expression. By contrast, treatment of CAECs with CR serum attenuated TNFalpha-induced ROS generation and prevented NF-kappaB activation and induction of inflammatory genes. siRNA knockdown of SIRT1 mitigated the anti-oxidant and anti-inflammatory effects of CR serum. CR exerts anti-oxidant and anti-inflammatory vascular effects, which are likely mediated by circulating factors, in part, via a SIRT1-dependent pathway.

Topics: Aging; Animals; Anti-Inflammatory Agents; Antioxidants; Caloric Restriction; Coronary Vessels; Endothelial Cells; Inflammation; Male; NF-kappa B; Oxidative Stress; Rats; Rats, Inbred F344; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes

Oxidative/nitrosative stress and generation of proinflammatory cytokines are hallmarks of inflammation. Because chronic inflammation is implicated in several pathologic conditions in humans, including cancers of the colon, anti-inflammatory compounds may be useful chemopreventive agents against colon cancer. Stilbenes, such as resveratrol, have diverse pharmacologic activities, which include anti-inflammation, cancer prevention, a cholesterol-lowering effect, enhanced insulin sensitivity, and increased life span. We previously showed that pterostilbene (trans-3,5-dimethoxy-4'-hydroxystilbene), a structural analogue of resveratrol, is present in blueberries and that pterostilbene inhibited expression of certain inflammation-related genes in the colon and suppressed aberrant crypt foci formation in rats. Here, we examined molecular mechanisms of the action of pterostilbene in colon cancer. Pterostilbene reduced cell proliferation, down-regulated the expression of c-Myc and cyclin D1, and increased the level of cleaved poly(ADP-ribose) polymerase. A combination of cytokines (tumor necrosis factor-alpha, IFN-gamma, and bacterial endotoxin lipopolysaccharide) induced inflammation-related genes such as inducible nitric oxide synthase and cyclooxygenase-2, which was significantly suppressed by treatment with pterostilbene. We further identified upstream signaling pathways contributing to the anti-inflammatory activity of pterostilbene by investigating multiple signaling pathways, including nuclear factor-kappaB, Janus-activated kinase-signal transducer and activator of transcription, extracellular signal-regulated kinase, p38, c-Jun NH(2)-terminal kinase, and phosphatidylinositol 3-kinase. Cytokine induction of the p38-activating transcription factor 2 pathway was markedly inhibited by pterostilbene among the different mediators of signaling evaluated. By silencing the expression of the p38 alpha isoform, there was significant reduction in cytokine induction of inducible nitric oxide synthase and cyclooxygenase-2. Our data suggest that the p38 mitogen-activated protein kinase cascade is a key signal transduction pathway for eliciting the anti-inflammatory action of pterostilbene in cultured HT-29 colon cancer cells.

Topics: Anti-Inflammatory Agents; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Cyclooxygenase 2; Cytokines; Humans; Inflammation; MAP Kinase Signaling System; Microscopy, Fluorescence; p38 Mitogen-Activated Protein Kinases; Poly(ADP-ribose) Polymerases; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes

Resveratrol, a polyphenol present in grapes and red wine, has been studied due to its vast pharmacological activity. It has been demonstrated that resveratrol inhibits production of inflammatory mediators in different in vitro and in vivo models. Our group recently demonstrated that resveratrol reduced the production of prostaglandin (PG) E2 and 8-isoprostane in rat activated microglia. In a microglial-neuronal coculture, resveratrol reduced neuronal death induced by activated microglia. However, less is known about its direct roles in neurons. In the present study, we investigated the effects of resveratrol on interleukin (IL)-1beta stimulated SK-N-SH cells. Resveratrol (0.1-5 microM) did not reduce the expression of cyclooxygenase (COX)-2 and microsomal PGE2 synthase-1 (mPGES-1), although it drastically reduced PGE2 and PGD2 content in IL-1beta-stimulated SK-N-SH cells. This effect was due, in part, to a reduction in COX enzymatic activity, mainly COX-2, at lower doses of resveratrol. The production of 8-iso-PGF2alpha, a marker of cellular free radical generation, was significantly reduced by resveratrol. The present work provides evidence that resveratrol reduces the formation of prostaglandins in neuroblastoma cells by reducing the enzymatic activity of inducible enzymes, such as COX-2, and not the transcription of the PG synthases, as demonstrated elsewhere.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cells, Cultured; Coculture Techniques; Dose-Response Relationship, Drug; Humans; Inflammation; Interleukin-1beta; Isoenzymes; Microglia; Neurons; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Resveratrol; Stilbenes

Currently available treatments for osteoarthritis (OA) are restricted to nonsteroidal anti-inflammatory drugs, which exhibit numerous side effects and are only temporarily effective. Thus novel, safe and more efficacious anti-inflammatory agents are needed for OA. Naturally occurring polyphenolic compounds, such as curcumin and resveratrol, are potent agents for modulating inflammation. Both compounds mediate their effects by targeting the NF-kappaB signalling pathway.. We have recently demonstrated that in chondrocytes resveratrol modulates the NF-kappaB pathway by inhibiting the proteasome, while curcumin modulates the activation of NF-kappaB by inhibiting upstream kinases (Akt). However, the combinational effects of these compounds in chondrocytes has not been studied and/or compared with their individual effects. The aim of this study was to investigate the potential synergistic effects of curcumin and resveratrol on IL-1beta-stimulated human chondrocytes in vitro using immunoblotting and electron microscopy.. Treatment with curcumin and resveratrol suppressed NF-kappaB-regulated gene products involved in inflammation (cyclooxygenase-2, matrix metalloproteinase (MMP)-3, MMP-9, vascular endothelial growth factor), inhibited apoptosis (Bcl-2, Bcl-xL, and TNF-alpha receptor-associated factor 1) and prevented activation of caspase-3. IL-1beta-induced NF-kappaB activation was suppressed directly by cocktails of curcumin and resveratrol through inhibition of Ikappakappa and proteasome activation, inhibition of IkappaBalpha phosphorylation and degradation, and inhibition of nuclear translocation of NF-kappaB. The modulatory effects of curcumin and resveratrol on IL-1beta-induced expression of cartilage specific matrix and proinflammatory enzymes were mediated in part by the cartilage-specific transcription factor Sox-9.. We propose that combining these natural compounds may be a useful strategy in OA therapy as compared with separate treatment with each individual compound.

