stilbenes and Atherosclerosis

Metabolic diseases (MDs), a series of chronic disorders, severely decreases the quality of life for patients but also cause a heavy economic burden. Emerging evidence suggests that Polydatin (PD), an important glucoside of resveratrol, is widely distributed in many plants and has shown good therapeutic potential in metabolic diseases.. To review the PD discovered before 2021 and their potential to treat metabolic diseases. The activities against diabetes, Obesity, atherosclerosis, NAFLD, NASH, hyperlipidemia, and gout with special emphasis on pharmacology, pharmacokinetics, mechanisms of action, possible roles in current medicine, and future perspectives are discussed.. A comprehensive search of published literature was conducted to locate original publications pertaining to polydatin and MDs through the end of 2021 using MEDLINE, Elsevier, Springer, PubMed, Scholar, and CNKI databases. The main inquiry used was for the presence of the following keywords in various combinations in the abstracts: 'Polydatin', 'Metabolic diseases', 'Pharmacology', 'Toxicology', 'Pharmacokinetics', 'Diabetes', 'Obesity', 'Atherosclerosis', 'Non-alcoholic fatty liver disease', 'Non-alcoholic steatohepatitis', 'Hyperlipidemia', and 'Gout'.. The search yielded 987 articles, of which 33 articles were included in this review. Studies have revealed that PD can promote insulin secretion, alleviate insulin resistance, regulate glucose and lipid metabolism, reduce liver lipid deposition, inhibit inflammation, oxidative stress, and decrease uric acid deposition in preclinical experiments. The underlying mechanisms of PD in treatment MDs may be attributed to the regulation of multiple signaling pathways, including. NF-κB, AGEs/RAGE, MAPK/ERK, AMPK/LDLR, IRS1/PI3K/AKT, LKB1/AMPK, PPARβ-NO, SIRT1-PGC-1α-SOD2, PKC, etc., The pharmacokinetic profiles of PD provide valuable information on therapeutic efficacy in treating metabolic diseases.. This review summarizes the available reports and evidence which support the use of PD as a potential candidate in the treatment of MDs and provides an overview of the modulatory effects of PD in metabolic diseases and cell signaling pathways, which may have important implications in its future clinical use.

Topics: AMP-Activated Protein Kinases; Atherosclerosis; Diabetes Mellitus; Glucosides; Gout; Humans; Non-alcoholic Fatty Liver Disease; Obesity; Phosphatidylinositol 3-Kinases; Quality of Life; Stilbenes

Polydatin (PD) is a monocrystalline metabolite from the underground parts of Polygonum cuspidatum Sieb. et Zucc., a member of the Polygonaceae family, which has been traditionally used in Asian countries as both foodstuffs and medicine. PD, also reckoned as pieceid, 3,4',5-trihydroxystilbene-3-β-D-glucoside, (E)-piceid, (E)-polydatin, and trans-polydatin. It possesses potent biological activities i.e. analgesic, anti-inflammatory, antidiabetic, anticancer, and anti-atherosclerotic properties. The initial part of this report specifically explains distinct sequential mechanisms underlying the initiation and development of atherosclerotic plaques and later part deals with the pharmacological efficacy of PD in the management of major cardiac event i.e. atherosclerotic cardiovascular diseases (ASCVD) via modulation of a set of molecular mechanisms i.e. antioxidant potential, lipid and lipoprotein metabolism including total cholesterol (TC) and low density lipoprotein (LDL) levels, β-hydroxy-β-methyl-glutaryl-CoA reductase (HMG-R) expression and functionality, SIRT signalling, LDL-receptor (LDL-R), LDL oxidation status (Ox-LDL), effects on endothelial cells (ECs), smooth muscle cells (SMCs), macrophage, foam cell formation and plaque stabilization, inflammatory signalling pathways and hypertension. In contrast, one of the major insight into the potential cardioprotective molecular mechanism is the PD-mediated targeting of proprotein convertase subtilisin/kexin type-9 (PCSK-9) and LDL-R pathway, both at transcriptional and protein functional level, which makes it a better alternative therapeutic medicinal candidate to treat hypercholesterolemia, especially for the patients facing inadequate lipid lowering with classical HMG-R inhibitors (statins) and statin intolerance. Finally, to sum up the whole, we concluded that PD may be promoted from alternative to mainstream medicine in targeting risk factors mediated ASCVD.

Topics: Anticholesteremic Agents; Atherosclerosis; Cholesterol, LDL; Endothelial Cells; Fallopia japonica; Glucosides; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipidemias; Lipoproteins, LDL; Plaque, Atherosclerotic; Receptors, LDL; Risk Factors; Stilbenes

With the advancement of science and technology, the living standards of human beings have continuously improved, but the incidence and mortality from atherosclerosis worldwide have also increased by year. Although interventional surgery and the continuous development of new drugs have significant therapeutic effects, their side effects cannot be ignored. Polydatin, an active ingredient isolated from the natural medicine Polygonum cuspidatum, has been shown to have a prominent role in the treatment of cardiovascular diseases. Polydatin treats atherosclerosis mainly from three aspects: anti-inflammatory, regulating lipid metabolism and anti-oxidative stress. This article will review the pharmacological mechanism of polydatin in anti-atherosclerosis, the biological characteristics of Polygonum cuspidatum, the toxicology and pharmacokinetics of polydatin and will provide ideas for further research.

Topics: Animals; Anti-Inflammatory Agents; Anticholesteremic Agents; Antioxidants; Arteries; Atherosclerosis; Cardiovascular Agents; Glucosides; Humans; Inflammation Mediators; Lipid Metabolism; Oxidative Stress; Plaque, Atherosclerotic; Signal Transduction; Stilbenes

Overproduction of hepatic apoB100-containing VLDL particles has been well documented in animal models and in humans with insulin resistance such as the metabolic syndrome and type 2 diabetes, and contributes to the typical dyslipidemia of these conditions. In addition, postprandial hyperlipidemia and elevated plasma concentrations of intestinal apoB48-containing chylomicron and chylomicron remnant particles have been demonstrated in insulin resistant states. Intestinal lipoprotein production is primarily determined by the amount of fat ingested and absorbed. Until approximately 10 years ago, however, relatively little attention was paid to the role of the intestine itself in regulating the production of triglyceride-rich lipoproteins (TRL) and its dysregulation in pathological states such as insulin resistance. We and others have shown that insulin resistant animal models and humans are characterized by overproduction of intestinal apoB48-containing lipoproteins. Whereas various factors are known to regulate hepatic lipoprotein particle production, less is known about factors that regulate the production of intestinal lipoprotein particles. Monosacharides, plasma free fatty acids (FFA), resveratrol, intestinal peptides (e.g. GLP-1 and GLP-2), and pancreatic hormones (e.g. insulin) have recently been shown to be important regulators of intestinal lipoprotein secretion. Available evidence in humans and animal models strongly supports the concept that the small intestine is not merely an absorptive organ but rather plays an active role in regulating the rate of production of chylomicrons in fed and fasting states. Metabolic signals in insulin resistance and type 2 diabetes and in some cases an aberrant intestinal response to these factors contribute to the enhanced formation and secretion of TRL. Understanding the regulation of intestinal lipoprotein production is imperative for the development of new therapeutic strategies for the prevention and treatment of dyslipidemia. Here we review recent developments in this field and present evidence that intestinal lipoprotein production is a process with metabolic plasticity and that modulation of intestinal lipoprotein secretion may be a feasible therapeutic strategy in the treatment of dyslipidemia and possibly prevention of atherosclerosis.

Topics: Animals; Apolipoprotein B-100; Apolipoprotein B-48; Atherosclerosis; Bile Acids and Salts; Cholesterol; Chylomicrons; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Dyslipidemias; Exenatide; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Resistance; Intestine, Small; Lipoproteins; Microbiota; Peptides; Receptors, Glucagon; Resveratrol; Secretory Rate; Stilbenes; Triglycerides; Venoms

Adiponectin is produced predominantly by adipocytes and plays an important role in metabolic and cardiovascular homeostasis through its insulin-sensitizing actions and anti-inflammatory and anti-atherogenic properties. Recently, it has been observed that lower levels of adiponectin can substantially increase the risk of developing type 2 diabetes, metabolic syndrome, atherosclerosis, and cardiovascular disease in patients who are obese. Circulating adiponectin levels are inversely related to the inflammatory process, oxidative stress, and metabolic dysregulation. Intensive lifestyle modifications and pharmacologic agents, including peroxisome proliferator-activated receptor-γ or α agonists, some statins, renin-angiotensin-aldosterone system blockers, some calcium channel blockers, mineralocorticoid receptor blockers, new β-blockers, and several natural compounds can increase adiponectin levels and suppress or prevent disease initiation or progression, respectively, in cardiovascular and metabolic disorders. Therefore, it is important for investigators to have a thorough understanding of the interventions that can modulate adiponectin. Such knowledge may lead to new therapeutic approaches for diseases such as type 2 diabetes, metabolic syndrome, cardiovascular disease, and obesity. This review focuses on recent updates regarding therapeutic interventions that might modulate adiponectin.

Topics: Adiponectin; Antihypertensive Agents; Atherosclerosis; Bariatric Surgery; Cardiovascular Diseases; Clinical Trials as Topic; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Reducing; Exercise; Humans; Hypoglycemic Agents; Insulin Resistance; Life Style; Metabolic Syndrome; Metabolism, Inborn Errors; Obesity; Peroxisome Proliferator-Activated Receptors; Receptors, Adiponectin; Resveratrol; Stilbenes

Resveratrol (3,5,4'-trihydroxystilbene) is a natural phytophenol. It is found in many plants, but the highest concentration was detected in different grape-derived products, especially in red wine. The substance is also an active ingredient of some over-the-counter diet supplements. High resveratrol popularity is a consequence of wide biological properties. Numbers of epidemiological and experimental studies have proved a complex chemiopreventive activity of resveratrol against various cardio-vascular disorders and cancer. Furthermore, the compound possesses anti-inflammatory activity and positively regulates glucose level and metabolism of adipose tissue. Diet rich in resveratrol promotes longevity and attenuates neurodegenerative diseases.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents; Atherosclerosis; Cardiovascular Diseases; Chemoprevention; Glucose; Humans; Longevity; Neoplasms; Neurodegenerative Diseases; Resveratrol; Stilbenes

Resveratrol, a natural polyphenol produced by plants in response to environmental stress, has received great attention during the past few years due to its beneficial roles in longevity and glucose homeostasis. Resveratrol has been found to display antioxidant, anti-inflammatory, antifibrotic, and cardioprotective properties. Resveratrol reduces platelet aggregation, induces vasorelaxation, limits endothelial activation, and modulates lipid and lipoprotein metabolism. Although the mechanisms of action of resveratrol have not been completely defined, there is evidence that some of the effects of resveratrol may be mediated via activation of sirtuin 1 and AMP-activated protein kinase and through inhibition of the pleiotropic transcription factor nuclear factor κB. Pathways proposed to underlie resveratrol-mediated cardioprotection include reduction of oxidative stress and activation of endothelial nitric oxide synthase. Adenosinergic mechanisms may play a role in its atheroprotective activity. The ability of the nutraceutical resveratrol to positively influence the future treatment of cardiovascular disease is discussed.

Topics: Angiogenesis Modulating Agents; Animals; Antioxidants; Atherosclerosis; Cardiotonic Agents; Cholesterol; Dietary Supplements; Humans; Resveratrol; Stilbenes; Vasodilator Agents

Several epidemiologic observations show that moderate wine drinking reduces cardiovascular morbidity and mortality. Wine contains several polyphenols, and among them, resveratrol in particular has been shown to exert a number of important biologic activities on the cardiovascular system that may contribute to the protective effects of wine. The mechanisms through which resveratrol and other wine polyphenols protect from ischemic cardiovascular events are many, but protection from oxidative stress and radical oxygen species production, a facilitating activity on nitric oxide production and activity and the ability to modulate the expression of adhesive molecules by blood cells and the vascular wall seem to be the most important. In this overview, the in vitro and in vivo evidence on the activity of resveratrol on vascular function and circulating blood cells, with a special emphasis on blood platelets, is thoroughly presented.

