stilbenes and Reperfusion-Injury

Polydatin(PD), a natural active ingredient isolated from traditional Chinese herb Polygonum cuspidatum, is also found in daily foods such as grapes and red wine. It might play a potential therapeutic role in human health through its anti-inflammatory, anti-oxidant, anti-ischemia injury, anti-apoptosis, conditioning blood lipids and other effects, which makes it increasingly become a hotspot of research. Various studies have shown that PD has a protective effect in the ischemia-reperfusion injury of heart, lungs, kidneys, gastrointestinal tract, cerebra and other organs. However, the specific mechanism of action is less and not completely clear. In this study, we aim to review the protective mechanism of PD in the ischemia-reperfusion injury of various organs, and provide inspiration for future studies.

Topics: Animals; Drugs, Chinese Herbal; Fallopia japonica; Glucosides; Humans; Medicine, Chinese Traditional; Molecular Conformation; Protective Agents; Reperfusion Injury; Stilbenes

Resveratrol, a polyphenol extracted from red wine, possesses potential antioxidative and anti-inflammatory effects, including the reduction of free radicals and proinflammatory mediators overproduction, the alteration of the expression of adhesion molecules, and the inhibition of neutrophil function. A growing body of evidence indicates that resveratrol plays an important role in reducing organ damage following ischemia- and hemorrhage-induced reperfusion injury. Such protective phenomenon is reported to be implicated in decreasing the formation and reaction of reactive oxygen species and pro-nflammatory cytokines, as well as the mediation of a variety of intracellular signaling pathways, including the nitric oxide synthase, nicotinamide adenine dinucleotide phosphate oxidase, deacetylase sirtuin 1, mitogen-activated protein kinase, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, hemeoxygenase-1, and estrogen receptor-related pathways. Reperfusion injury is a complex pathophysiological process that involves multiple factors and pathways. The resveratrol is an effective reactive oxygen species scavenger that exhibits an antioxidative property. In this review, the organ-protective effects of resveratrol in oxidative stress-related reperfusion injury will be discussed.

Topics: Animals; Oxidative Stress; Protective Agents; Reactive Oxygen Species; Reperfusion Injury; Resveratrol; Signal Transduction; Stilbenes; Wine

Resveratrol is a polyphenol present in grapes, some nuts and dried fruits, and red wine. A number of beneficial properties have been attributed to this compound. Its potential neuroprotective effects are the subject of much research today.. To review the effects of resveratrol, and more particularly those related to its capacity to offer protection against the neurodegeneration associated with several pathologies and traumatic injuries in the central nervous system.. It has been suggested that the daily consumption of red wine, and therefore of resveratrol, could account for the so-called 'French paradox', according to which the population in the south of France, despite eating a diet that is relatively high in saturated fats, presents a low risk of heart disease. From this first evidence of the cardioprotective properties of resveratrol, its study has been extended and equally attractive biopharmacological effects have now been found in many different fields. Thus, neuroprotective effects have been found in models of neurodegeneration (Alzheimer's, Parkinson's or Huntington's disease, or diverse neuropathies), of ischaemia and of brain and spinal cord injury, but further clinical data are still needed in this regard.. Although few studies have been conducted in humans, recent findings in experimental models of neurological pathology are encouraging and open up the doors to future clinical studies that will allow the therapeutic value of resveratrol to be determined.

Topics: Amyloid beta-Peptides; Animals; Antioxidants; Biological Availability; Cardiotonic Agents; Cell Survival; Cerebrovascular Disorders; Diet, Mediterranean; DNA Repair; Humans; Nerve Tissue Proteins; Neurodegenerative Diseases; Neuroprotective Agents; Peripheral Nervous System Diseases; Reperfusion Injury; Resveratrol; Sirtuin 1; Spinal Cord; Stilbenes; Trauma, Nervous System; Vitis; Wine

Several recent studies have shown the protective effects of resveratrol in various experimental conditions and pathological animal models. Clinical studies also indicate the beneficial effects of resveratrol in different human diseases. Resveratrol produces a cascade against of events from the initial death-provoking signal, DNA fragmentation, and cell death. Researchers recognized the beneficial effect of resveratrol, as an important component, of the overall injury that occurs in various disorders such as oxidative stress, myocardial injury, anticancer activity, antidiabetic activity, and antihypercholesterolemic effects. Many mechanisms have been proposed for the initiation of protective effects of resveratrol in various pathological events, and considerable evidence exists to indicate that many mediators are involved in the resveratrol-induced protection. The present review focuses on the history, and the beneficial effects and mechanisms of resveratrol in oxidative stress, myocardial injury, anticancer-, antidiabetic- and antihypercholesterolemic activities, and discusses those therapeutic tools, which warrant becoming clinically important.

Topics: Antineoplastic Agents; Antioxidants; Cell Death; Cytoprotection; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Ischemic Preconditioning, Myocardial; Oxidative Stress; Phytotherapy; Plant Preparations; Reperfusion Injury; Resveratrol; Stilbenes

Oxidative stress, favoring disease progression by a rapid degeneration of endothelial cell function is deeply involved in Systemic Sclerosis (SSc) pathogenesis. Raynaud's phenomenon (RP), present in 90% of patients with SSc, provoking frequent daily episodes of hypoxia-reperfusion injury, produces several episodes of free radicals-mediated endothelial derangement. These events results in a positive feedback effect of luminal narrowing and ischemia and therefore to the birth of a vicious cycle of oxygen free radicals (OFR) generation, leading to endothelial damage, intimal thickening and fibrosis. Thus ischemia and reperfusion are two criticals events that may induce oxidative stress and inactivation of antioxidant enzymes. In RP and SSc, a reduced concentration of ascorbic acid, alpha-tocopherol and beta-carotene as well as low values of Selenium have been reported. This antioxidative potential deficiency increases the propensity to oxidative stress. favoring the development of injury mediated by OFR. We reviewed several antioxidant compounds, aiming at their capacity of reverting endothelial dysfunction and damage, scavenging lipid peroxidation and reducing multiple episodes of hypoxia-reperfusion injury. In order to interrupt SSc vicious cycle, we propose a main strategy for SSc treatment by a supplementation of antioxidants and different kind of drugs with antioxidant property, such as Lazaroids, Resveratrol, Melatonin and Probucol.

Topics: Antioxidants; Ascorbic Acid; beta Carotene; Endothelium, Vascular; Humans; In Vitro Techniques; Melatonin; Nitric Oxide; Oxidative Stress; Pregnatrienes; Probucol; Raynaud Disease; Reactive Oxygen Species; Reperfusion Injury; Resveratrol; Scleroderma, Systemic; Selenium; Stilbenes; Vitamin E

Epidemiological studies suggest that the consumption of wine, particularly of red wine, reduces the incidence of mortality and morbidity from coronary heart disease. This has given rise to what is now popularly termed the "French paradox". The cardioprotective effect has been attributed to antioxidants present in the polyphenol fraction of red wine. Grapes contain a variety of antioxidants, including resveratrol, catechin, epicatechin and proanthocyanidins. Of these, resveratrol is present mainly in grape skin while proanthocyanidin is present in the seeds. In this report, we provide evidence that red wine extract as well as resveratrol and proanthocyanidins are equally effective in reducing myocardial ischemic reperfusion injury, which suggests that these red wine polyphenolic antioxidants play a crucial role in cardioprotection.

Topics: Antioxidants; Coronary Disease; Flavonoids; Humans; Phenols; Plant Extracts; Platelet Aggregation Inhibitors; Polymers; Polyphenols; Reperfusion Injury; Resveratrol; Stilbenes; Wine

Hepatic ischemia/reperfusion (I/R) injury contributes to morbidity and mortality during liver resection or transplantation, with limited effective treatments available. Here, we investigated the potential benefits and underlying mechanisms of pterostilbene (Pt), a natural component of blueberries and grapes, in preventing hepatic I/R injury. Male C57BL/6 mice subjected to partial warm hepatic I/R and human hepatocyte cell line L02 cells exposed to anoxia/reoxygenation (A/R) were used as in vivo and in vitro models, respectively. Our findings showed that pretreatment with Pt ameliorated hepatic I/R injury by improving liver histology, decreasing hepatocyte apoptosis, and reducing plasma ALT and AST levels. Likewise, cell apoptosis, mitochondrial membrane dysfunction, and mitochondrial ROS overproduction in L02 cells triggered by the A/R challenge in vitro were reduced due to Pt administration. Mechanistically, Pt treatment efficiently enhanced mitophagy and upregulated PINK1, Parkin, and LC3B expression. Notably, the protective effect of Pt was largely abrogated after cells were transfected with PINK1 siRNA. Moreover, Pt pretreatment promoted hepatocyte proliferation and liver regeneration in the late phase of hepatic I/R. In conclusion, our findings provide evidence that Pt exerts hepatoprotective effects in hepatic I/R injury by upregulating PINK1-mediated mitophagy.

Topics: Animals; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Gene Expression Regulation; Hepatic Infarction; Hepatocytes; Humans; Liver Regeneration; Male; Mice, Inbred C57BL; Mitophagy; Protein Kinases; Reperfusion Injury; Stilbenes; Up-Regulation

Contractile dysfunction and fatal arrhythmias are the hallmarks of myocardial ischemia/reperfusion (I/R) injury. Pterostilbene has notable cardioprotective effects, but its main mechanisms are not fully understood. Here, we investigated the effect of PTE on myocardial hemodynamics, arrhythmias, inflammatory/oxidative responses, and the causal role of the JAK2/STAT3 pathway in rats with acute myocardial I/R injury. Sixty male 7-8 months Sprague-Dawley rats (n=10/each group) experienced in vivo model of myocardial I/R injury through 40-min LAD coronary artery occlusion and subsequent 24-h reperfusion. PTE at concentrations of 5 and 25 mg/kg was intraperitoneally administered to rats five min before reperfusion. Cardiac hemodynamics, reperfusion-induced ventricular arrhythmias, infarct size, inflammatory cytokines, oxidative stress markers, the activity of the JAK2/STAT3 pathway were measured as the endpoints. Administration of PTE to I/R-injured rats recovered myocardial contractile function and reduced infarct size and ventricular arrhythmias counts and incidence in a dose-dependent manner. PTE at 25 mg/kg significantly and more potently reduced the levels of inflammatory mediators NF-?B, TNF-?, and IL-1?, suppressed intracellular ROS production, augmented the activity of glutathione, and manganese-superoxide dismutase, and upregulated the JAK2 and STAT3 phosphorylation. Importantly, pretreatment of rats with Ag490 as a JAK2 inhibitor significantly abolished the cardioprotective and signaling effects of PTE in I/R rats. PTE exerts significant protective effects on reducing arrhythmias and myocardial infarction and enhancing cardiac function by stimulating JAK2/STAT3-related suppression of inflammatory and oxidative reactions in the I/R injury setting.

Topics: Animals; Apoptosis; Cytokines; Glutathione; Inflammation Mediators; Interleukin-1; Janus Kinase 2; Male; Manganese; Myocardial Infarction; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Stilbenes; Superoxide Dismutase

Topics: Animals; Female; Glucosides; Humans; Male; Mice; Mitochondria; NF-E2-Related Factor 2; Reperfusion Injury; Signal Transduction; Spinal Cord; Spinal Cord Ischemia; Stilbenes

Piceatannol is a natural plant-derived compound with protective effects against cardiovascular diseases. However, its effect on cerebral ischaemia-reperfusion injury (CIRI) induced by oxidative stress remains unclear. This study aimed to investigate piceatannol's antioxidation in CIRI. An in vitro oxygen-glucose deprivation followed by reoxygenation model was used and cell viability was measured. A middle cerebral artery occlusion followed by reperfusion model was used in vivo. Neurological function, encephalisation quotient, oedema, and volume of the cerebral infarction were then evaluated. The effects of piceatannol on histopathological findings, as well as the ultrastructure of the cortex, were analysed. The activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and lactate dehydrogenase (LDH) and the malondialdehyde (MDA) content was measured both in vitro and in vivo. Finally, the expression of nuclear factor erythroid-2-related factor 2 (Nrf2), hemeoxygenase-1 (HO-1), and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1 (NQO1) in cerebral tissue was detected using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting. Our results demonstrated that cell viability in the piceatannol groups was increased. The SOD, GSH-Px activities were increased as LDH activity and MDA content decreased in the piceatannol groups both in vitro and in vivo, reflecting a decrease in oxidative stress. The neurological severity score and infarction volume in the piceatannol groups at doses of 10 and 20 mg/kg were lower than those of the model group. Furthermore, the damage seen on histopathological examination was partially attenuated by piceatannol. RT-qPCR and western blot analysis indicated that the expression of Nrf2, HO-1, and NQO1 were significantly increased by piceatannol. The results of the study demonstrate that piceatannol exerts a protective effect against CIRI.

Topics: Animals; Brain; Cell Hypoxia; Cell Survival; Glucose; Heme Oxygenase-1; Infarction, Middle Cerebral Artery; Male; Membrane Proteins; Mice, Inbred ICR; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Oxygen; Reperfusion Injury; Signal Transduction; Stilbenes

Isorhapontigenin (ISO) has been shown to have antioxidant activity. This study aimed to investigate the antioxidant effects of ISO on cerebral ischemia/reperfusion (I/R) injury and its possible molecular mechanisms.. Focal cerebral ischemia-reperfusion injury (MCAO/R) model and primary cortical neurons were established an oxygen-glucose deprivation (OGD / R) injury model. After 24 hr of reperfusion, the neurological deficits of the rats were analyzed and HE staining was performed, and the infarct volume was calculated by TTC staining. In addition, the reactive oxygen species (ROS) in rat brain tissue, the content of 4-Hydroxynonenal (4-HNE), and 8-hydroxy2deoxyguanosine (8-OHdG) were detected. Neuronal cell viability was determined by MTT assay. Western blot analysis was determined for protein expression.. ISO treatment significantly improved neurological scores, reduced infarct volume, necrotic neurons, ROS production, 4-HNE, and 8-OHdG levels. At the same time, ISO significantly increased the expression of Nrf2 and HO-1. The neuroprotective effects of ISO can be eliminated by knocking down Nrf2 and HO-1. In addition, knockdown of the PKCε blocked ISO-induced nuclear Nfr2, HO-1 expression.. ISO protected against oxidative damage induced by brain I/R, and its neuroprotective mechanism may be related to the PKCε/Nrf2/HO-1 pathway.

Topics: Animals; Brain Ischemia; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Stilbenes

Isorhapontigenin (ISO) is one of the main bioactive components of Gnetum cleistostachyum and was shown to possess antioxidant and antitumor functions. Herein, we hope to examine the neuroprotection impacts of ISO in rats subjected to transient middle cerebral artery occlusion/reperfusion (MCAO/R, 2/24 h) injuries. ISO was injected intraperitoneally into the rats immediately after cerebral ischemia. After 24 h of the reperfusion, infarct volume, brain water contents, neurological deficit, and cerebral blood flow were assessed. Hippocampus histopathology change was detected by H&E and TUNEL staining. The expressions of cleaved caspase-3, Bax and Bcl-2, and phospho-Akt (p-Akt) were investigated by real-time RT-PCR or western blot analysis. We found that ISO significantly suppressed the infarct volumes, brain water contents, and neurological deficit, increased CBF, and relieved histopathologic change in a dose-dependent manner. Reduced malondialdehyde (MDA) and elevated activities of superoxide dismutase (SOD) and GSH and glutathione peroxidase (GSH-PX) were observed in ISO group. ISO remarkably decreased caspase-3 and Bax and increased levels of Bcl-2. Additionally, ISO upregulated p-Akt expression. Blocking of PI3K activities by wortmannin can abolish the ISO-caused decrease in infarct volumes and neurologic deficit scores and abrogate the promotion of p-Akt. The data indicated that ISO played neuroprotective impacts against focal I/R injuries, possibly related to the activating of PI3K/Akt signaling.

Topics: Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Disease Models, Animal; Hippocampus; Infarction, Middle Cerebral Artery; Male; Neuroprotective Agents; Oxidative Stress; Phosphatidylinositol 3-Kinase; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Stilbenes

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

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

Reperfusion is a critical therapeutic intervention used following acute ischemic stroke; however, it may cause cerebral ischemia/reperfusion injury (CIRI) and aggravate brain damage. Piceatannol (Pic), a hydroxylated analog of resveratrol, has been reported to exhibit anti‑inflammatory effects. However, the detailed molecular mechanisms and its effects on CIRI have not been sufficiently assessed, and, to the best of our knowledge, current methods of prevention of CIRI are limited. The aim of the present study was to investigate the effects of Pic on improving neurological function in a mouse model of CIRI. For the animal experiments, 8‑week‑old C57BL/6 mice were raised and randomly grouped, and an in vivo model of CIRI was established. Mice were administered a low (10 mg/kg/day) or high‑dose (20 mg/kg/d) of Pic 1 h after CIRI orally and once daily for the next 6 days. Neurological dysfunction was assessed using a modified neurological severity score and a rotarod test 1 week after CIRI establishment, and the cognitive status of the mice was assessed using a Morris water maze. Hematoxylin and eosin staining was used to evaluate the histopathological changes. The expression levels of sirtuin 1 (Sirt1), FoxO1, cleaved caspase‑3 (CC‑3), Bax and Bcl‑2 were measured using western blotting. Intracellular reactive oxygen species (ROS) generation, antioxidant enzymes [superoxide dismutase, glutathione (GSH) peroxidase and catalase] and non‑enzymatic antioxidants (GSH) were also detected using spectrophotometry. After inhibition of the Sirt1/FoxO1 pathway, a TUNEL assay was used for the detection of apoptotic cells in vitro and in vivo. The co‑localization of neuron‑specific nuclear protein and CC‑3 was assessing using immunofluorescent staining. Pic improved neurological functions and ameliorated hippocampal neuronal pathology following CIRI. In addition, the expression levels of CC‑3 and Bax and intracellular ROS levels were increased, while levels of antioxidant and non‑enzymatic enzymes were decreased in the mouse model of CIRI. Low and high doses of Pic significantly decreased ROS production and the expression levels of apoptosis‑related proteins, but increased antioxidant enzyme levels. However, a high‑dose of Pic did not result in increased levels of non‑enzymatic enzymes. Furthermore, low and high doses of Pic treatment significantly activated the Sirt1/FoxO1 pathway. Following inhibition of the Sirt1/FoxO1 pathway, the percentage of TUNEL‑positive cells an

Topics: Animals; Antioxidants; Apoptosis; Brain Ischemia; Caspase 3; Forkhead Box Protein O1; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Reperfusion Injury; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Stroke

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

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

Resveratrol has been demonstrated to have cardioprotective effects by attenuating ischemia/reperfusion (I/R)-induced oxidative stress injury, but its in-depth molecular mechanisms against I/R-induced oxidative stress is not fully elaborated. DJ-1 plays a role in maintenance of mitochondrial complex I activity and is closely associated with oxidative stress. Therefore, this study sought to determine the contribution of DJ-1-mediated maintenance of mitochondrial complex I activity to the anti-oxidative stress effect of Resveratrol in the H9c2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R). The results showed that Resveratrol significantly attenuated the H/R-induced viability loss and lactate dehydrogenase leakage, accompanied by decreases in intracellular reactive oxygen species (ROS) and malondialdehyde contents and increases in the reduced glutathione/oxidized glutathione ratio. Furthermore, Resveratrol increased the expression and mitochondrial translocation of DJ-1 and promoted the direct binding of DJ-1 with complex I subunits ND1 and NDUFS4, which in turn improved mitochondrial complex I activity and inhibited mitochondria-derived ROS production after H/R. Intriguingly, the anti-oxidative stress effect of Resveratrol could be partially blocked by DJ-1 siRNA and Complex I inhibitor Rotenone, respectively. Conclusively, these results indicated that DJ-1 is necessary for Resveratrol-mediated cardioprotective effects against H/R-induced oxidative stress damage, at least in part, through preserving mitochondrial complex I activity, and subsequently decreasing mitochondrial ROS generation.