Topics: Anti-Inflammatory Agents; Apoptosis; Blotting, Western; Cell Proliferation; Cells, Cultured; Chondrocytes; Curcumin; Drug Synergism; Humans; Inflammation; Interleukin-1beta; Microscopy, Electron, Transmission; NF-kappa B; Resveratrol; Signal Transduction; Stilbenes

Aged mice treated peripherally with lipopolysaccharide (LPS) show an exaggerated neuroinflammatory response and cognitive deficits compared to adults. Considerable evidence suggests resveratrol, a polyphenol found in red grapes, has potent antiinflammatory effects in the periphery, but its effects on the central inflammatory response and cognitive behavior are unknown. Therefore, the current study investigated if resveratrol dietary supplementation would inhibit neuroinflammation as well as behavioral and cognitive deficits in aged mice given LPS to mimic a peripheral infection. In initial studies, adult (3-6 months) and aged (22-24 months) mice were provided control or resveratrol-supplemented diet for 4 weeks and then injected intraperitoneally (i.p.) with saline or LPS, and locomotor activity and spatial working memory were assessed. As anticipated, deficits in locomotor activity and spatial working memory indicated aged mice are more sensitive to LPS compared to adults. More importantly, the LPS-induced deficits in aged animals were mitigated by dietary supplementation of resveratrol. In addition, resveratrol consumption reduced LPS-induced interleukin-1beta (IL-1beta) in plasma and the IL-1beta mRNA in the hippocampus of aged mice. Finally, pretreatment of BV-2 microglial cells with resveratrol potently inhibited LPS-induced IL-1beta production. These data show that aged mice are more sensitive than adult mice to both the inflammatory and cognitive effects of peripheral immune stimulation and suggest that resveratrol may be useful for attenuating acute cognitive disorders in elderly individuals with an infection.

Topics: Aging; Animals; Behavior, Animal; Dietary Supplements; Gene Expression Regulation; Hippocampus; Inflammation; Interleukin-1beta; Lipopolysaccharides; Male; Maze Learning; Memory, Short-Term; Mice; Mice, Inbred BALB C; Microglia; Nervous System; Resveratrol; Stilbenes

The effects of anti-inflammatory plant extracts, such as black tea extract (BTE) and resveratrol (RSV) could modulate cell activation leading to atherosclerosis, however there is little comparative information about how different endothelial cell types are affected by these compounds. In order to compare human endothelial cells derived from different origins (umbilical vein or HUVEC, coronary artery or HCAEC, microvascular or HMVEC) and their interleukin-1beta (IL-1beta) responsiveness, IL-6 ELISA, RT-PCR, tissue factor assay, and prostacyclin responses using 6-keto PGF1alpha ELISA were determined. The IL-1beta-induced IL-6 levels were dose-dependent with highest responses seen in HCAEC. Significant inhibition of IL-1beta responses was achieved with BTE and RSV, with the largest decrease of IL-6 and TF seen in HCAEC. Prostacyclin levels were highest in HUVEC and were inhibited by RSV in all cell types. The differences between the endothelial cell types could account for greater susceptibility of coronary arteries to inflammation and atherogenesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antioxidants; Blood Coagulation; Cells, Cultured; Coronary Vessels; Dose-Response Relationship, Drug; Endothelial Cells; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Plant Extracts; Resveratrol; Stilbenes; Tea; Thromboplastin

A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.

Topics: Age Factors; Aging; Animals; Antioxidants; Apoptosis; Caloric Restriction; Cardiovascular System; Energy Intake; Food Deprivation; Food, Formulated; Gene Expression Regulation; Inflammation; Longevity; Male; Mice; Mice, Inbred C57BL; Osteoporosis; Resveratrol; Stilbenes; Transcription, Genetic; Treatment Outcome

Resveratrol (RESV; trans-3,5,4'-trihydroxystilbene), a phytoalexin that is produced by some plants, among other effects has well-known antioxidant, anti-inflammatory and immunomodulatory activities in mammals. In the present study, the effects of RESV on several functions of turbot, Psetta maxima (L.), kidney leucocytes (KLs) related to the innate and inflammatory responses were investigated. RESV exerted a dose-dependent inhibitory effect on the migratory response and on the production of reactive oxygen species in KL, after stimulation of the respiratory burst activity with phorbol myristate acetate (PMA). RESV also significantly inhibited the generation of the pro-inflammatory mediator prostaglandin E(2) (PGE(2)) in the supernatant of KL cultures stimulated with acidic sulphated polysaccharides (ASPs) from the seaweed Ulva rigida. The effects of the polyphenol on enzymatic activity and on myeloperoxidase (MPO) gene expression in neutrophils were also tested. It was found that RESV strongly inhibited intracellular and extracellular MPO activity, behaving as a noncompetitive and reversible inhibitor, and also induced a decrease in MPO mRNA levels in turbot neutrophils. These findings indicate that RESV exerts important modulatory effects on inflammatory responses in fish, and considering the importance of innate immunity in these vertebrates and the similarities with mammals, it may be possible to use fish for analysis of the effects of different substances on inflammatory responses.