Topics: Antioxidants; Atherosclerosis; Blood Platelets; Cell Adhesion Molecules; Endothelium, Vascular; Flavonoids; Humans; Nitric Oxide; Oxidative Stress; Phenols; Polyphenols; Reactive Oxygen Species; Resveratrol; Stilbenes; Wine

The term FRENCH PARADOX was coined in 1992 to describe the relatively low incidence of cardiovascular disease in the French population, despite a relatively high dietary intake of saturated fats, and potentially attributable to the consumption of red wine. After nearly 20 years, several studies have investigated the fascinating, overwhelmingly positive biological and clinical associations of red wine consumption with cardiovascular disease and mortality. Light to moderate intake of red wine produces a kaleidoscope of potentially beneficial effects that target all phases of the atherosclerotic process, from atherogenesis (early plaque development and growth) to vessel occlusion (flow-mediated dilatation, thrombosis). Such beneficial effects involve cellular signaling mechanisms, interactions at the genomic level, and biochemical modifications of cellular and plasma components. Red wine components, especially alcohol, resveratrol, and other polyphenolic compounds, may decrease oxidative stress, enhance cholesterol efflux from vessel walls (mainly by increasing levels of high-density lipoprotein cholesterol), and inhibit lipoproteins oxidation, macrophage cholesterol accumulation, and foam-cell formation. These components may also increase nitric oxide bioavailability, thereby antagonizing the development of endothelial dysfunction, decrease blood viscosity, improve insulin sensitivity, counteract platelet hyperactivity, inhibit platelet adhesion to fibrinogen-coated surfaces, and decrease plasma levels of von Willebrand factor, fibrinogen, and coagulation factor VII. Light to moderate red wine consumption is also associated with a favorable genetic modulation of fibrinolytic proteins, ultimately increasing the surface-localized endothelial cell fibrinolysis. Overall, therefore, the "French paradox" may have its basis within a milieu containing several key molecules, so that favorable cardiovascular benefits might be primarily attributable to combined, additive, or perhaps synergistic effects of alcohol and other wine components on atherogenesis, coagulation, and fibrinolysis. Conversely, chronic heavy alcohol consumption and binge drinking are associated with increased risk of cardiovascular events. In conclusion, although mounting evidence strongly supports beneficial cardiovascular effects of moderate red wine consumption (one to two drinks per day; 10-30 g alcohol) in most populations, clinical advice to abstainers to initiate daily alcohol consumption h

Topics: Alcohol Drinking; Antioxidants; Atherosclerosis; Blood Pressure; Cardiovascular Diseases; Cholesterol, HDL; Coronary Artery Disease; Endothelium, Vascular; Fibrinolysis; Hemostasis; Humans; Resveratrol; Stilbenes; Wine

Resveratrol (RS), a polyphenol compound found in grapes and grape products, including wine, peanuts and berries, exists in cis- and trans-isomeric forms. RS is believed to decrease circulating low-density lipoprotein cholesterol levels and reduce cardiovascular disease (CVD) risk. However, it is possible that RS has other mechanisms to reduce the risk of CVD without altering lipid levels. The objective of this review is to critically examine results from recent research concerning potential effects of RS on CVD. RS exerts several health benefits including anti-atherogenic, anti-inflammatory and anti-cancer effects. RS may also prevent lipid oxidation, platelet aggregation, arterial vasodilation and modulates the levels of lipids and lipoproteins. As a potent, anti-oxidant RS reduces oxidative stress and regenerates alpha-tocopherol, which further strengthens the anti-oxidant defense mechanism. RS has been considered safe as no significant toxic effects have been identified, even when consumed at higher concentrations. This evidence identified RS as an effective anti-atherogenic agent, which could be used in the prevention and treatment of CVD.

Topics: Animals; Antioxidants; Atherosclerosis; Cardiovascular Diseases; Humans; Lipids; Phytotherapy; Plant Extracts; Resveratrol; Stilbenes; Vitis

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

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

Growing evidence from tissue culture, animal, and clinical models suggests that the flavonoid-rich fruits of the North American cranberry and blueberry (Vaccinium spp.) have the potential ability to limit the development and severity of certain cancers and vascular diseases including atherosclerosis, ischemic stroke, and neurodegenerative diseases of aging. The fruits contain a variety of phytochemicals that could contribute to these protective effects, including flavonoids such as anthocyanins, flavonols, and proanthocyanidins; substituted cinnamic acids and stilbenes; and triterpenoids such as ursolic acid and its esters. Cranberry and blueberry constituents are likely to act by mechanisms that counteract oxidative stress, decrease inflammation, and modulate macromolecular interactions and expression of genes associated with disease processes. The evidence suggests a potential role for dietary cranberry and blueberry in the prevention of cancer and vascular diseases, justifying further research to determine how the bioavailability and metabolism of berry phytonutrients influence their activity in vivo.

Topics: Animals; Anthocyanins; Anticarcinogenic Agents; Antioxidants; Atherosclerosis; Blueberry Plants; Flavonoids; Humans; Neoplasms; Phytotherapy; Proanthocyanidins; Stilbenes; Stroke; Triterpenes; Vaccinium macrocarpon; Vascular Diseases

Numerous epidemiological studies indicate that a moderate intake of alcohol is associated with a reduced risk of morbidity and mortality secondary to cardiovascular diseases. Alcohol intake from any type of alcoholic beverage appears beneficial, but red wine seems to confer additional health benefits because of the presence of red wine polyphenolic compounds (RWPC). On the basis of clinical and experimental data, the favourable effect of moderate intake of alcohol results to its action on lipid profile, hemostatic parameters, and reduction of inflammation markers. RWPC exert numerous effects including antioxidant and free radical properties, anti-aggregatory platelet and anti-thrombotic activities. Moreover, RWPC are powerful vasodilators and contribute to the preservation of the integrity of the endothelium and inhibition of smooth muscle cell proliferation and migration. All these effects of red wine might interfere with atherosclerotic plaque development and stability, vascular thrombosis and occlusion. Although, red wine might be of therapeutic benefit in cardiovascular diseases, prospective controlled clinical studies are still lacking.

Topics: Alcohol Drinking; Animals; Aorta; Atherosclerosis; Cardiovascular Diseases; Color; Endothelium, Vascular; Flavonoids; Humans; Models, Animal; Phenols; Polyphenols; Resveratrol; Risk Assessment; Stilbenes; Thrombosis; Vascular Diseases; Vasodilator Agents; Wine

Angiogenesis, the formation of new blood vessels from preexisting vascular network is a driving force of organ development in ontogeny, is necessary for ovulation and hair growth, and is prerequisite for proper wound healing. It is also a critical mechanism of numerous diseases, the most important of which are cancer and atherosclerosis. Therefore, modulation of angiogenesis is considered as therapeutic strategies of great importance for human health. Numerous bioactive plant compounds, often referred to as nutraceuticals are recently tested for the potential clinical applications. Among the most frequently studied are resveratrol, a polyphenol present in red-wine and grape-seed, epigallocatechin-3-gallate (EGCG) from green tea and curcumin from Curcuma longa. It is also possible that components of other plants, including the constituents of local food diet may find application for modulation of angiogenesis, provided that their effectiveness will be confirmed in controlled, scientifically validated trials.

Topics: Angiogenesis Inhibitors; Animals; Atherosclerosis; Catechin; Curcumin; Dietary Supplements; Flavonoids; Humans; Neoplasms; Neovascularization, Pathologic; Phenols; Polyphenols; Resveratrol; Stilbenes; Vascular Endothelial Growth Factor A

Resveratrol has been reported to have potent anti-atherosclerotic effects in animal studies. However, there are few interventional studies in human patients with atherosclerogenic diseases. The cardio-ankle vascular index (CAVI) reflects arterial stiffness and is a clinical surrogate marker of atherosclerosis. The aim of the present study was to investigate the effect of resveratrol on arterial stiffness assessed by CAVI in patients with type 2 diabetes mellitus (T2DM).In this double-blind, randomized, placebo-controlled study, 50 patients with T2DM received supplement of a 100mg resveratrol tablet (total resveratrol: oligo-stilbene 27.97 mg/100 mg/day) or placebo daily for 12 weeks. CAVI was assessed at baseline and the end of study. Body weight (BW), blood pressure (BP), glucose and lipid metabolic parameters, and diacron-reactive oxygen metabolites (d-ROMs; an oxidative stress marker) were also measured.Resveratrol supplementation decreased systolic BP (-5.5 ± 13.0 mmHg), d-ROMs (-25.6 ± 41.8 U.CARR), and CAVI (-0.4 ± 0.7) significantly (P < 0.05) and decreased BW (-0.8 ± 2.1 kg, P = 0.083) and body mass index (-0.5 ± 0.8 kg/m

Topics: Administration, Oral; Ankle Brachial Index; Antioxidants; Atherosclerosis; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Oxidative Stress; Resveratrol; Retrospective Studies; Stilbenes; Treatment Outcome; Vascular Stiffness

Topics: Atherosclerosis; Double-Blind Method; Endothelium, Vascular; Female; Gene Expression Regulation; Humans; Male; Resveratrol; Stilbenes

It is suggested that polyphenols back the cardiovascular protection offered by the Mediterranean diet. This study evaluates the association of specific types of dietary polyphenols with prevalent subclinical atherosclerosis in middle-aged subjects.. Ultrasonography and TC were performed on 2318 men from the Aragon Workers Health Study, recruited between 2011 and 2014, to assess the presence of plaques in carotid and femoral arteries and coronary calcium. Polyphenol intake was assessed using a validated semi-quantitative 136-item food frequency questionnaire. The Phenol Explorer database was used to derive polyphenol class intake. Logistic and linear regressions were used to estimate the cross-sectional association of polyphenols intake with femoral and carotid subclinical atherosclerosis and coronary calcium.. A higher intake of flavonoids (third vs. first tertile) was associated with a lower risk of both carotid (OR 0.80: CI 95% 0.62-1.02; P trend 0.094) and femoral (0.62: 0.48-0.80, P trend < 0.001) subclinical atherosclerosis. A higher intake of stilbenes was associated with a lower risk of femoral subclinical atherosclerosis (0.62: 0.46-0.83; P trend 0.009) and positive coronary calcium (0.75: 0.55-1.03; P trend 0.131). A higher intake of tyrosols was also associated with a lower risk of positive coronary calcium (0.80: 0.62-1.03; P trend 0.111). The associations remained similar when adjusted for blood lipids and blood pressure.. Dietary flavonoids, stilbenes, and tyrosols, whose main sources are red wine and virgin olive oil, are associated with lower prevalence of subclinical atherosclerosis in middle-aged subjects.

Topics: Atherosclerosis; Calcium; Calcium, Dietary; Cross-Sectional Studies; Femoral Artery; Flavonoids; Humans; Male; Middle Aged; Olive Oil; Phenylethyl Alcohol; Polyphenols; Risk Factors; Stilbenes; Wine

Atherosclerosis is a disease in which lipids and inflammatory factors accumulate on the walls of arteries, forming plaques that eventually block the flow of blood. Polydatin was derived from plant knotweed, which could play an important role in inhibiting the progression of atherosclerosis. However, the mechanism by which polydatin regulates the genesis and development of atherosclerosis remains unclear. To detect the function of polydatin in atherosclerosis, the proliferation, apoptosis and migration of human umbilical vein endothelial cells (HUVECs) was detected using 5-ethynyl-2'-deoxyuridine staining, flow cytometry and transwell assays, respectively. In addition, the branch points and capillary length of HUVECs were observed using a tube formation assay, and the lipid accumulation was tested by Oil-red O staining assay. Dual luciferase reporter assays were performed to confirm the association between microRNA (miR)-26a-5p and BH3 interacting domain death agonist (BID) in HUVECs. The data suggested oxidized low-density lipoprotein (oxLDL) notably inhibited the viability of HUVECs in a dose-dependent manner, and polydatin reversed the oxLDL-induced inhibition of HUVECs viability and proliferation. In addition, polydatin inhibited the apoptosis, migration and epithelial mesenchymal transition (EMT) process in oxLDL-treated HUVECs. Polydatin reversed oxLDL-induced lipid accumulation and angiogenesis inhibition in HUVECs. Furthermore, BID was targeted by miR-26a-5p, and polydatin reversed the oxLDL-induced apoptosis of HUVECs via regulating the miR-26a-5p/BID axis. In summary, polydatin reversed the oxLDL-induced apoptosis of HUVECs via regulating the miR-26a-5p/BID axis. Therefore, polydatin could act as a new agent for atherosclerosis treatment.

Topics: Apoptosis; Atherosclerosis; Glucosides; Human Umbilical Vein Endothelial Cells; Humans; Lipoproteins, LDL; MicroRNAs; Stilbenes

Polydatin has been reported to possess remarkable anti-atherosclerotic activities. However, there are different opinions on its regulatory mechanisms. It remains unclear whether the anti-atherosclerotic mechanism of polydatin is related to its autophagic restoration or not. The aim of this study was to explore the question.. Using atherosclerotic model induced by high-fat diet in apolipoprotein E-deficient mice, the investigation was performed with polydatin alone or in combination with autophagic inhibitor or inducer intervention. Inhibitory sites of polydatin to PI3K were identified by molecular docking.. Polydatin can significantly inhibit PI3K/Akt/mTOR pathway proteins expression, improve autophagic dysfunction and reduce atherosclerotic lesions. These effects could be antagonized and reinforced by adding autophagic inhibitor and inducer, respectively. Inhibitory sites of polydatin to PI3K were found to be ASP-810, SER-854, VAL-851, LEU-807, SER-774, LYS-802, ASP-933, SER-919, ASN-920, PHE-930, MEF-922, GLN-859 of PI3Kα.. The mechanism of polydatin to alleviate atherosclerotic lesions was achieved by autophagic restoration.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Autophagy; Diet, High-Fat; Glucosides; Male; Mice, Knockout, ApoE; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Plaque, Atherosclerotic; Proto-Oncogene Proteins c-akt; Stilbenes; TOR Serine-Threonine Kinases

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

Recent studies have demonstrated that trans-3, 5, 4'-Trimethoxystilbene (TMS), a novel derivative of resveratrol, may suppress the foam cells formation and restrain atherosclerosis in vitro and in vivo. Herein, the molecular mechanisms underlying the protective effects of TMS against atherosclerosis are further delineated.. In conclusion, TMS may inhibit the progress of atherosclerosis through regulating cholesterol homeostasis and inhibiting macrophage-derived foam cells formation.

