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Resveratrol Alleviates Endotoxin-Induced Myocardial Toxicity via the Nrf2 Transcription Factor  [PDF]
Enkui Hao, Fangfang Lang, Yong Chen, Huilin Zhang, Xiao Cong, Xiaoqian Shen, Guohai Su
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069452
Abstract: Background/Aims Septic cardiomyopathy is a severe condition that remains a challenge for clinical management. This study investigated whether the natural polyphenolic compound resveratrol could be used as a prophylactic treatment to alleviate sepsis-related myocardial injury; the underlying molecular mechanisms were deciphered by both in vitro and in vivo experiments. Methods A mouse model of endotoxin-induced cardiomyopathy was developed by intraperitoneal injection of LPS, and resveratrol was administered prophylatically to the animals. Serum LDH and CK activities were measured to detect myocardial injury, and echocardiography was performed to monitor cardiac structure and function. Various cytokines/chemokines and the Nrf2 antioxidant defense system were examined in the heart tissue. The effects of resveratrol on LPS-induced Nrf2 activation, ROS generation, and apoptotic cell death were further investigated in cultured primary human cardiomyocytes. An Nrf2 specific siRNA was used to define its role in resveratrol-mediated cardiomyocyte protective effect. Results Resveratrol pretreatment significantly attenuated LPS-induced myocardial injury in mice, which was associated with suppressed proinflammatory cytokine production and enhanced Nrf2 activation in the heart. In cultured primary human cardiomyocytes, resveratrol activated Nrf2, inhibited LPS-induced ROS generation, and effectively protected the cells from LPS-induced apoptotic cell death. Knockdown of Nrf2 abrogated resveratrol-mediated protection of the cells from LPS-induced cell death. Conclusion Resveratrol effectively alleviates endotoxin-induced cardiac toxicity through mechanisms that involve the Nrf2 antioxidant defense pathway. Our data suggest that resveratrol might be developed as a useful prophylactic management for septic cardiomyopathy.
Renal Protective Effects of Resveratrol  [PDF]
Munehiro Kitada,Daisuke Koya
Oxidative Medicine and Cellular Longevity , 2013, DOI: 10.1155/2013/568093
Abstract: Resveratrol (3,5,4′-trihydroxystilbene), a natural polyphenolic compound found in grapes and red wine, is reported to have beneficial effects on cardiovascular diseases, including renal diseases. These beneficial effects are thought to be due to this compound’s antioxidative properties: resveratrol is known to be a robust scavenger of reactive oxygen species (ROS). In addition to scavenging ROS, resveratrol may have numerous protective effects against age-related disorders, including renal diseases, through the activation of SIRT1. SIRT1, an NAD+-dependent deacetylase, was identified as one of the molecules through which calorie restriction extends the lifespan or delays age-related diseases, and this protein may regulate multiple cellular functions, including apoptosis, mitochondrial biogenesis, inflammation, glucose/lipid metabolism, autophagy, and adaptations to cellular stress, through the deacetylation of target proteins. Previous reports have shown that resveratrol can ameliorate several types of renal injury, such as diabetic nephropathy, drug-induced injury, aldosterone-induced injury, ischemia-reperfusion injury, sepsis-related injury, and unilateral ureteral obstruction, in animal models through its antioxidant effect or SIRT1 activation. Therefore, resveratrol may be a useful supplemental treatment for preventing renal injury. 1. Introduction Chronic kidney disease (CKD), which is characterized by a chronic reduction in the glomerular filtration rate (GFR) and the presence of proteinuria or albuminuria, is recognized as an independent risk factor for both end-stage renal disease (ESRD) and cardiovascular disease, leading to a decrease in quality of life and an increased risk of mortality [1]. Acute kidney injury (AKI) is common in the setting of critical illness and is associated with a high risk of death [2]. In addition, AKI can directly cause ESRD and can increase the risks of the development of incident CKD and the worsening of underlying CKD [3]. Therefore, additional treatment to prevent both chronic and acute kidney injury is necessary. Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenolic phytoalexin that occurs naturally in many plant parts and products, such as grapes, berries, red wine, and peanut skins [4], and has numerous beneficial health effects. Previous epidemiological studies have revealed an inverse correlation between red wine consumption and the incidence of cardiovascular disease, a phenomenon known as the “French Paradox.” The French population has relatively low rates of cardiovascular disease despite
Resveratrol Improves Survival, Hemodynamics and Energetics in a Rat Model of Hypertension Leading to Heart Failure  [PDF]
Stéphanie Rimbaud, Matthieu Ruiz, Jér?me Piquereau, Philippe Mateo, Dominique Fortin, Vladimir Veksler, Anne Garnier, Renée Ventura-Clapier
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026391