Topics: Animals; Cell Movement; Cells, Cultured; Dinoprostone; Flatfishes; Gene Expression Regulation; Immunity, Innate; Inflammation; Kidney; Leukocytes; Peroxidase; Respiratory Burst; Resveratrol; Stilbenes; Tetradecanoylphorbol Acetate

Myeloid dendritic cells (mDC) activated with a B7-DC-specific cross-linking IgM Ab (B7-DC XAb) take up and retain Ag and interact with T cell compartments to affect a number of biologic changes that together cause strong antitumor responses and blockade of inflammatory airway disease in animal models. The molecular events mediating the initial responses in mDC remain unclear. In this study we show that B7-DC XAb caused rapid phosphorylation of the adaptor protein DAP12 and intracellular kinases Syk and phospholipase C-gamma1. Pretreatment of mDC with the Syk inhibitor piceatannol blocked B7-DC XAb-induced Ag uptake with a concomitant loss of tumor protection in mice. Vaccination with tumor lysate-pulsed wild-type B7-DC XAb-activated mDC, but not TREM-2 knockout XAb-activated mDC, protected mice from lethal melanoma challenge. Multimolecular caps appeared within minutes of B7-DC XAb binding to either human or mouse mDC, and FRET analysis showed that class II, CD80, CD86, and TREM-2 are recruited in tight association on the cell surface. When TREM-2 expression was reduced in wild-type mDC using short hairpin RNA or by using mDC from TREM-2 knockout mice, in vitro DC failed to take up Ag after B7-DC XAb stimulation. These results directly link TREM-2 signaling with one change in the mDC phenotype that occurs in response to this unique Ab. The parallel signaling events observed in both human and mouse mDC support the hypothesis that B7-DC cross-linking may be useful as a therapeutic immune modulator in human patients.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antibodies; Antigens; B7-1 Antigen; B7-2 Antigen; Dendritic Cells; Gene Expression Regulation; Histocompatibility Antigens Class II; Humans; Immunologic Capping; Inflammation; Intracellular Signaling Peptides and Proteins; Melanoma; Membrane Glycoproteins; Membrane Proteins; Mice; Mice, Knockout; Myeloid Cells; Neoplasms, Experimental; Phospholipase C gamma; Phosphorylation; Protein-Tyrosine Kinases; Receptors, Immunologic; Respiration Disorders; Signal Transduction; Stilbenes; Syk Kinase; T-Lymphocytes

Parkinson's disease (PD) is a movement disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Microglia activation and neuroinflammation have been associated with the pathogenesis of PD. Indeed, cytokines have been proposed as candidates that mediate the apoptotic cell death of dopaminergic neurons seen in PD. In this study, we investigated the effect of two natural polyphenols, resveratrol and quercetin, on neuroinflammation. For glial cells, we observed that lipopolysaccharide (LPS)-induced mRNA levels of two proinflammatory genes, interleukin 1-alpha and tumor necrosis factor-alpha, are strongly decreased by treatments with resveratrol or quercetin. We also undertook microglial-neuronal coculture to examine the influence of resveratrol and quercetin on dopaminergic neuronal cell death evoked by LPS-activated microglia. Cytotoxicity assays were performed to evaluate the percentage of cell death, with apoptotic cells identified by both the TdT-mediated dUTP nick end labeling technique and the detection of cleaved caspase-3. We report that treatment of N9 microglial cells with resveratrol or quercetin successfully reduced the inflammation-mediated apoptotic death of neuronal cells in our coculture system. Altogether our results demonstrate that resveratrol and quercetin diminished apoptotic neuronal cell death induced by microglial activation and suggest that these two phytoestrogens may be potent antiinflammatory compounds.

Topics: Animals; Apoptosis; Cell Line; Coculture Techniques; Flavonoids; Fluorescent Antibody Technique; Gene Expression; In Situ Nick-End Labeling; Inflammation; Interleukin-1alpha; Lipopolysaccharides; Microglia; Neurons; Neuroprotective Agents; Phenols; Polyphenols; Quercetin; Rats; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Tumor Necrosis Factor-alpha

1. In coronary artery disease, the typical atheromatous plaque consists of a lipid core containing various inflammatory cells and a fibrous cap composed mostly of extracellular matrix. Both matrix metalloproteinases (MMPs) and inflammation are involved in the initiation of atherosclerotic plaques and plaque instability. 2. 2,3,4 cent,5-Tetrahydroxystilbene-2-O-beta-D-glucoside (TSG) reduces the blood lipid content and prevents the atherosclerotic process, but the mechanism of action of TSG is unclear. The purpose of the present study was to test whether TSG can suppress MMP activation and inflammation in atherosclerotic rats. 3. Sixty male Sprague-Dawley rats were randomly divided into six groups. Atherosclerosis was induced by feeding rats a hyperlipidaemic diet; TSG (120, 60 or 30 mg/kg per day) was administered by oral gavage. After 12 weeks of treatment, rats were killed (ethyl carbamate 1200 mg/kg) and serum lipids, C-reactive protein (CRP), interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha were measured. Haematoxylin-eosin (H&E) staining was used to examine histopathological changes in the aorta. The mRNA and protein expression of MMPs were assayed by reverse transcription-polymerase chain reaction, immunohistochemistry and western blotting. Simvastatin (2 mg/kg per day) was administered as a positive control, whereas the vehicle (0.9% NaCl) group served as the untreated control. 4. In the present study, TSG significantly and dose-dependently attenuated the hyperlipidaemic diet-induced alterations in serum lipid profile and increases in CRP, IL-6 and TNF-a levels. In addition, TSG normalized the structure of the aortic wall and suppressed the expression of MMP-2 and MMP-9 at both the mRNA and protein level in the rat aortic wall. 5. In summary, TSG suppresses the expression of MMP-2 and MMP-9 and inhibits inflammation in the diet-induced atherosclerotic rats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Atherosclerosis; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Glucosides; Inflammation; Male; Matrix Metalloproteinases; Rats; Rats, Sprague-Dawley; Simvastatin; Stilbenes