Topics: Animals; Atherosclerosis; ATP Binding Cassette Transporter 1; Cholesterol; Foam Cells; Heme Oxygenase-1; Humans; Lipoproteins, LDL; Male; Mice, Inbred C57BL; Mice, Knockout, ApoE; NF-E2-Related Factor 2; Resveratrol; Scavenger Receptors, Class A; Stilbenes; Triggering Receptor Expressed on Myeloid Cells-1

Red wine compounds have been reported to reduce the rate of atherosclerosis by inducing nitric oxide (NO) production and antioxidant enzyme expression in vascular endothelial cells (VECs). The present study compared the effects of the three red wine compounds resveratrol and its dimers, ε-viniferin and δ-viniferin, on VECs function for the first time. Both 5 μM ε-viniferin and δ-viniferin, but not 5 μM resveratrol, significantly stimulated wound repair of VECs. Increased levels of wound repair induced by 10 and 20 μM ε-viniferin were significantly higher than those stimulated by 10 and 20 μM resveratrol, respectively. These stimulatory effects of the three compounds were suppressed by the NO synthase inhibitor L-NAME. When VECs were exposed to each compound, endothelial NO synthase was activated and the expression of sirtuin 1 (SIRT1) and HO-1 was induced. Addition of the SIRT1 and HO-1 inhibitors EX527 and ZnPPiX, respectively, suppressed wound repair stimulated by the three compounds, demonstrating that SIRT1 and HO-1 are involved in these wound repair processes. Furthermore, each compound induced the suppression of H

Topics: Animals; Antioxidants; Atherosclerosis; Benzofurans; Carbazoles; Catalase; Cell Line; Cell Survival; Dimerization; Endothelial Cells; Enzyme Inhibitors; Gene Expression Regulation; Heme Oxygenase-1; Humans; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; Protoporphyrins; Resorcinols; Resveratrol; Sirtuin 1; Stilbenes; Swine; Wine

As a major bioactive compound from grapes, piceatannol (PIC) has been reported to exert anti-atherosclerotic activity in various studies. Nevertheless, the mechanism underlying the effect of piceatannol against atherosclerosis (AS) is elusive. Our study identified miR-200a/Nrf2/GSDMD signaling pathway as critical mediators in the effect of piceatannol on macrophages. In the present study, we confirmed that treatment of piceatannol repressed the oxLDL-induced lipid storage in macrophages. Compared with control group, piceatannol inhibited TG storage and the activity of caspase1. It is noting that in response to oxLDL challenge, piceatannol abated the pyroptosis in RAW264.7 cells, with a decreased expression of caspase1, gasdermin D (GSDMD), IL-18, IL-1β and NLRP3. Moreover, we investigated the role of microRNA (miR)-200a/Nrf2 signaling pathway in the effect of piceatannol. The results declared that after transfection of si-miR-200a or si-Nrf2 plasmids, the effects of piceatannol on macrophages were converted, including lipid storage and pyroptosis. Importantly, si-miR-200a plasmid reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), indicating that miR-200a acted as an enhancer of Nrf2 in macrophages. Collectively, our findings demonstrate that piceatannol exerts anti-atherosclerotic activity on RAW264.7 cells by regulating miR-200a/Nrf2/GSDMD signaling. The present study is the first time to identify miR-200a as a candidate target in AS and declared an association between miR-200a and pyroptosis, which provides a novel therapy for the treatment of AS.

Topics: Animals; Atherosclerosis; Caspase 1; Drug Evaluation, Preclinical; Gene Knockdown Techniques; Humans; Intracellular Signaling Peptides and Proteins; Lipoproteins, LDL; Mice; MicroRNAs; NF-E2-Related Factor 2; Phosphate-Binding Proteins; Pyroptosis; RAW 264.7 Cells; RNA, Small Interfering; Signal Transduction; Stilbenes

Atherosclerosis, the major risk of cardiovascular events, is a chronic vascular inflammatory disease. Pterostilbene is a naturally occurring dimethylated analogue of resveratrol and has recently been demonstrated to be beneficial against cardiovascular diseases. However, the underlying mechanisms of pterostilbene on atherosclerosis remain elusive. Experimental atherosclerosis was induced by a high-fat diet (HFD) in apolipoprotein E knockout (ApoE

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Catalase; Glycogen Synthase Kinase 3 beta; Humans; Hydrogen Peroxide; Interferon-gamma; Interleukin-6; Lipoproteins, LDL; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Oxidation-Reduction; Stilbenes

Topics: Aging; Animals; Aorta; Atherosclerosis; Diet, High-Fat; Glucosides; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Receptors, LDL; Stilbenes

Polydatin has been recently shown to possess extensive cardiovascular pharmacological activities. However, its protective effect against atherosclerosis in vivo remains poorly understood. The aim of the present study was to evaluate the potential effects of polydatin on high fat diet (HFD)-induced atherosclerosis using ApoE. after 12 weeks treatment, serum samples, mouse aorta, liver, peritoneal macrophages were collected to determine lipid profiles, atherosclerotic lesions, hepatic steatosis, foam cell formation and expression of related molecules. RAW264.7 macrophages were used to study cholesterol efflux.. Polydatin improved serum lipid profiles, attenuated atherosclerosis and hepatic steatosis. Furthermore, polydatin may facilitate RCT by stimulating cholesterol efflux through ATP-binding cassette transporters (ABC) A1, ABCG1 and scavenger receptor class B type I (SR-BI) in macrophages, increasing serum levels of high density lipoprotein and apolipoprotein A-I, promoting of SR-BI-mediated cholesterol uptake of liver, increasing secretion of cholesterol into bile by ABCG5/ABCG8 and improving cholesterol metabolism by CYP7A1 pathway. Polydatin also regulated the protein expressions of hepatic fatty acid synthase and peroxisome proliferator-activated receptor-α. Additionally, polydatin reduced hepatic and aortic reactive oxygen species generation, normalized activities of antioxidant enzymes and increased protein expressions of NADPH-oxidase (NOX) 2 and NOX4 in liver. Polydatin also prevented hepatic and aortic inflammation as evidenced by the reduced macrophage infiltration and mRNA expressions of tumor necrosis factor-α and interleukin-6 in both aorta and liver.. These findings indicated that polydatin can inhibit atherosclerosis through enhancement of overall RCT. In addition, anti-oxidative and anti-inflammatory effect of polydatin may also contribute to its inhibitory effects on atherosclerosis.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; Biological Transport; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Diet, High-Fat; Fatty Liver; Foam Cells; Glucosides; Lipid Metabolism; Macrophages, Peritoneal; Male; Mice, Inbred C57BL; Mice, Knockout, ApoE; Stilbenes

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

Abdominal obesity is recognized as the main reason of metabolic syndrome, which is closely related to disordered skeletal and/or abdominal muscle metabolic functions. Metabolomics is a comprehensive assessment system in biological metabolites. The aim of our present study is to investigate the diet-induced metabolic risk factors by metabolic in the abdominal muscles and clarify the relationship between atheroprotective effects of Resveratrol (Rev) and abdominal muscles metabolic components during the development of atherosclerosis.. The mice were randomly divided into three groups including normal group (N), high fat diet (HFD or H) group and high fat diet with Rev treated group (HR). GC-MS combined with pattern recognition approaches were employed to obtain comprehensive metabolic signatures and related differential metabolites after 24 week HFD feeding. Oil Red O staining and Electron microscopy technology (EMT) were employed to detect the size of fatty plaques and intracellular lipid accumulation, respectively.. The result indicated that 22 types of metabolites in the abdominal muscles were obviously altered by HFD feeding group. Moreover, Rev treatment obviously increased 11 different kinds of metabolites, most of which were involved in the carbohydrate, amino acid and lipid metabolisms. Importantly, these elevated different metabolites were involved in pathways mainly related to galactose metabolism, alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism in abdominal muscles. Oil Red O staining and Electron microscopy showed less lipid accumulation in the lesions and decreased intracellular lipid deposition in the foam cells in HR group.. We concluded that Rev produced a beneficial effect partially by modulating multiple metabolism pathways and metabolites in the abdominal muscles, which may provide a new protective mechanism of Rev on the progression of atherosclerosis. These notably changed metabolites might be potential biomarkers or therapeutic targets during development of metabolic syndrome and atherosclerosis.

Topics: Abdominal Muscles; Amino Acids; Animals; Apolipoproteins E; Atherosclerosis; Carbohydrate Metabolism; Diet, High-Fat; Discriminant Analysis; Gas Chromatography-Mass Spectrometry; Least-Squares Analysis; Lipid Metabolism; Lipids; Metabolic Diseases; Mice; Mice, Knockout; Microscopy, Electron; Monosaccharides; Resveratrol; Risk Factors; Stilbenes

Cholesterol metabolism becomes imbalanced during the formation of macrophage-derived foam cells. Pre-B-cell colony-enhancing factor (PBEF) has recently been found to affect lipid deposition and inflammation in atherosclerosis. Here, we aimed to study the effects and molecular mechanism of Polydatin on atherosclerosis in ApoE-knockout (ApoE

Topics: Animals; Atherosclerosis; Cholesterol; Cytokines; Down-Regulation; Drugs, Chinese Herbal; Glucosides; Macrophages; Mice; Mice, Knockout; Nicotinamide Phosphoribosyltransferase; Phytotherapy; RAW 264.7 Cells; RNA, Small Interfering; 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

The gut microbiota is found to be strongly associated with atherosclerosis (AS). Resveratrol (RSV) is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear. Therefore, we sought to determine whether the anti-AS effects of RSV were related to changes in the gut microbiota. We found that RSV attenuated trimethylamine-N-oxide (TMAO)-induced AS in ApoE(-/-) mice. Meanwhile, RSV decreased TMAO levels by inhibiting commensal microbial trimethylamine (TMA) production via gut microbiota remodeling in mice. Moreover, RSV increased levels of the genera Lactobacillus and Bifidobacterium, which increased the bile salt hydrolase activity, thereby enhancing bile acid (BA) deconjugation and fecal excretion in C57BL/6J and ApoE(-/-) mice. This was associated with a decrease in ileal BA content, repression of the enterohepatic farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) axis, and increased cholesterol 7a-hydroxylase (CYP7A1) expression and hepatic BA neosynthesis. An FXR antagonist had the same effect on FGF15 and CYP7A1 expression as RSV, while an FXR agonist abolished RSV-induced alterations in FGF15 and CYP7A1 expression. In mice treated with antibiotics, RSV neither decreased TMAO levels nor increased hepatic BA synthesis. Additionally, RSV-induced inhibition of TMAO-caused AS was also markedly abolished by antibiotics. In conclusion, RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling, and the BA neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis.. Recently, trimethylamine-N-oxide (TMAO) has been identified as a novel and independent risk factor for promoting atherosclerosis (AS) partially through inhibiting hepatic bile acid (BA) synthesis. The gut microbiota plays a key role in the pathophysiology of TMAO-induced AS. Resveratrol (RSV) is a natural phytoalexin with prebiotic benefits. A growing body of evidence supports the hypothesis that phenolic phytochemicals with poor bioavailability are possibly acting primarily through remodeling of the gut microbiota. The current study showed that RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling. And RSV-induced hepatic BA neosynthesis was partially mediated through downregulating the enterohepatic farnesoid X receptor-fibroblast growth factor 15 axis. These results offer new insights into the mechanisms responsible for RSV's anti-AS effects and indicate that the gut microbiota may become an interesting target for pharmacological or dietary interventions to decrease the risk of developing cardiovascular diseases.

Topics: Animals; Atherosclerosis; Bacteria; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase; Female; Gastrointestinal Microbiome; Humans; Liver; Methylamines; Mice; Mice, Inbred C57BL; Resveratrol; Stilbenes

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

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

Resveratrol is a bioactive molecule used in dietary supplements and herbal medicines and consumed worldwide. Numerous investigations by our group and others have indicated cardioprotective and anti-inflammatory properties of resveratrol. The present study explored potential atheroprotective actions of resveratrol on cholesterol efflux in cultured human macrophages exposed to plasma from systemic lupus erythematosus (SLE) patients. These results were confirmed in ApoE(-/-)Fas(-/-) double knockout mice, displaying a lupus profile with accelerated atherosclerosis. Resveratrol treatment attenuated atherosclerosis in these mice. THP-1 human macrophages were exposed to 10% pooled or individual plasma from patients who met diagnostic criteria for SLE. Expression of multiple proteins involved in reverse cholesterol transport (ABCA1, ABCG1, SR-B1, and cytochrome P450 27-hydroxylase) was assessed using QRT-PCR and Western blotting techniques. Ten-week-old ApoE(-/-)Fas(-/-) double knockout mice (n = 30) were randomly divided into two equal groups of 15, one of which received 0.01% resveratrol for 10 consecutive weeks. Atherosclerosis progression was evaluated in murine aortas. Bone marrow-derived macrophages (BMDM) were cultured and expression of cholesterol efflux proteins was analyzed in each group of mice. Our data indicate that inhibition of cholesterol efflux by lupus plasma in THP-1 human macrophages is rescued by resveratrol. Similarly, administration of resveratrol in a lupus-like murine model reduces plaque formation in vivo and augments cholesterol efflux in BMDM. This study presents evidence for a beneficial role of resveratrol in atherosclerosis in the specific setting of SLE. Therefore, resveratrol may merit investigation as an additional resource available to reduce lipid deposition and atherosclerosis in humans, especially in such vulnerable populations as lupus patients.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Cholesterol; fas Receptor; Humans; Lupus Erythematosus, Systemic; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Resveratrol; Stilbenes

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

To study the effect of polydatin on the expression level of miR-214 and liver function in atherosclerotic mice.. Forty male ApoE(-/-) mice were randomly allocated into 4 groups (n=10), namely the model group, low- and high-dose polydatin groups, and simvastin group, with 10 male C57BL/6J mice serving as the normal control group. Mouse models of atherosclerosis were established by feeding the ApoE(-/-) mice with a high-fat diet. After 12 weeks of treatment, blood levels of glucose, lipids, AST, and ALT and the contents of T-SOD and MDA in the liver tissue were detected. The pathologies of the liver were examined with HE staining, and miR-214 expression in the liver was detected using quantitative real-time PCR.. Compared with the normal control mice, the mice in the model group showed significantly increased blood glucose, serum TC, TG, LDL-C, ALT, and AST levels, and MDA contents in the liver (P<0.01), with significantly decreased serum HDL-C level and SOD and miR-214 levels in liver (P<0.01). Polydatin treatment significantly ameliorated such changes in blood glucose, serum ALT, AST, TC, TG, LDL-C, and HDL-C levels, and MDA, SOD, and miR-214 contents in liver tissue (P<0.05).. s Polydatin can reduce blood glucose and lipid levels and protect the liver function in atherosclerotic mice possibly by up-regulating the expression of miR-214 and T-SOD and down-regulating MDA in the liver.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Blood Glucose; Diet, High-Fat; Disease Models, Animal; Drugs, Chinese Herbal; Glucosides; Lipids; Liver; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Stilbenes; Superoxide Dismutase

Hyperlipidemia, a major pathological condition associated with disrupted lipid levels and physiological redox homeostasis. The excessive release of reactive oxygen species (ROS) leads to enhanced lipid peroxidation, aggravated atherosclerosis and oxidative stress. Integration of natural antioxidant blends in alone or with conventional treatments can alleviate these issues synergistically contributing least side effects. Published literature reported the efficacy of natural antioxidants as individual and in combinations in various conditions but less data is available on their evaluation in low dose ratio blends particularly in hypercholesterolemic diet.. Antihyperlipidemic effects of selected natural antioxidants; the phenolic oligomeric proanthocyanidins (OPC) and pterostilbene (PT) with niacin (NA) were investigated in current study. Their effects on lipid profile, lipid peroxidation and their aptitude to establish redox state between oxidants and antioxidants in body were evaluated in high cholesterol diet fed animal model. Male albino rabbits (n = 6) weighing 1.2-1.6 kg, supplemented with high cholesterol diet (400 mg/kg) for 12 weeks were used in the experiment. Antioxidants were administered individual high (100 mg/kg) and in low dose combinations (total dose = 100 mg/kg). Student's t test and one way analysis of variance (ANOVA) followed by Dunnet's test were used as statistical tools for evaluation.. The results showed synergistic effects of low dose antioxidant blends. Therapies retarded elevation in blood lipid levels, lipid peroxidation and blood antioxidant depletion and consequently contributed in reestablishing redox homeostasis. The LDL/HDL ratio and atherogenic index were suppressed significantly in blend therapies with maximum effects of 59.3 and 25 % (p >0.001) observed in 50:30:20 ratios of OPC, NA and PT, compared to individual therapies 37 and 18 % max respectively. Moreover the results were also in close proximity with the statin therapy (52.66, 26.28 %).. This study provides an evidence for natural antioxidants blends superiority over individual therapy in chronic diseases like hyperlipidemia. Such therapies in human equivalent doses can help in mitigating chronic illnesses in general populations.