Topics: Animals; Cardiotonic Agents; Cell Line; Electron Transport Complex I; Hypoxia; L-Lactate Dehydrogenase; Mitochondria; Myocytes, Cardiac; Oxidative Stress; Protein Deglycase DJ-1; Rats; Reactive Oxygen Species; Reperfusion Injury; Resveratrol; RNA, Small Interfering; Stilbenes

This study aims to evaluate the putative roles of a single acute dose of resveratrol (RVT) in preventing cerebral oxidative stress induced by bilateral common carotid artery occlusion, followed by reperfusion (BCCAO/R) and to investigate RVT's ability to preserve the neuronal structural integrity. Frontal and temporal-occipital cortices were examined in two groups of adult Wistar rats, sham-operated and submitted to BCCAO/R. In both groups, 6 h before surgery, half the rats were gavage-fed with a single dose of RVT (40 mg/per rat in 300 µL of sunflower oil as the vehicle), while the second half received the vehicle alone. In the frontal cortex, RVT pre-treatment prevented the BCCAO/R-induced increase of lipoperoxides, augmented concentrations of palmitoylethanolamide and docosahexaenoic acid, increased relative levels of the cannabinoid receptors type 1 (CB1) and 2 (CB2), and peroxisome-proliferator-activated-receptor (PPAR)-α proteins. Increased expression of CB1/CB2 receptors mirrored that of synaptophysin and post-synaptic density-95 protein. No BCCAO/R-induced changes occurred in the temporal-occipital cortex. Collectively, our results demonstrate that, in the frontal cortex, RVT pre-treatment prevents the BCCAO/R-induced oxidative stress and modulates the endocannabinoid and PPAR-α systems. The increased expression of synaptic structural proteins further suggests the possible efficacy of RVT as a dietary supplement to preserve the nervous tissue metabolism and control the physiological response to the hypoperfusion/reperfusion challenge.

Topics: Animals; Arterial Occlusive Diseases; Carotid Artery Diseases; Frontal Lobe; Gene Expression Regulation; Male; Oxidative Stress; Rats; Rats, Wistar; Receptors, Cannabinoid; Reperfusion Injury; Resveratrol; Stilbenes

The gastrointestinal tract is extremely sensitive to ischemia and reperfusion (I/R). Studies have reported that resveratrol (RSV) is able to combat damage caused by intestinal I/R. Because of its effectiveness in increasing the permanence and bioavailability of resveratrol in the intestinal epithelium, we investigated whether the effect of resveratrol-loaded in poly(anhydride) nanoparticles reduce oxidative stress and promote myenteric neuroprotection in the ileum of rats subjected to I/R. Physicochemical evaluations were performed on nanoparticles. The animals were divided into nine groups (n = 6/group) and treated every 48 h. Treatments with resveratrol (7 mg/kg of body weight) were applied 5 days before surgery and continued for 7 days after surgery (reperfusion period). The superior mesenteric artery was occluded to cause I/R injury. Oxidative stress, myeloperoxidase, nitrite, aspartate aminotransferase, alanine aminotransferase, immunolabeling of myenteric neurons and glial cells, and gastrointestinal transit was evaluated. Both nanoparticle formulations presented negative charge with homogeneous distribution, and the payload, showed an encapsulation efficiency of 60%. Resveratrol administered in free form prevented alterations that were caused by I/R. The results of the groups treated with RSV-loaded nanoparticles presented similar results to the group treated with free resveratrol. Treatment with empty nanoparticles showed that poly(anhydride) is not an ideal nanocarrier for application in in vivo models of intestinal I/R injury, because of hepatotoxicity that may be caused by epithelial barrier dysfunction that triggers the translocation of nanoparticles.

Topics: Animals; Antioxidants; Drug Carriers; Gastrointestinal Transit; Ileum; Intestinal Diseases; Male; Nanoparticles; Oxidative Stress; Particle Size; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; Stilbenes

Ischemia-reperfusion injury (IRI) is one of the major causes of postoperative renal allograft dysfunction, which is mainly the result of proinflammatory reactions including inflammatory responses, oxidative stress, and metabolic disorders. Resveratrol (RSV) plays an important role in protecting various organs in IRI because it reduces oxidative stress, lessens the inflammatory response, and exerts anti-apoptotic effects. The aim of this study was to demonstrate the renoprotective effect of RSV in inhibiting inflammatory responses, reducing oxidative stress, and decreasing cell apoptosis in vivo and in vitro.. RSV was administered before renal ischemia and H2O2 induction. Serum and kidneys were harvested 24 h after reperfusion and NRK-52E cells were collected 4 h after H2O2 stimulation. Serum creatinine and blood urea nitrogen were used to assess renal function. Hematoxylin and eosin staining was performed to assess histological injury. Quantitative real-time PCR and enzyme-linked immunosorbent assay were used to assess proinflammatory cytokine expression. Oxidative stress-related proteins, such as Nrf2 and TLR4, were evaluated by western blot. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay was used to detect apoptotic cells in tissues, and western blot was used to evaluate the expression of caspase-3, -8, and -9 in this study.. RSV inhibited inflammatory responses and improved renal function after renal IRI. Additionally, RSV decreased oxidative stress and reduced cell apoptosis by upregulating Nrf2 expression, downregulating the TLR4/NF-κB signaling pathway, and by decreasing caspase-3 activity and caspase cascades.. Our study demonstrated the mechanisms underlying RSV renoprotection. We found that RSV exerts its greatest effects by blocking inflammatory responses, lowering oxidative stress, and reducing apoptosis via the Nrf2/TLR4/NF-κB pathway.

Topics: Animals; Caspase 3; Cell Line; Cell Survival; Cytokines; Disease Models, Animal; Hydrogen Peroxide; Kidney; Male; Matrix Metalloproteinase 13; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; RNA Interference; Signal Transduction; Stilbenes; Superoxide Dismutase; Toll-Like Receptor 4

It is well accepted that both rosuvastatin and resveratrol exert neuroprotective effects on cerebral ischemia/reperfusion injury through some common pathways. Resveratrol has also been demonstrated to protect against cerebral ischemia/reperfusion injury through enhancing autophagy. Thus, we hypothesized that combined rosuvastatin and resveratrol pretreatment had synergistic effects on cerebral ischemia/reperfusion injury.. Adult male Sprague Dawley rats receiving middle cerebral artery occlusion surgery as animal model of cerebral ischemia/reperfusion injury were randomly assigned to 4 groups: control, resveratrol alone pretreatment, rosuvastatin alone pretreatment, and combined rosuvastatin and resveratrol pretreatment. Rosuvastatin (10 mg/kg) or resveratrol (50 mg/kg) was administrated once a day for 7 days before cerebral ischemia onset.. We found that combined rosuvastatin and resveratrol pretreatment not only significantly decreased the neurologic defective score, cerebral infarct volume, the levels of caspase-3, and Interleukin-1β (IL-1β) but also significantly increased the ratios of Bcl-2/Bax and LC3II/LC3I, as well as the level of Becline-1, compared with resveratrol alone or rosuvastatin alone pretreatment group. Rosuvastatin alone pretreatment significantly increased the ratio of LC3II/LC3I and the level of Beclin-1. However, there were no significant differences in the neurologic defective score, cerebral infarct volume, the levels of caspase-3, IL-1β, and Beclin-1, and the ratios of Bcl-2/Bax and LC3II/LC3I between resveratrol pretreatment group and rosuvastatin pretreatment group.. Synergistically enhanced antiapoptosis, anti-inflammation, and autophagy activation might be responsible for the synergistic neuroprotective effects of combining rosuvastatin with resveratrol on cerebral ischemia/reperfusion injury.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Proteins; Brain; Cytoprotection; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Infarction, Middle Cerebral Artery; Inflammation Mediators; Male; Neuroprotective Agents; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Rosuvastatin Calcium; Signal Transduction; Stilbenes

Piceatannol, a grape-derived polyphenol, has been linked to proarrhythmic properties by aggravating inhomogeneous conduction delay in the ischemia-reperfusion (IR) zone to enhance arrhythmogenic alternans in heart failure (HF) rabbits. The underlying molecular mechanisms of piceatannol-induced conduction disturbance were unclear in this model.. HF was induced by 4 weeks' rapid ventricular pacing. IR injury was induced in vivo using a protocol of left coronary artery ligation and release. Left ventricular cardiomyocytes were isolated enzymatically for whole-cell patch-clamp studies. Piceatannol (10 μM) was administrated to test its inhibitory effect on sodium current (I. Peak I. Downregulation of NaV 1.5 protein expression and reduced peak I

Topics: Animals; Blotting, Western; Down-Regulation; Heart Failure; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Rabbits; Reperfusion Injury; Stilbenes

This study was carried out to investigate the expression pattern and role of osteopontin (OPN) in late global ischemia-reperfusion (I/R) injury with or without resveratrol (RES) pre-treatment. Young male rats were divided into 3 groups (n = 12) of I) sham, II) I/R model group and III) I/R + RES. Vehicle and RES (20 mg/kg) were administered to designed groups intraperitoneally 30 days prior global I/R injury (2-VO) induction and continued for 7 days, later. Then, percentages of infarct areas, mRNA levels of OPN, inducible nitric oxide synthase (iNOS) and other biochemical parameter related to endogenous antioxidants activities and inflammation were measured in the cerebral cortices of all groups. Significant elevations in the levels of malondialdehyde (MDA), the inflammatory mediator interleukin 1β (IL-1β), chemokines (KC and MIP-2) and adhesive molecules (ICAM-1) as well as parallel reductions in enzymes activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and chloramphenicol acetyltransferase (CAT) were observed in the cerebral homogenates of rats with late I/R injury. Associated with these changes, mRNA levels of OPN were significantly downregulated and those of iNOS and Bax were upregulated. All these changes were reversed by in 2-VO I/R induced rats pre-administered RES. These findings suggest that inhibition of sustained inflammatory response driven by IL-1β, decreased activities of endogenous antioxidants and downregulation of OPN induced upregulation of iNOS play important roles in the pathogenesis of neurodegeneration during late cerebral I/R injury, effects that can be modulated by RES which might explain its neuroprotection effect during late global ischemia.

Topics: Animals; bcl-2-Associated X Protein; Brain Ischemia; Catalase; Cerebral Cortex; Chemokine CXCL2; Chemokines; Glutathione Peroxidase; Intercellular Adhesion Molecule-1; Interleukin-1beta; Male; Neuroprotective Agents; Nitric Oxide Synthase Type II; Osteopontin; Oxidative Stress; Rats, Wistar; Reperfusion Injury; Resveratrol; Stilbenes; Superoxide Dismutase; Up-Regulation

Ischemia reperfusion (I/R) injury is a leading cause of acute kidney injury with high morbidity and mortality due to limited therapy. NMDA receptor inhibitor (DAP5) and resveratrol (Res) could ameliorate kidney I/R injury, but their use is limited by low aqueous solubility and poor stability. Here, we examined the potential protective effects of Res-DAP5 nanoparticles (NP) against renal I/R injury. Mice were subjected to renal ischemia for 30 min followed by reperfusion for 24 h. The results showed that Res-DAP5-NP could decreased serum creatinine (Cr) and urea nitrogen (BUN), alleviated tubular damage and oxidative stress. In addition, Res-DAP5-NP suppressed cell apoptosis, promoted the expression of p-DAPK, and inhibited the expression of p-CaMK and p-AKT. Furthermore, Res-DAP5-NP decreased the production of pro-inflammatory cytokines such as tumor necrosis factor-α, IL-1β, IL-6, and p-IκBα induced by renal I/R injury. In addition, Res-DAP5-NP also attenuated renal I/R injury in vivo, as manifested by increase in cell viability, SOD level, and the expression of p-DAPK, decreases in intracellular Ca2+ concentration and the expression of p-CaMK. Taken together, our findings indicates that Res-DAP5-NP could effectively protect renal I/R injury by inhibiting apoptosis and inflammation responses, possibly through AKT/NMDA/CaMK/DAPK and NF-κB pathways.

Topics: Animals; Apoptosis; Biomarkers; Calcium; Caspase 3; Cell Line; Cell Survival; Cytokines; Disease Models, Animal; Drug Delivery Systems; Humans; Inflammation Mediators; Kidney Diseases; Kidney Function Tests; Male; Nanoparticles; Oxidative Stress; Protective Agents; Rats; Reactive Oxygen Species; Reperfusion Injury; Resveratrol; Stilbenes

Resveratrol has been reported to protect against cerebral ischemia/reperfusion (I/R) injury in rats, but the underlying mechanism is unclear. In the current study, we examined whether resveratrol ameliorates cerebral I/R injury by inhibiting NLRP3 inflammasome-derived inflammation and whether autophagy is involved in this process. In addition, we explored the role of Sirt1 in resveratrol-mediated protective effects. To answer these questions, healthy male Sprague-Dawley rats were exposed to middle cerebral artery occlusion for 1h followed by 24h reperfusion. We found that cerebral I/R increased levels of activated NLRP3 inflammasome, caspase-1, IL-1β, and IL-18 and enhanced autophagy activity (ratio of LC3B-II/LC3B-I and p62/SQSTM1). Treatment with resveratrol, a specific Sirt1 agonist, attenuated I/R-induced NLRP3 inflammasome-derived inflammation but upregulated autophagy. Furthermore, resveratrol treatment clearly reduced cerebral infarct volume, decreased brain water content, and improved neurological scores. In addition, inhibition of autophagy using 3-MA intracerebroventricular injection blocked the inhibitory effect of resveratrol on NLRP3 inflammasome activation. Finally, Sirt1 knockdown with siRNA significantly blocked resveratrol-induced enhancement of autophagy activity and suppression of NLRP3 inflammasome activation. In conclusion, our results demonstrate that resveratrol protects against cerebral I/R injury by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy activity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Autophagy; Brain Ischemia; Cerebral Arteries; Disease Models, Animal; Humans; Inflammasomes; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Sirtuin 1; Stilbenes

Hepatic ischemia/reperfusion injury (IRI), an inevitable antigen-independent inflammation response in cadaveric liver transplantation, correlates with poor early graft function, rejection episodes, and contributes to donor organ shortage. Sirtuin 1 (SIRT1) is a histone deacetylase that may regulate inflammatory cell activity and manage liver function in IRI, though its functional role and clinical relevance remains to be elucidated. We investigated the efficacy of SIRT1 activation in a murine liver IRI model and verified the concept of putative SIRT1-mediated hepatoprotection in clinical liver transplantation. In the experimental arm, mice were subjected to 90 minutes of liver partial warm ischemia followed by 6 hours of reperfusion with or without adjunctive SIRT1 activation in vivo (resveratrol [Res]). In parallel, bone marrow-derived macrophage (BMDM) or spleen lymphocyte cultures were treated with Res. In the clinical arm, liver biopsies from 21 adult primary liver transplant patients (2 hours after reperfusion) were divided into "low" (n = 11) versus "high" (n = 10) SIRT1 expression groups, assessed by Western blots. Treatment with Res attenuated murine liver IRI while up-regulating SIRT1, suppressing leukocyte infiltration, and decreasing proinflammatory cytokine programs. SIRT1 silencing (small interfering RNA) in BMDM cultures enhanced inflammatory cytokine programs, whereas addition of Res decreased proinflammatory response in a SIRT1-dependent manner. In addition, Res decreased interferon γ production in liver-infiltrating and spleen lymphocyte cultures. Human liver transplants with high SIRT1 levels showed improved hepatocellular function and superior survival (P = 0.04), accompanied by lower proinflammatory cytokine profile. In conclusion, our translational study is the first to identify SIRT1 as a regulator of hepatocellular function in human liver transplant recipients under ischemia/reperfusion stress. By targeting innate and adaptive immune activation, manipulation of SIRT1 signaling should be considered as a novel means to combat inflammation in liver transplantation. Liver Transplantation 23 1282-1293 2017 AASLD.

Topics: Adult; Allografts; Animals; Biopsy; Cells, Cultured; Cytokines; Disease Models, Animal; End Stage Liver Disease; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Kaplan-Meier Estimate; Liver; Liver Transplantation; Lymphocytes; Macrophages; Male; Mice; Mice, Inbred C57BL; Middle Aged; Reperfusion Injury; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Young Adult

Intestinal ischemia/reperfusion (IIR) leads to acute lung injury (ALI) distally by aggravating pulmonary oxidative stress. Resveratrol is effective in attenuating ALI through its antioxidant capacity. This study aimed to determine the effects of resveratrol on IIR-induced ALI and to explore the role of mast cells (MCs) activation in a rat model of IIR.. Adult Sprague-Dawley rats were subjected to IIR by occluding the superior mesenteric artery for 60min followed by 4-hour reperfusion. Resveratrol was intraperitoneally injected at a dose of 15mg/kg for 5days before IIR. MCs stabilizer/inhibitor cromolyn sodium and degranulator compound 48/80 were used to explore the interaction between resveratrol and MCs. Lung tissues were collected for pathological detection and MCs staining. Pulmonary protein expression of surfactant protein-C (SP-C), tryptase, p47. At the end of IIR, lung injury was significantly increased and was associated with decreased expression of SP-C and increased lung oxidative stress. Increased inflammation as well as activation of MCs was also observed in the lungs after IIR. All these changes were prevented or reversed by resveratrol pretreatment or MCs inhibition with cromolyn sodium. However, these protective effects of resveratrol or cromolyn sodium were reduced by MCs degranulator compound 48/80.. These findings reveal that resveratrol attenuates IIR-induced ALI by reducing NADPH oxidase protein expression and inflammation through stabilizing MCs.

Topics: Acute Lung Injury; Animals; Antioxidants; Disease Models, Animal; Intestinal Diseases; Male; Mast Cells; NADPH Oxidases; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes

Ischemia/reperfusion (I/R) injury induces apoptosis in retinal ganglion cells (RGCs). Resveratrol (Res) is a potent natural antioxidant with beneficial effects in many ocular diseases, such as age-related macular degeneration, diabetic retinopathy, and glaucoma. Because caspase-3 expression is highly correlated with activation of the apoptotic pathway, the present study aimed to determine whether Res regulates the expression of caspase-3 using an I/R retinal injury mouse model.. Male C57BL/6J mice were injected with Res for 2 consecutive days before I/R retinal injury. I/R retinal injury was induced by increasing the intraocular pressure for 1 h. Res was then injected for 3 consecutive days. Changes in retinal morphology were monitored for 3 days after injury by histochemistry using hematoxylin and eosin staining. mRNAs and proteins were extracted 2 days after injury. The expression levels of caspase-8 and caspase-3 mRNA and protein were determined using reverse-transcriptase polymerase chain reaction (RT-PCR) and western blot analyses.. I/R injury induced declines in retinal thickness and number of RGCs during 5 days after injury. Caspase-8 and caspase-3 mRNA and protein activation increased. Res treatment reduced the significant loss of retinal morphology and downregulated the expression of mRNA and activation of caspase-8 and caspase-3 protein.. The observed changes in retinal morphology suggest that I/R injury promotes retinal degeneration. Increased expression of caspase-8 and caspase-3 mRNA indicates apoptosis activation. Res, however, suppresses apoptosis via downregulation of caspase-8 and caspase-3 expression.