Resveratrol administration after adverse circulatory conditions is known to be protective, however, the mechanism by which resveratrol produces the salutary effects remains unknown. Recently, it was shown that resveratrol activates estrogen receptor (ER) in endothelial cells. We hypothesized that resveratrol administration in males after trauma-hemorrhage decreases cytokine production and protects against hepatic injury through an ER-dependent pathway. To study this, male Sprague-Dawley rats were subjected to trauma-hemorrhage (mean blood pressure, 40 mmHg for 90 min) then resuscitation. A single dose of resveratrol (30 mg/kg of body weight) with or without an ER antagonist (ICI 182,780), ICI 182,780, or vehicle was administered i.v. during resuscitation. Tissue myeloperoxidase activity (a marker of neutrophil sequestration), cytokine-induced neutrophil chemoattractant 1 (CINC-1), CINC-3, intercellular adhesion molecule 1, and interleukin 6 (IL-6) levels in the liver and plasma aspartate aminotransferase and alanine aminotransferase concentrations were measured at 2 and 24 h postresuscitation (n = 6 rats per group). One-way ANOVA and Tukey test were used for statistical analysis. Results showed that trauma-hemorrhage increased hepatic myeloperoxidase activity, CINC-1, CINC-3, intercellular adhesion molecule 1, and IL-6 levels and plasma aspartate aminotransferase and alanine aminotransferase concentrations. These parameters were significantly improved in the resveratrol-treated rats at both 2 and 24 h postresuscitation. Coadministration of the ER antagonist ICI 182,780 prevented the beneficial effects of resveratrol administration on postresuscitation proinflammatory responses and hepatic injury. Thus, resveratrol administration after trauma-hemorrhage attenuated hepatic injury, likely through reduction of proinflammatory mediators. Resveratrol-mediated hepatic preservation seemed to progress via an ER-related pathway.

Topics: Animals; Antioxidants; Chemokine CXCL1; Chemokines, CXC; Estradiol; Fulvestrant; Hemorrhage; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Liver; Male; Rats; Receptors, Estrogen; Resveratrol; Shock, Hemorrhagic; Stilbenes

The purpose of medical treatment in the caustic esophageal burns (CEB) is to decrease inflammatory reaction and to prevent stricture formation. Resveratrol has anti-inflammatory and antifibrotic properties. The aim of this study is to investigate potential therapeutic effects of resveratrol in experimental CEB. We divided 42 male Wistar albino rats into five groups: a control group, caustic groups 4 and 28 (esophageal burns were created), and resveratrol groups 4 and 28 (esophageal burns were created and resveratrol was administered). We used 25% NaOH to form CEB following the method of Gehanno and Guedon as modified by Liu and Richardson. Animals were killed on the 4th and 28th days for biochemical and histopathological examinations. We found that the mean malondialdehyde and nitric oxide assays of the caustic groups were significantly higher than that of the resveratrol groups (P < 0.05). On the other hand, glutathione assay of the resveratrol groups was significantly higher than that of the caustic groups (P < 0.05). Histologically, edema, inflammation and necrosis were found to be significantly lower in the resveratrol 4 group compared with the caustic 4 group (P < 0.05). Submucosal and muscular collagen accumulation were found significantly lower in the resveratrol 28 group compared with the caustic 28 group (P < 0.05). We conclude that resveratrol decreased both the inflammatory reaction and the stricture formation in experimental CEB.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Burns, Chemical; Caustics; Collagen; Disease Models, Animal; Esophageal Stenosis; Esophagitis; Glutathione; Inflammation; Male; Malondialdehyde; Nitric Oxide; Rats; Rats, Wistar; Research Design; Resveratrol; Stilbenes

Chronic low-grade inflammation characterized by adipose tissue macrophage accumulation and abnormal cytokine production is a key feature of obesity and type 2 diabetes. Adipose-tissue-derived monocyte chemoattractant protein (MCP)-1, induced by cytokines, has been shown to play an essential role in the early events during macrophage infiltration into adipose tissue. In this study we investigated the effects of resveratrol upon both tumor necrosis factor (TNF)-alpha-induced MCP-1 gene expression and its underlying signaling pathways in 3T3-L1 adipocytes. Resveratrol was found to inhibit TNF-alpha-induced MCP-1 secretion and gene transcription, as well as promoter activity, which based on down-regulation of TNF-alpha-induced MCP-1 transcription. Nuclear factor (NF)-kappaB was determined to play a major role in the TNF-alpha-induced MCP-1 expression. Further analysis showed that resveratrol inhibited DNA binding activity of the NF-kappaB complex and subsequently suppressed NF-kappaB transcriptional activity in TNF-alpha-stimulated cells. Finally, the inhibition of MCP-1 may represent a novel mechanism of resveratrol in preventing obesity-related pathologies.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Anti-Inflammatory Agents; Chemokine CCL2; Dose-Response Relationship, Drug; Inflammation; Mice; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

The dietary polyphenolic compound resveratrol, by activating the protein deacetylase enzyme silent information regulator 2/sirtuin 1 (SIRT1), prolongs life span in evolutionarily distant organisms and may mimic the cytoprotective effects of dietary restriction. The present study was designed to elucidate the effects of resveratrol on cigarette smoke-induced vascular oxidative stress and inflammation, which is a clinically highly relevant model of accelerated vascular aging. Cigarette smoke exposure of rats impaired the acetylcholine-induced relaxation of carotid arteries, which could be prevented by resveratrol treatment. Smoking and in vitro treatment with cigarette smoke extract (CSE) increased reactive oxygen species production in rat arteries and cultured coronary arterial endothelial cells (CAECs), respectively, which was attenuated by resveratrol treatment. The smoking-induced upregulation of inflammatory markers (ICAM-1, inducible nitric oxide synthase, IL-6, and TNF-alpha) in rat arteries was also abrogated by resveratrol treatment. Resveratrol also inhibited CSE-induced NF-kappaB activation and inflammatory gene expression in CAECs. In CAECs, the aforementioned protective effects of resveratrol were abolished by knockdown of SIRT1, whereas the overexpression of SIRT1 mimicked the effects of resveratrol. Resveratrol treatment of rats protected aortic endothelial cells against cigarette smoking-induced apoptotic cell death. Resveratrol also exerted antiapoptotic effects in CSE-treated CAECs, which could be abrogated by knockdown of SIRT1. Resveratrol treatment also attenuated CSE-induced DNA damage in CAECs (comet assay). Thus resveratrol and SIRT1 exert antioxidant, anti-inflammatory, and antiapoptotic effects, which protect the endothelial cells against the adverse effects of cigarette smoking-induced oxidative stress. The vasoprotective effects of resveratrol will likely contribute to its antiaging action in mammals and may be especially beneficial in pathophysiological conditions associated with accelerated vascular aging.