Topics: Animals; Antioxidants; Atherosclerosis; Biological Products; Drug Synergism; Humans; Hypolipidemic Agents; Lipid Metabolism; Lipid Peroxidation; Lipids; Male; Niacin; Oxidative Stress; Proanthocyanidins; Rabbits; Reactive Oxygen Species; Stilbenes

Endothelial dysfunction plays an important role in the pathogenesis of atherogenesis. 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), an active component of the rhizome extract from Polygonum multiflorum (PM), exhibits significant anti-atherosclerotic activity. Here, we used human umbilical vein endothelial cells (HUVECs) induced by tumor necrosis factor-α (TNF-α) in vitro to investigate the cytoprotective effects of TSG on TNF-α-induced endothelial injury and the related mechanisms. Pretreatment with 50 and 100 μM TSG markedly attenuated TNF-α-induced loss of cell viability and release of lactate dehydrogenase (LDH) and inhibited TNF-α-induced cell apoptosis. The inhibition of vimentin expression was involved in the cytoprotection afforded by TSG. Using inhibitors for PI3K and TGFβ or siRNA for Akt and Smad2, we found that vimentin production in HUVECs is regulated by TGFβ/Smad signaling, but not by PI3K-Akt-mTOR signaling. Meanwhile, TSG inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by TNF-α. These results suggest that TSG protects HUVECs against TNF-α-induced cell damage by inhibiting vimentin expression via the interruption of the TGFβ/Smad signaling pathway.

Topics: Active Transport, Cell Nucleus; Apoptosis; Atherosclerosis; Cells, Cultured; Cytoprotection; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Gene Expression Regulation, Developmental; Glucosides; Humans; L-Lactate Dehydrogenase; Polygonum; Signal Transduction; Smad Proteins; Stilbenes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Umbilical Veins; Vimentin

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

Smooth muscle cells (SMCs) migration and matrix metalloproteinase-2 (MMP-2) activation are main roles in atherosclerosis. Pterostilbene (trans-3, 5-dimethoxy-4-hydroxystilbene) is known to have various pharmacologic effects such as anti-inflammatory and anticarcinogenic properties. The present study aimed to investigate the anti-atheroscleroic property of pterostilbene in the rat smooth muscle cell (SMC) A7r9 cell lines and the underlying mechanisms. In this study, pterostilbene treatment significantly inhibited migration/invasion capacities of in A7r9 cell. Pterostilbene was also found to significantly decreased MMP-2 activity and expression by gelatin zymography and western blot assay in SMC. In the MAPK signaling pathway, western blot assay also indicated that pterostilbene up-regulated the phosphorylation of extracellular-signal-regulated kinase (Erk)1/2. Moreover, inhibition of Erk1/2 by specific inhibitors significantly abolished the pterostilbene-decreased expression of MMP-2 and migration/invasion capacities. These findings suggest that pterostilbene inhibited SMC migration and that MMP-2 activation could be mediated via Erk1/2 phosphorylation. It is further possible that pterostilbene could play a novel role in the treatment of atherosclerosis.. Pterostilbene is a plant polyphenol compound that is principally found in blueberries. In this study, we found that pterostilbene could inhibit SMCs migration via down-regulation of MMP-2. Particularly, expression of MMP-2 was found to be strongly associated with the phosphorylation of Erk1/2.

Topics: Animals; Aorta; Atherosclerosis; Blueberry Plants; Cell Movement; Down-Regulation; Male; Matrix Metalloproteinase 2; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Plant Extracts; Rats; Signal Transduction; Stilbenes; Up-Regulation

Macrophages play a key role in atherosclerotic plaque formation and rupture. These phagocytic cells are important in the scavenging of modified lipoproteins, unwanted or dead cells and cellular debris through efferocytosis. Sirtuin1 (Sirt1), a member of the conserved sirtuin family and a key regulator in the progression of atherosclerosis exerts protective effects by regulating autophagy, a well-known survival mechanism. Inhibition of autophagy may also result in defective efferocytosis. This study aimed to investigate the effect of Sirt1 on the efferocytosis of oxidized low-density lipoprotein (ox-LDL)-induced apoptotic RAW264.7 cells through upregulation of autophagy. The apoptotic cells were incubated with high and low concentrations of Sirt1 activator resveratrol (RSV) and Sirt1 inhibitor nicotinamide (NAM) as well as autophagy inhibitor 3-methyl-adenine (3-MA) + low concentration RSV. Apoptosis was determined by flow cytometry (FCM) of annexin-V/propidium iodide (AV/PI) dual staining. Total proteins were extracted and protein levels were detected through western blot analysis. The ox-LDL uptake and efferocytosis of apoptotic RAW264.7 cells were detected by oil red O staining and calculation of the phagocytic index of apoptotic RAW264.7 cells. The expression of Sirt1 and autophagy marker proteins was simultaneously increased with the stimulation of low concentration RSV (all P<0.05) and decreased in low and high NAM groups (all P<0.05), compared with the control group. Efferocytosis was highest in the low concentration RSV group (P<0.001) and relatively lower in the low and high concentration NAM groups (both P<0.05) compared with the control group, which was similar to the change in the expression of Sirt1 and autophagy marker proteins. The results showed that the efferocytosis of apoptotic RAW264.7 cells was significantly improved with the upregulation of Sirt1‑mediated autophagy. Therefore, Sirt1 may serve as a novel therapeutic target for the treatment of atherosclerosis.

Topics: Apoptosis; Atherosclerosis; Autophagy; Cell Line; Gene Expression Regulation; Humans; Lipoproteins, LDL; Molecular Targeted Therapy; Resveratrol; Sirtuin 1; Stilbenes

Studying human vascular disease in conventional cell cultures and in animal models does not effectively mimic the complex vascular microenvironment and may not accurately predict vascular responses in humans. We utilized a microfluidic device to recapitulate both shear stress and O2 levels in health and disease, establishing a microfluidic vascular model (μVM). Maintaining human endothelial cells (ECs) in healthy-mimicking conditions resulted in conversion to a physiological phenotype namely cell elongation, reduced proliferation, lowered angiogenic gene expression and formation of actin cortical rim and continuous barrier. We next examined the responses of the healthy μVM to a vasotoxic cancer drug, 5-Fluorouracil (5-FU), in comparison with an in vivo mouse model. We found that 5-FU does not induce apoptosis rather vascular hyperpermeability, which can be alleviated by Resveratrol treatment. This effect was confirmed by in vivo findings identifying a vasoprotecting strategy by the adjunct therapy of 5-FU with Resveratrol. The μVM of ischemic disease demonstrated the transition of ECs from a quiescent to an activated state, with higher proliferation rate, upregulation of angiogenic genes, and impaired barrier integrity. The μVM offers opportunities to study and predict human ECs with physiologically relevant phenotypes in healthy, pathological and drug-treated environments.

Topics: Animals; Atherosclerosis; Capillary Permeability; Endothelial Cells; Endothelium, Vascular; Fluorouracil; Humans; Ischemia; Mice; Microfluidic Analytical Techniques; Oxygen Consumption; Resveratrol; Stilbenes; Stress, Mechanical; Vascular Diseases

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

A number of studies support the anti-atherogenic effect of wine compounds. The scope of this study was to examine the effect of a red (Cabernet Sauvignon-CS) and a white (Robola-R) wine, as well as resveratrol and quercetin, on the platelet activating factor (PAF) biosynthetic enzymes, acetyl-CoA:lyso-PAF acetyltransferase (lyso-PAF-AT) and DTT-insensitive CDP-choline 1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase (PAF-CPT), and its main catabolic enzyme (PAF acetylhydrolase; PAF-AH), on U937 cells, in cell free and in intact cell experiments. In cell free experiments, phenolic compounds and wine extracts inhibited PAF biosynthetic enzymes, however in higher concentrations than intact cell experiments. In the latter cases, polar lipids of both wines inhibited in the same order of magnitude the action of lyso-PAF-AT and of PAF-CPT. The water fractions possessed a dual action, in lower concentrations they activated both enzymes, while in higher concentrations only inhibited PAF-CPT. All fractions either did not affect or slightly activated PAF-AH activity. In conclusion, wine compounds may exert their anti-inflammatory activity by reducing PAF levels through modulation of the PAF metabolic enzymes.

Topics: Atherosclerosis; Humans; Platelet Activating Factor; Resveratrol; Stilbenes; U937 Cells; Wine

Fluid shear stress has been revealed to differentially regulate endothelial nitric oxide synthase (eNOS) distribution in vessels. eNOS, a key enzyme in controlling nitric oxide (NO) release, has a crucial role in mediating oxidative stress, and resveratrol (RSV)‑mediated eNOS also attenuates oxidative damage and suppresses endothelial dysfunction. To observe the protective effect of RSV on low shear stress (LSS)‑induced oxidative damage and the potential mechanisms involved, a parallel‑plate flow chamber, which imposed a low level of stress of 2 dynes/cm2 to cells, was employed. Reactive oxygen species (ROS), NO and apoptotic cells were examined in LSS‑treated endothelial cells (ECs) with or without RSV. Western blot analysis was used to examine LSS‑regulated eNOS‑Ser1177, Thr495 and Ser633, which were tightly associated with NO release. To further determine the underlying signaling pathways involved, extracellular signal‑regulated kinase (ERK), a possible upstream target of eNOS‑Thr495, was investigated, followed by examination of eNOS‑Thr495 in ERK‑inhibited cells. Additionally, eNOS mRNA expression levels were analyzed in cells challenged with LSS. The results revealed that RSV markedly decreased LSS‑induced oxidative damage in ECs. Furthermore, eNOS‑Ser1177 and Thr495 as well as phospho‑ERK were time‑dependently activated by LSS. The ERK inhibitor deactivated eNOS‑Thr495, which was accompanied by increased intracellular superoxide dismutase (SOD) levels. Of note, the activation effect of LSS on ERK/eNOS was markedly eliminated by RSV. In conclusion, RSV exerts antioxidant effects by suppressing LSS-activated ERK/eNOS and may provide a potential therapeutic target for atherosclerosis.

Topics: Antioxidants; Atherosclerosis; Cell Survival; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Human Umbilical Vein Endothelial Cells; Humans; L-Lactate Dehydrogenase; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Phosphorylation; Reactive Oxygen Species; Resveratrol; RNA, Messenger; Shear Strength; Stilbenes; Threonine

Endothelial cell dysfunction triggered by oxidized low-density lipoprotein (oxLDL) is the main event occurring during the development of atherosclerosis. 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), an active component of the rhizome extract from Polygonum multiflorum, exhibits significant anti-atherosclerotic activity. However, the protective effects of TSG against oxLDL-induced endothelial dysfunction have not been clarified. We investigated the cytoprotective effects of TSG in human umbilical vein endothelial cells (HUVECs) and explored underlying mechanisms.. TSG pretreatment markedly attenuated oxLDL-mediated loss of cell viability, release of lactate dehydrogenase (LDH), cell apoptosis, and monocyte adhesion. OxLDL increased vimentin mRNA and protein levels, vimentin cleavage, caspase-3 activation, adhesion molecules levels and their colocalization with vimentin in HUVECs. These alterations were attenuated by pretreatment with TSG. Meanwhile, TSG inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by oxLDL. Using shRNA, oxLDL-induced cell apoptosis and monocyte adhesion were significantly inhibited by vimentin suppression in HUVECs.. These results suggest that TSG protects HUVECs against oxLDL-induced endothelial dysfunction through inhibiting vimentin expression and cleavage, and the expression of adhesion molecules and their colocalization with vimentin. The interruption of TGFβ/Smad pathway and caspase-3 activation appears to be responsible for the downregulation of TSG on vimentin expression and fragmentation, respectively.