Topics: Animals; Antioxidants; Apoptosis; Blotting, Western; Caspase 3; Caspase 8; Disease Models, Animal; Down-Regulation; Gene Expression Regulation, Enzymologic; In Situ Nick-End Labeling; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Resveratrol; Retinal Degeneration; RNA, Messenger; Stilbenes

Resveratrol, a naturally occurring polyphenolic compound, exhibits a neuroprotective role in models of central nervous system diseases, including cerebral ischemia/reperfusion injury. Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme that contributes to base excision repair of oxidative DNA damage and redox activation of transcription factors, associated with neuronal survival against hypoxic‑ischemic injury. It was hypothesized that resveratrol protects HT22 cells against oxygen‑glucose deprivation and re‑oxygenation (OGD/R)‑induced injuries through upregulation of APE1. It was demonstrated that resveratrol pretreatment significantly increased the viability of HT22 cells and decreased the release of lactate dehydrogenase (LDH), accompanied by the upregulation of APE1 mRNA, and protein levels, as well as the activity of APE1 under OGD/R conditions. In addition, resveratrol reversed OGD/R‑induced oxidative DNA damage as evidenced by the decreases in the levels of 8‑hydroxy‑2'‑deoxyguanosine and APE sites. However, APE1 knockdown using short hairpin RNA sequence targeting APE1 abolished resveratrol‑elicited beneficent effects against OGD/R‑induced cytotoxicity and oxidative stress. This was indicated by decreased cell viability, superoxide dismutase activity and glutathione levels, and increased LDH release and reactive oxygen species levels. The results of the present study indicate that APE1 contributes to the protective effects of resveratrol against neonatal hypoxic‑ischemic brain injuries, and suggest that DNA repair enzymes, including APE1, may be a unique strategy for neuroprotection against this disease.

Topics: Cell Line, Tumor; Cell Survival; DNA Damage; DNA Repair; DNA-(Apurinic or Apyrimidinic Site) Lyase; Gene Knockdown Techniques; Glucose; Humans; Neuroprotection; Oxidation-Reduction; Oxidative Stress; Oxygen; Reactive Oxygen Species; Reperfusion Injury; Resveratrol; Stilbenes

Our study aimed to investigate the possible modifying effects of leptin and combined use of resveratrol on rat renal I/R injury and their relationship on signal pathways and apoptosis-related mechanisms.. Renal ischemia-reperfusion (I/R) injury is an important cause of acute renal failure.. Male Sprague Dawley rats were divided into 5 groups: Control, I/R, I/R+leptin, I/R+resveratrol and I/R+leptin+resveratrol. Leptin (10 μg/kg BW) was administered (i.p.) 30 min prior to I/R. Resveratrol was administered by gavage at 20 mg/kg BW per d for 12 d prior to I/R. The left renal artery was exposed to 1 h of ischemia and 1 h of reperfusion.. Resveratrol treatment alone increased TNF-α, TNF-α R1, NF-κB, SIRT-1, STAT1 and STAT3 mRNA levels and decreased caspase 3 protein levels. Leptin treatment alone significantly decreased the caspase 3 protein levels. The combined use of resveratrol and leptin significantly increased STAT3, and caspase 3 mRNA levels, and decreased the caspase 3 protein levels. Apoptosis was significantly decreased especially in the leptin and leptin+resveratrol groups.. The present study suggest that a combined use of resveratrol and leptin has preventive and regulatory effects on renal I/R injury; the mechanism involves decreasing apoptosis, likely by altering the JAK/STAT pathway and SIRT1 expression (Fig. 8, Ref. 24).

Topics: Animals; Antioxidants; Apoptosis; Caspase 3; Gene Expression; Kidney; Leptin; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor; Reperfusion Injury; Resveratrol; RNA, Messenger; Signal Transduction; Sirtuin 1; STAT1 Transcription Factor; STAT3 Transcription Factor; Stilbenes; Tumor Necrosis Factor-alpha

Intestinal ischemia is often caused by a malperfusion of the upper mesenteric artery. Since the intestinal mucosa is one of the most rapidly proliferating organs in human body, this tissue can partly regenerate itself after the onset of ischemia and reperfusion (I/R). Therefore, we investigated whether glycine, sodium pyruvate, and resveratrol can either support or potentially harm regeneration when applied therapeutically after reperfusion injury.. I/R of the small intestine was initiated by occluding and reopening the upper mesenteric artery in rats. After 60 min of ischemia and 300 min of reperfusion, glycine, sodium pyruvate, or resveratrol was administered intravenously. Small intestine regeneration was analyzed regarding tissue damage, activity of saccharase, and Ki-67 positive cells. Additionally, systemic parameters and metabolic ones were obtained at selected periods.. Resveratrol failed in improving the outcome after I/R, while glycine showed a partial beneficial effect. Sodium pyruvate ameliorated metabolic acidosis, diminished histopathologic tissue injury, and increased cell proliferation in the small intestine.. While glycine could improve in part regeneration but not proliferation, sodium pyruvate seems to be a possible therapeutic agent to facilitate proliferation and to support mucosal regeneration after I/R injury to the small intestine.

Topics: Animals; beta-Fructofuranosidase; Cell Proliferation; Disease Models, Animal; Glycine; Injections, Intravenous; Intestinal Mucosa; Intestine, Small; Ki-67 Antigen; Mesenteric Arteries; Pyruvic Acid; Rats; Regeneration; Reperfusion Injury; Resveratrol; Stilbenes

The natural polyphenol resveratrol (RSV) has been shown to ameliorate ischemia/reperfusion (I/R)-induced damage. Therefore, a rat model of I/R-induced AKI equipped with intensive monitoring was utilized to examine direct renal protection by RSV in vivo.. AKI was induced by bilateral renal clamping (45 min) followed by reperfusion (3 h). Solvent-free RSV was continuously infused intravenously (0.056 and 0.28 mg/kg) in a total volume of 7 ml/kg/h starting from 30 min before renal clamping. At a mean arterial blood pressure below 70 mmHg for more than 5 min, bolus injections of 0.5 ml 0.9% NaCl solution were administered repetitively (max. 5 ml/kg/h).. No differences could be found between normoxic control groups with/without RSV. Bilateral renal clamping and subsequent reperfusion caused a progressive rise in creatinine, cystatin C, and CK, a decrease in cellular ATP content and diuresis. Infusion of RSV increased sirtuin 1 expression after ischemia/reperfusion and was associated with decreased blood pressure during ischemia and early reperfusion accompanied by an increased requirement of bolus injections as well as with increased expression of TNFα.. RSV did not exert protective effects on I/R-induced AKI in the present short-term in vivo rat model. The lack of protection is potentially connected to aggravation of blood pressure instability.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Ischemia; Rats; Reperfusion Injury; Resveratrol; Sirtuin 1; Stilbenes; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Angiogenesis Inducing Agents; Angiotensin I; Animals; Blotting, Western; Brain Injuries; Brain Ischemia; Fallopia multiflora; Glucosides; Infarction, Middle Cerebral Artery; Male; Neovascularization, Physiologic; Neuroprotective Agents; Platelet Endothelial Cell Adhesion Molecule-1; Rats; Rats, Sprague-Dawley; Receptor, TIE-2; Reperfusion Injury; Stilbenes; Stroke; Vascular Endothelial Growth Factor A

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

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

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

To study the role of Notch1 signaling pathway in the myocardial protective effects of resveratrol pro-treatment after hepatic ischemia/reperfusion injury.. Thirty-six healthy male SD rats were randomly divided into 3 groups:sham control (SC) group, hepatic ischemic/reperfusion (HIR) group, and pro-treatment resveratrol (Res) group,12 rats in each group. After each group with hepatic ischemia 40 min reperfusion 2 h (SC group placing equal time), the left ventricular function including left ventricular pressure (LVP), left ventricular systolic pressure (LVSP) and its derivate (±dp/dt) was measured; the serum activities of creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH) and tumor necrosis factorα(TNF-α) and interleukin-6(IL-6) were detected. The activity of myocardial su-peroxide dismutase(SOD) and contents of myocardial malonaldehyde (MDA) were determined; Notch intracellular domain (NICD) expressions were detected with Western blot; the mRNA levels of Notch1 and TNF-αwere detected by real-time PCR.. Compared with SC group, the left ventricular functions in the HIR group were significantly decreased. With decreasing the expression of NICD and Notchl, the activities of CK-MB, LDH, TNF-αand IL-6 in the serum were evidently increased(. The findings indicate that resveratrol has protective effect on myocardial injury during the hepatic ischemia/reperfusion, and its mecha-nisms may be related to anti-inflammation and anti-oxidative stress

Topics: Animals; Cardiotonic Agents; Heart; Liver; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes

The polyphenol resveratrol has shown regulatory effects on hippocampal neurogenesis, which according to the neurovascular niche hypothesis, is likely to involve stimulation of angiogenesis. In rodents, global cerebral ischemia leads to selective CA1 neuronal damage, spatial memory impairments, lasting changes in corticosterone (CORT) secretion, and increased neurogenesis. This study examined dose-related effects of 21-day RSV treatment on markers associated with neurogenesis (DCX, PSA-NCAM) and angiogenesis (CD31) in the hippocampus at short (7-day) and long-term (85-day) intervals following global ischemia. In parallel, post-ischemic and stress-induced CORT levels and spatial memory in the Morris water maze were determined.. Five groups of male Wistar rats were included: sham/saline, ischemia/saline, ischemia/1 mg/kg RSV, ischemia/10 mg/kg RSV, and sham/10 mg/kg RSV. Changes in expression of plasticity markers were paralleled by assessment of basal- and stress-induced CORT secretions, and spatial memory performance.. Our findings revealed a significant attenuation of ischemia-induced DCX/PSA-NCAM expression in RSV-treated rats, whereas RSV treatment increased angiogenesis in the injured CA1 region. RSV attenuated CORT levels 3 days post-ischemia and a trend toward attenuating CORT secretion in response to 15 minutes restraint stress. Increased swimming latencies in the target quadrant during the MWM probe trial in RSV-treated ischemic rats support beneficial effects of RSV on spatial memory retention.. Our findings uncover time- and dose-related effects of RSV and global ischemia on the regulation of hippocampal plasticity. Changes in neuro- and angiogenesis are consistent with RSV neuroprotective effects, but appear independent of RSV regulatory effects on corticosterone secretion.

Topics: Adrenal Cortex; Animals; Behavior, Animal; Biomarkers; Brain Ischemia; CA1 Region, Hippocampal; Corticosterone; Dose-Response Relationship, Drug; Doublecortin Protein; Injections, Intraperitoneal; Male; Neovascularization, Physiologic; Neurogenesis; Neuronal Plasticity; Neurons; Neuroprotective Agents; Random Allocation; Rats, Wistar; Reperfusion Injury; Resveratrol; Spatial Memory; Stilbenes

Ischemia reperfusion (IR) injury (IRI) is harmful to the cerebral system and causes mitochondrial oxidative stress. The antioxidant response element (ARE)-mediated antioxidant pathway plays an important role in maintaining the redox status of the brain. Heme oxygenase-1 (HO-1), combined with potent AREs in the promoter of HO-1, is a highly effective therapeutic target for protection against cerebral IRI. Pterostilbene (PTE), a natural dimethylated analog of resveratrol from blueberries, is a strong natural antioxidant. PTE has been shown to be beneficial for some nervous system diseases and may regulate HO-1 signaling. This study was designed to investigate the protective effects of PTE on cerebral IRI and to elucidate potential mechanisms underlying those effects. Mouse brains and cultured HT22 neuron cells were subjected to IRI. Prior to this procedure, the brains or cells were exposed to PTE in the absence or presence of the HO-1 inhibitor ZnPP or HO-1 small interfering RNA (siRNA). PTE conferred a cerebral protective effect, as shown by increased neurological scores, viable neurons and decreased brain edema as well as a decreased ion content and apoptotic ratio in vivo. PTE also increased the cell viability and decreased the lactate dehydrogenase (LDH) leakage and apoptotic ratio in vitro. ZnPP and HO-1 siRNA both blocked PTE-mediated cerebral protection by inhibiting HO-1 signaling and further inhibited two HO-1 signaling-related antioxidant molecules:. quinone oxidoreductase 1 (NQO1) and glutathione S-transferases (GSTs), which are induced by PTE. PTE also promoted a well-preserved mitochondrial membrane potential (MMP), mitochondria complex I activity, and mitochondria complex IV activity, increased the mitochondrial cytochrome c level, and decreased the cytosolic cytochrome c level. However, this PTE-elevated mitochondrial function was reversed by ZnPP or HO-1 siRNA treatment. In summary, our results demonstrate that PTE treatment attenuates cerebral IRI by reducing IR-induced mitochondrial oxidative damage through the activation of HO-1 signaling.

Topics: Animals; Apoptosis; Brain; Brain Edema; Brain Ischemia; Cell Line; Cell Survival; Glutathione Transferase; Heme Oxygenase-1; Ions; L-Lactate Dehydrogenase; Male; Mice, Inbred C57BL; Mitochondria; NAD(P)H Dehydrogenase (Quinone); Neurons; Oxidative Stress; Protoporphyrins; Reperfusion Injury; RNA, Small Interfering; Signal Transduction; Stilbenes

Nitroxides have been exploited as profluorescent probes for the detection of oxidative stress. In addition, they deliver potent antioxidant action and attenuate reactive oxygen species (ROS) in various models of oxidative stress, with these results ascribed to superoxide dismutase or redox and radical-scavenging actions. Our laboratory has developed a range of novel, biostable, isoindoline nitroxide-based antioxidants, DCTEIO and CTMIO. In this study we compared the efficiency of these novel compounds as antioxidant therapies in reducing ROS both in vivo (rat model) and in vitro (661W photoreceptor cells), with the established antioxidant resveratrol. By assessing changes in fluorescence intensity of a unique redox-responsive probe in the rat retina in vivo, we evaluated the ability of antioxidant therapy to (1) ameliorate ROS production and (2) reverse the accumulation of ROS after complete, acute ischemia followed by reperfusion (I/R). I/R injury induced a marked decrease in fluorescence intensity over 60 min of reperfusion, which was successfully ameliorated with each of the antioxidants. DCTEIO and CTMIO reversed the accumulation of ROS when administered intraocularly post ischemic insult, whereas, the effect of resveratrol was not significant. We also investigated our novel agents' capacity to prevent ROS-mediated metabolic dysfunction in the 661W photoreceptor cell line. Cellular stress induced by the oxidant, tert-butyl hydroperoxide, resulted in a loss of spare mitochondrial respiratory capacity (SMRC) and in the extracellular acidification rate in 661W cells. DCTEIO antioxidant administration successfully reduced the loss of SMRC. Together, these findings show we can quantify dynamic changes in cellular oxidative status in vivo and suggest that nitroxide-based antioxidants may provide greater protection against oxidative stress than the current state-of-the-art antioxidant treatments for ROS-mediated diseases.

Topics: Animals; Antioxidants; Cell Line; Extracellular Space; Female; Mitochondria; Neuroprotective Agents; Nitrogen Oxides; Oxidative Stress; Photoreceptor Cells, Vertebrate; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Resveratrol; Retinal Vessels; Stilbenes

Restoration of blood supply to ischemic myocardium causes cardiomyocyte damage, a process known as ischemia-reperfusion injury. Excess reactive oxygen species and intracellular calcium contribute to cell damage but the involvement of sirt1, a versatile protein deacetylase in reperfusion-induced cell damage remains unknown. Here, we found that hypoxia-reoxygenation, an in vitro model of ischemia-reperfusion injury, induced H9c2 cardiomyocyte apoptosis as revealed by caspase-3 assay, Hoechst 33258 staining, flow cytometric analysis and JC-1 staining. Molecular docking analysis showed that, pterostilbene, a natural dimethyl ether derivative of resveratrol, binds to the enzymatic active pocket of sirt1. Importantly, application of pterostilbene at low concentrations of 0.1-3.0 μM rescued H9c2 cells from apoptosis, an effect comparable with resveratrol at 20 μM. Mechanistically, pterostilbene exerted its cardioprotective effects via 1) stimulation of sirt1 activity, since pretreatment of H9c2 cells with splitomicin, an antagonist of sirt1, removed the effects of pterostilbene, and 2) enhancement of sirt1 expression. Therefore, the present study demonstrates that activation of sitr1 during ischemia-reperfusion is cardioprotective and that the natural compound-pterostilbene-could be used therapeutically to alleviate ischemia-reperfusion injury.

Topics: Animals; Apoptosis; Catalytic Domain; Cell Hypoxia; Cell Line; Cell Survival; Down-Regulation; Enzyme Activation; Mitochondria; Molecular Docking Simulation; Myocytes, Cardiac; Oxygen; Rats; Reperfusion Injury; Sirtuin 1; Stilbenes

To evaluate protective effect of pterostilbene against testicular ischemia/reperfusion (I/R) injury, which results in increased formation of oxidative stress, leading to testicular apoptosis and impaired spermatogenesis.. Thirty two pubertal male Sprague-Dawley rats weighing 180-220g were selected and randomly divided into the following four groups: group A (normal control group), group B (sham-operated group), group C (induced I/R injury group), group D (induced I/R injury group receiving pterostilbene treatment). Johnsen's scores and mean seminiferous tubule diameters were evaluated for histopathologic assessment; germinal cell apoptosis was evaluated by the transferase dUTP nick end labeling (TUNEL) assay and immunohistochemistry for caspases. Malondialdehyde (MDA) levels were assessed as an indicator of oxidative stress and total antioxidant capacity (TAC) was measured.. Germ cell apoptosis and MDA level significantly increased whereas TAC significantly decreased in group C; moreover, abnormal morphology and impaired spermatogenesis were observed in group C. In contrast, treatment with pterostilbene inhibited lipid peroxidation and apoptosis induced by ROS and restored the antioxidant capacity in group D.. These results show that treatment with pterostilbene may be a promising therapy for testicular I/R injury.