Abstract: Heart failure (HF) is characterized by contractile dysfunction associated with altered energy metabolism. This study was aimed at determining whether resveratrol, a polyphenol known to activate energy metabolism, could be beneficial as a metabolic therapy of HF. Survival, ventricular and vascular function as well as cardiac and skeletal muscle energy metabolism were assessed in a hypertensive model of HF, the Dahl salt-sensitive rat fed with a high-salt diet (HS-NT). Resveratrol (18 mg/kg/day; HS-RSV) was given for 8 weeks after hypertension and cardiac hypertrophy were established (which occurred 3 weeks after salt addition). Resveratrol treatment improved survival (64% in HS-RSV versus 15% in HS-NT, p<0.001), and prevented the 25% reduction in body weight in HS-NT (P<0.001). Moreover, RSV counteracted the development of cardiac dysfunction (fractional shortening ?34% in HS-NT) as evaluated by echocardiography, which occurred without regression of hypertension or hypertrophy. Moreover, aortic endothelial dysfunction present in HS-NT was prevented in resveratrol-treated rats. Resveratrol treatment tended to preserve mitochondrial mass and biogenesis and completely protected mitochondrial fatty acid oxidation and PPARα (peroxisome proliferator-activated receptor α) expression. We conclude that resveratrol treatment exerts beneficial protective effects on survival, endothelium–dependent smooth muscle relaxation and cardiac contractile and mitochondrial function, suggesting that resveratrol or metabolic activators could be a relevant therapy in hypertension-induced HF.
Changes of protein expression profile in vascular tissues of spontaneously hypertensive rats treated by a compound Chinese herbal medicine  [cached]
Rong Fan,Guang-wei Zhong
Zhong Xi Yi Jie He Xue Bao , 2011,
Abstract: Objective: To investigate the effects of a Chinese herbal formula for calming liver and suppressing yang on the protein expressions of vascular tissues in spontaneously hypertensive rats (SHRs), and to explore the mechanism of efficacy. Methods: Twenty SHRs were randomly divided into model group and treatment group. Another 10 Wistar-Kyoto rats were selected as a normal control. SHRs in the treatment group were administered with the formula for calming liver and suppressing Yang for 4 weeks. During the course of treatment, blood pressure and heart rates were monitored every week and the ethology of rats, including irritability and rotation endurance was also evaluated. After treatment, thoracic aorta was obtained and its proteins were separated by 2-dimensional gel electrophoresis (2-DE). The differentially expressed proteins were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and database query.Results: The formula for calming liver and suppressing yang not only decreased the systolic blood pressure and heart rate, but also improved irritability degree and rotation endurance time of SHRs. This experiment had established the 2-DE graph of protein expressions of vascular tissues in SHRs. Compared with the normal group, the expressions of 15 proteins were down-regulated, and 12 proteins were up-regulated in vascular tissues of the model group. The formula for calming liver and suppressing yang treatment up-regulated expressions of 10 proteins in the 15 down-regulated proteins, and down-regulated 8 proteins in the 12 up-regulated proteins in vascular tissues of SHRs. After analysis, 16 obviously differentially expressed proteins were found, and 13 of them were identified.Conclusion: The formula for calming liver and suppressing yang can improve the ethology of SHRs. The mechanism is probably concerned with regulating the protein expressions of vascular tissues.
Resveratrol Treatment Reduces Cardiac Progenitor Cell Dysfunction and Prevents Morpho-Functional Ventricular Remodeling in Type-1 Diabetic Rats  [PDF]
Francesca Delucchi, Roberta Berni, Caterina Frati, Stefano Cavalli, Gallia Graiani, Roberto Sala, Christine Chaponnier, Giulio Gabbiani, Luca Calani, Daniele Del Rio, Leonardo Bocchi, Costanza Lagrasta, Federico Quaini, Donatella Stilli
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039836
Abstract: Emerging evidence suggests that both adult cardiac cell and the cardiac stem/progenitor cell (CSPC) compartments are involved in the patho-physiology of diabetic cardiomyopathy (DCM). We evaluated whether early administration of Resveratrol, a natural antioxidant polyphenolic compound, in addition to improving cardiomyocyte function, exerts a protective role on (i) the progenitor cell pool, and (ii) the myocardial environment and its impact on CSPCs, positively interfering with the onset of DCM phenotype. Adult Wistar rats (n = 128) with streptozotocin-induced type-1 diabetes were either untreated (D group; n = 54) or subjected to administration of trans-Resveratrol (i.p. injection: 2.5 mg/Kg/day; DR group; n = 64). Twenty-five rats constituted the control group (C). After 1, 3 or 8 weeks of hyperglycemia, we evaluated cardiac hemodynamic performance, and cardiomyocyte contractile properties and intracellular calcium dynamics. Myocardial remodeling and tissue inflammation were also assessed by morphometry, immunohistochemistry and immunoblotting. Eventually, the impact of the diabetic “milieu” on CSPC turnover was analyzed in co-cultures of healthy CSPCs and cardiomyocytes isolated from D and DR diabetic hearts. In untreated animals, cardiac function was maintained during the first 3 weeks of hyperglycemia, although a definite ventricular remodeling was already present, mainly characterized by a marked loss of CSPCs and adult cardiac cells. Relevant signs of ventricular dysfunction appeared after 8 weeks of diabetes, and included: 1) a significant reduction in ±dP/dt in comparison with C group, 2) a prolongation of isovolumic contraction/relaxation times, 3) an impaired contraction of isolated cardiomyocytes associated with altered intracellular calcium dynamics. Resveratrol administration reduced atrial CSPC loss, succeeded in preserving the functional abilities of CSPCs and mature cardiac cells, improved cardiac environment by reducing inflammatory state and decreased unfavorable ventricular remodeling of the diabetic heart, leading to a marked recovery of ventricular function. These findings indicate that RSV can constitute an adjuvant therapeutic option in DCM prevention.