Topics: Acetylcholine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Apoptosis; Arteries; Carotid Arteries; Cells, Cultured; Coronary Vessels; Cytoprotection; DNA Damage; Endothelial Cells; Inflammation; Inflammation Mediators; Male; Mitochondria; Models, Animal; NF-kappa B; Oxidative Stress; Phenotype; Rats; Rats, Wistar; Reactive Oxygen Species; Resveratrol; Sirtuin 1; Sirtuins; Smoke; Smoking; Stilbenes; Vasodilation; Vasodilator Agents

Topics: Animals; Anti-Inflammatory Agents; Cell Movement; Flavonoids; Humans; Inflammation; Lysophospholipids; Neovascularization, Pathologic; NF-kappa B; Phenols; Polyphenols; Propiophenones; Resveratrol; Sphingosine; Stilbenes; Vitis

Biological activities of peanut stilbenoids, mainly resveratrol and its derivatives, have attracted increased attention and interest because of peanut being a potent producer and a dietary channel to convey these polyphenols to the human body. As arachidin-1 and piceatannol are structurally close to resveratrol, it is worthy to investigate their immunological activities on inhibition of lipopolysaccharide (LPS)-induced production of PGE2 and NO and mediation of the related transcription factors (NF-kappaB and C/EBP) of RAW 264.7 macrophage cells. Productions of PGE2 and NO were inhibited by all the test stilbenoids in a dose-dependent manner while gene and protein expressions of COX-2 and iNOS were not inhibited. As shown by NF-kappaB-driven luciferase assay, LPS-induced NF-kappaB activities were also reduced by the stilbenoids. In further, when these stilbenoids were subjected to monitoring their inhibitory effectiveness on LPS-induced transcription factor expressions of C/EBPdelta and C/EBPbeta, only C/EBPdelta expressions were reduced. Thus, these stilbenoids were effective in inhibition of PGE2- or NO-mediated inflammation and NF-kappaB- or C/EBPdelta-mediated inflammatory gene expression. In comparison, the highest inhibitory activity on LPS-induced PGE2/NO production, C/EBPdelta gene expression, and NF-kappaB activation was piceatannol which was followed in order by arachidin-1 and resveratrol. The observed anti-inflammatory activities of these peanut stilbenoids are of merit in further consideration for nutraceutical applications.

Topics: Animals; Anti-Inflammatory Agents; Arachis; Cell Line; Inflammation; Lipopolysaccharides; Macrophages; Mice; Resveratrol; Stilbenes

Myosin-induced autoimmune myocarditis of rats is a model of human dilated cardiomyopathy. Resveratrol is a natural polyphenol found in grapes and wine that is reported to have cardioprotective and immunomodulatory effects.. To examine the effect of resveratrol on myocarditis, vehicle or resveratrol (50 mg/kg per day) was administered to cardiac myosin immunized rats 1 day before the immunization. At 14 days after immunization, resveratrol had preserved cardiac function of myosin-immunized rats according to echocardiographic analysis. The heart weight/tibial length ratio of vehicle-treated myosin-immunized rats was increased by 1.8-fold compared with unimmunized rats, and resveratrol attenuated the heart weight increase. Resveratrol significantly decreased cellular infiltration, fibrosis, and expression of inflammatory cytokines in the myocardium. Expressions of antioxidant genes were increased in myosin-immunized hearts, and resveratrol decreased those expressions. Resveratrol also attenuated myocarditis 21 days after immunization. SIRT1, a potential effector of resveratrol, was increased in the myocardium of myosin-immunized rats compared with unimmunized rats. The SIRT1 protein was localized mainly in infiltrating mononuclear cells.. Resveratrol significantly ameliorated myocardial injury and preserved cardiac function in a rat model of autoimmune myocarditis. Resveratrol may be a therapeutic modality for myocarditis.

Topics: Animals; Autoimmune Diseases; Cardiomegaly; Cardiomyopathy, Dilated; Cardiotonic Agents; Chemotaxis, Leukocyte; Disease Models, Animal; Electrocardiography; Female; Inflammation; Leukocytes, Mononuclear; Myocarditis; Myosins; Rats; Rats, Inbred Lew; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes

The synthesis of resveratrol fatty alcohols (RFAs), a new class of small molecules presenting strong potential for the treatment of neurological diseases, is described. RFAs, hybrid compounds combining the resveratrol nucleus and omega-alkanol side chains, are able to modulate neuroinflammation and to induce differentiation of neural stem cells into mature neurons. Acting on neuroprotection and neuroregeneration, RFAs represent an innovative approach for the treatment or cure of neuropathies.

Topics: Animals; Cell Differentiation; Cell Line; Fatty Alcohols; Inflammation; Mice; Nervous System; Resveratrol; Stem Cells; Stilbenes

Neutrophil infiltration, proinflammatory cytokines, eicosanoid generation and oxidative stress have been implicated in colitis. Resveratrol is a polyphenolic compound found in grapes and wine, with multiple pharmacological actions, including anti-inflammatory, antioxidant, antitumour and immunomodulatory activities. In a previous report, we documented that resveratrol decreases the degree of inflammation associated with acute experimental colonic inflammation, but its effects on chronic experimental colitis remain undetermined. The aim of this research was to investigate the effects of resveratrol on the chronic colonic injury caused by intracolonic instillation of trinitrobenzenesulphonic acid (TNBS) in rats. The inflammatory response was assessed by histology and myeloperoxidase activity. Tumour necrosis factor alpha (TNF-alpha) production, histological and histochemical analysis of the lesions were also carried out. We determined the production of prostaglandin (PG) E2 and D2 in colon mucosa, as well as cyclooxygenase (COX)-1 and -2 and nuclear transcription factor NF-kappa B (NF-kappaB) p65 protein expression. Finally, since resveratrol has been found to modulate apoptosis, we intended to elucidate its effects on colonic mucosa under chronic inflammatory conditions. Resveratrol (10 mg kg(-1) day(-1)) significantly attenuated the damage score and corrected the disturbances in morphology associated to injury. In addition, the degree of neutrophil infiltration and the levels of TNF-alpha were significantly ameliorated. Resveratrol did not modify PGD2 levels but returned the decreased PGE2 values to basal levels and also reduced COX-2 and the NF-kappaB p65 protein expression. Furthermore, treatment of rats with resveratrol caused a significant increase of TNBS-induced apoptosis in colonic cells. In conclusion, resveratrol reduces the damage in chronic experimentally induced colitis, alleviates the oxidative events, returns PGE2 production to basal levels and stimulates apoptosis in colonic cells.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colon; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Gene Expression Regulation; Inflammation; Male; Membrane Proteins; NF-kappa B; Peroxidase; Phytoalexins; Prostaglandin D2; Rats; Rats, Wistar; Resveratrol; Sesquiterpenes; Stilbenes; Terpenes; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha; Wine