Topics: Animals; Antioxidants; Apoptosis; Biomarkers; Lipid Peroxidation; Male; Malondialdehyde; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Spermatic Cord Torsion; Stilbenes; Testis; Treatment Outcome

The purpose of this study was to investigate the protective effect of resveratrol against hepatic ischemia reperfusion injury (HIRI) and explore the potential underlying mechanism. Resveratrol-pretreated BRL-3A (rat liver) cells and rats underwent hypoxia/reoxygenation and hepatic ischemia/reperfusion, respectively. BRL-3A cell damage was evaluated, and the mRNA and protein expression of related signal molecules was assessed in cell model. The protein expression of related signal molecules was also assessed in rat model. Inflammatory cytokines levels were determined in the cell supernatant and rat serum while rat liver function and hepatocyte apoptosis were assessed. The results revealed that resveratrol significantly enhanced cell viability, inhibited cell apoptosis, and decreased levels of lactate dehydrogenase (LDH) and production of tumor necrosis factor-α (TNF-α) and interleukin-(IL)-1β in the cell supernatant. In addition, resveratrol ameliorated elevated Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB, and the depressed inhibitor of NF-κB (IκB)-α caused by hypoxia/reoxygenation stimulation in BRL-3A cells. Moreover, resveratrol inhibited the translocation of NF-κB p65 after the stimulation of hypoxia/reoxygenation in BRL-3A cells. In vivo assays revealed that resveratrol reduced levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and liver pathological changes, while it alleviated hepatocyte apoptosis, negatively mediated the production of TNF-α and IL-1β in serum, and reversed TLR4/NF-κB signaling pathway caused by hepatic ischemia/reperfusion stimulation in liver tissues. The results indicate that resveratrol protected hepatocytes against HIRI, which may be mediated in part via the TLR4/NF-κB signaling pathway.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Apoptosis; Cell Line; Disease Models, Animal; Hepatocytes; Humans; Interleukin-1beta; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Signal Transduction; Stilbenes; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

In the current study, we aimed to investigate the mechanistic role of DJ-1/PI3K/Akt survival pathway in ischemia/reperfusion (I/R) induced cerebral damage and to investigate if the resveratrol (RES) mediates its ischemic neuroptotection through this pathway. RES administration to Sham rats boosted glutathione level and superoxide dismutase activity and downregulated inducible nitric oxide synthase expression without affecting redox levels of DJ-1 forms or components of PI3K/Akt pathway including PTEN, p-Akt or p/p-GSK3b. However, RES pre-administration to I/R rats reduced infarction area, oxidative stress, inflammation and apoptosis. Concomitantly, RES ameliorated the decreased levels of oxidized forms of DJ-1 and enhancing its reduction, increased the nuclear protein expression of Nfr-2 and led to activation of PI3K/Akt survival pathway. In conclusion, overoxidation of DJ-1 is a major factor that contributes to post-I/R cerebral damage and its reduction by RES could explain the neuroprotection offered by RES.

Topics: Animals; Antioxidants; Apoptosis; Blotting, Western; Brain Ischemia; Glycogen Synthase Kinase 3 beta; Immunoenzyme Techniques; Male; Neuroprotective Agents; Oxidative Stress; Phosphatidylinositol 3-Kinases; Protein Deglycase DJ-1; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Stilbenes

It is well accepted that repetitive resveratrol (RV) pretreatment (PRC) exerts neuroprotective effect on ischemic stroke. RV was shown to be able to enhance the production of T regulatory cells (Tregs) in autoimmune diseases whereas Tregs are considered to be the cerebroprotective immunomodulator in ischemic stroke. Thus, we hypothesized whether Tregs contributed to PRC-induced neuroprotection against cerebral ischemia/reperfusion (I/R) injury.. Cerebral I/R injury was induced by middle cerebral artery occlusion for 90 minutes in rats. Adult male Sprague-Dawley rats were randomly assigned to 2 groups: I/R and RV I/R. RV (50 mg/kg) was administrated intraperitoneally once a day for 7 days prior to ischemia onset.. PRC significantly ameliorated neurological defects and reduced cerebral infarct volume, accompanied by the significantly increased frequencies of Tregs in the spleens and ischemic hemisphere, the significantly increased levels of interleukin-10 (IL-10) in the plasma and ischemic hemisphere, and the significantly decreased levels of tumor necrosis factor-α and IL-6 in the plasma and ischemic hemisphere at 24 hours after ischemia onset. In addition, we also found that PRC significantly improved the frequency and suppressive function of Tregs in the spleens prior to ischemia onset.. Thus, PRC-induced neuroprotection was in part mediated by more Treg accumulation and activation in vivo prior to ischemia onset except for less inflammation response at 24 hours after ischemia onset.

Topics: Animals; Antioxidants; Brain; Cytokines; Disease Models, Animal; Drug Administration Schedule; Flow Cytometry; Infarction, Middle Cerebral Artery; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Spleen; Stilbenes; T-Lymphocytes, Regulatory

Ischemia reperfusion (IR) injury is harmful to skeletal muscles and causes mitochondrial oxidative stress. Pterostilbene (PTE), an analogue of resveratrol, has organic protective effects against oxidative stress. However, no studies have investigated whether PTE can protect against IR-related skeletal muscular injury. In this study, we sought to evaluate the protective effect of PTE against IR-related skeletal muscle injury and to determine the mechanisms in this process. Male Sprague-Dawley rats were pretreated with PTE for a week and then underwent limb IR surgery. The IR injury induced segmental necrosis and apoptosis, myofilament disintegration, thicker interstitial spaces, and inflammatory cell infiltration. Furthermore, mitochondrial respiratory chain activity in the muscular tissue was inhibited, methane dicarboxylic aldehyde concentration and myeloperoxidase activity were up-regulated, and superoxide dismutase was down-regulated after IR. However, these effects were significantly inhibited by PTE in a dose-dependent manner. The mechanism underlying IR injury is attributed to the down-regulation of silent information regulator 1 (SIRT1)-FOXO1/p53 pathway and the increase of the Bax/Bcl2 ratio, Cleaved poly ADP-ribose polymerase 1, Cleaved Caspase 3, which can be reversed with PTE. Furthermore, EX527, an SIRT1 inhibitor, counteracted the protective effects of PTE on IR-related muscle injury. In conclusion, PTE has protective properties against IR injury of the skeletal muscles. The mechanism of this protective effect depends on the activation of the SIRT1-FOXO1/p53 signaling pathway and the decrease of the apoptotic ratio in skeletal muscle cells.

Topics: Animals; Antioxidants; Apoptosis; Caspase 3; Down-Regulation; Male; Mitochondria; Muscle, Skeletal; Myocardial Reperfusion Injury; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Sirtuin 1; Stilbenes; Superoxide Dismutase; Up-Regulation

Successful liver transplantation from non-heart-beating donors (NHBDs) might enlarge donor source. Some studies have reported that resveratrol (RES), an activator of sirtuins, has cytoprotective effects on ischemia-reperfusion (I/R) injury. The purpose of this study was to investigate the effects of RES on warm I/R injury in rats.. Male Wister rats were divided into 5 groups: (1) the heart-beating (HB) group, whose livers were retrieved from HB donors; (2) the NHB group, whose livers were retrieved under apnea-induced NHB conditions; (3) the ethanol group, retrieved in the same manner as the NHB group with ethanol (10 μL) as a solvent; (4) the RES-1 group, retrieved in the same manner as the NHB group and pretreated with RES (0.4 mg/kg, dissolved in 10 μL ethanol); and (5) the RES-2 group, retrieved in the same manner as the NHB group and pretreated with RES (2 mg/kg, dissolved in 10 μL ethanol). The resected livers were perfused for 60 minutes with Krebs-Henseleit bicarbonate buffer after 6 hours of cold preservation, after which the perfusate and liver tissues were investigated.. The bile production, portal vein flow volume, tumor necrosis factor-α level, and adenosine triphosphate level in the RES-2 group were significantly improved compared with in the NHB group. Histology revealed numerous well-preserved sinusoidal endothelial cells in the RES-2 group.. RES might reduce warm I/R injury and improve the viability of liver grafts from NHBDs. We considered that this method may represent a promising approach for clinical liver transplantation from NHBDs.

Topics: Animals; Liver Transplantation; Male; Protective Agents; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; Stilbenes; Treatment Outcome; Warm Ischemia

This study was designed to elucidate the neuroprotective effect of resveratrol in a mouse model of bilateral common carotid artery occlusion (BCCAO).. Sixty male C57BL/6 mice, weighing 20-24 g, were used in our experiments. The mice were randomly assigned into three groups: control group, BCCAO group and BCCAO+Resveratrol group. Neurological score was assessed 24h, 48h, 72h after BCCAO, respectively. Hematoxylin and eosin (H&E) staining, NeuN and TUNEL were performed to detect the neuronal death and survival. The expression of Bcl-2, Bax, caspase-3, and cleaved caspase-3 were also detected to assess the anti-apoptotic effect of resveratrol by Western Blot.. Resveratrol significantly improved neurological score in BCCAO mice. Besides, it attenuates neuronal apoptosis via increasing the expression of Bcl-2 and decreasing the expression of Bax, caspase-3, and cleaved caspase-3. Resveratrol promotes neuronal survival in mice subjected to BCCAO.. Resveratrol is beneficial in the model of BCCAO, which is associated with its anti-apoptotic effect.

Topics: Animals; Apoptosis; Caspase 3; Cell Survival; Disease Models, Animal; Ischemic Attack, Transient; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Reperfusion Injury; Resveratrol; Stilbenes

Polydatin, a glucoside of resveratrol, recently has been demonstrated possibly to exert its biological effects by targeting sonic hedgehog (Shh). However, whether Shh signaling pathway is involved in the therapeutic effects of polydatin for renal ischemia/reperfusion (I/R) injury has not been evaluated. Our results showed that I/R induced the secretion of Shh, upregulated Patched and Smoothened, and enhanced the nuclear translocation and target gene transcription of Glioblastoma 1 in renal I/R injury models, which were further upregulated after the administration of polydatin significantly and in turn exerted prominent nephroprotective effects against cell apoptosis and oxidative stress. The treatment with cyclopamine (a specific inhibitor of Smoothened) or 5E1 (an anti-Shh antibody) not only markedly inhibited the activation of the Shh pathway, but also dramatically suppressed the nephroprotective effects of polydatin above-mentioned. These results advance our knowledge that polydatin can provide protection for kidneys against I/R injury by enhancing antioxidant capacity and decreasing cell apoptosis through activating Shh signaling pathway.

Topics: Animals; Antioxidants; Apoptosis; Blotting, Western; Cell Proliferation; Cells, Cultured; Drugs, Chinese Herbal; Gene Expression Regulation; Glucosides; Hedgehog Proteins; Male; Mice; Mice, Inbred BALB C; Oxidative Stress; Proto-Oncogene Proteins c-akt; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes

The present study evaluated the effects of resveratrol in the myenteric plexus after intestinal ischemia-reperfusion (I/R) injury caused by occluding the superior mesenteric artery for 45min, followed by 7days of reperfusion.. Forty-two male Wistar rats were divided into seven groups: control (C group), untreated sham surgery control (SC group), sham surgery control treated with resveratrol before surgery (STA group), sham surgery control treated with resveratrol before and after surgery (STAD group), ischemic control (IRC group), ischemic treated before I/R (IRTA group), and ischemic treated before and after I/R (IRTAD group). Resveratrol (10mg/kg) was administered for 4days and 2h prior to surgery and/or 7days later. Morphometric analyses were performed, and the density of the general neuronal population (HuC/D-immunoreactive [IR]), nitrergic subpopulation (neuronal nitric oxide synthase [nNOS]-IR), vasoactive intestinal peptide (VIP)ergic varicosities (VIP-IR), and glial cells (S100-IR) was determined.. Injury that was caused by I/R significantly reduced (p<0.01) the HuC/D-IR general neuronal population. Treatment with resveratrol before and after ischemia had a neuroprotective effect. Morphometric changes caused by I/R in nitrergic neurons and varicosities were also attenuated by resveratrol. Ischemia/reperfusion promoted the proliferation of enteric glial cells, and resveratrol treatment before and after I/R reversed this effect.. Resveratrol had neuroprotective effects, showing promise for application in intestinal surgery and transplants.

Topics: Animals; Antioxidants; Cell Proliferation; Ileum; Male; Myenteric Plexus; Neuroglia; Neurons; Neuroprotection; Neuroprotective Agents; Nitric Oxide Synthase Type I; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; Stilbenes

The neuroprotective effect of polydatin (PD) against hemorrhagic shock-induced mitochondrial injury has been described previously, and mitochondrial dysfunction and apoptosis were reportedly involved in ischemic stroke. In the present study the neuroprotective effect of PD in preventing apoptosis was evaluated following induction of focal cerebral ischemia by middle cerebral artery occlusion (MCAO) in rats. PD (30 mg/kg) was administered by caudal vein injection 10 min prior to ischemia/reperfusion (I/R) injury. 24 h following I/R injury, ameliorated modified neurological severity scores (mNSS) and reduced infarct volume were observed in the PD treated group. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and Annexin V/propidium iodide assays demonstrated the anti-apoptotic effect of PD in the ischemic cortex. In addition, PD improved I/R injury‑induced mitochondrial dysfunction, reflected by morphological observations and measurements of mitochondrial membrane potential and intracellular ATP measurement. Western blot analysis revealed an increase in B‑cell lymphoma 2 apoptosis regulator (Bcl-2) expression, and a decrease in Bcl‑2‑associated protein X apoptosis regulator expression in the PD group in comparison with the vehicle treated group. PD treatment also prevented the release of cytochrome c from mitochondria into the cytoplasm, and blunted the activities of caspase‑9 and caspase‑3. Furthermore, PD treatment decreased the levels of reactive oxygen species in neurons isolated from the ischemic cortex. The findings of this study, therefore, suggest that PD has a dual effect, ameliorating both oxidative stress and mitochondria‑dependent apoptosis, making it a promising new therapy for the treatment of ischemic stroke.

Topics: Adenosine Triphosphate; Animals; Apoptosis; bcl-2-Associated X Protein; Biomarkers; Brain Ischemia; Cerebral Cortex; Cytochromes c; Disease Models, Animal; Glucosides; Male; Membrane Potential, Mitochondrial; Mitochondria; Neurons; Neuroprotective Agents; Proto-Oncogene Proteins c-bcl-2; Rats; Reactive Oxygen Species; Reperfusion Injury; Signal Transduction; Stilbenes

Renal ischemia-reperfusion (I/R) is a severe clinical complication with no specific treatment. Resveratrol has been shown as a promising experimental agent in renal I/R due to its effect on cellular energy metabolism, oxidative stress, and inflammation. Recently, we identified two biologically active resveratrol analogues (RSVAs), RSVA405 and RSVA314. We hypothesized that both RSAVs would attenuate I/R-induced renal injury.. Adult male rats were subjected to renal I/R through bilateral renal pedicle clamping for 60 min, followed by reperfusion. RSVA405 (3 mg/kg Body Weight), RSVA314 (3 mg/kg Body Weight), or vehicle (10% dimethyl sulfoxide and 33% Solutol in phosphate buffered saline) were administered by intraperitoneal injection 1 h before ischemia. Blood and renal tissues were collected 24 h after I/R for evaluation.. Administration of RSVA405 and RSVA314 significantly reduced the serum levels of renal dysfunction and injury markers, including creatinine, blood urea nitrogen, aspartate aminotransferase, and lactate dehydrogenase, compared with vehicle. The protective effect of RSVA405 and RSVA314 was also reflected on histologic evaluation. Both RSVAs reduced the number of apoptotic cells by more than 60% as determined by transferase dUTP nick end labeling assay, compared with vehicle. The renal adenosine triphosphate levels of the vehicle group was decreased to 52.4% of control, whereas those of the RSVA405 and RSVA314 groups were restored to 72.3% and 79.6% of control, respectively. Both RSVAs significantly reduced the protein expression of inducible nitric oxide synthase and nitrotyrosine and the messenger RNA levels of tumor necrosis factor-α, interleukin-6, and interleukin-1β.. RSVA405 and RSVA314 attenuate I/R-induced renal injury through the modulation of energy metabolism, oxidative stress, and inflammation.

Topics: Acute Kidney Injury; Adenosine Triphosphate; Aminophenols; Animals; Apoptosis; Drug Evaluation, Preclinical; Hydrazones; Kidney; Male; Oxidative Stress; Random Allocation; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes

Intestinal ischemia/reperfusion injury can be caused by surgical procedures and inflammatory bowel disease. It is normally associated with the increased production of free radicals and changes in the enteric nervous system.. Given the antioxidant and neuroprotective properties of resveratrol, the present study assessed its influence on oxidative stress in the intestinal wall and the morphology of myenteric neurons in the ileum of rats subjected to ischemia/reperfusion.. Resveratrol was orally administered daily at a dose of 10 mg/kg for 5 days. Changes in the ileum response to ischemia after 45 min were investigated followed by 3 h reperfusion. Lipoperoxide and carbonylated protein levels, and the activity of the antioxidant enzymes glutathione reductase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase were measured following ischemia/reperfusion injury.. The density and morphometry of the general neuronal population, nitrergic neurons and glial cells, and morphometry of VIP varicosities in the ileum were also studied. Lipoperoxide and carbonylated protein levels were 171 and 40% higher during the ischemia/reperfusion, respectively, compared to control cohorts, and resveratrol attenuated these values. The glutathione ratio was 64% lower during ischemia/reperfusion, compared to control cohorts. Resveratrol increased the reduced/oxidized glutathione ratio, attenuated the changes in the activity of the antioxidant enzymes and the detrimental morphologic changes caused by ischemia/reperfusion in the general neuronal population and nitrergic neurons.. Oral treatment with resveratrol reduced the oxidative stress in the ileum and attenuated the morphologic changes that occurred in the myenteric plexus of the ileum in rats subjected to ischemia/reperfusion.

Topics: Administration, Oral; Animals; Antioxidants; Disease Models, Animal; Glucosephosphate Dehydrogenase; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Ileal Diseases; Ileum; Lipid Peroxidation; Male; Myenteric Plexus; Neuroprotective Agents; Nitrergic Neurons; Oxidative Stress; Protein Carbonylation; Rats, Wistar; Reperfusion Injury; Resveratrol; Stilbenes

Pterostilbene (3,5-dimethoxy-4-hydroxystilbene) is a component of blueberry. It has been reported that long-term treatment with blueberry has a neuroprotective effect. However, it has not been reported whether pterostilbene is effective in attenuating cerebral ischemia/reperfusion (I/R) injury. In the present study, focal cerebral ischemia was induced by middle cerebral artery occlusion for 90min followed by reperfusion. To observe the dose-dependent effect, pterostilbene (2.5-80mg/kg, ig) was administered for 3days before ischemia. To determine the time-dependent effect, pterostilbene (10mg/kg, ig) was administered as a single dose at 0, 1, or 3h after reperfusion. Twenty-four hours after I/R, pterostilbene dose-dependently improved neurological function, reduced brain infarct volume, and alleviated brain edema. The most effective dose was 10mg/kg; the therapeutic time window was within 1h after I/R and treatment immediately after reperfusion showed the best protective effect. The protective effect is further confirmed by the results that post-ischemic treatment with pterostilbene (10mg/kg) significantly improved motor function, alleviated blood brain barrier disruption, increased neurons survival and reduced cell apoptosis in cortical penumbra after cerebral I/R. We also found that pterostilbene (10mg/kg) significantly reversed the increased content of malondialdehyde and the decreased activity of superoxide dismutase in the ipsilateral hemisphere. Furthermore, pterostilbene decreased the oxidative stress markers 4-hydroxynonenal and 8-hydroxyguanosine positive cells in the cortical penumbra. All these findings indicate that pterostilbene dose- and time-dependently exerts a neuroprotective effect against acute cerebral I/R injury. This neuroprotective effect of pterostilbene may be associated with its inhibition of oxidative stress and subsequent neuronal apoptosis in the cortical penumbra.