Topics: Apoptosis; Atherosclerosis; Caspase 3; Cells, Cultured; Cytoskeleton; Down-Regulation; Endothelial Cells; Glucosides; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Adhesion Molecule-1; Lipoproteins, LDL; NF-kappa B; Protective Agents; Signal Transduction; Smad Proteins, Receptor-Regulated; Stilbenes; Vascular Cell Adhesion Molecule-1; Vimentin

We sought to investigate whether TSG suppressed the ICAM-1/VCAM-1 expression in dietary atherosclerotic rats and in Ox-LDL-induced U937 cells. For this purpose, 60 male Sprague-Dawley rats were randomly-and-equally divided into six groups. Atherosclerosis was induced by feeding rats a hyperlipidemic diet. TSG (120, 60 or 30 mg/kg/day) was administered by oral gavage. Simvastatin (2 mg/kg/day) was administered as positive control whereas physiological saline (0.9% NaCl) served as untreated control. After 12 weeks, rats were euthanized by ethyl carbonate (1,200 mg/kg) and aortic wall samples were collected. Besides, U937 cells were stimulated for 48 h by Ox-LDL (80 μg/mL) with and without TSG (120, 60, 30 μg/L) or simvastatin (100 μg/L). ICAM-1/VCAM-1 mRNA expression was determined by RT-PCR and protein expression was detected by immunohistochemistry and/or western blotting. The data show that ICAM-1/VCAM-1 mRNA/protein expression was significantly enhanced in atherosclerotic aortas compared with normal diet group. Ox-LDL-induced ICAM-1/VCAM-1 mRNA/protein expression in U937 cells. Importantly, TSG significantly inhibited ICAM-1/VCAM-1 expression in atherosclerotic aortas in a dose-dependent manner. TSG-pretreatment also inhibited ICAM-1/VCAM-1 expression in Ox-LDL-induced U937 cells. Therefore, we concluded that TSG suppressed the expression of adhesion (ICAM-1/VCAM-1) molecules both in vivo (in aortic wall of dietary atherosclerotic rats) and in vitro (U937 cells).

Topics: Animals; Aorta; Atherosclerosis; Cell Adhesion Molecules; Diet, High-Fat; Gene Expression Regulation; Glucosides; Humans; Intercellular Adhesion Molecule-1; Lipoproteins, LDL; Male; Monocyte-Macrophage Precursor Cells; Rats; Rats, Sprague-Dawley; RNA, Messenger; Simvastatin; Stilbenes; U937 Cells; Vascular Cell Adhesion Molecule-1

Abnormal proliferation of vascular smooth muscle cells (VSMCs) is an important factor during the progression of atherosclerosis. In this study, we investigated the effects of resveratrol on atherosclerosis-associated proliferation of VSMCs. We utilized an oxidized phospholipid, 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine (POVPC) to induce abnormal proliferation of VSMCs. Our results showed the treatments with resveratrol dose-dependently abolished POVPC-induced VSMC proliferation, as evidenced by the decreased [(3)H]thymidine incorporated into VSMCs and reduced percentage of 5-ethynyl-2'-deoxyuridine (EdU)-positive VSMCs. Cell cycle analysis demonstrated that resveratrol inhibited POVPC-induced increase in the S phase cell population and DNA synthesis. Our study further indicated that POVPC-induced VSMC proliferation was associated with a significant increase in the phosphorylation of Cx43, which was a consequence of activation of MAPK signaling. Interestingly, treatment with resveratrol abolished POVPC-induced phosphorylation of Cx43 as a result of inhibiting activation of Src, MEK, and ERK1/2. Our results provided a novel mechanism by which resveratrol may contribute to cardiovascular protection.

Topics: Animals; Aorta; Atherosclerosis; Cell Cycle; Cell Line; Cell Proliferation; Cells, Cultured; Connexin 43; Down-Regulation; Humans; Myocytes, Smooth Muscle; Oxidation-Reduction; Phospholipids; Phosphorylation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Inflammation serves as the initial pathologic step of cardiovascular diseases including atherosclerosis. Resveratrol possesses many pharmacological properties including antioxidant, cardioprotective and anti-cancer effects. In this study, we investigate the anti-inflammatory effect and mechanisms of resveratrol in an atherosclerotic rabbit model.. Rabbit were assigned to six groups (n = 10 each): control, high fat diet group, resveratrol low, medium and high dose groups, resveratrol pretreatment group. The serum tumor necrosis factor-α (TNF- α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were analyzed by Enzyme-linked immuno sorbent assay(ELISA). Phosphorylation levels of mitogen-activated protein kinases (MAPKs) cascades and NF-κB were determined by Western blot.. Compared with the control group, the expression of serum inflammatory factors IL-1β, IL-6, TNF-α were increased in high-fat group (all P < 0.05). Compared with high-fat group, the expressions of IL-6, IL-1β, TNF-α were significantly reduced in resveratrol low, medium, high dose groups and resveratrol pretreatment group (all P < 0.01), and this effect is dose-dependent. In addition, the NF-κB, p38MAPK, JNK, ERK1/2 protein phosphorylation in high-fat group were significantly upregulated compared with control group (P < 0.05), which (except ERK1/2 phosphorylation level) were significantly downregulated in resveratrol treatment group and resveratrol pretreatment group.. This study indicates that resveratrol reduces serum inflammatory cytokines in this atherosclerotic rabbit model via down-regulation phosphorylation of NF-κB, and MAPKs signaling, which might serve as the anti-inflammatory molecular basis of resveratrol.

Topics: Animals; Atherosclerosis; Disease Models, Animal; Interleukin-1beta; Interleukin-6; Male; Mitogen-Activated Protein Kinases; NF-kappa B; Phosphorylation; Rabbits; Resveratrol; Signal Transduction; Stilbenes; Tumor Necrosis Factor-alpha

Resveratrol is a bioactive molecule used in dietary supplements and herbal medicines and consumed worldwide. Known cardioprotective and anti-inflammatory properties of resveratrol have spurred investigation of the mechanisms involved. The present study explored potential atheroprotective actions of resveratrol on cholesterol metabolism in cells of the arterial wall, including human macrophages and arterial endothelium. Using QRT-PCR and Western blotting techniques, we measured expression of the proteins involved in reverse cholesterol transport (ABCA1, ABCG1 and SR-B1) and the scavenger receptors responsible for uptake of modified cholesterol (CD36, SR-A1 and LOX-1). We analyzed the effect of resveratrol on apoA-1-and HDL-mediated cholesterol efflux in human THP-1 macrophages. The effect of resveratrol on oxLDL internalization and foam cell formation were evaluated using confocal and light microscopy. Our data indicate that resveratrol regulates expression of major proteins involved in cholesterol transport, promotes apoA-1 and HDL-mediated efflux, downregulates oxLDL uptake and diminishes foam cell formation. Mechanistically, resveratrol effects were dependent upon PPAR-γ and adenosine 2A receptor pathways. For the first time we demonstrate that resveratrol regulates expression of the cholesterol metabolizing enzyme cytochrome P450 27-hydroxylase, providing efficient cholesterol elimination via formation of oxysterols. This study establishes that resveratrol attenuates lipid accumulation in cultured human macrophages via effects on cholesterol transport. Further in vivo studies are needed to determine whether resveratrol may be an additional resource available to reduce lipid deposition and atherosclerosis in humans.

Topics: Adenosine; Animals; Apolipoprotein A-I; Atherosclerosis; Biological Transport; CD36 Antigens; Cell Line; Cholesterol; Endothelium; Foam Cells; Gene Expression Regulation; Humans; Lipoproteins, HDL; Lipoproteins, LDL; Macrophages; Monocytes; PPAR gamma; Receptors, Adenosine A2; Resveratrol; Stilbenes

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 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

Metabolic and cardiovascular diseases (CVDs) have risen to alarming proportions, and there is a need for therapeutic and preventive measures. The polyphenol resveratrol (RES) protects against CVDs, but in vivo molecular mechanisms responsible for protection are not yet understood. Peripheral blood mononuclear cells (PBMNCs) are involved in the development of atherosclerosis and metabolic disorders. The identification of PBMNCs genes responding to dietary compounds might help to understand the mechanisms underlying the effects of polyphenols. We determined gene expression differences between PBMNCs from pigs fed a high-fat diet manifesting a mild increase of cholesterol and pigs fed a high-fat diet containing low doses of RES. Although the consumption of RES did not modify the levels of cholesterol, microarray analyses indicated that some of the differentially expressed genes, collagens (COL1A, COL3A), lipoprotein lipase (LPL) and fatty-acid binding proteins (FABPs) involved in CVDs and lipid metabolism were up-regulated by the high-fat diet and down-regulated by RES. Reverse transcriptase polymerase chain reaction confirmed that RES and RES-containing grape extract prevented the induction of FABP4 in PBMNCs in female pigs fed a high-fat diet. Low micromolar concentrations of RES and its metabolite dihydroresveratrol exerted a minor but significant reducing effect on the induction of FABP4 expression in human macrophages treated with oxidized low-density lipoprotein. Our results show that the consumption of low doses of RES modulates the expression of genes related to lipid metabolism and metabolic disorders that are affected by a high-fat diet and suggest that some of the circulating RES metabolites may contribute to these effects.

Topics: Animals; Atherosclerosis; Cholesterol; Diet, High-Fat; Dietary Fats; Dose-Response Relationship, Drug; Down-Regulation; Fatty Acid-Binding Proteins; Female; Hypercholesterolemia; Leukocytes, Mononuclear; Lipid Metabolism; Lipoprotein Lipase; Lipoproteins, LDL; Male; Microarray Analysis; Resveratrol; Stilbenes; Swine; Transcriptome; Up-Regulation

Vascular endothelial cell (VEC) apoptosis is the main event occurring during the development of atherosclerosis. Pterostilbene (PT), a natural dimethylated analog of resveratrol, has been the subject of intense research in cancer and inflammation. However, the protective effects of PT against oxidized low-density lipoprotein (oxLDL)-induced apoptosis in VECs have not been clarified. We investigated the anti-apoptotic effects of PT in vitro and in vivo in mice. PT at 0.1-5 μM possessed antioxidant properties comparable to that of trolox in a cell-free system. Exposure of human umbilical vein VECs (HUVECs) to oxLDL (200 μg/ml) induced cell shrinkage, chromatin condensation, nuclear fragmentation, and cell apoptosis, but PT protected against such injuries. In addition, PT injection strongly decreased the number of TUNEL-positive cells in the endothelium of atherosclerotic plaque from apoE(-/-) mice. OxLDL increased reactive oxygen species (ROS) levels, NF-κB activation, p53 accumulation, apoptotic protein levels and caspases-9 and -3 activities and decreased mitochondrial membrane potential (MMP) and cytochrome c release in HUVECs. These alterations were attenuated by pretreatment with PT. PT inhibited the expression of lectin-like oxLDL receptor-1 (LOX-1) expression in vitro and in vivo. Cotreatment with PT and siRNA of LOX-1 synergistically reduced oxLDL-induced apoptosis in HUVECs. Overexpression of LOX-1 attenuated the protection by PT and suppressed the effects of PT on oxLDL-induced oxidative stress. PT may protect HUVECs against oxLDL-induced apoptosis by downregulating LOX-1-mediated activation through a pathway involving oxidative stress, p53, mitochondria, cytochrome c and caspase protease. PT might be a potential natural anti-apoptotic agent for the treatment of atherosclerosis.

Topics: Animals; Apoptosis; Atherosclerosis; Endothelial Cells; Humans; Lipoproteins, LDL; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protective Agents; Stilbenes

Resveratrol protects the cardiovascular system by a number of mechanisms, including antioxidant and anti-platelet activities.. To assess the potential anti-inflammatory and antiatherogenic effects of resveratrol using rabbits fed a hypercholesterolemic diet (1% cholesterol).. Twenty white male rabbits were selected and divided into two groups: control group (CG), 10 rabbits; and resveratrol group (RG), 10 rabbits. The animals were fed a hypercholesterolemic diet for 56 days. For the RG diet, resveratrol (2 mg/kg weight/day) was added from days 33-56.. There was no significant difference in the total serum cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides between the groups. Of the CG, 70% had advanced aortic atherosclerotic lesions (types III, IV, V, or VI). All animals from the RG had mild aortic atherosclerotic lesions (types I or II, or no lesions). The intima area and the intima/media layer area ratio was significantly lower in the RG as compared to the CG (p<0.001). Positive areas for VCAM-1 molecules were lower in the RG (p=0.007). The MCP-1 and IL-6 concentrations were lower in the RG than the CG (p=0.039 and p=0.015, respectively).. Resveratrol had significant anti-atherogenic and anti-inflammatory effects in an animal model with rabbits fed a hypercholesterolemic diet (1% cholesterol).

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Atherosclerosis; Cholesterol, Dietary; Disease Models, Animal; Drug Evaluation, Preclinical; Hypercholesterolemia; Male; Platelet Aggregation Inhibitors; Rabbits; Random Allocation; Resveratrol; Statistics, Nonparametric; Stilbenes

The combination of a lipid-lowering diet and scientifically proven nutraceutical supplements has the ability to significantly reduce low-density lipoprotein (LDL) cholesterol, increase LDL particle size, decrease LDL particle number, lower trigylcerides and very LDL levels, and increase total and high-density lipoprotein 2b cholesterol. In addition, inflammation, oxidative stress, and immune responses are decreased. In several prospective clinical trials, coronary heart disease and cardiovascular disease have been reduced with many nutraceutical supplements. This nutritional and nutraceutical supplement treatment is a valid alternative for patients who are intolerant to statins, cannot take other drugs for the treatment of dyslipidemia, or prefer alternative treatments. This new approach to lipid management to decrease vascular disease utilizes a functional medicine approach with a broader treatment program that will address the multitude of steps involved in lipid-induced vascular damage.