Resveratrol (3,4',5-trihydroxystilbene) has a very broad range of biological properties, including antiplatelet and antioxidative activity. We investigated in vitro the effect of resveratrol on carbonylation of proteins (indicators of oxidative stress) in blood platelets treated with peroxynitrite (ONOO(-)), a strong biological oxidant and inflammatory mediator. We observed that carbonylation of proteins induced by ONOO(-) (0.1 mmol/l), in the presence of resveratrol (0.25-0.1 mmol/l) is reduced. Resveratrol may scavenge ONOO(-), and may be useful in the prevention of ONOO(-)-related diseases, such as inflammatory and cardiovascular diseases.

Topics: Antioxidants; Blood Platelets; Carbon; Colorimetry; Enzyme-Linked Immunosorbent Assay; Humans; Inflammation; Lipid Peroxidation; Oxygen; Peroxynitrous Acid; Phenol; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Resveratrol; Stilbenes

Consumption of a naturally occurring polyphenol, resveratrol, in particular through drinking moderate amounts of red wine, has been suggested to be beneficial to health. A plethora of in vitro studies published demonstrate various anti-inflammatory actions of resveratrol. The aim of this research was to determine whether any of these anti-inflammatory effects translate in vivo in a rodent model of LPS induced airway inflammation. Resveratrol reduced lung tissue neutrophilia to a similar magnitude as that achieved by treatment with budesonide. This was associated with a reduction in pro-inflammatory cytokines and prostanoid levels. Interestingly, the reduction did not appear to be due to an impact on NF-kappaB activation or the expression of the respective genes as suggested by various in vitro publications. These results suggest that resveratrol may possess anti-inflammatory properties via a novel mechanism. Elucidation of this mechanism may lead to potential new therapies for the treatment of chronic inflammation.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Budesonide; Cytokines; Dinoprostone; DNA; Gene Expression; Inflammation; Inflammation Mediators; Lipopolysaccharides; Lung; Male; Neutrophils; NF-kappa B; Nitric Oxide Synthase Type II; Peritoneum; Peroxidase; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Resveratrol; Stilbenes; Wine

Inflammatory processes are involved in the etiology of diseases. We analyzed the effect of resveratrol, piceatannol, synthetic tri-acetoxystilbene (TAS), and genistein (Bonistein(TM)) on the production of inflammatory mediators including prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha), interleukins, and chemokines, which participate in the progression of inflammation. In order to induce inflammatory responses, human peripheral blood mononuclear and/or polymorphonuclear leukocytes were stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN(gamma)) and the production of PGE2, interleukin-8 (IL-8), and TNF-alpha was determined. In response to the stimuli, genes were substantially activated within < 2 h (e. g., TNF-alpha, IL-1alpha), or at a later stage, (e. g., COX-2, IL-6, IL-8). Unlike genistein, resveratrol and related compounds dose-dependently reduced PGE2 production. Genistein, piceatannol, and TAS diminished secretion of TNF-alpha, and IL-8. TAS reduced mRNA levels of COX-2, TNF-alpha, IL-8, IL-6, and IL-1alpha, while resveratrol impaired early expression of IL-8 and TNF-alpha. Piceatannol out-performed resveratrol, yet without matching TAS. Genistein downregulated TNF-alpha and IL-8 expression. These substances altered the LPS/IFNgamma-induced gene expression in mononuclear cells rather than in polymorphonuclear leukocytes. Immunoblot analyses corroborated the distinct activity pattern of resveratrol and genistein. In conclusion, resveratrol and their derivatives attenuated the inflammatory response of PBLs at several levels, whereas genistein acts on cytokines and pro-inflammatory interleukins.

Topics: Cell Survival; Cyclooxygenase 2; Dinoprostone; Gene Expression; Genistein; Humans; Inflammation; Interferon-gamma; Interleukin-1; Interleukin-6; Interleukin-8; Leukocytes; Leukocytes, Mononuclear; Lipopolysaccharides; Membrane Proteins; Neutrophils; Prostaglandin-Endoperoxide Synthases; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Tumor Necrosis Factor-alpha

Resveratrol (trans-3,4',5-trihydroxystilbene) is a phytoalexin found in high concentration in the skins of grapes and red wines which has been shown to have antiinflammatory, anticancerogen and antioxidant properties. Resveratrol is a potent and specific inhibitor of nuclear factor kappa B (NF-kappaB). Resveratrol also inhibits COX-2 gene expression and enzyme activity. We aimed to determine the in vivo effects of intra-articular injections of resveratrol on cartilage and synovium in an experimental osteoarthritis (OA) model in rabbits.. As OA model, rabbits underwent unilateral anterior cruciate ligament transection (ACLT). Five weeks after test group was injected with 10 microMol/kg resveratrol in dimethylsulphoxide (DMSO) in the knees once daily for two weeks and as the control group at the same time DMSO was injected into the knees. All rabbits were killed one week after the last injection. Cartilage tissue and synovium were evaluated with a histological scoring system.. Histological evaluation of cartilage tissue by H&E staining revealed a significantly reduced average cartilage tissue destruction score of 1.7 in the resveratrol group versus 2.8 in the control group (p = 0.016). Loss of matrix proteoglycan content in cartilage was also much lower, as determined by safranin O staining. Scores of synovial inflammation didn't show difference between groups (1.3 vs 2.2; p = 0.057).. A characteristic parameter in arthritis is the progressive loss of articular cartilage. This study suggests that intraarticular injections of resveratrol starting at the onset of disease may protect cartilage against the development of experimentally induced OA.