Topics: Administration, Oral; Animals; Apoptosis; Blood-Brain Barrier; Brain Ischemia; Cell Survival; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Male; Malondialdehyde; Mice; Neuroprotective Agents; Oxidative Stress; Postural Balance; Psychomotor Performance; Reperfusion Injury; Stilbenes; Superoxide Dismutase

Cerebral ischemia-reperfusion (I/R) is associated with increased levels of reactive oxygen species (ROS) and brain edema, which lead to the deterioration of patient prognosis. Resveratrol serves a neuroprotective role in I/R injury, and this role may be associated with its anti‑oxidative effects. However, resveratrol's mechanism of action in cerebral I/R injury remains to be fully understood. In order to investigate the effect of resveratrol in cerebral I/R‑induced injury, male Sprague‑Dawley rats were randomly assigned to four groups: The sham‑operation group, the I/R group and the edaravone and resveratrol groups (I/R + E and I/R + R groups). Infarct volume was evaluated by 2,3,5‑tripenyltetrazolium chloride staining, brain edema was evaluated by the water content in the reperfused brain and malondialdehyde (MDA) was measured by the thiobarbituric acid method. Superoxide dismutase (SOD) levels were measured using the Total Superoxide Dismutase Assay kit. Inducible nitric oxide synthase (iNOS) levels in the hippocampus and cortex were measured by ELISA, and aquaporin 4 (AQP4) expression was measured by immunohistochemical staining and western blot analysis. The results demonstrated that resveratrol reduced the infarct volume and the incidence of brain edema and reduced neurological deficits. These outcomes were accompanied by reduced levels of MDA, iNOS and AQP4, and increased SOD levels in cerebral I/R injury. In conclusion, resveratrol protected against cerebral I/R injury by ameliorating oxidative stress and reducing AQP4 expression.

Topics: Animals; Antioxidants; Aquaporin 4; Brain; Brain Ischemia; Male; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes

Oxidative stress and inflammation are involved in the pathogenesis in renal ischemia/reperfusion (I/R) injury. It has been demonstrated that polydatin processed the antioxidative, anti-inflammatory, and nephroprotective properties. However, whether it has beneficial effects and the possible mechanisms on renal I/R injury remain unclear. In our present study I/R models were simulated both in vitro and in vivo. Compared with vehicle control, the administration of polydatin significantly improved the renal function, accelerated the mitogenic response and reduced cell apoptosis in renal I/R injury models, strongly suppressed the I/R-induced upregulation of the expression of tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, inducible nitric oxide synthase, prostaglandin E-2, and nitric oxide levels, and dramatically decreased contents of malondialdehyde, but it increased the activity of superoxide dismutase, glutathione transferase, glutathione peroxidase and catalase, and the level of glutathione. Further investigation showed that polydatin upregulated the phosphorylation of Akt in kidneys of I/R injury dose-dependently. However, all beneficial effects of polydatin mentioned above were counteracted when we inhibited PI3K/Akt pathway with its specific inhibitor, wortmannin. Taken together, the present findings provide the first evidence demonstrating that PD exhibited prominent nephroprotective effects against renal I/R injury by antioxidative stress and inflammation through PI3-K/Akt-dependent molecular mechanisms.

Topics: Animals; Antioxidants; Cyclooxygenase 2; Disease Models, Animal; Glucosides; Interleukin-1beta; Kidney; Male; Mice; Mice, Inbred BALB C; Nitric Oxide Synthase Type II; Oxidative Stress; Oxidoreductases; Phosphatidylinositol 3-Kinases; Protective Agents; Proto-Oncogene Proteins c-akt; Reperfusion Injury; Signal Transduction; Stilbenes; Tumor Necrosis Factor-alpha; Up-Regulation

The aim of this study was to assess the effect of combined 1,25-dihydroxyvitamin D (1,25 D) and resveratrol on cardiac arrhythmias, infarct size, and transcription of catalase, thioredoxin-1 and B-cell lymphoma 2 (Bcl-2), following myocardial ischemia-reperfusion (IR) in male rats. Ligation of coronary artery was performed in rats (n = 6 per group) without any treatment (IR group), pretreated with 0.1 μg/kg/day of 1,25 D (1,25 D + IR), 1 mg/kg/day of resveratrol (Res + IR) or a combination (1,25 D + Res + IR) for 14 days. Arrhythmias were analyzed according to the Lambeth conventions, and infarct size was measured by 2,3,5-triphenyl-2H-tetrazolium chloride staining. Expression of prosurvival genes was evaluated by real-time polymerase chain reaction. In the 1,25 D + Res + IR group the mean infarct size was 17.6 ± 3.5 %, which was significantly less than that in the IR, 1,25 D + IR, and Res + IR groups (p < 0.001). Although the single therapy of either 1,25 D or resveratrol did not change the incidence of arrhythmias significantly, a reduction in the number of ventricular ectopic beats was noted in group 1,25 D + Res + IR (179.19 ± 58.87, p < 0.001 vs IR; p < 0.05 vs Res + IR; p < 0.01 vs Vit D + IR). Combination of 1,25 D and resveratrol increased transcription of catalase by 119 ± 37 % (p < 0.001 vs IR, p < 0.01 vs Res + IR, p < 0.001 vs 1,25 D + IR). Our study showed that combination of a non-hypotensive dose of 1,25 D and resveratrol can be a novel and effective strategy for protecting against ischemia.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arrhythmias, Cardiac; Calcium; Drug Therapy, Combination; Male; Myocardial Infarction; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Resveratrol; RNA, Messenger; Stilbenes; Vitamin D; Vitamins

The present study demonstrates the benefits of combinatorial antioxidant therapy in the treatment of ischemic stroke. Male Sprague-Dawley rats were anaesthetised and the middle cerebral artery (MCA) was occluded for 30 minutes followed by 5.5 hours of reperfusion. Pretreatment with resveratrol 30 minutes prior to MCA occlusion resulted in a significant, dose-dependent decrease in infarct volume (p<0.05) compared to vehicle-treated animals. Neuroprotection was also observed when resveratrol (2 × 10(-3) mg/kg; iv) was administered within 60 minutes following the return of blood flow (reperfusion). Pretreatment with non-neuroprotective doses of resveratrol (2 × 10(-6) mg/kg) and lipoic acid (LA; 0.005 mg/kg) in combination produced significant neuroprotection as well. This neuroprotection was also observed when resveratrol and LA were administered 15 minutes following the onset of MCA occlusion. Subsequently, we synthetically combined resveratrol and LA in both a 1 ∶ 3 (UPEI-200) and 1 ∶ 1 (UPEI-201) ratio, and screened these new chemical entities in both permanent and transient ischemia models. UPEI-200 was ineffective, while UPEI-201 demonstrated significant, dose-dependent neuroprotection. These results demonstrate that combining subthreshold doses of resveratrol and LA prior to ischemia-reperfusion can provide significant neuroprotection likely resulting from concurrent effects on multiple pathways. The additional protection observed in the novel compound UPEI 201 may present opportunities for addressing ischemia-induced damage in patients presenting with transient ischemic episodes.

Topics: Animals; Antioxidants; Brain Ischemia; Disease Models, Animal; Humans; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Stroke; Thioctic Acid

Ischemia/reperfusion is a leading cause of liver damage after surgical intervention, trauma, and transplantation. It has been reported that the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 attenuates myocardial, cerebral, and renal ischemia/reperfusion damage. This study aimed to investigate the involvement of sirtuin 1-mediated p66shc inhibition in liver ischemia/reperfusion and explore the effect of carnosic acid and ischemic preconditioning on liver ischemia/reperfusion-induced damage.. Laboratory investigation.. University laboratory.. Male Sprague-Dawley rats and HepG2 cells.. The rats were subjected to 45 minutes of ischemia to 70% of the liver, followed by 3-hour reperfusion. The HepG2 cells were subjected to hypoxia/reoxygenation-induced injury.. In the rats with liver ischemia/reperfusion injury, carnosic acid pretreatment and ischemic preconditioning dramatically reduced the serum aminotransferase activity and proinflammatory chemokine levels and improved the liver histological evaluations. Carnosic acid and ischemic preconditioning also increased manganese superoxide dismutase and Bcl-xL, but down-regulated cleaved caspase-3. Interestingly, the protective effect of carnosic acid and ischemic preconditioning was positively associated with sirtuin 1 activation. By contrast, p66shc, a kinase that promotes oxidative injury and apoptosis, was inhibited by carnosic acid and ischemic preconditioning. Sirtuin 1 small interfering RNA knockdown experiments confirmed that carnosic acid increased sirtuin 1-mediated repression of p66shc in HepG2 cells and that the protective effect of carnosic acid against hypoxia/reoxygenation injury was inhibited by the sirtuin 1 inhibitor nicotinamide. These results suggest that carnosic acid protects hepatocytes from hypoxia/reoxygenation damage through sirtuin 1-mediated p66shc suppression. To support this notion, we further demonstrated that the sirtuin 1 activator resveratrol achieved a protective effect similar to that of carnosic acid against hypoxia/reoxygenation injury, whereas sirtuin 1 small interfering RNA and nicotinamide had the opposite effect.. Carnosic acid and ischemic preconditioning protect against ischemia/reperfusion-induced liver injury. Mechanistically, the protective effect involves the sirtuin 1-mediated inhibition of p66shc, suggesting that this pathway is a novel potential therapeutic target for protecting the liver from ischemia/reperfusion injury.

Topics: Abietanes; Analysis of Variance; Animals; Caspases; Enzyme Inhibitors; Hep G2 Cells; Humans; In Situ Nick-End Labeling; Ischemia; Ischemic Preconditioning; Liver; Male; Niacinamide; Plant Extracts; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; RNA, Small Interfering; Shc Signaling Adaptor Proteins; Sirtuin 1; Src Homology 2 Domain-Containing, Transforming Protein 1; Stilbenes; Superoxide Dismutase; Transaminases

The purpose of this study was to identify changes taking place in the rat testis at the 24th hour of reperfusion following testicular torsion and to evaluate the effects of resveratrol (RSV), a powerful antioxidant, in preventing these changes using novel biochemical parameters and histopathology.. Eighteen adult male rats were divided into three groups: Sham-operated (S), torsion/detorsion (T/D), and T/D+RSV groups. In the T/D group, testicular ischemia was achieved by rotating the left testis 720° clockwise for 4h. In the T/D+RSV group, 20mg/kg RSV was administered intraperitoneally 30 min before detorsion. All rats were sacrificed 24h after detorsion. Serum and tissue malondialdehyde (MDA) concentrations, ischemia modified albumin (IMA), total oxidative status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), and histopathological damage score were analyzed.. Serum MDA, IMA, TOS, and OSI levels rose significantly in the T/D group. Serum MDA and IMA values were lower in the T/D+RES groups, but not significantly. OSI and TOS values were lower in the T/D+RES group, and the difference was significant. TAS values decreased significantly in the T/D group and rose in the T/D+RSV group, but not significantly. Ipsilateral tissue MDA values were significantly elevated in the T/D group and decreased in the T/D+RSV group, but not significantly. Apoptosis and histopathological damage increased significantly in the T/D group and decreased significantly in the T/D+RSV group. In the contralateral testis, apoptosis increased significantly in the T/D group. It decreased significantly in the T/D+RSV group.. Our findings show that RSV had a protective effect against oxidative damage induced with a testicular T/D model, especially at the antiapoptotic and histopathological level. OSI may be a good guide to the clinical status of testicular T/D.

Topics: Albumins; Animals; Antioxidants; Apoptosis; Drug Evaluation, Preclinical; Injections, Intraperitoneal; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Spermatic Cord Torsion; Spermatozoa; Stilbenes; Testis

Spinal cord ischemia-reperfusion (I/R) involves two-phase injury, including an initial acute ischemic insult and subsequent inflammatory reperfusion injury, resulting in blood-spinal cord barrier (BSCB) dysfunction involving the TLR₄ pathway. However, the correlation between TLR₄/MyD₈₈-dependent and TLR₄/TRIF-dependent pathways in BSCB dysfunction is not fully understood. The aim of this study is to characterize inflammatory responses in spinal cord I/R and the events that define its clinical progression with delayed neurological deficits, supporting a bimodal mechanism of injury.. Rats were intrathecally pretreated with TAK-242, MyD₈₈ inhibitory peptide, or Resveratrol at a 12 h interval for 3 days before undergoing 14-minute occlusion of aortic arch. Evan's Blue (EB) extravasation and water content were detected at 6, 12, 18, 24, 36, 48, and 72 h after reperfusion. EB extravasation, water content, and NF-κB activation were increased with time after reperfusion, suggesting a bimodal distribution, as maximal increasing were detected at both 12 and 48 h after reperfusion. The changes were directly proportional to TLR₄ levels determined by Western blot. Double-labeled immunohistochemical analysis was also used to detect the relationship between different cell types of BSCB with TLR₄. Furthermore, NF-κB and IL-1β were analyzed at 12 and 48 h to identify the correlation between MyD₈₈-dependent and TRIF-dependent pathways.. Rats without functional TLR₄ and MyD₈₈ attenuated BSCB leakage and inflammatory responses at 12 h, suggesting the ischemic event was largely mediated by MyD₈₈-dependent pathway. Similar protective effects observed in rats with depleted TLR₄, MyD₈₈, and TRIF receptor at 48 h infer that the ongoing inflammation which occurred in late phase was mainly initiated by TRIF-dependent pathway and such inflammatory response could be further amplified by MyD₈₈-dependent pathway. Additionally, microglia appeared to play a major role in early phase of inflammation after I/R injury, while in late responding phase both microglia and astrocytes were necessary.. These findings indicate the relevance of TLR4/MyD₈₈-dependent and TLR₄/TRIF-dependent pathways in bimodal phases of inflammatory responses after I/R injury, corresponding with the clinical progression of injury and delayed onset of symptoms. The clinical usage of TLR₄ signaling inhibitors at different phases may be a therapeutic option for the prevention of delayed injury.

Topics: Adaptor Proteins, Vesicular Transport; Animals; Antioxidants; Calcium-Binding Proteins; Capillary Permeability; CD13 Antigens; Disease Models, Animal; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Microfilament Proteins; Myeloid Differentiation Factor 88; Peptides; Rats; Reperfusion Injury; Resveratrol; Signal Transduction; Spinal Cord; Spinal Cord Ischemia; Stilbenes; Sulfonamides; Time Factors; Toll-Like Receptor 4

Lung ischemia and reperfusion (I/R) injury is one of the major causes of postoperative pulmonary dysfunction after cardiopulmonary surgery and thoracic organ transplantation. Recent studies suggest that lung I/R injury may be associated with defects in pulmonary mitochondrial function, in addition to damage from reactive oxygen species. In this study, we examined effects of one lung I/R injury on the other lung, and the protective efficacy of resveratrol on mitochondrial biogenesis in lungs.. Studies were performed in male Sprague-Dawley rats in 3 groups: sham-operated, lung I/R injury, and treated with resveratrol before lung I/R injury (20 mg/kg/d, orally). Lung ischemia was established by occluding the lung left hilum for 60 minutes, followed by releasing the occlusion and closing the chest. Four days after ischemia, we assessed the lung water content and protein concentration in lung lavage of the nonischemic lung; lung inflammation and pulmonary oxidative stress were assessed by leukocyte counts and tissue content of malondialdehyde (MDA), respectively. The level of mitochondrial biogenesis was determined according to PGC1-α mRNA expression.. The left lung I/R injury significantly suppressed right lung PGC1-α mRNA expression, increasing pulmonary oxidative stress, lung water content, and lavage leukocyte count and protein concentration (P < .05). Resveratrol treatment attenuated lung injury as well as increasing PGC1-α mRNA expression.. Resveratrol treatment protects lung against I/R injury through improving mitochondrial biogenesis and reducing oxidative stress and leukocyte infiltration.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Capillaries; Cytoprotection; Leukocytes; Lung; Lung Injury; Male; Malondialdehyde; Mitochondria; Mitochondrial Turnover; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; RNA, Messenger; Stilbenes; Transcription Factors

Ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) is evoked by diverse pathophysiological conditions and/or surgical procedures. Here, we evaluated the nephropreventive effect of sulfotransferase (SULT) inhibitors, quercetin, and resveratrol, which hamper hepatic indoxyl sulfate (IS) production. I/R of the kidney caused severe renal injury with marked accumulation of serum and renal IS and urinary excretion of kidney injury molecule-1. Oral administration of AST-120 resulted in a significant restoration of kidney injury, suggesting that uremic toxins, which can be suppressed or adsorbed by AST-120 in the intestine, contribute to the progression or development of I/R-induced AKI. Oral administration of resveratrol or quercetin, SULT inhibitors, suppressed IS accumulation, accompanied by significant amelioration of renal dysfunction. The expression of nuclear factor E2-related factor 2 (Nrf2) in the renal nuclear fractions was markedly elevated by renal I/R, but suppressed by treatment with SULT inhibitors. IS is primarily taken up by HK-2 cells derived from human proximal tubular cells via organic anion transporters, which then evokes activation of Nrf2, most likely due to intracellular oxidative stress. Renal basolateral organic anion transporters OAT1 and OAT3, which mediate renal tubular uptake of IS in basolateral membrane, were markedly downregulated by renal I/R, but restored by SULT inhibitors. Our results suggest that renal accumulation of IS in ischemic AKI induces oxidative stress and downregulation of organic anion transporters resulting in kidney damage, which could be restored to some extent by inhibiting hepatic SULT activity as a nephropreventive target.

Topics: Acute Kidney Injury; Animals; Blotting, Western; Carbon; Cell Line; Chromatography, High Pressure Liquid; Enzyme Inhibitors; Humans; Indican; Isothiocyanates; Lipid Peroxidation; Liver; Male; NF-E2-Related Factor 2; Oxides; Quercetin; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Sulfotransferases; Sulfoxides

Hypoxia-inducible factor-1α (HIF-1α) is overexpressed in many human tumors and their metastases, and is closely associated with a more aggressive tumor phenotype. The aim of the present study was to investigate the effect of resveratrol (RES) on the expression of ischemic-induced HIF-1α and vascular endothelial growth factor (VEGF) in rat liver.. Twenty-four rats were randomized into Sham, ischemia/reperfusion (I/R), and RES preconditioning groups. I/R was induced by portal pedicle clamping for 60 minutes followed by reperfusion for 60 minutes. The rats in RES group underwent the same surgical procedure as I/R group, and received 20 mg/kg resveratrol intravenously 30 min prior to ischemia. Blood and liver tissue samples were collected and subjected to biochemical assays, RT-PCR, and Western blot assays.. I/R resulted in a significant (P<0.05) increase in liver HIF-1α and VEGF at both mRNA and protein levels 60 minutes after reperfusion. The mRNA and protein expressions of HIF-1α and VEGF decreased significantly in RES group when compared to I/R group (P<0.05).. The inhibiting effect of RES on the expressions of HIF-1α and VEGF induced by I/R in rat liver suggested that HIF-1α/VEGF could be a promising drug target for RES in the development of an effective anticancer therapy for the prevention of hepatic tumor growth and metastasis.