Topics: Atherosclerosis; Dietary Fats; Dietary Supplements; Dyslipidemias; Humans; Lipoproteins; Lipoproteins, VLDL; Oxidative Stress; Pantetheine; Resveratrol; Stilbenes; Tocotrienols; Triglycerides; Vascular Diseases; Vasodilator Agents

The presence of grape and wine polyphenol resveratrol (RES) in the diet is negligible. Therefore, the cardiovascular benefits of this molecule, in a dietary context, remain to be established. We aimed to investigate, through dietary intervention, the effects of a resveratrol-rich grape extract (GE-RES) on the prevention of early aortic lesions in pigs fed an atherogenic diet (AD). These effects were compared with those produced by a grape extract lacking RES (GE) or RES alone. Pigs fed the AD for 4 months showed early atherosclerotic lesions in the thoracic aorta: degeneration and fragmentation of elastic fibers, increase of intima thickness, subendothelial fibrosis, and accumulation of fatty cells and anion superoxide radicals. GE-RES was the most effective treatment and prevented the disruption of aortic elastic fibers, decreased their alteration (57%), and reduced the intima thickness (33%) and the accumulation of fatty cells (42%) and O(2)(•-) (38%) in aortic tissue. In addition, GE-RES moderately downregulated the expression of the suppressors of cytokine signaling 1 (SOCS1) and 3 (SOCS3), key regulators of vascular cell responses, in peripheral mononuclear blood cells. Our results suggest that the consumption of this GE-RES nutraceutical, in a dietary prevention context, could prevent early atherosclerotic events. The presence of RES in the grape extract strengthened these effects.

Topics: Animals; Aorta; Atherosclerosis; Diet, Atherogenic; Disease Models, Animal; Female; Humans; In Vitro Techniques; Male; Plant Extracts; Resveratrol; Stilbenes; Swine; Swine, Miniature; Vitis

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Atherosclerosis; Cholesterol, Dietary; Hypercholesterolemia; Male; Platelet Aggregation Inhibitors; Stilbenes

Mitochondrial DNA damage, increased production of reactive oxygen species and progressive respiratory chain dysfunction, together with increased deposition of cholesterol and cholesteryl esters, are hallmarks of atherosclerosis. This study investigated the role of mitochondrial function in regulation of macrophage cholesterol efflux to apolipoprotein A-I, by the addition of established pharmacological modulators of mitochondrial function.. Murine RAW 264.7 macrophages were treated with a range of concentrations of resveratrol, antimycin, dinitrophenol, nigericin and oligomycin, and changes in viability, cytotoxicity, membrane potential and ATP, compared with efflux of [3H]cholesterol to apolipoprotein (apo) A-I. The effect of oligomycin treatment on expression of genes implicated in macrophage cholesterol homeostasis were determined by quantitative polymerase chain reaction, and immunoblotting, relative to the housekeeping enzyme, Gapdh, and combined with studies of this molecule on cholesterol esterification, de novo lipid biosynthesis, and induction of apoptosis. Significant differences were determined using analysis of variance, and Dunnett's or Bonferroni post t-tests, as appropriate.. The positive control, resveratrol (24 h), significantly enhanced cholesterol efflux to apoA-I at concentrations ≥30 μM. By contrast, cholesterol efflux to apoA-I was significantly inhibited by nigericin (45%; p<0.01) and oligomycin (55%; p<0.01), under conditions (10 μM, 3 h) which did not induce cellular toxicity or deplete total cellular ATP content. Levels of ATP binding cassette transporter A1 (ABCA1) protein were repressed by oligomycin under optimal efflux conditions, despite paradoxical increases in Abca1 mRNA. Oligomycin treatment did not affect cholesterol biosynthesis, but significantly inhibited cholesterol esterification following exposure to acetylated LDL, and induced apoptosis at ≥30 μM. Finally, oligomycin induced the expression of genes implicated in both cholesterol efflux (Abca1, Abcg4, Stard1) and cholesterol biosynthesis (Hmgr, Mvk, Scap, Srebf2), indicating profound dysregulation of cholesterol homeostasis.. Acute loss of mitochondrial function, and in particular Δψm, reduces cholesterol efflux to apoA-I and dysregulates macrophage cholesterol homeostasis mechanisms. Bioavailable antioxidants, targeted to mitochondria and capable of sustaining effective mitochondrial function, may therefore prove effective in maintenance of arterial health.

Topics: Animals; Antimycin A; Apolipoproteins A; Atherosclerosis; Cell Line; Cell Survival; Cholesterol; Cholesterol Esters; DNA, Mitochondrial; Macrophages; Membrane Potential, Mitochondrial; Mice; Mitochondria; Nigericin; Oligomycins; Reactive Oxygen Species; Resveratrol; RNA, Messenger; Stilbenes

Chronic inflammation and proatherogenic lipids are important risk factors of cardiovascular disease (CVD). Specific dietary constituents such as polyphenols and fish oils may improve cardiovascular risk factors and may have a beneficial effect on disease outcomes. We hypothesized that the intake of an antiinflammatory dietary mixture (AIDM) containing resveratrol, lycopene, catechin, vitamins E and C, and fish oil would reduce inflammatory risk factors, proatherogenic lipids, and endpoint atherosclerosis. AIDM was evaluated in an inflammation model, male human C-reactive protein (CRP) transgenic mice, and an atherosclerosis model, female ApoE*3Leiden transgenic mice. Two groups of male human-CRP transgenic mice were fed AIDM [0.567% (wt:wt) powder and 0.933% (wt:wt oil)] or placebo for 6 wk. The effects of AIDM on basal and IL-1β-stimulated CRP expression were investigated. AIDM reduced cytokine-induced human CRP and fibrinogen expression in human-CRP transgenic mice. In the atherosclerosis study, 2 groups of female ApoE*3Leiden transgenic mice were fed an atherogenic diet supplemented with AIDM [0.567% (wt:wt) powder and 0.933% (wt:wt oil)] or placebo for 16 wk. AIDM strongly reduced plasma cholesterol, TG, and serum amyloid A concentrations compared with placebo. Importantly, long-term treatment of ApoE*3Leiden mice with AIDM markedly reduced the development of atherosclerosis by 96% compared with placebo. The effect on atherosclerosis was paralleled by a reduced expression of the vascular inflammation markers and adhesion molecules inter-cellular adhesion molecule-1 and E-selectin. Dietary supplementation of AIDM improves lipid and inflammatory risk factors of CVD and strongly reduces atherosclerotic lesion development in female transgenic mice.

Topics: Acute-Phase Proteins; Animals; Antioxidants; Apolipoprotein E3; Ascorbic Acid; Atherosclerosis; Biomarkers; C-Reactive Protein; Carotenoids; Catechin; Diet; Female; Fish Oils; Humans; Lycopene; Male; Mice; Mice, Transgenic; Resveratrol; Risk Factors; Stilbenes; Vitamin E

Resveratrol is a strong candidate for explaining an irreversible correlation between red wine consumption and coronary heart disease. The present study examined the effect of ε-viniferin, a dehydrodimer of resveratrol, on vascular smooth muscle cells (VSMCs), because ε-viniferin functions are poorly understood in spite of its comparable content to resveratrol in red wines and grapes. Both ε-viniferin and resveratrol inhibited platelet-derived growth factor-induced cell proliferation, migration, and reactive oxygen species (ROS) production, in addition to inducing nitric oxide generation. ε-Viniferin was more effective than resveratrol in these effects, except for inhibiting ROS production. The compounds also increased the expression of the antioxidant enzyme, hemeoxygenase-1, via transcription factor Nrf2. The phosphatidylinositol 3-kinase-Akt pathway was implicated in resveratrol-dependent nuclear Nrf2 accumulation, whereas extracellular signal-regulated kinase and p38 were involved in ε-viniferin-induced Nrf2 accumulation. These data suggest that ε-viniferin may function more effectively than resveratrol in different mechanisms and cooperatively with resveratrol in preventing atherosclerosis.

Topics: Animals; Atherosclerosis; Benzofurans; Cell Movement; Cell Proliferation; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Heme Oxygenase-1; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitric Oxide; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Resveratrol; Stilbenes; Wine

Accelerated atherosclerosis is a major diabetic complication initiated by the enhanced recruitment of monocytes into the vasculature. In this study, we examined the therapeutic potential of the phytonutrients ursolic acid (UA) and resveratrol (RES) in preventing monocyte recruitment and accelerated atherosclerosis.. Dietary supplementation with either RES or UA (0.2%) protected against accelerated atherosclerosis induced by streptozotocin in high-fat diet-fed LDL receptor-deficient mice. However, mice that received dietary UA for 11 weeks were significantly better protected and showed a 53% reduction in lesion formation while mice fed a RES-supplemented diet showed only a 31% reduction in lesion size. Importantly, UA was also significantly more effective in preventing the appearance of proinflammatory GR-1(high) monocytes induced by these diabetic conditions and reducing monocyte recruitment into MCP-1-loaded Matrigel plugs implanted into these diabetic mice. Oxidatively stressed THP-1 monocytes mimicked the behavior of blood monocytes in diabetic mice and showed enhanced responsiveness to monocyte chemoattractant protein-1 (MCP-1) without changing MCP-1 receptor (CCR2) surface expression. Pretreatment of THP-1 monocytes with RES or UA (0.3-10μM) for 15h resulted in the dose-dependent inhibition of H(2)O(2)-accelerated chemotaxis in response to MCP-1, but with an IC(50) of 0.4μM, UA was 2.7-fold more potent than RES.. Dietary UA is a potent inhibitor of monocyte dysfunction and accelerated atherosclerosis induced by diabetes. These studies identify ursolic acid as a potential therapeutic agent for the treatment of diabetic complications, including accelerated atherosclerosis, and provide a novel mechanism for the anti-atherogenic properties of ursolic acid.

Topics: Animals; Aortic Diseases; Atherosclerosis; Cardiovascular Agents; Cell Line; Chemokine CCL2; Chemotaxis, Leukocyte; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Dose-Response Relationship, Drug; Female; Humans; Hyperlipidemias; Kidney; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Oxidative Stress; Receptors, CCR2; Receptors, LDL; Resveratrol; Stilbenes; Time Factors; Triterpenes; Ursolic Acid

We undertook this study to investigate the roles of SIRT1 in high glucose-induced endothelial impairment and their association with diabetic atherosclerosis.. Otsuka Long-Evans Tokushima Fatty (OLETF) rats and nondiabetic rats of the same genetic background were included. Real-time PCR was used to detect SIRT1 mRNA expression in abdominal aorta at week 42. To further investigate the roles of SIRT1 on the function of endothelial cells in high glucose, human endothelial cells were treated with SIRT1 activator resveratrol for 24 h before being cultured in high glucose medium for 48 h.. Along with the early manifestation of atherosclerosis, SIRT1 mRNA level in OLETF group was significantly lower than that in control group (p <0.05). Compared with control cells, high glucose decreased nitric oxide (NO) secretion, but resveratrol treatment increased the expression of SIRT1 and the secretion of NO. After interfering with the expression of SIRT1 using SIRT1 siRNA, the effects of resveratrol on NO secretion were impaired. SIRT1 also counteracted the other pro-atherosclerotic effects of high glucose including the upregulating roles of high glucose on the expression of E-selectin mRNA and the downregulating roles of high glucose on the expression of endothelial nitric oxide synthase.. Decreased expression of SIRT1 in artery may be involved in the initiation and development of diabetic atherosclerosis. Increasing SIRT1 expression may hold great promise in the prevention and therapy of atherosclerosis in diabetic patients.

Topics: Atherosclerosis; Base Sequence; Cells, Cultured; Diabetic Angiopathies; DNA Primers; Endothelium, Vascular; Glucose; Humans; Nitric Oxide; Real-Time Polymerase Chain Reaction; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Sirtuin 1; Stilbenes

Arteriosclerotic vascular disease is a major cardiac health problem in westernized countries and the primary cause of mortality in diabetic patients. Recent data have raised serious safety concerns with the antidiabetic rosiglitazone, a thiazolidinedione with peroxisome proliferator-activated receptor γ (PPAR-γ) agonistic activity, in regard to cardiovascular risks. A common feature of atherosclerosis is vascular mineralization. The latter is formed by vascular smooth muscle cells (VSMC) through complex processes that are similar to mineralization in bone. The aim of the current study was to investigate the effect of rosiglitazone on mineralization in cultured human VSMCs. We found that rosiglitazone stimulated mineralization by, at least in part, induction of caspase-dependent apoptosis. Furthermore, rosiglitazone-induced oxidative stress was correlated with stimulated osteoblast-like differentiation of VSMCs. Treatment of rosiglitazone-supplemented VSMC cultures with the caloric restriction mimetic and antioxidant resveratrol diminished rosiglitazone-induced oxidative stress, osteoblast-like differentiation and mineralization. In conclusion, this study reveals novel insights into the relationship of rosiglitazone and cardiovascular events by providing a model that links rosiglitazone-induced osteoblast-like differentiation, oxidative stress and apoptosis with mineralization in VSMCs. In addition, we position resveratrol in this model acting to reduce rosiglitazone-induced oxidative stress, osteoblast-like VSMC differentiation and mineralization.

Topics: Apoptosis; Atherosclerosis; Caspases; Cell Differentiation; Cells, Cultured; Diabetes Mellitus; Humans; Hypoglycemic Agents; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oxidative Stress; Resveratrol; Rosiglitazone; Signal Transduction; Stilbenes; Thiazolidinediones; Up-Regulation

Sirtuins (SIRTs) are NAD(+)-dependent deacetylases that regulate metabolism and life span. We used peripheral blood mononuclear cells (PBMCs) to determine ex vivo whether insulin resistance/metabolic syndrome influences SIRTs. We also assessed the potential mechanisms linking metabolic alterations to SIRTs in human monocytes (THP-1) in vitro.. SIRT1-SIRT7 gene and protein expression was determined in PBMCs of 54 subjects (41 with normal glucose tolerance and 13 with metabolic syndrome). Insulin sensitivity was assessed by the minimal model analysis. Subclinical atherosclerosis was assessed by carotid intima-media thickness (IMT). In THP-1 cells exposed to high glucose or fatty acids in vitro, we explored SIRT1 expression, p53 acetylation, Jun NH(2)-terminal kinase (JNK) activation, NAD(+) levels, and nicotinamide phosphoribosyltransferase (NAMPT) expression. The effects of SIRT1 induction by resveratrol and of SIRT1 gene silencing were also assessed.. In vivo, insulin resistance and metabolic syndrome were associated with low PBMC SIRT1 gene and protein expression. SIRT1 gene expression was negatively correlated with carotid IMT. In THP-1 cells, high glucose and palmitate reduced SIRT1 and NAMPT expression and reduced the levels of intracellular NAD(+) through oxidative stress. No effect was observed in cells exposed to linoleate or insulin. High glucose and palmitate increased p53 acetylation and JNK phosphorylation; these effects were abolished in siRNA SIRT1-treated cells. Glucose- and palmitate-mediated effects on NAMPT and SIRT1 were prevented by resveratrol in vitro.. Insulin resistance and subclinical atherosclerosis are associated with SIRT1 downregulation in monocytes. Glucotoxicity and lypotoxicity play a relevant role in quenching SIRT1 expression.