Topics: Animals; Cartilage; Disease Models, Animal; Inflammation; Osteoarthritis; Rabbits; Resveratrol; Stilbenes

Oxidative stress, neutrophil infiltration, proinflammatory cytokines and eicosanoid generation are clearly involved in the pathogenesis of intestinal bowel disease. Resveratrol, a polyphenolic compound found in grapes and wine, has been shown to have anti-inflammatory, antioxidant, antitumour and immunomodulatory activities, however, its effects on experimental colitis remain unknown. We have investigated the effects of resveratrol on the colon injury caused by intracolonic instillation of trinitrobenzenesulphonic acid (TNBS) in rats. We determined the production of prostaglandin (PG)E(2) and PGD(2) in colon mucosa and the expression of cyclo-oxygenases (COX)-1 and -2 immunohistochemically. The inflammatory response was assessed by histology and myeloperoxidase activity, as an index of neutrophil infiltration. Interleukin-1 beta production, histological and histochemical analysis of the lesions were also carried out. Finally, since resveratrol has been found to modulate apoptosis we intended to elucidate its effects on colonic mucosa under early acute inflammatory conditions. Resveratrol (5-10mg/kg/day) significantly reduced the degree of colonic injury, the index of neutrophil infiltration and the levels of the cytokine. Resveratrol did not revert the increased PGE(2) levels but produced a significant fall in the PGD(2) concentration. Compared with inflamed colon, no changes in staining for COX-1 were observed in colon of resveratrol and TNBS-treated rats. In contrast, COX-2 expression was decreased. Furthermore, resveratrol enhanced apoptosis compared with already high level induced by TNBS. In conclusion, resveratrol reduces the damage in experimentally induced colitis, alleviates the oxidative events and stimulates apoptosis.

Topics: Animals; Antioxidants; Apoptosis; Colitis; Flavonoids; Inflammation; Male; Oxidative Stress; Phenols; Polyphenols; Rats; Rats, Wistar; Resveratrol; Stilbenes; Vitis

Interferon regulatory factor 3 (IRF3) mediates the transcriptional induction of interferon-stimulated genes (ISGs) in response to viral and bacterial infections. Here we show that the hydroxystilbene piceatannol inhibits the LPS-mediated activation of IRF3 and subsequent ISG induction. Consequently, piceatannol blocks the LPS-induced up-regulation of critical mediators of the inflammatory response such as interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule 1 (ICAM-1), and macrophage chemoattractant protein (MCP-1). Furthermore, the LPS-mediated induction of tissue factor (TF), a cell surface protein responsible for initiating the coagulation cascade, is also inhibited by piceatannol. The effectiveness of piceatannol in blocking both the inflammatory response and the coagulation pathway is evidenced by its ability to confer protection against LPS-induced septic shock in a murine model. Thus, IRF3 appears to be a promising target for pharmacologic intervention in the prevention or treatment of septic shock syndrome.

Topics: Animals; Cell Line; Cell Line, Tumor; Chemokine CCL2; DNA-Binding Proteins; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interferon Regulatory Factor-3; Interferons; Interleukin-6; Lipopolysaccharides; Mice; Protein-Tyrosine Kinases; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleases; Sepsis; Shock; Stilbenes; Time Factors; Transcription Factors; Transcription, Genetic; Transfection; Tumor Necrosis Factor-alpha

Resveratrol (3,4',5-trihydroxystilbene) is a polyphenolic stilbene found in the skins of red fruits, including grapes, that may be responsible for some of the health benefits ascribed to consumption of red wine. Resveratrol has been shown to have antioxidant properties and can act as an estrogen agonist. This study examined the anti-inflammatory effects of resveratrol on human airway epithelial cells. Resveratrol and the related molecule quercetin, but not deoxyrhapontin, inhibited IL-8 and granulocyte-macrophage colony-stimulating factor release from A549 cells. Neither the estrogen receptor antagonist tamoxifen nor the glucocorticoid antagonist mifepristone altered the inhibitory effect of resveratrol. The mechanism of resveratrol action was investigated further using luciferase reporter genes stably transfected into A549 cells. Resveratrol and quercetin inhibited NF-kappaB-, activator protein-1-, and cAMP response element binding protein-dependent transcription to a greater extent than the glucocorticosteroid dexamethasone. These compounds also had no significant effect on acetylation or deacetylation of core histones. Resveratrol, but not estradiol or N-acetyl cysteine, inhibited cytokine-stimulated inducible nitric oxide synthase expression and nitrite production (IC50 = 3.6 +/- 2.9 microM) in human primary airway epithelial cells. Resveratrol also inhibited granulocyte-macrophage colony-stimulating factor release (IC50 = 0.44 +/- 0.17 microM), IL-8 release (IC50 = 4.7 +/- 3.3 microM), and cyclooxygenase-2 expression in these cells. This study demonstrates that resveratrol and quercetin have novel nonsteroidal anti-inflammatory activity that may have applications for the treatment of inflammatory diseases.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cell Culture Techniques; Cell Line; Dexamethasone; Granulocyte-Macrophage Colony-Stimulating Factor; Inflammation; Kinetics; Lung; Quercetin; Respiratory Mucosa; Resveratrol; Stilbenes; Transfection

Humans have two isoforms of Prostaglandin H Synthase or cyclooxygenase: COX-1 and COX-2. COX-1 is cytoprotective. COX-2 inhibitors reduce inflammation without the risk of ulceration and kidney damage. The ideal nutraceutical would inhibit COX-2 synthesis while preserving COX-1 synthesis. The hypothesis for this research was that COX inhibitors would fall primarily into three categories: COX-2 specific inhibition, non-specific inhibition (COX-1 and COX-2), and minimal inhibition. The human Cayman COX inhibitor screening assay was used to determine the inhibitory concentration 50 (IC50) of COX-1/ COX-2 activity of each nutraceutical. The assay was run, in duplicate, with three concentrations of a suspected inhibitor, a standard curve of eight concentrations, a non-specific binding sample, and a maximum binding sample. The inhibition and concentration of each sample was then put on a multiple regression best-fit line and the IC50 determined. For comparison, ibuprofen, rofecoxib, naproxen, and indomethacin were used. Positive results were seen for ipriflavone, resveratrol, MSV-60, amentoflavone, ruscus extract and notoginseng. Glucosamine, nexrutine, and berberine did not inhibit either isoform.