Calcium Channel Blockers, More than Diuretics, Enhance Vascular Protective Effects of Angiotensin Receptor Blockers in Salt-Loaded Hypertensive Rats  [PDF]
Eiichiro Yamamoto, Keiichiro Kataoka, Yi-Fei Dong, Nobutaka Koibuchi, Kensuke Toyama, Daisuke Sueta, Tetsuji Katayama, Osamu Yasuda, Hisao Ogawa, Shokei Kim-Mitsuyama
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039162
Abstract: The combination therapy of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB) or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 6 groups, and they were orally administered (1) vehicle, (2) olmesartan, an ARB, (3) azelnidipine, a CCB, (4) hydrochlorothiazide, a diuretic, (5) olmesartan combined with azelnidipine, or (6) olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS) pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB.
Protective Effects of Resveratrol against Chronic Immobilization Stress on Testis  [PDF]
Gulsah Bitgul,Isil Tekmen,Didem Keles,Gulgun Oktay
ISRN Urology , 2013, DOI: 10.1155/2013/278720
Abstract: Objective. The aim of this study was to investigate protective effects of resveratrol, a strong antioxidant, against possible negative effects of chronic immobilization stress on testes of male rats histochemically, immunohistochemically, ultrastructurally, and biochemically. Material and Methods. Male Wistar rats were divided into 4 groups ( ). Group I, control group (C), was not exposed to stress. Group II, stress group (S), was exposed to chronic immobilization stress. In Group III, low dose resveratrol + stress group (LRS), rats were given 10?mg/kg/day resveratrol just before the stress application. In Group IV, high dose resveratrol + stress group (HRS), rats were given 20?mg/kg/day resveratrol just before the stress application. For chronic immobilization stress application animals were put in the plastic tubes (6?cm in diameter, 15?cm in length) during 32 days for 6 hours. All animals were sacrificed 18 hours after the last stress application. Results. Histochemical and ultrastructural investigations showed that in stress group there was germ cell deprivation in seminiferous tubules and increase of connective tissue on interstitial area. No significant changes were seen in low and high dose resveratrol groups. After immunohistochemical investigations, TUNEL (+) and Active Caspase-3 (+) cells were increased in seminiferous tubules of stress group compared with those control group, but they were decreased in low and high dose resveratrol groups. According to biochemically results, MDA, GSH, and testosterone levels in stress group showed no significant difference when compared with those of the other groups. Conclusion. The chronic immobilization stress increases oxidative stress and apoptosis and causes histological tissue damages; resveratrol can minimize the histological damage in testes significantly. 1. Introduction In this modern world, stress is an unavoidable phenomenon. Stressful situations can lead to many physiological and psychological alterations [1]. Adverse effects of stress on male reproductive system have already been described. Stauber showed how occupational stress in man could affect sperm concentration, motility, and morphology, with these effects being reverted after removal of the stress factor [2]. Apoptotic germ cell death is an important mechanism in testicular development [3] and elimination of germ cells under normal physiological and pathological conditions [4, 5]. It has been show that testicular germ cell apoptosis increases in experimental cryptorchidism [6], local heat stress [7], immobilisation stress [8–13],
Protective Effects of Resveratrol in Experimental Retinal Detachment  [PDF]
Wei Huang, Guorong Li, Jianming Qiu, Pedro Gonzalez, Pratap Challa
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075735