Topics: Animals; Gene Expression Regulation; Hypoxia-Inducible Factor 1, alpha Subunit; Liver; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; RNA, Messenger; Stilbenes; Vascular Endothelial Growth Factor A; Warm Ischemia

To detect the role of surviving (SVV) in the protective effect of resveratrol against hypoxia/reperfusion injury (H/RI) of cardiac microvascular endothelial cells (CMECs).. CMECs isolated from the hearts of adult rats were exposed to hypoxia (94% N₂, 5% CO₂, 1% O₂) for 2 h followed by 4 h reoxygenation (95% O₂, 5% CO₂). The cell proliferation of CMECs was measured by MTT assay and Transwell method was used to detect migration ability of CMEC, PI-AnnexinV double staining and flow cytometry technique were employed to observe the apoptotic rate of CMECs. The SVV protein expression was detected with Western blot method.. Compared to control group, the proliferation (0.19 ± 0.03 vs. 0.42 ± 0.07, P < 0.01) and migration ((28 ± 2)/5HPF vs. (50 ± 3)/5 HPF, P < 0.01) abilities were impaired and the apoptosis index ((19.7 ± 0.8)% vs. (5.4 ± 0.3)%, (P < 0.05) of CMEC was increased after H/RI. The proliferation (0.36 ± 0.07 vs. 0.19 ± 0.03, P < 0.05) and migration ((55 ± 3)/5HPF vs. (28 ± 2)/5HPF, P < 0.05) abilities of CMEC were significantly improved while the apoptosis index ((9.6 ± 0.7)% vs. (19.7 ± 0.8)%, P < 0.05) was significantly decreased in H/RI+resveratrol group compared to H/RI group.SVV protein expression was also upregulated in H/RI+resveratrol group compared to H/RI group (P < 0.05). To further ascertain the role of SVV in the protective effects of resveratrol, PI3K specific inhibitor LY294002 was added to H/RI+resveratrol group, the proliferation (0.25 ± 0.05 vs. 0.36 ± 0.07, P < 0.05) and migration ((34 ± 3)/5HPF vs. (55 ± 3)/5HPF, P < 0.05) abilities were significantly decreased, the apoptosis index ((16.2 ± 0.6)% vs. (9.6 ± 0.7)%, P < 0.05) was increased and the protein expression of SVV was downregulated (P < 0.05) in LY294002+H/RI+resveratrol group compared to H/RI+resveratrol group.. Resveratrol could significantly reduce H/RI induced apoptosis and attenuate H/RI induced cardiac microvascular endothelial cells dysfunction through up-regulating PI3K/Akt/SVV pathways.

Topics: Animals; Apoptosis; Cell Proliferation; Chromones; Endothelial Cells; Enzyme Inhibitors; Heart; Hypoxia; Morpholines; Myocardium; Myocytes, Cardiac; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Up-Regulation

Polydatin is a monocrystaline compound isolated from Polygonum cuspidatum Sieb. et Zucc. (Polygonaceae) with biological properties, such as anti-inflammation, anti-oxidative and nephroprotective effects. Increasing number of studies have demonstrated the protective effect of polydatin on renal ischemia reperfusion injury. However, the possible mechanisms of this protection are not fully elucidated. This study aimed to investigate the effect of polydatin on ischemia-reperfusion induced expression of toll-like receptor4 (TLR4) in rat renal tubular epithelia cells (NRK-52E), and analyze the mechanism of polydatin on TLR4 signal pathway. The cultured NRK-52E cells were incubated in three gas incubators for a period of 6 h at hypoxia and 24h at reoxygenation to simulate the ischemia-reperfusion injury in vitro. TLR4 mRNA level was analyzed by real-time-PCR, and the protein expression of TLR4 and NF-κB by Western blotting, while TNF-α and IL-1β proteins expressions were detected by ELISA. Polydatin downregulated I/R induced mRNA and protein expressions of TLR4, and decreased the protein expression of NF-κB, TNF-α and IL-1β. The TLR4 blocker partially antagonized the effect of I/R on NF-κB signaling, and such inhibitory effect was markedly enhanced by polydatin. In the present study, polydatin protects NRK-52E cells from I/R injury possibly by relieving the inflammatory response through regulation of TLR4/NF-κB signaling pathway.

Topics: Animals; Cell Line; Drugs, Chinese Herbal; Gene Expression; Glucosides; Humans; Rats; Reperfusion Injury; Stilbenes; Toll-Like Receptor 4

Previous studies have provided evidences that resveratrol can protect the brain from ischemia/reperfusion injury; the mechanisms of its neuroprotective effects remain unknown. To investigate whether resveratrol has neuroprotective effects on ischemia and reperfusion injury and whether resveratrol exerts its neuroprotective effects through inhibition of calpain proteolysis of TRPC6, a transient middle cerebral artery occlusion (MCAO) model was employed in rats. Western blot analysis was performed to detect the protein levels of aII-spectrin, transient receptor potential canonical (subtype) 6 (TRPC6) and phosphorylated cAMP/Ca(2+) response element-binding protein (p-CREB). The immunoreactivity of p-CREB and TRPC6 were measured by quantum dot-based immunofluorescence analysis. Our results showed that MCAO rats showed large cortical infarct volumes and neurological scores. By contrast, resveratrol, when applied for 7 days before MCAO onset, significantly reduced infarct volumes and enhanced neurological scores at 24 h after reperfusion, and these results were accompanied by elevated TRPC6 and p-CREB activity and decreased calpain activity. When MEK or CaMKIV activity was inhibited by the addition of PD98059 or KN62, the neuroprotective effects of resveratrol were attenuated, and we observed a correlated decrease in CREB activity. Our results demonstrated that resveratrol prevented the brain from ischemia/reperfusion injury through the TRPC6-MEK-CREB and TRPC6-CaMKIV-CREB pathways.

Topics: Animals; Calpain; Cyclic AMP Response Element-Binding Protein; Infarction, Middle Cerebral Artery; Male; Neuroprotective Agents; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Signal Transduction; Stilbenes; TRPC Cation Channels

Resveratrol has been shown to attenuate reactive oxygen species formation and protect against ischemia-reperfusion (I/R) injury. However, the effects of resveratrol against subacute intestinal I/R injury are not clearly elucidated. Therefore, this study was designed to investigate the effects and possible protective mechanisms of resveratrol on subacute intestinal I/R injury in mice.. BALB/c mice were subjected to 1 h ischemia by occluding the superior mesenteric artery and 24 h reperfusion. Histologic injury; myeloperoxidase, superoxide dismutase, and glutathione peroxidase activity; malondialdehyde level; inducible nitric oxide synthase (iNOS), Ac-NF-κBp65, and sirtuin 1 (SIRT1) expression; NF-κB translocation; and nitric oxide (NO) production were examined in treated with or without resveratrol in the absence or presence of pharmacologic inhibitors.. Resveratrol significantly ameliorated subacute intestinal I/R injury accompanied with the decrease of NO production as well as iNOS expression. In addition, resveratrol obviously upregulated the expression of SIRT1 and inhibited the activity of NF-κB. After application of iNOS inhibitor S-methylisothiourea and NF-κB inhibitor pyrrolidine dithiocarbamate, the protective effect of resveratrol was significantly augmented by attenuating iNOS and NO production, indicating that resveratrol exerted its protective effect on intestinal I/R injury via NF-κB-mediated iNOS pathway. Furthermore, the protective effect of resveratrol was correlated with SIRT1, because application of SIRT1 inhibitor nicotinamide strikingly weakened the protective effect of resveratrol.. Taken together, our findings showed that resveratrol protects intestinal subacute I/R injury via the SIRT1-NF-κB pathway in an iNOS-NO-dependent manner. Therefore, resveratrol has a potential clinical prospect for further development of anti-injury therapy.

Topics: Animals; Antioxidants; Intestine, Small; Male; Mesenteric Artery, Superior; Mice; Mice, Inbred BALB C; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Reperfusion Injury; Resveratrol; Sirtuin 1; Stilbenes

Resveratrol, a dietary polyphenol with antioxidant and anti-inflammatory activity, has been shown to provide neuroprotection in models of ischemia. However, the mechanism of action of resveratrol-induced neuroprotection remains unclear. Previous work in our laboratory has provided evidence that acute, systemic administration of resveratrol is neuroprotective in a permanent model of cerebral ischemia, an effect that was blocked when animals received the non-selective estrogen receptor antagonist, ICI, 182,780. The present study was designed to investigate whether the source of neuroprotection afforded by resveratrol action within the cerebral cortex itself is mediated preferentially via selective activation of either α or β estrogen receptor subtype. Intracortical injection of resveratrol (0.1 and 1.0 μM) 10 min prior to 30 min of ischemia followed by 5.5h of reperfusion significantly reduced infarct volume in the prefrontal cortex. This neuroprotective effect was significantly attenuated when resveratrol injection (1.0 μM) was preceded by injection of a selective estrogen receptor α antagonist, 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1N-pyrozole dihydrochloride (MPP) or a selective estrogen receptor beta (ERβ) antagonist, 4-[2-phenyo-5,7-bis(trifluoromrthyl)pyrazolo(1,5-a)pyrimidin-3-yl]phenol (PHTPP). These results provide evidence for rapidly induced neuroprotection mediated by resveratrol activation of either estrogen receptor subtype within the ischemic cortex of rats.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Estrogen Receptor alpha; Estrogen Receptor beta; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Treatment Outcome

To observe the protective effect of retrograde venous perfusion of cryogenic liquid via accessory hemiazygos vein and treated with resveratrol on spinal cord injury and evaluate the expression changes of microtubule-associated protein 2 (MAP-2) after spinal cord ischemia reperfusion injury (SCII) in swine.. Eighteen swine were divided into 3 groups: group I/R (n = 6, operation group), group CL (n = 6, retrograde venous perfusion of cryogenic liquid), group CL+Res (n = 6, retrograde venous perfusion of cryogenic liquid and treated with resveratrol after ischemia). In the group I/R, the aorta was clamped for 60 minutes and then removed. In the group CL and CL+Res, 9 g/L cold (4 °C) saline solution (perfusion rate, 16.65 ml/min) was infused into the accessory hemiazygos vein during ischemia.In the group CL+Res, the swine were treated with resveratrol (10 mg/kg) after spinal cord ischemia. Arterial pressure, blood gas analysis and the spinal canal and nasopharyngeal temperature changes were monitored during the surgery. Nervous function were assessed at 6 hours, 1, 2 days, 1, 2, 4 weeks and MAP-2 expression were detected at 4 weeks after reperfusion by using Western blot analysis in spinal cord tissue.. After operation 18 swine were all survival. Behavioral scores of all groups decreased until 1 week after reperfusion and increased as time went by. The scores of group CL and CL+Res were higher than group I/R (F = 8.612, 17.276 and 11.985, P = 0.035,0.011 and 0.023) at 6 hours, 1, 2 days, group CL+Res were higher than group CL(P = 0.021) at 1 days after surgery. After descending aortic cross clamping, the spinal canal and nasopharyngeal temperature were obviously decreased in all groups and dropped to the lowest at 60 minutes after ischemia and 20 minutes after reperfusion in group I/R and the other groups respectively(F = 23.187-55.029, P < 0.01).In group CL(0.54 ± 0.26) and CL+Res (0.66 ± 0.31), the MAP-2 expression were higher than group I/R(0.37 ± 0.18) (F = 9.381, P = 0.037) , and the level in group CL+Res was higher than in group CL (P = 0.021) .. Retrograde venous perfusion of cryogenic liquid via accessory hemiazygos vein and treated with resveratrol can relieve the ischemia-induced spinal cord injury in swine.

Topics: Animals; Hypothermia, Induced; Male; Microtubule-Associated Proteins; Reperfusion Injury; Resveratrol; Spinal Cord; Spinal Cord Injuries; Stilbenes; Swine

Retinal ischemia-associated ocular disorders, such as retinal occlusive disorders, neovascular age-related macular degeneration, proliferative diabetic retinopathy, and glaucoma are vision-threatening. In this study, we examined whether and by what mechanisms resveratrol, a polyphenol found in red wine, is able to protect against retinal ischemia/reperfusion injury.. In vivo rat retinal ischemia was induced by high intraocular pressure (HIOP), namely, 120 mmHg for 60 min. The mechanism and management was evaluated by electroretinogram (ERG) b-wave amplitudes measurement, immunohistochemistry, and real-time polymerase chain reaction.. The HIOP-induced retinal ischemic changes were characterized by a decrease in ERG b-wave amplitudes, a loss of choline acetyltransferase immunolabeling of amacrine cell bodies/neuronal processes, and increased vimentin immunoreactivity, which is a marker of Müller cells, together with upregulation of matrix metalloproteinase-9 (MMP-9), heme oxygenase-1 (HO-1), and inducible nitric oxide (iNOS), and downregulation of Thy-1, both at the mRNA level. The detrimental effects due to the ischemia were concentration-dependent (weaker effect at 0.05 nmole) and/or significantly (at 0.5 nmole) altered when resveratrol was applied 15 min before or after retina ischemia.. This study supports the hypothesis that resveratrol may be able to protect the retina against ischemia by downregulation of MMP-9 and iNOS, and upregulation of HO-1.

Topics: Animals; Dose-Response Relationship, Drug; Down-Regulation; Electroretinography; Heme Oxygenase-1; Intraocular Pressure; Matrix Metalloproteinase 9; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Resveratrol; Retina; Retinal Vessels; RNA, Messenger; Stilbenes; Thy-1 Antigens; Up-Regulation; Vimentin

The purpose of the present study was to investigate whether systemically administered resveratrol can protect against acute retinal ischemic reperfusion injury. Two groups of adult male Sprague Dawley rats (n = 6 per group) were used for this study. Resveratrol (30 mg/kg) or an equal volume of vehicle (30% Solutol HS 15 in 0.9% saline) was administered daily for 5 days via intraperitoneal injection. On the third day of treatment, retinal ischemic injury was induced by elevation of intraocular pressure for 45 min. Prior to resveratrol administration and one-week following ischemic insult, retinal function was measured by scotopic electroretinography (ERG). Retinas were harvested and morphologically analyzed one week after ischemic insult. ERG a- and b-wave amplitudes were significantly reduced following ischemic reperfusion injury. Resveratrol treatment attenuated ischemic-induced loss of retinal function. In control vehicle-treated rats, ischemic reperfusion injury elicited marked thinning of inner retinal layers. Resveratrol prophylactic treatment reduced ischemia-mediated thinning of the whole retina and in particular the inner retinal layers. Therefore, resveratrol may have therapeutic value for the management of retinal ischemic disorders.

Topics: Animals; Cytoprotection; Disease Models, Animal; Electroretinography; Injections, Intraperitoneal; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Retina; Retinal Diseases; Stilbenes; Time Factors

To observe the effect of resveratrol and propofol, used either alone or in combination, on hepatocyte apoptosis in rats with hepatic ischemia-reperfusion injury (HIRI).. A total of 144 male SD rats were randomized into 8 equal groups, including a sham-operated group and 7 HIRI (established using Pringle method) groups with pretreatments with normal saline, Tween80, propofol (10 or 20 mg·kg(-1)·h(-1)), or resveratrol (10 or 20 mg/kg), or both propofol and resveratrol 10 min before hepatic portal vein occlusion. At 1, 3 and 6 h after the reperfusion, 6 rats from each group were sacrificed for histopathological examination of the liver tissue, detection of hepatocyte apoptosis using TUNEL assay, and measurement of Bcl-2, Bax and caspase-3 protein expressions using immunohistochemistry.. Compared with normal saline and Tween80, propofol and resveratrol at different doses used alone or in combination all significantly alleviated the hepatic pathologies, lowered the apoptosis index (P<0.05), increased Bcl-2 expression (P<0.05), and reduced Bax and caspase-3 expressions in the liver tissues following HIRI (P<0.05). Compared with low doses of propofol and resveratrol used alone, their combination showed more obvious protective effects against hepatocyte apoptosis (P<0.05), but at higher doses, propofol and resveratrol either alone or in combination produced similar effects.. Propofol and resveratrol can suppress HIRI-induced hepatocyte apoptosis by up-regulating Bcl-2 and down-regulating Bax and caspase-3 expressions, and their combined use can reduce the effective doses of the drugs.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Hepatocytes; Ischemic Preconditioning; Liver Diseases; Male; Propofol; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes

Endoplasmic reticulum (ER) stress has been demonstrated to contribute to neurodegeneration in multiple ocular diseases. However, whether ER stress can induce vascular degeneration in the retina remains unknown. We investigated the possible role of ER stress in retinal vascular degeneration in vivo, and the effects of resveratrol on tunicamycin and ischemia and reperfusion (I/R)-induced retinal vascular degeneration.. Different dosages of tunicamycin, an ER stress inducer, were injected into the vitreous of mouse eyes. Retinal I/R injury was induced by elevating the intraocular pressure for 60 minutes followed by reperfusion in mice. Two dosages of resveratrol (5 and 25 mg/kg body weight per day) were administrated 2 days before retinal I/R injury, while 100 μM resveratrol were injected into the vitreous together with tunicamycin. Formation of acellular capillaries was assessed 7 days after I/R injury and tunicamycin injection, while cell bodies in ganglion cell layer and brain-specific homeobox/POU domain protein 3A (Brn3a) staining on retinal flat-mounts were analyzed 4 days after I/R injury. ER stress markers, including eukaryotic initiation factor 2α (eIF2α), CCAAT enhancer-binding protein homologous protein (CHOP), immunoglobulin binding protein (Bip), inositol requiring enzyme 1α (IRE1α), C-jun N-terminal kinase (JNK)1/2 and Xbp1 splicing, were examined by RT-PCR, or Western blots or immunostaining from retinas 1 or 2 days after tunicamycin injection and I/R injury.. Tunicamycin caused ER stress and capillary degeneration in vivo, both of which were inhibited by resveratrol. Pretreatment of high dosage of resveratrol also significantly inhibited retinal I/R injury-induced capillary degeneration; however, neither of the dosages prevented the injury-induced neurodegeneration. Levels of CHOP, phosphorylated eIF2α, IRE1α, phosphorylated JNK1/2, Xbp1 splicing and Bip were elevated after I/R injury. High dosage of resveratrol pretreatment inhibited the injury-induced up-regulation of eIF2α-CHOP and IRE1α-XBP1 pathways.. ER stress is an important contributor to vascular degeneration in retina. Resveratrol suppresses I/R injury and tunicamycin-induced vascular degeneration by inhibiting ER stress.