Topics: Angiogenesis Inhibitors; Atherosclerosis; Carotid Arteries; Down-Regulation; Glucose; Glucose Tolerance Test; Humans; Insulin Resistance; Longevity; Metabolic Syndrome; Monocytes; Palmitic Acid; Reference Values; Resveratrol; Sirtuin 1; Stilbenes; Tunica Intima; Tunica Media

Advanced glycosylation end products (AGE) and its receptor (RAGE) axis is involved in the regulation of lipid homeostasis and is critical in the pathogenesis of diabetic atherosclerosis. We investigated the protective role of resveratrol against the AGE-induced impairment on macrophage lipid homeostasis. In THP-1-derived macrophages, RAGE was dose-dependently induced by AGE and played a key role in the AGE-induced cholesterol accumulation. Resveratrol markedly reduced RAGE expression via peroxisome proliferator-activated receptor (PPAR) gamma but not PPARalpha or AMP-activated protein kinase. Importantly, pretreatment with resveratrol significantly ameliorated AGE-induced up-regulation of scavenger receptor-A (SR-A) and down-regulation of ATP-binding cassette (ABC) A1 and ABCG1 and thus effectively prevented the cholesterol accumulation in macrophages as shown by cellular cholesterol analysis and oil red O staining. Moreover, blockade of PPARgamma abolished all these effects of resveratrol. Collectively, our results indicate that resveratrol prevents the impairment of AGE on macrophage lipid homeostasis partially by suppressing RAGE via PPARgamma activation, which might provide new insight into the protective role of resveratrol against diabetic atherosclerosis.

Topics: Adenylate Kinase; Animals; Antioxidants; Atherosclerosis; Cholesterol; Diabetes Complications; Diabetes Mellitus; Glycation End Products, Advanced; Homeostasis; Humans; Lipid Metabolism; Macrophages; PPAR gamma; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Resveratrol; Stilbenes

Smooth muscle cell (SMC) proliferation is a major feature in atherosclerosis, since it contributes to the formation of the fibrous cap, thus to plaque stability, but also to arterial stenosis and post-angioplasty restenosis. Among the various mitogenic signaling pathways involved in SMC proliferation, the mTOR pathway regulates both the cell cycle and cell growth. Resveratrol, a polyphenolic compound from grapes and red wine, has potential anti-atherogenic and anti-cancer properties. This work was designed to investigate the activation of the mTOR pathway by the proatherogenic oxidized LDL (oxLDL) in SMC, and the potential inhibitory effect of resveratrol.. mTOR and its downstream target p70S6 kinase are phosphorylated and activated by mitogenic concentrations of oxLDL (50 microg/ml), and are involved in SMC proliferation, as assessed by the inhibitory effect of the mTOR inhibitor rapamycin. The activation of mTOR signaling by oxLDL, requires the upstream activation of PI3K and Akt, as assessed by the inhibitory effect of the PI3K inhibitor Ly294002 on mTOR activation and DNA synthesis. Resveratrol blocked the oxLDL-induced phosphorylation and activation of the PI3K/Akt/mTOR/p70S6K pathway and strongly inhibited both the DNA synthesis and proliferation of SMC. This activity is independent of the anti-oxidant effect and of AMPK activation by resveratrol.. These data indicate that the mTOR pathway is activated by oxLDL via PI3K/PDK1/Akt, and is required for SMC proliferation. Resveratrol blocks specifically this pathway, thereby inhibiting oxLDL-induced SMC proliferation. These data highlight a new property for resveratrol that could contribute to the general anti-atherogenic properties of this polyphenol.

Topics: Angiogenesis Inhibitors; Animals; Antioxidants; Atherosclerosis; Cell Proliferation; Flavonoids; Humans; Lipoproteins, LDL; Myocytes, Smooth Muscle; Phenols; Phosphatidylinositol 3-Kinases; Polyphenols; Protein Kinases; Rabbits; Resveratrol; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Stilbenes; TOR Serine-Threonine Kinases

The beneficial action of moderate wine consumption is increasingly being attributed to resveratrol (trans-3,4',5-trihydroxystilbene). To test the safety of resveratrol use as a dietary supplement, 24 male Wistar rats were initially divided into three groups: (C, n=6) was given standard chow and water; (R, n=6) received standard chow and 6 mg/l resveratrol in its drinking water (1mg/kg/day), and (HFD, n=12) received high-fat diet and water. In order to more appropriately study the effects of resveratrol on high-fat diet, after 30 days of treatments, HFD-rats were divided into two subgroups (n=6/group):(HFD) remained receiving high-fat diet and water; (HFD-R) given high-fat diet and 6 mg/l resveratrol in its drinking water (1mg/kg/day). The total experimental period was 45 days. The resveratrol dose took into account its average concentration in wine, the time variability of wine ingestion, and so of resveratrol consumption in humans. HFD-rats had hyperglycaemia, dyslipidemia, increased serum oxidized-LDL (ox-LDL) and hepatic oxidative stress. Comparing HFD-R and HFD-rats, resveratrol improved lipid profile and glucose level, enhanced superoxide dismutase, thus reducing ox-LDL and hepatic oxidative stress. Resveratrol, in standard-fed-rats reduced glutathione-antioxidant defense system and enhanced hepatic lipid hydroperoxide. In conclusion, based on the results of this single dose preliminary study with resveratrol in the drinking water of male Wistar rats for 30 days, it may be concluded that resveratrol may have beneficial effects in high-fat diets (e.g. ox-LDL, decreased serum and hepatic oxidativestress), but not in standard-fed diets (effects produced include enhanced hepatic oxidative stress). Further studies are indicated.

Topics: Animals; Antioxidants; Atherosclerosis; Blood Glucose; Body Weight; Diet; Dietary Fats; Dietary Supplements; Glutathione; Lipid Peroxides; Lipids; Lipoproteins, LDL; Liver; Male; Organ Size; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Risk Factors; Stilbenes; Triglycerides; Wine

2,3,4',5-Tetrahydroxystilbene 2- O-beta- D-glucoside (TSG), an active component extracted from Polygonum multiflorum, has been found to have an anti-atherosclerotic effect. The aim of this study was to investigate whether the TSG could prevent the development of atherosclerosis through influencing endothelial function in atherogenic-diet rats and to explore the possible mechanisms. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, transmission electron microscopy of the aorta, and levels of nitrate/nitrite (NOx) in serum and aorta. Endothelial nitric oxide (NO) synthase (eNOS) and inducible NO synthase (iNOS) mRNA and protein expression were also measured. After 12 weeks treatment, TSG improved acetylcholine-induced endothelium-dependent relaxation, prevented intimal remodeling, inhibited the decreased NOx content in serum and aorta in atherogenic-diet rats. Furthermore, the observed decreased eNOS mRNA and protein expression and increased iNOS mRNA and protein expression in atherogenic-diet rats were attenuated by TSG treatment. These results suggest that TSG could restore vascular endothelial function, which may be related to its ability to prevent changes of eNOS and iNOS expression, leading to preservation of NO bioactivity.

Topics: Animals; Aorta; Atherosclerosis; Disease Models, Animal; Drugs, Chinese Herbal; Endothelium, Vascular; Glucosides; Male; Microscopy, Electron, Transmission; Nitrates; Nitric Oxide Synthase; Nitrites; Polygonum; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stilbenes

Atherosclerotic plaque formation results from a combination of local shear stress patterns and inflammatory processes. This study investigated the endothelial response to shear stress in combination with the inflammatory cytokine TNF-alpha in a simplified model of arterial bifurcation.. Human umbilical vein endothelial cells (ECs) were exposed to laminar or non-uniform shear stress in bifurcating flow-through slides, followed by stimulation with TNF-alpha. To study cell adhesion, ECs were perfused with medium containing THP-1 monocytic cells. Endothelial protein expression was determined by immunofluorescence.. Adhesion of monocytic cells to unstimulated ECs was nearly undetectable under laminar shear stress and was slightly increased under non-uniform shear stress. Exposure of ECs to non-uniform shear stress in combination with TNF-alpha induced a 12-fold increase in monocytic cell recruitment and a significant induction of endothelial E-selectin and VCAM-1 expression. Both these effects were prevented in ECs exposed to laminar shear stress. The significant differences in TNF-alpha-induced monocytic cell recruitment and adhesion molecule expression between laminar and non-uniform shear stress regions were abolished in the absence of shear stress preconditioning. Simvastatin (1 micromol/L) suppressed the non-uniform shear stress- and TNF-alpha-induced increase in monocytic cell adhesion by about 30% via inhibition of VCAM-1 expression. Resveratrol, the active component of red wine, inhibited the expression of both VCAM-1 and E-selectin, and reduced monocytic cell recruitment by 50% at 20 micromol/L.. Non-uniform shear stress induces endothelial susceptibility to circulating TNF-alpha and adhesion of monocytic cells. Interference with this process may inhibit inflammatory response in atherosclerosis-prone regions.

Topics: Anti-Inflammatory Agents; Atherosclerosis; Cell Adhesion; Cell Culture Techniques; Cells, Cultured; Computer Simulation; E-Selectin; Endothelial Cells; Fluorescent Antibody Technique; Humans; Models, Cardiovascular; Monocytes; NF-kappa B; Numerical Analysis, Computer-Assisted; Resveratrol; Simvastatin; Stilbenes; Stress, Mechanical; Stress, Physiological; Time Factors; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Resveratrol, a polyphenolic constituent of red wine, is known for its anti-atherogenic properties and is thought to be beneficial in reducing the incidence of cardiovascular diseases (CVD). However, the mechanism of action by which it exerts its anti-atherogenic effect remains unclear. In this study, we investigated the relationship between the antioxidant effects of resveratrol and its ability to promote cholesterol efflux. We measured the formation of conjugated dienes and the rate of lipid peroxidation, and observed that resveratrol inhibited copper- and irradiation-induced LDL and HDL oxidation as observed by a reduction in oxidation rate and an increase in the lag phase (p<0.05). We used DPPH screening to measure free radical scavenging activity and observed that resveratrol (0-50microM) significantly reduced the content of free radicals (p<0.001). Respect to its effect on cholesterol homeostasis, resveratrol also enhanced apoA-1-mediated cholesterol efflux (r(2)=0.907, p<0.05, linear regression) by up-regulating ABCA-1 receptors, and reduced cholesterol influx or uptake in J774 macrophages (r(2)=0.89, p<0.05, linear regression). Incubation of macrophages (J774, THP-1 and MPM) with Fe/ascorbate ion, attenuated apoA-1 and HDL(3)-mediated cholesterol efflux whereas resveratrol (0-25microM) significantly redressed this attenuation in a dose-dependent manner (p<0.001). Resveratrol thus appears to be a natural antioxidant that enhances cholesterol efflux. These properties make it a potential natural antioxidant that could be used to prevent and treat CVD.

Topics: Animals; Apolipoprotein A-I; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Biological Transport; Cell Line; Cholesterol; Dose-Response Relationship, Drug; Free Radical Scavengers; Humans; Kinetics; Linear Models; Lipid Peroxidation; Lipoproteins, HDL; Lipoproteins, LDL; Macrophages; Mice; Oxidation-Reduction; Resveratrol; Stilbenes

Vascular smooth muscle cell (SMC) migration is an important mechanism in atherogenesis and postangioplasty arterial remodeling. Previously, we demonstrated that the proinflammatory cytokine interleukin (IL)-18 is a potent inducer of SMC migration. Since extracellular matrix metalloproteinase inducer (EMMPRIN) stimulates ECM degradation and facilitates cell migration, we investigated whether IL-18 and EMMPRIN regulate each other's expression, whether their cross talk induces SMC migration, and whether the phytoalexin resveratrol inhibits IL-18-EMMPRIN signaling and SMC migration. Our studies demonstrate that 1) IL-18 induces EMMPRIN mRNA and protein expressions and stimulates EMMPRIN secretion from human aortic SMCs; 2) IL-18 stimulates EMMPRIN expression via oxidative stress and phosphatidylinositol 3-kinase (PI3K)-Akt-ERK signaling; 3) IL-18-stimulated SMC migration is significantly blunted by EMMPRIN knockdown, EMMPRIN function-blocking antibodies, or adenoviral transduction of mutant EMMPRIN; 4) conversely, EMMPRIN stimulates IL-18 expression and secretion via PI3K, Akt, and ERK; and 5) resveratrol attenuates IL-18- and EMMPRIN-mediated PI3K, Akt, and ERK activations; blunts IL-18-mediated oxidative stress; blocks IL-18-EMMPRIN cross-regulation; and inhibits SMC migration. Collectively, our results demonstrate that the coexpression and regulation of IL-18 and EMMPRIN in the vessel wall may amplify the inflammatory cascade and promote atherosclerosis and remodeling. Resveratrol, via its antioxidant and anti-inflammatory properties, has the potential to inhibit the progression of atherosclerosis by blocking IL-18 and EMMPRIN cross-regulation and SMC migration.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aorta; Atherosclerosis; Basigin; Cell Movement; Cells, Cultured; Cross-Linking Reagents; Extracellular Signal-Regulated MAP Kinases; Humans; Interleukin-18; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Resveratrol; RNA, Small Interfering; Signal Transduction; Stilbenes; Vasculitis

To observe the changes of MMP-2, 9 level on atherosclerosis in experimental rats by treatment of 2,3,4',5-tetrahydroxystilbene-2-0-beta-D glucoside (TSG) and to investigate the mechanism of TSG in stabilizing plaque and anti-atherosclerosis.. The atherosclerosis model of rat was made by feeding high grease food and injecting VitD3. Sixty male SD rats were randomly divided into six groups: control, Simvastatin, model and TSG 120 mg x kg(-1) x d(-1), TSG 60 mg x kg(-1) x d(-1) and TSG 30 mg x kg(-1) x d(-1). After 12 weeks, several aorta were randomly tested, model and TSG 120 mg x kg(-1) x d(-1), TSG 60 mg kg(-1) x d(-1) and TSG 30 mg x kg(-1) x d(-1). After 12 weeks, several aorta were randomly tested, model made was successful when we found plaque. And after six weeks treating, the mRNA expressions of MMP-2 and MMP-9 were measured by RT-PCR. The activities of MMP-2 and MMP-9 were measured by Western blot. The levels of CRP, IL-6 and TNF-alpha in serum were measured in biochemical method.. Data of the study demonstrated that the level of TNF-alpha, IL-6, CRP, MMP-2 and MMP-9 were remarkably decreased by TSG60, 120 mg x kg(-1) x d(-1) groups, which showed a dose-dependent effect.. TSG has the effect of anti-atherogenic and stabilizing plaque on the experimental rats with atherosclerosis, which are induced by the high cholesterol feeding and VitD3 injecting. The effect of TSG seems to be closely involved in regulating the expressions of MMP-2 and MMP-9, and inhibiting inflammation.