Abstract: Background Oxidative stress is one of the major factors that trigger photoreceptor apoptosis. To investigate whether resveratrol, a potent antioxidant and small molecule activator of the FoxO pathway, would be neuroprotective against photoreceptor cell death in a rodent model of retinal detachment. Methods Retinal detachment was created in adult Brown Norway rats by subretinal injection of sodium hyaluronate. The animals were treated daily with vehicle or resveratrol (20mg/kg) intraperitoneal injection. Photoreceptor death was assessed by counting the number of apoptotic cells with TdT-dUTP terminal nick-end labeling (TUNEL) and measurement of the outer nuclear layer (ONL) thickness 3 days after RD. Changes in expression of FoxO1a, FoxO3a, and FoxO4 were analyzed by western blot. The activity of caspase 3, caspase 8, caspase 9, spectrin and their cleavage forms were studied. Results Three days after retinal detachment, caspase 3, caspase 8 and caspase 9 were significantly activated in the detached retina. Spectrin cleavage products at 120 and 145 kDa were also detected. Both caspase and calpain activation are involved in apoptotic photoreceptor cell death in detached retinas. Treatment with resveratrol increases FoxO1a, FoxO3a, and FoxO4 protein expression in detached retinas only. Resveratrol treatment decreases activation of intrinsic and extrinsic caspase apoptotic pathways triggered by RD. The number of TUNEL-positive cells decreases from 1301±51 cells/mm2 in control groups to 430±35 cells/mm2 in treatment groups (p<0.05). Resveratrol treatment also demonstrates 59% less ONL thickness loss compared to controls. Conclusions Resveratrol treatment up-regulates the FoxO family and blocks Caspase3, 8, and 9 activation. Resveratrol has the potential to be used as a novel therapeutic agent for preventing vision loss in diseases characterized by photoreceptor detachment.
Resveratrol and its biological actions  [cached]
Shah Praharsh,Patel Jagruti
International Journal of Green Pharmacy , 2010,
Abstract: Resveratrol is a phytoalexin that is found in a few edible food materials such as grape skins, pea-nuts and red wine. Numerous reports exists in the literature suggesting that dietary resveratrol may act as an antioxidant, promotes nitric oxide production, inhibits platelet aggregation and increases high-density lipoprotein cholesterol, and subsequently may serve as a cardio-protective agent. Recent reports demonstrated that resveratrol can function as a cancer chemopreventive agent, exhibiting anti-inflammatory, neuroprotective, anti-ageing and antiviral properties. However, most of these effects are yet to be confirmed in humans. In the only clinical trial, high doses of special proprietary formulation has demonstrated blood sugar-lowering effects of resveratrol in type 2 diabetes mellitus. As with many polyphenols, resveratrol is reasonably well absorbed but has low bioavailability. It is metabolized by hydroxylation, glucuronidation, sulfation and hydrogenation. We reviewed the published literature and reports to consolidate information available on the biological activity of resveratrol using electronic databases as well as handpicked articles to summarize the biological effects of resveratrol and its clinical benefits against human diseases.
Different Effects of Resveratrol on Dose-Related Doxorubicin-Induced Heart and Liver Toxicity
Jaroslaw Dudka,Renata Gieroba,Agnieszka Korga,Franciszek Burdan,Wlodzimierz Matysiak,Barbara Jodlowska-Jedrych,Slawomir Mandziuk,Elzbieta Korobowicz,Marek Murias
Evidence-Based Complementary and Alternative Medicine , 2012, DOI: 10.1155/2012/606183
Abstract: The aim of the study was to evaluate the effect of resveratrol in doxorubicin-induced cardiac and hepatic toxicity. Doxorubicin was administered once a week throughout the period of 7 weeks with 1.0 or 2.0 mg/kg body weight or concomitantly with resveratrol (20 mg/kg of feed). Heart and liver toxicity was histologically and biochemically evaluated. Resveratrol protected from the heart lipid peroxidation caused by 1 mg doxorubicin and it sharply diminished superoxide dismutase activity. An insignificant effect of resveratrol on the lipid peroxidation level and the superoxide dismutase activity was observed in the hearts of rats administered a higher dose of doxorubicin. However, resveratrol attenuate necrosis and other cardiac histopathological changes were induced by a high dose of doxorubicin. Interestingly, it slightly intensified adverse cardiac histological changes in rats receiving a lower dose of doxorubicin. Resveratrol did not have any protective effect on the hepatic oxidative stress, while exerting a mild beneficial effect on the morphological changes caused by doxorubicin. All in all, this study has shown different effects of resveratrol on dose-related doxorubicin-induced heart and liver toxicity. Resveratrol may modulate the hepatic and cardiac effect of doxorubicin, depending on the drug dose.
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