Topics: Angiogenesis Inhibitors; Animals; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Disease Models, Animal; DNA-Binding Proteins; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Mice; Mice, Inbred C57BL; Oligopeptides; Protein Serine-Threonine Kinases; Regulatory Factor X Transcription Factors; Reperfusion Injury; Resveratrol; Retinal Degeneration; Retinal Ganglion Cells; Retinal Vessels; Reverse Transcriptase Polymerase Chain Reaction; RNA; Stilbenes; Transcription Factor CHOP; Transcription Factors; Tunicamycin; Up-Regulation; X-Box Binding Protein 1

Accumulating evidence indicates that resveratrol potently protects against cerebral ischemia damage due to its oxygen free radicals scavenging and antioxidant properties. However, cellular mechanisms that may underlie the neuroprotective effects of resveratrol in brain ischemia are not fully understood yet. This study aimed to investigate the potential association between the neuroprotective effect of resveratrol and the apoptosis/survival signaling pathways, in particular the glycogen synthase kinase 3 (GSK-3β) and cAMP response element-binding protein (CREB) through phosphatidylinositol 3-kinase (PI3-K)-dependent pathway. An experimental model of global cerebral ischemia was induced in rats by the four-vessel occlusion method for 10 min and followed by different periods of reperfusion. Nissl staining indicated extensive neuronal death at 7 days after ischemia/reperfusion. Administration of resveratrol by i.p. injections (30 mg/kg) for 7 days before ischemia significantly attenuated neuronal death. Both GSK-3β and CREB appear to play a critical role in resveratrol neuroprotection through the PI3-K/Akt pathway, as resveratrol pretreatment increased the phosphorylation of Akt, GSK-3β and CREB in 1 h in the CA1 hippocampus after ischemia/reperfusion. Furthermore, administration of LY294002, an inhibitor of PI3-K, compromised the neuroprotective effect of resveratrol and decreased the level of p-Akt, p-GSK-3β and p-CREB after ischemic injury. Taken together, the results suggest that resveratrol protects against delayed neuronal death in the hippocampal CA1 by maintaining the pro-survival states of Akt, GSK-3β and CREB pathways. These data suggest that the neuroprotective effect of resveratrol may be mediated through activation of the PI3-K/Akt signaling pathway, subsequently downregulating expression of GSK-3β and CREB, thereby leading to prevention of neuronal death after brain ischemia in rats.

Topics: Animals; Apoptosis; Brain Ischemia; CA1 Region, Hippocampal; Chromones; Cyclic AMP Response Element-Binding Protein; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Morpholines; Neurons; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; Signal Transduction; Stilbenes

This study was designed to investigate whether Resveratrol (Res) could be a prophylactic factor in the prevention of I/R injury and to shed light on its underlying mechanism. Primary culture of neonatal rat cardiomyocytes were randomly distributed into three groups: the normal group (cultured cardiomyocytes were in normal conditions), the I/R group (cultured cardiomyocytes were subjected to 2 h simulated ischemia followed by 4 h reperfusion), and the Res+I/R group (100 µmol/L Res was administered before cardiomyocytes were subjected to 2 h simulated ischemia followed by 4 h reperfusion). To test the extent of cardiomyocyte injury, several indices were detected including cell viability, LDH activity, Na(+)-K(+)-ATPase and Ca(2+)-ATPase activity. To test apoptotic cell death, caspase-3 activity and the expression of Bcl-2/Bax were detected. To explore the underlying mechanism, several inhibitors, intracellular calcium, SOD activity and MDA content were used to identify some key molecules involved. Res increased cell viability, Na(+)-K(+)-ATPase and Ca(2+)-ATPase activity, Bcl-2 expression, and SOD level. While LDH activity, capase-3 activity, Bax expression, intracellular calcium and MDA content were decreased by Res. And the effect of Res was blocked completely by either L-NAME (an eNOS inhibitor) or MB (a cGMP inhibitor), and partly by either DS (a PKC inhibitor) or Glybenclamide (a K(ATP) inhibitor). Our results suggest that Res attenuates I/R injury in cardiomyocytes by preventing cell apoptosis, decreasing LDH release and increasing ATPase activity. NO, cGMP, PKC and K(ATP) may play an important role in the protective role of Res. Moreover, Res enhances the capacity of anti-oxygen free radical and alleviates intracellular calcium overload in cardiomyocytes.

Topics: Animals; Animals, Newborn; Apoptosis; bcl-2-Associated X Protein; Calcium; Calcium-Transporting ATPases; Cardiotonic Agents; Caspase 3; Cell Survival; Gene Expression Regulation; Intracellular Space; L-Lactate Dehydrogenase; Myocytes, Cardiac; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Sodium-Potassium-Exchanging ATPase; Stilbenes

Repetitive enteral or intraperitoneal administration of resveratrol at high doses has recently been found to protect the small intestine against acute ischemia/reperfusion (I/R) injury. In the present work, the protective potential of solvent-free continuous intravenous infusions of small amounts of resveratrol was studied in a model of severe intestinal I/R injury.. Mesenteric ischemia was induced in male Wistar rats (six animals/group) by superior mesenteric artery occlusion (SMAO, 90 min) and reperfusion (120 min) by reopening of the microvascular clamp. Resveratrol (0.056 or 0.28 mg/kg) was continuously perfused into the jugular vein (0.014 or 0.07 mg/kg × h) starting 30 min before SMAO; an SMAO control group and sham groups (no SMAO) receiving either 0.9% NaCl solution or resveratrol (0.28 mg/kg) were included. During the experimental procedure, isotonic saline was given at a systolic blood pressure below 90 mmHg, and several parameters including those of biomonitoring and blood gas analysis were measured. Small intestine injury was assessed macroscopically, from released plasma enzyme activities, from the tissue contents of thiobarbituric acid-reactive substances and hemoglobin, from the tissue myeloperoxidase activity, and histopathologically.. Resveratrol at only 0.056 mg/kg significantly decreased the macroscopic damage score, the tissue myeloperoxidase activity, the hemoglobin content, the histopathologic score, and the plasma glutamate-pyruvate transaminase activity, but it did not improve the systemic and metabolic parameters. Instead, during reperfusion, significantly higher volumes of saline were administered to animals receiving the polyphenol, although resveratrol did not significantly affect any parameters in sham-operated animals.. Low doses of intravenously administered resveratrol considerably protected the rat small intestine against severe I/R injury, despite some adverse effects on blood pressure under these conditions.

Topics: Animals; Antioxidants; Blood Pressure; Dose-Response Relationship, Drug; Infusions, Intravenous; Intestine, Small; Male; Models, Animal; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; Severity of Illness Index; Stilbenes

Oxidative stress damage plays a vital role in cerebral ischemia/reperfusion (I/R) pathogenesis. The nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway can be activated by pharmacological and dietary means to attenuate cellular oxidative stress. Resveratrol, a plant-derived polyphenolic compound, has antioxidant property. Recent studies have demonstrated that resveratrol has protective effects against cerebral I/R injury. However, little is known about its mechanism. Hence, this study identified the neuroprotective effect of resveratrol pretreatment and elucidate the Nrf2/ARE signaling mechanism after focal cerebral I/R injury in rats. Adult male Sprague-Dawley rats were randomly assigned to sham-operated group, ischemia/reperfusion physiological saline-treated group, and ischemia/reperfusion resveratrol-pretreatmented (15 and 30 mg/kg) groups. Rats were pretreatmented with resveratrol or physiological saline of corresponding volume administered intraperitoneally for 7 days before surgery and 30 min before middle cerebral artery occlusion. At 24 h after reperfusion, neurological score, infarct volume, and brain water content were assessed. Oxidative stress was evaluated by malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. Pathological changes of brain tissue were observed by HE staining. RT-PCR and Western blot analysed the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). TUNEL staining detected apoptotic cells. The protein expression of Caspase-3 were studied by immunohistochemistry. Resveratrol pretreatment significantly ameliorated neurological scores, reduced infarct volume and brain water content, decreased MDA levels, restored the SOD activity, upregulated the protein and mRNA expression of Nrf2 and HO-1, downregulated the protein expression of caspase-3. TUNEL-positive cells significantly decreased compared with the physiological saline-treated group. HE staining also showed that resveratrol significantly improved neuronal injury. These results showed that resveratrol pretreatment had neuroprotective effects on cerebral I/R injury. This neuroprotective effect is likely exerted by upregulated expression of transcription factor Nrf2 and HO-1 to ameliorate oxidative damage, decreased the protein expression of caspase-3. Our finding is important for understanding the neuroprotective mechanism of resveratrol and promoting its clinical the

Topics: Animals; Antioxidants; Brain Ischemia; Caspase 3; DNA Fragmentation; Down-Regulation; Heme Oxygenase-1; Infarction, Middle Cerebral Artery; Male; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Up-Regulation

Neuroprotective effects of parthenocissin A (PA), a novel antioxidant and free radical scavenger, were studied in a transient middle cerebral artery (MCA) occlusion model in rats for the first time. The animals were treated intraperitoneally with PA at 2.5, 5 or 10 mg/kg, for both 30 min before MCA occlusion and 6 h after reperfusion. The MCA was occluded for 1 h in anesthetized Sprague-Dawley rats. Compared with vehicle-treated controls, MCA occluded animals treated with PA showed dose-dependent reductions in brain infarction size with improved neurological and motor outcome. Biomedical assay showed that the PA treatment suppressed lipid peroxidation and restored superoxide dismutase (SOD) activity in brain tissue. In addition, the ischemia/reperfusion (I/R) induced elevation of nitric oxide (NO) production and nitric oxide synthase (NOS) activity in brain tissue was also inhibited. Thus, PA demonstrated a neuroprotective effect in the I/R model and the beneficial effects of the compound may result from the reduction of oxidative stress and the inhibition of NO production induced by I/R. The neuroprotective effects of PA have highlighted the potential use of stilbene oligomers in stroke therapy.

Topics: Animals; Brain; Brain Ischemia; Cerebral Infarction; Free Radical Scavengers; Indenes; Infarction, Middle Cerebral Artery; Lipid Peroxidation; Male; Molecular Structure; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Rats; Reperfusion Injury; Resorcinols; Stilbenes; Superoxide Dismutase; Vitaceae

This study compared two dietary phytochemicals, grape-derived resveratrol and palm oil-derived γ-tocotrienol, either alone or in combination, on the contribution of autophagy in cardioprotection during ischaemia and reperfusion. Sprague-Dawley rats weighing between 250 and 300 g were randomly assigned to one of the following groups: vehicle, ischaemia/reperfusion (I/R), resveratrol + I/R, γ-tocotrienol + I/R, resveratrol +γ-tocotrienol + I/R. For resveratrol treatments, the rats were gavaged with resveratrol (2.5 mg/kg) for 15 days while for γ-tocotrienol experiments the rats were gavaged with γ-tocotrienol (0.3 mg/kg) for 30 days. For the combined resveratrol +γ-tocotrienol experiments, the rats were gavaged with γ-tocotrienol for 15 days, and then gavaging continued with resveratrol along with γ-tocotrienol for a further period of 15 days. After 30 days, isolated perfused hearts were subjected to 30 min. of global ischaemia followed by 2 hrs of reperfusion. Our results showed for the first time that at least in part, the cardioprotection (evidenced from the ventricular performance, myocardial infarct size and cardiomyocyte apoptosis) with resveratrol and γ-toctrienol was achieved by their abilities to induce autophagy. Most importantly, resveratrol and γ-tocotrienol acted synergistically providing greater degree of cardioprotection simultaneously generating greater amount of survival signal through the activation of Akt-Bcl-2 survival pathway. Autophagy was accompanied by the activation of Beclin and LC3-II as well as mTOR signalling, which were inhibited by either 3-methyl adenine (3-MA) or Wortmannin. The autophagy was confirmed from the results of transmission electron microscopy and light microscopy as well as with confocal microscopy. It is tempting to speculate that during ischaemia and reperfusion autophagy along with enhanced survival signals helps to recover the cells from injury.

Topics: Animals; Antioxidants; Apoptosis; Autophagy; Cardiotonic Agents; Chromans; Drug Synergism; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Signal Transduction; Stilbenes; Vitamin E

Oxidative and inflammatory processes are elicited during hepatic post-ischemic reperfusion and generate liver damage. This study investigated the early anti-inflammatory effect of trans-resveratrol (T-res) and its consequences on the late self-aggravating inflammatory process in liver ischemia-reperfusion (I/R). Partial hepatic ischemia was initiated in rats for 1 h and T-res (0.02 and 0.2 mg/kg) was administered intravenously 5 min before starting reperfusion for 3 h. Plasma levels of aminotransferases and cytokines (tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6) and hepatic neutrophil recruitment were assessed. Hepatic expression of stress protein (heat-shock protein (HSP-70), heme oxygenase-1(HO-1)) and cytokine (TNF-alpha, IL-1beta, keratinocyte chemoattractant (KC)) mRNA was investigated. I/R caused an increase in aminotransferase levels and increased polymorphonuclear cell infiltration. Post-ischemic treatment with T-res (0.02 and 0.2 mg/kg) resulted in a significant decrease in aminotransferase, IL-1beta and IL-6 plasma levels by about 40%, 60% and 40%, respectively, compared to the vehicle I/R group. Post-ischemic treatment with T-res (0.02 mg/kg) also significantly decreased hepatic neutrophil recruitment. TNF-alpha, IL-1beta, KC and HO-1 hepatic mRNA expression was reduced by T-res without any change in HSP-70 mRNA. This T-res mediated decrease in early release of cytokines and neutrophil recruitment led to a reduction in the late inflammatory process. T-resveratrol might be useful in the prevention of inflammation secondary to hepatic surgery or liver transplantation.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemokines, CXC; Heme Oxygenase-1; Interleukin-1beta; Interleukin-6; Liver; Male; Neutrophil Infiltration; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; RNA, Messenger; Stilbenes; Tumor Necrosis Factor-alpha

To investigate the protective effects of preconditioning human umbilical vein endothelial cells (HUVECs) with Polygonum multiflorum stilbeneglycoside (PMS) under anoxia/reoxygenation (A/R), and the mechanism of protection.. Prior to A/R, HUVECs were incubated with PMS (0.6 x 10(-11), 1.2 x 10(-11), or 2.4 x 10(-11) mol/L) for 3 h. Cell injury was subsequently evaluated by measuring cell viability with an MTT assay and lactate dehydrogenase (LDH) release, whereas lipid peroxidation was assayed by measuring malondialdehyde (MDA) content. Antioxidant capacity was quantified by superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity. Nitric oxide (NO) production was determined by nitrite accumulation. Endothelial NO synthase (eNOS) and inducible NOS (iNOS) protein expression was detected by Western blotting. Guanylate cyclase activity and cyclic GMP (cGMP) activity were assessed by an enzyme immunoassay kit.. PMS incubation attenuated A/R-induced injury in a concentration-dependent manner, as evidenced by a decrease in LDH activity and an increase in cell viability. PMS exerted its protective effect by inhibiting the A/R-mediated elevation of MDA content, as well as by promoting the recovery of SOD and GSH-Px activities. Additionally, PMS incubation enhanced NO and cGMP formation by increasing iNOS expression and guanylate cyclase activity. The protective effects of PMS were markedly attenuated by NOS inhibitor L-NAME, soluble guanylate cyclase inhibitor ODQ or PKG inhibitor KT5823.. PMS preincubation resulted in the enhancement of antioxidant activity and anti-lipid peroxidation. The NO/cGMP/cGMP-dependent protein kinase (PKG) signaling pathway was involved in the effect of PMS on HUVECs.

Topics: Antioxidants; Cell Survival; Cells, Cultured; Drugs, Chinese Herbal; Endothelial Cells; Glutathione Peroxidase; Glycosides; Guanylate Cyclase; Humans; L-Lactate Dehydrogenase; Lipid Peroxidation; Nitric Oxide; Nitric Oxide Synthase; Polygonum; Reperfusion Injury; Stilbenes; Superoxide Dismutase; Umbilical Veins

To investigate the neuroprotective mechanism of tetrahydroxystilbene glucoside (TSG), a Chinese medicine, on rats after cerebral ischemia-reperfusion.. A total of 96 Sprague-Dawley male rats were divided into 4 groups (n=24): a control group, an ischemia-reperfusion (I/R) model group, a low dose TSG [60 mg/(kg.d)]group, and a high dose TSG [120 mg/(kg.d)]group. After 6 days intragastric (ig) administration of TSG or natural saline (I/R group), reversible middle cerebral artery occlusion (MCAO) model was established by intraluminal suture technique. The rats of control group were operated on while the middle cerebral artery was not blocked. At 6 h, 24 h, 48 h, and 7 d after the reperfusion, behavior test was used to evaluate the neurological deficiency of each group. The protein expressions of nerve growth factor (NGF), growth associated protein (GAP)-43, and protein kinase A catalytic subunit (PKAc) in the cortex were measured by immunohistochemical method.. Compared with the I/R group, the neurological defect scores of the 2 TSG groups were significantly lower except at 6 h after the reperfusion. Compared with the I/R group, the protein expression of NGF, GAP-43, and PKAc after the reperfusion of the 2 TSG groups increased significantly.. The protein expression of NGF may increase when treated with TSG after cerebral ischemia-reperfusion, which activates the PKA pathway and increases the protein expression of GAP-43 that protects the neuron.

Topics: Animals; GAP-43 Protein; Glucosides; Infarction, Middle Cerebral Artery; Male; Nerve Growth Factor; Neuroprotective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Stilbenes

Polygonum cuspidatum is a potent anti-oxidant herb that is well known for its various bioactivities. The current study investigates which compound group is most effective, to establish the key compound groups for quality assessment, especially in terms of neuroprotective effects. The roots of P. cuspidatum were extracted with 85% methanol and fractionated with hexane, ethyl acetate, n-butanol and water. Each fraction was applied to an in vitro radical scavenging assay, a lipid peroxidation assay in brain homogenates and an in vivo assay using a transient focal cerebra ischemia model induced by a middle cerebral artery occlusion in a Sprague-Dawley rat. The ethyl acetate fraction was the most effective fraction in both in vitro and in vivo assays, having the highest stilbene and anthraquinone contents. These results suggest that stilbenes and anthraquinones may be key compound groups for the quality assessment of the anti-oxidative and neuroprotective effects of P. cuspidatum.

Topics: 1-Butanol; Acetates; Animals; Anthraquinones; Cerebrovascular Disorders; Chemical Fractionation; Chromatography, High Pressure Liquid; Fallopia japonica; Hexanes; Lipid Peroxidation; Male; Neuroprotective Agents; Phytotherapy; Plant Extracts; Plant Roots; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Rotarod Performance Test; Stilbenes

Txnip (thioredoxin-interacting protein) is a protein with multifunctional roles in cellular responses and stress-related diseases. Txnip is involved in intracellular redox regulation and has been recently described as a possible link between redox state and metabolism. trans-Resveratrol (T-res) is a natural phytoalexin with antiproliferative, antiapoptotic and antioxidative effects. However, to date there have been no reports of the implication of Txnip in a model of liver acute stress such as ischemia-reperfusion (I/R) and no work has looked for a T-res effect on Txnip. Here we studied the effects of a post-ischemic treatment of T-res on the liver thioredoxin (Trx)/Txnip system and investigated whether the T-res effects were dependent on *NO production. In this work, liver I/R induced hepatic Txnip expression and T-res inhibited I/R Txnip expression. This decrease in Txnip expression by T-res was associated with an increase in liver Trx redox activity and a decrease in hepatic I/R-induced Trx-1 expression with no effect on Trx-2, on plasma Trx redox activity or on liver and plasma Trx reductase activity, independently of *NO production. In conclusion, these results show that in our model, not only did T-res protect Trx redox activity by diminishing the Txnip protein expression; it also reduced secretion of Trx1. This is the first report of a major implication of the Trx1/Txnip system in hepatic I/R injuries. It also affirms the importance of the antioxidant effect of T-res on the Trx1/Txnip system.