Topics: Animals; Atherosclerosis; C-Reactive Protein; Glucosides; Interferon-alpha; Interleukin-6; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Polygonum; Rats; Rats, Sprague-Dawley; RNA, Messenger; Stilbenes

Atherosclerosis is a chronic inflammatory disease of the arteries resulting from interactions between lipids, monocytes, and arterial wall cells. The effects of resveratrol supplements (RV, 0.02% and 0.06% each, w/w) with regard to the modulation of lipid profiles, cholesterol synthesis, and anti-atherogenesis were examined in apo E-deficient (apo E(-/-)) mice fed a normal diet. The concentration of total-cholesterol (total-C) and LDL-cholesterol (LDL-C) in plasma was significantly lower in the resveratrol-supplemented groups compare to the control group over the entire experimental period. The plasma HDL-C concentration was significantly elevated, and the ratio of HDL-C/total-C was significantly higher in the CF and RV groups than in the control group. Plasma paraoxonase (PON) activity was significantly higher in the 0.06% resveratrol group. The hepatic HMG-CoA reductase (HMGR) activity was significantly lower in the clofibrate and resveratrol groups than in the control group. Resveratrol supplements attenuated the presence of atherosclerotic lesions and periarterial fat deposition in the apo E(-/-) mice. The presence of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in atherosclerotic vessels was diminished in the resveratrol-supplemented apo E(-/-) mice. These results provide new insight into the anti-atherogenic and hypocholesterolemic properties of resveratrol in apo E(-/-) mice that were fed a normal diet.

Topics: Acetyl-CoA C-Acetyltransferase; Animals; Antioxidants; Aorta; Apolipoproteins E; Aryldialkylphosphatase; Atherosclerosis; Cholesterol; Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; Lipid Peroxidation; Liver; Male; Mice; Mice, Mutant Strains; Resveratrol; Stilbenes; Thiobarbituric Acid Reactive Substances

To investigate the effects of TSG on the content of nitric oxide synthase and the expression of endothelium nitric oxide synthase in artery vessels of experimental atherosclerotic rats.. The atherosclerosis model of rat was made by feeding high grease food and injecting Vit D3. Sixty male rats were randomly divided into six groups: normal control; model control; TSG high dose; TSG middle dose; TSG low dose; Simvastatin. After 12 weeks, several aorta were randomly tested, and the model made was successful when we found plaque. And after six weeks of treatment, the levels of NOS in serum were measured with a biochemical method. The biochemical method was adopted to detect the content of nitric oxide synthase and half-quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to detect eNOS and iNOS gene expression in artery vessels.. Data of the study demonstrated that compared with model group, the activity of NOS and the gene expression of eNOS were increased remarkably, and however the gene expression of iNOS was reduced markedly in simvastatin group and TSG 60, 120 mg x kg(-1) x d(-1) group.. TSG can enhance the expression of eNOS gene and reduce the expression of iNOS gene in aorta vessels of experimental atherosclerotic rats, which may be one of the anti-atherosclerosis mechanisms of TSG.

Topics: Animals; Arteries; Atherosclerosis; Gene Expression Regulation, Enzymologic; Glucosides; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rats; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes

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

Oxidation of LDL is hypothesised as an early and critical event in atherogenesis. Oxidised LDL (oxLDL) favour the transformation of macrophages into foam cells, an important cell involved in atherosclerosis. Furthermore, oxLDL cause multiple changes in macrophage functions. Thus, oxLDL induces certain genes, suppresses others and alters cell lipid metabolism. Consumption of a Mediterranean diet is associated with a low incidence of atherosclerotic disease, but data about the specific dietary constituents involved and mechanisms conferring cardioprotection are still sparse. The aim of the present study was to determine the effect of representative minor components of wine and olive oil on reactive oxygen species and eicosanoid synthesis induced by oxLDL-stimulated macrophages. We observed that exposure to non-toxic oxLDL concentrations leads to the production of H2O2 by RAW 264.7 macrophages and this effect was reverted by apocynin, a NADPH oxidase inhibitor. Moreover, oxLDL induced arachidonic acid (AA) release, cyclo-oxygenase-2 overexpression and subsequent PGE2 release. We observed that resveratrol and tyrosol revert H2O2 production induced by oxLDL as well as AA release and PGE2 synthesis and that these effects were not as a consequence of these compounds interfering with the oxLDL binding to their receptors. Interestingly, beta-sitosterol presence enhances these polyphenol actions. Thus, we found a synergistic action of polyphenols of olive oil and wine and beta-sitosterol of olive oil led to the modulation of the effects of oxLDL on oxidative stress and PGE2 synthesis.

Topics: Animals; Antioxidants; Arachidonic Acid; Atherosclerosis; Cells, Cultured; Dinoprostone; Hydrogen Peroxide; Lipid Metabolism; Lipoproteins, LDL; Macrophages; Mice; Olive Oil; Oxidative Stress; Phenylethyl Alcohol; Plant Oils; Protein Binding; Resveratrol; Sitosterols; Stilbenes; Wine

A strong negative correlation between polyphenols consumption and coronary heart disease has been extensively documented. These results prompted investigations on the mechanisms responsible for polyphenols effects in cardiovascular disease. The aim of this work was to investigate in apoE KO mice the effect of P183/1 (a mixture of cathechin, caffeic acid and resveratrol) on atherosclerosis and gene expression patterns in the vascular wall. ApoE KO mice were fed a diet supplemented with P183/1, 40 and 160 mg/kg body weight/day for 8 weeks. The supplementation with the high dose of P183/1 significantly reduced the presence of atherosclerotic plaque by 40 and 36% in the aortic sinus and in the ascending aorta, respectively. This reduction was associated with a reduced expression of markers for macrophages, lymphocytes (both Th1 and Th2) and of MCP-1, MIP-1alpha, MIP-1beta, CCR1, CCR2 and ET1 in the vascular wall. In conclusion, P183/1 supplementation significantly decreases atherosclerosis in ApoE KO mice by affecting inflammatory cells recruitment and expression of pro-inflammatory chemokines in the vascular wall.

Topics: Animals; Anti-Inflammatory Agents; Aorta; Apolipoproteins E; Atherosclerosis; Caffeic Acids; Cardiovascular Agents; Catechin; Cytokines; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Gene Expression; Mice; Mice, Knockout; Receptors, Chemokine; RNA, Messenger; Stilbenes

Because polyphenols may have beneficial effects on dyslipidemia, which accelerates atherosclerosis in diabetes, we examined the effect of polyphenols on hepatocellular AMP-activated protein kinase (AMPK) activity and lipid levels, as well as hyperlipidemia and atherogenesis in type 1 diabetic LDL receptor-deficient mice (DMLDLR(-/-)). In HepG2 hepatocytes, polyphenols, including resveratrol (a major polyphenol in red wine), apigenin, and S17834 (a synthetic polyphenol), increased phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase (ACC), and they increased activity of AMPK with 200 times the potency of metformin. The polyphenols also prevented the lipid accumulation that occurred in HepG2 cells exposed to high glucose, and their ability to do so was mimicked and abrogated, respectively, by overexpression of constitutively active and dominant-negative AMPK mutants. Furthermore, treatment of DMLDLR(-/-) mice with S17834 prevented the decrease in AMPK and ACC phosphorylation and the lipid accumulation in the liver, and it also inhibited hyperlipidemia and the acceleration of aortic lesion development. These studies 1) reveal that inactivation of hepatic AMPK is a key event in the pathogenesis of hyperlipidemia in diabetes, 2) point to a novel mechanism of action of polyphenols to lower lipids by activating AMPK, and 3) emphasize a new therapeutic avenue to benefit hyperlipidemia and atherosclerosis specifically in diabetes via activating AMPK.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Apigenin; Atherosclerosis; Benzopyrans; Carcinoma, Hepatocellular; Cell Line, Tumor; Diabetes Mellitus, Experimental; Enzyme Activation; Flavonoids; Glucose; Humans; Hypolipidemic Agents; Lipid Metabolism; Lipids; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Multienzyme Complexes; Phenols; Phosphorylation; Polyphenols; Protein Serine-Threonine Kinases; Receptors, LDL; Resveratrol; Stilbenes

Moderate consumption of red wine is associated with a reduced risk of coronary heart disease (CHD). This phenomenon is based on data from epidemiological observations known as the French paradox, and has been attributed to CHD-protective phytochemicals, e.g. resveratrol in red wine. Since red wine also contains alcohol, it is conceivable that alcohol interacts with resveratrol to elicit the observed cardioprotective effects. To determine whether resveratrol has alcohol-independent affects, we compared cardioprotective properties of dealcoholized Chinese red wine with alcohol-containing Chinese red wine having comparable amounts of resveratrol, using a hypercholesterolemic rabbit model and resveratrol as a reference. Animals fed a high cholesterol (1.5%) diet were simultaneously given water containing resveratrol (3 mg/kg/day) or red wine (4 ml/kg/day) containing 3.98 mg/l and 3.23 mg/l resveratrol for regular and dealcoholized red wine, respectively, for a 12-week duration. Total, HDL- and LDL-cholesterol and triglyceride levels in the plasma were measured before and after the cholesterol challenge. Atherosclerotic plaques in the thoracic aorta were evaluated using histochemical methods. Vascular and endothelial functions in the femoral artery were also assessed by ultrasonographic image analysis. High cholesterol-fed animals showed a significant increase in plasma levels of total, HDL- and LDL-cholesterol, but not triglycerides, compared to those fed a regular diet. Dietary cholesterol-elicited lipid changes were similarly observed in animals concurrently fed dealcoholized red wine, red wine or resveratrol. In contrast, whereas atherosclerotic lesions were clearly evident in specimens prepared from the thoracic aorta of high cholesterol-fed animals, the size, density, and mean area of atherosclerotic plaques, and thickness of the intima layer were significantly reduced in rabbits given dealcoholized red wine, red wine, or resveratrol. These results were in agreement with data obtained by an ultrasound analysis of endothelial function, which showed a 25% reduction in flow-mediated dilation (FMD) in rabbits fed a high cholesterol diet compared to animals on control diet. This decrease was effectively prevented by the simultaneous exposure to dealcoholized red wine, red wine, or resveratrol. Our study shows that animals given dealcoholized red wine exhibited cardio-active effects comparable to those of animals orally administered resveratrol, and suggests t

Topics: Analysis of Variance; Animals; Aorta, Thoracic; Atherosclerosis; Body Weight; Cholesterol, Dietary; Dose-Response Relationship, Drug; Ethanol; Femoral Artery; Hypercholesterolemia; Lipids; Male; Rabbits; Resveratrol; Stilbenes; Vasodilation; Vasodilator Agents; Wine

Polygonum multiflorum stilbeneglycoside (PMS) is a water-soluble fraction of Polygonum multiflorum Thunb., one of the most famous tonic traditional Chinese medicines, that has protective effects on the cardiovascular system. The purpose of the present study is to elucidate the effects of PMS on macrophage-derived foam cell functions and the reduction of severity of atherosclerosis in hypercholesterolemic New Zealand White (NZW) rabbits. NZW rabbits were fed for 12 weeks with a normal diet, a high cholesterol diet, or a high cholesterol diet associated with irrigation with different doses of PMS (25, 50, or 100 mg/kg). Treatment of NZW rabbits fed with high cholesterol diet with 100 mg/kg PMS attenuated the increase in plasma cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and plasma triglyceride. Treatment with 50 and 100 mg/kg PMS caused 43% and 60% decrease in atherosclerotic lesioned area ratio to total surface area, respectively. In U937 foam cells, PMS could decrease the high expression of intercellular adhesion molecule (ICAM)-1 protein and the vascular endothelial growth factor (VEGF) protein levels in the medium induced by oxidized lipoprotein when analyzed by flow cytometry. The results proved that PMS is a powerful agent against atherosclerosis and that PMS action could possibly be through the inhibition of the expression of ICAM-1 and VEGF in foam cells.

Topics: Animals; Atherosclerosis; Cholesterol; Cholesterol, Dietary; Foam Cells; Glucosides; Humans; Intercellular Adhesion Molecule-1; Male; Medicine, Chinese Traditional; Polygonum; Rabbits; Stilbenes; Triglycerides; U937 Cells; Vascular Endothelial Growth Factor A

Topics: Animals; Arteriosclerosis; Atherosclerosis; Chickens; Cholesterol; Diet; Humans; Stilbenes