Topics: Biflavonoids; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Humans; Inflammation; Isoenzymes; Isoflavones; Membrane Proteins; Neoplasms; Plant Extracts; Prostaglandin-Endoperoxide Synthases; Resveratrol; Ruscus; Stilbenes

Moderate consumption of red wine has been shown to exert cardioprotection against ischemia/reperfusion. Because oxidant-dependent leukocyte infiltration plays a critical role in ischemia/reperfusion-induced tissue injury, we hypothesized that resveratrol, a red wine constituent polyphenol would attenuate postischemic leukocyte recruitment and subsequent endothelial dysfunction. Intravital microscopic approaches were used to quantify leukocyte/endothelial cell interactions and venular protein leakage in rat mesenteries exposed to either 20 min ischemia and 60 min reperfusion (I/R), oxidants generated by the reaction of hypoxanthine and xanthine oxidase (HX/XO), platelet-activating factor (PAF), or leukotriene B4 (LTB4). I/R or HX/HX produced marked increases in the number of adherent (LA) and emigrated (LE) leukocytes, which were associated with significant increases in venular albumin leakage (VAL). Intravenous administration of resveratrol or superoxide dismutase (SOD) attenuated these increases in LA, LE, and VAL. Superfusion of the mesentery with PAF or LTB4 also markedly increased LA, LE, and VAL. While resveratrol attenuated the proinflammatory effects of PAF, LTB4-induced changes were not affected by resveratrol. Resveratrol prevents leukocyte recruitment and endothelial barrier disruption induced by a number of superoxide-dependent proinflammatory stimuli, including I/R, HX/XO, or PAF. These salutary effects appear to be related to the antioxidant properties of resveratrol and contribute to the cardioprotective actions associated with consumption of red wine.

Topics: Animals; Antioxidants; Cell Adhesion; Flavonoids; Free Radicals; Hypoxanthine; Inflammation; Leukocytes; Leukotriene B4; Male; Oxidants; Phenols; Platelet Activating Factor; Polyphenols; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Superoxide Dismutase; Superoxides; Time Factors; Xanthine Oxidase

The antioxidative effects of mulberroside A and oxyresveratrol obtained from Mori Cortex were examined. Mulberroside A and oxyresveratrol showed an inhibitory effect against FeSO4/H2O2-induced lipid peroxidation in rat microsomes and a scavenging effect on 1,1-diphenyl-2-picrylhydrazyl radical. The anti-inflammatory effects of mulberroside A and oxyresveratrol using the carrageenin-induced model of inflammation were investigated in rats. Mulberroside A and oxyresveratrol significantly reduced paw edema. To investigate the mechanism of the anti-inflammatory action of these compounds, we examined the effects of oxyresveratrol on lipopolysaccharide (LPS)-induced responses in murine macrophage cell line RAW 264.7. Exposure of LPS-stimulated cells to oxyresveratrol inhibited nitrite accumulation in the culture medium. Oxyresveratrol also inhibited the LPS-stimulated increase of inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner; however, it had little effect on iNOS enzyme activity, suggesting that the inhibitory activity of oxyresveratrol is mainly due to the inhibition of iNOS expression rather than iNOS enzyme activity. Oxyresveratrol significantly inhibited LPS-evoked nuclear translocation of NF-kappaB and cyclooxygenase-2 (COX-2) activity in RAW 264.7 cells. The results suggest that the anti-inflammatory properties of oxyresveratrol might be correlated with inhibition of the iNOS expression through down-regulation of NF-kappaB binding activity and significant inhibition of COX-2 activity.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cells, Cultured; Dinoprostone; Disaccharides; Edema; Inflammation; Lipid Peroxidation; Male; Microsomes, Liver; Morus; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phytotherapy; Plant Extracts; Plant Preparations; Rats; Rats, Sprague-Dawley; Stilbenes

The peripheral antinociceptive effect of the selective COX-2 inhibitor celecoxib in the formalin-induced inflammatory pain was compared with that of resveratrol (COX-1 inhibitor) and diclofenac (non-selective COX inhibitor). Rats received local pretreatment with saline, celecoxib, diclofenac or resveratrol followed by 50 microl of either 1% or 5% formalin. Peripheral administration of celecoxib did not produce antinociception at either formalin concentration. In contrast, diclofenac and resveratrol produced a dose-dependent antinociceptive effect in the second phase of both 1% and 5% formalin test. The peripheral antinociception produced by diclofenac or resveratrol was due to a local action, as drug administration in the contralateral paw was ineffective. Results indicate that the selective COX-2 inhibitor celecoxib does not produce peripheral antinociception in formalin-induced inflammatory pain. In contrast, selective COX-1 and non-selective COX inhibitors (resveratrol and diclofenac, respectively) are effective drugs in this model of pain.

Topics: Analgesia; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Celecoxib; Cyclooxygenase Inhibitors; Diclofenac; Female; Formaldehyde; Inflammation; Pain; Pyrazoles; Rats; Rats, Wistar; Resveratrol; Stilbenes; Sulfonamides

Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antimutagenic Agents; Carcinogens; Cell Differentiation; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Female; Fruit; Humans; Inflammation; Isoenzymes; Mammary Neoplasms, Experimental; Membrane Proteins; Mice; Neoplasms, Experimental; Peroxidases; Precancerous Conditions; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Resveratrol; Skin Neoplasms; Stilbenes; Tumor Cells, Cultured

Topics: Anti-Inflammatory Agents; Biphenyl Compounds; Chemistry, Pharmaceutical; Ethers; Inflammation; Oxazoles; Phenyl Ethers; Research; Stilbenes

Topics: Amidines; Anti-Inflammatory Agents; Humans; Inflammation; Stilbenes

Topics: Estrogens; Estrone; Female; Humans; Inflammation; Stilbenes; Vagina