Topics: Amidohydrolases; Animals; Antioxidants; Blotting, Western; Carrier Proteins; Cell Cycle Proteins; Down-Regulation; Injections, Intravenous; Liver; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Thioredoxin-Disulfide Reductase; Thioredoxins

To investigate the effects of terahydroxy stilbene glucoside (TSG) on neurological deficits, the expressions of nerve growth factor (NGF) and growth associated protein43 (GAP43) in rats after Cerebral Ischemia-reperfusion.. 96 Sprague-Dawley male rats were divided into four groups (n = 24): control group, ischemia-reperfusion (I/R) model group, low dose TSG (60 mg/kg) group and high dose TSG (120 mg/kg) group. After 6 days' administration of TSG or natural saline (model group), reversible middle cerebral artery occlusion (MCAO) model was established by intraluminal suture technique. Rats in control group were operated while middle cerebral artery were not blocked. At 6, 24, 48 h and 7 d after reperfusion, behavior test was used to evaluate the neurological deficiency of each group. The expressions of NGF and GAP-43 in the cortex were measured by immunohistochemical method.. Compared with model group, both dose of TSG could decrease the grade of the rat neurological defects except at 6 h of ter reperfusion and increase the protein expressions of NGF and GAP-43 after reperfusion.. TSG can improve the neurological function through increasing the expressions of NGF and GAP-43 of cerebral ischemia-reperfusion rats.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Disease Models, Animal; GAP-43 Protein; Glucosides; Immunohistochemistry; Infarction, Middle Cerebral Artery; Male; Nerve Growth Factor; Neuroprotective Agents; Polygonaceae; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Stilbenes

Resveratrol, a constituent of red wine, is important for cardioprotection. MicroRNAs are known regulators for genes involved in resveratrol-mediated cardiac remodeling and the regulatory pathway involving microRNA has not been studied so far.. We explored the cardioprotection by resveratrol in ischemia/reperfusion model of rat and determined cardiac functions. miRNA profile was determined from isolated RNA using quantitative Real-time PCR based array. Systemic analyses of miRNA array and theirs targets were determined using a number of computational approaches.. Cardioprotection by resveratrol and its derivative in ischemia/reperfusion [I/R] rat model was examined with miRNA expression profile. Unique expression pattern were found for each sample, particularly with resveratrol [pure compound] and longevinex [commercial resveratrol formulation] pretreated hearts. Longevinex and resveratrol pretreatment modulates the expression pattern of miRNAs close to the control level based on PCA analyses. Differential expression was observed in over 25 miRNAs, some of them, such as miR-21 were previously implicated in cardiac remodeling. The target genes for the differentially expressed miRNA include genes of various molecular function such as metal ion binding, sodium-potassium ion, transcription factors, which may play key role in reducing I/R injury.. Rats pretreated with resveratrol for 3 weeks leads to significant cardioprotection against ischemia/reperfusion injury. A unique signature of miRNA profile is observed in control heart pretreated with resveratrol or longevinex. We have determined specific group of miRNA in heart that have altered during IR injuries. Most of those altered microRNA expressions modulated close to their basal level in resveratrol or longevinex treated I/R mice.

Topics: Animals; Cardiotonic Agents; Computational Biology; Heart; Male; Mice; MicroRNAs; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Software; Stilbenes

Resveratrol increases longevity through SirT1, which is activated with NAD(+) supplied by an anti-aging enzyme PBEF. SirT1 interacts with an anti-aging transcription factor, FoxO1, which is negatively regulated by Akt. Since white wine could have similar health benefits as red wine, we determined if white wine and its cardioprotective components possess anti-aging properties by feeding rats with these compounds. The hearts expressed SirT, FoxO, and PBEF in the order of white wine>resveratrol>tyrosol>hydroxytyrosol>red wine, while cardioprotection shown by reduction of infarct size and cardiomyocyte apoptosis followed a different pattern: resveratrol>red wine>hydroxytyrosol>white wine>tyrosol, suggesting the existence of different signaling mechanisms for the induction of longevity and survival.

Topics: Aging; Animals; Apoptosis; Cardiotonic Agents; Forkhead Transcription Factors; In Situ Nick-End Labeling; Myocytes, Cardiac; Nerve Tissue Proteins; Nicotinamide Phosphoribosyltransferase; Oncogene Protein v-akt; Phenylethyl Alcohol; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Signal Transduction; Sirtuins; Stilbenes; Transcriptional Activation; Wine

The intestine is highly susceptible to ischemia/reperfusion (I/R) injury. Splanchnic ischemia is the initial event that releases injurious factors, leading to systemic disorders with high morbidity and mortality. Oxidative stress mediators are believed to contribute to the intestinal I/R injury. Resveratrol, a polyphenol found in grapes, is shown to be a strong antioxidant in various tissues, with a property of an estrogen-receptor agonist. Therefore, we investigated the effects of resveratrol on oxidative injury in the intestine. Female Wistar rats were randomly allocated into four groups (n = 8, each). The sham group was only subjected to surgical procedures, while other animals were subjected to intestinal ischemia (60 min) and subsequent reperfusion (60 min). One group received resveratrol (15 mg/kg, 0.3 ml/day intraperitoneally) for both 5 days before surgery and 15 min before ischemia, while the other was treated intraperitoneally with 0.5% ethyl alcohol as vehicle (0.3 ml/day). In the I/R rat intestines, we detected severe tissue injuries (p < 0.001), the significant increases in the tissue levels of malondialdehyde (MDA), nitric oxide (NO), and myeloperoxidase (MPO) (p < 0.001), and the decrease in superoxide dismutase (SOD) activity (p < 0.001), compared to the sham control. Resveratrol significantly ameliorated the intestinal injury, decreased MDA, NO and MPO levels to the sham control levels, and decreased bacterial translocation in mesentery lymph nodes, liver and spleen (p < 0.001). Resveratrol also restored the SOD activity. These results suggest that resveratrol could protect intestinal tissue against I/R injury with its potent antioxidant properties.

Topics: Animals; Antioxidants; Bacterial Translocation; Female; Free Radical Scavengers; Intestinal Mucosa; Intestines; Malondialdehyde; Nitrates; Nitric Oxide; Nitrites; Peroxidase; Proteins; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; Stilbenes; Superoxide Dismutase

The aim of this study was to determine whether resveratrol could prevent intestinal tissue injury induced by ischemia-reperfusion (I/R).. Intestinal I/R was induced in rats' intestines by 60-min occlusion of the superior mesenteric artery, followed by a 60-min reperfusion. Thirty rats were divided into three groups as follows: sham (group 1), control (group 2), and the treatment groups (group 3). The rats in the treatment group received resveratrol both before ischemia and before reperfusion. In all groups, serum aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels were determined. Total antioxidant capacity (TAC), catalase, total oxidative status (TOS), oxidative stress index (OSI), and myeloperoxidase (MPO) in the intestinal tissue were measured. Intestinal tissue histopathology was also evaluated by light microscopy.. The levels of liver enzymes in group 3 were significantly lower than those in group 2 (P < 0.05). TAC in the intestinal tissue was significantly higher in group 3 than in group 2 (P < 0.05). TOS, OSI, and MPO in the intestinal tissue were significantly lower in group 3 than in group 2 (P < 0.05 for all). Histological tissue damage was milder in the resveratrol treatment group than in the control group.. The results of this study indicated that resveratrol treatment limits the oxidative injury of the small intestine induced by I/R in rats. However, more precise investigations are required to evaluate the antioxidative effect of resveratrol on small intestine tissue damage in clinical and experimental models.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Biomarkers; Catalase; Disease Models, Animal; Intestine, Small; L-Lactate Dehydrogenase; Liver; Male; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; Stilbenes

Topics: Animals; Antioxidants; Disease Models, Animal; Humans; Intestine, Small; Liver; Oxidative Stress; Rats; Reperfusion Injury; Resveratrol; Stilbenes; Wine

To investigate protective effects of polydatin(PD) during lung ischemia/reperfusion in rabbits and its potential mechanisms.. Rabbit lung model of ischemia/reperfusion (I/R) injury was constituted in vivo. Thirty rabbits were divided into groups randomly: Control (C), I/R, PD group, respectively. Endotoxin (ET) in plasma was analyzed by End-point Chromogenic Assay, the expression of Toll-like receptor 4 (TLR4) mRNA, nuclear factor (NF)-kappaBp65 mRNA, intracellular adhesion molecule-1 (ICAM-1) mRNA were measured by RT-PCR, the morphological changes of lung tissue were observed with hematoxylin-eosin (HE) staining.. There was no significant difference in ET concentration of plasma between groups (all of P > 0.05). The expression of TLR-4 mRNA, NF-kappaBp65 mRNA and ICAM-1mRNA in I/R group were significantly increased as compared to C group and PD group, while those expressions in PD group were evidently higher than those in C group (all of P < 0.01). Light microscope showed that the lung pathological injuries in PD group were obviously alleviated as compared to I/R group.. PD might have a protective effect on lung ischemia/reperfusion injury by down-regulating TLR4 and NF-kappaB expression, then inhibiting the release of mediators of inflammation as ICAM-1.

Topics: Animals; Female; Glucosides; Intercellular Adhesion Molecule-1; Ischemia; Lung; Male; Protective Agents; Rabbits; Reperfusion Injury; RNA, Messenger; Signal Transduction; Stilbenes; Toll-Like Receptor 4; Transcription Factor RelA

It has been reported recently that resveratrol preconditioning can protect the brain from ischemia-reperfusion injury. However, it was unclear whether resveratrol administration after stroke was beneficial to the delayed phases after focal cerebral ischemia injury. This study investigated the effects and possible protective mechanism of resveratrol on the delayed phase after focal cerebral ischemia injury in mice.. Mice were randomly assigned to five groups according to the time of administration of resveratrol. Control group mice received a corresponding volume of saline solution (0.9% NaCl) containing 20% hydroxypropyl h-cyclodextrin by gavage and were exposed to middle cerebral artery (MCA) occlusion and reperfusion injury. The treatment groups received resveratrol (50 mg/kg/d, gavage) until day 7. Ischemia group mice received their first dose 5 minutes before MCA ischemia, reperfusion group mice received their first dose 5 minutes before MCA reperfusion, first-day, group mice received their first dose 24 hours after MCA reperfusion, and third-day group mice received their first dose at 72 hours after MCA reperfusion. Brain injury was evaluated by triphenyltetrazolium chloride staining and neurologic examination 7 days after reperfusion. The microvascular cell number was examined with immunohistochemistry staining. Effect of resveratrol on matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) gene expression was investigated with reverse transcriptase-polymerase chain reaction and Western blot.. The mean neurologic scores and infarct volumes of the ischemia and reperfusion groups were lower than that of the control group at 7 days after MCA reperfusion (P < .05). Immunohistochemistry staining showed significantly less reduction in the number of microvessels in the cortical area of mice of the ischemia and reperfusion groups compared with controls. The ischemic hemispheres of the ischemia and reperfusion groups showed significantly (P < .05) elevated levels of protein of MMP-2 and VEGF.. Resveratrol administration by gavage provided an important neuroprotective effect on focal cerebral ischemic injury in the delayed phase. The elevated MMP-2 and VEGF levels might be important in the neuroprotective effect of resveratrol administration by inducing angiogenesis.

Topics: Angiogenic Proteins; Animals; Blotting, Western; Brain; Coloring Agents; Disease Models, Animal; Drug Administration Schedule; Immunohistochemistry; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred BALB C; Microcirculation; Motor Activity; Neovascularization, Physiologic; Neuroprotective Agents; Reperfusion Injury; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Stroke; Tetrazolium Salts; Time Factors; Up-Regulation; Vascular Endothelial Growth Factor A

Resveratrol (RSV), a polyphenol phytoalexin abundantly found in grape skins and in wines, is currently the focus of intense research as a pharmacological preconditioning agent in kidney, heart, and brain from ischemic injury. However, the exact molecular mechanism of RSV preconditioning remains obscure. The data from current studies indicate that pharmacological preconditioning with RSV were attributed to its role as intracellular antioxidant, anti-inflammatory agent, its ability to induce nitric oxide synthase (NOS) expression, its ability to induce angiogenesis, and its ability to increases sirtuin 1 (SIRT1) activity. Peroxisome proliferators-activated receptor (PPAR) gamma co-activator-1alpha (PGC-1alpha) is a member of a family of transcription coactivators that owns mitochondrial biogenesis, antioxidation, growth factor signaling regulation, and angiogenesis activities. And, almost all the signaling pathways activated by RVS involve in PGC-1alpha activity. Moreover, it has been proofed that RVS could mediate an increase PGC-1alpha activity. These significant conditions support the hypothesis that RSV exerts pharmacological preconditioning by activating PGC-1alpha. Attempts to confirm this hypothesis will provide new directions in the study of pharmaceutical preconditioning and the development of new treatment approaches for reducing the extent of ischemia/reperfusion injury.

Topics: Antioxidants; Humans; Ischemic Preconditioning; Models, Biological; Models, Theoretical; Neovascularization, Pathologic; Nitric Oxide Synthase; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma; Reperfusion Injury; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes; Trans-Activators; Transcription Factors; Transcriptional Activation

To investigate the effects of resveratrol on liver ischemia/reperfusion (I/R) injury in rats.. A total of 40 male Sprague-Dawley rats weighing 240-290 g were randomized into four groups of ten: (1) controls: data from unmanipulated animals; (2) sham group: rats subjected to the surgical procedure, except for liver I/R, and given saline; (3) I/R group: rats underwent liver ischemia for 45 min followed by reperfusion for 45 min; (4) I-R/Resveratrol group: rats pretreated with resveratrol (10 micromol/L, iv). Liver tissues were obtained to determine antioxidant enzyme levels and for biochemical and histological evaluation.. Plasma aminotransferase activities were higher in the I/R group than in the I-R/Resveratrol group. Malondialdehyde levels and the hepatic injury score decreased, while superoxide dismutase, catalase, and glutathione peroxidase levels increased in group 4 compared to group 3. In group 4, histopathological changes were significantly attenuated in resveratrol-treated livers.. These results suggest that resveratrol has protective effects against hepatic I/R injury, and is a potential therapeutic drug for ischemia reperfusion-related liver injury.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Catalase; Disease Models, Animal; Glutathione Peroxidase; Ligation; Liver; Liver Diseases; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Superoxide Dismutase

To observe protective effects of polydatin (PD) during lung ischemia/reperfusion injury (LI/RI) and investigate its potential mechanism .. Rabbit lung model of ischemia/reperfusion injury was constituted in vivo. The 40 rabbits were randomly divided into four groups (n = 10): control group (C group), ischemia/reperfusion group (I/R), PD + I/R group (PD) and PD+ polymyxin B (PMB) + I/R group (PMB). The blood specimen gathered at different time points were tested for the content of melondialdehyde (MDA) and the enzyme activity of superoxide dismutase (SOD). The lung tissue sampled at the end of the experiment were assayed for wet/dry weight ratio (W/D), injured alveoli rate (IAR) and observing ultrastructure changes under electron micro scope.. (1) The activity of SOD showed a similar time-dependent decline in I/R group and PMB group during I/R, while in PD group this tendency was milder (P < 0.01 vs I/R group). (2) In contrast to the results above, the level of MDA markedly increased in I/R and PMB group, but was slowed down in PD group (P < 0.01 vs I/R group). (3) The value of W/D) and IAR was much higher in I/R and PMB group (P < 0.05 or P < 0.01 vs C group). In PD group, it was decreased (P < 0.01 vs I/R group or PMB group). (4) Electron microscope showed obvious ultrastructure injury brought by LI/RI in I/R group and PMB group, which was greatly attenuated in PD group.. PD can protect lung from LI/RI, and PKC may participate in its mechanisms.

Topics: Animals; Female; Glucosides; Lung; Male; Protective Agents; Protein Kinase C; Rabbits; Random Allocation; Reperfusion Injury; Stilbenes

Previous work has shown that the Smilacis chinae rhizome (SCR) markedly inhibits amyloid beta protein (25-35)-induced neuronal cell damage in cultured rat cortical neurons. The present study was conducted to further verify the neuroprotective effect of SCR on excitotoxic and cerebral ischemic injury using both in vitro and in vivo studies. Exposure of cultured cortical neurons to 1 mM N-methyl-D-aspartate (NMDA) for 12 h induced neuronal cell death. SCR (10 and 50 microg/ml) inhibited NMDA-induced neuronal death, elevation of intracellular calcium ([Ca(2+)](i)), and generation of reactive oxygen species (ROS) in primary cultures of rat cortical neurons. In vivo, SCR prevented cerebral ischemic injury induced by 3-h middle cerebral artery occlusion (MCAO) and 24-h reperfusion. The ischemic infarct was significantly reduced in rats that received SCR (30 and 50 mg/kg, orally), with a corresponding improvement in neurological function. Moreover, SCR treatment significantly decreased the histological changes observed following ischemia. Oxyresveratrol and resveratrol isolated from SCR also inhibited NMDA-induced neuronal death, increase in [Ca(2+)](i), and ROS generation in cultured cortical neurons, suggesting that the neuroprotective effect of SCR may be attributable to these compounds. Taken together, these results suggest that the neuroprotective effect of SCR against focal cerebral ischemic injury is due to its anti-excitotoxic effects and that SCR may have a therapeutic role in neurodegenerative diseases such as stroke.

Topics: Animals; Calcium; Cell Death; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Infarction, Middle Cerebral Artery; Male; N-Methylaspartate; Neurons; Neuroprotective Agents; Plant Extracts; Plant Preparations; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Resveratrol; Rhizome; Smilax; Stilbenes; Time Factors

Liver ischemia-reperfusion (I/R) injury occurs in many clinical conditions, including liver surgery and transplantation. Oxygen free radicals generated during I/R reduce endogenous antioxidant systems and contribute to hepatic injury. trans-Resveratrol (trans-3,5,4'-trihydroxystilbene) is reported to have antioxidant properties. We investigated the effect of trans-resveratrol on liver injury induced by I/R. After 1 hour of ischemia, administered 5 minutes before 3 hours of reperfusion, trans-resveratrol was hepatoprotective at a low dose (0.02 mg/kg). It significantly decreased aminotransferase levels by about 40% and improved sinusoidal dilatation. trans-Resveratrol preserved antioxidant defense by preventing total and reduced glutathione depletion caused by I/R. At 0.2 mg/kg, trans-resveratrol significantly increased glutathione reductase, Cu/Zn-superoxide dismutase, and catalase activities. However, at a high dose (20 mg/kg), trans-resveratrol became prooxidant with an aggravation of liver injury evaluated by aminotransferase release and histological analysis and associated with a depletion of total and reduced glutathione levels and a decrease of antioxidant enzyme activities. In conclusion, a prereperfusion treatment by trans-resveratrol only at low doses decreases liver injury induced by I/R by protecting against antioxidant defense failure. This administration protocol could reduce liver damage during surgery or transplantation.

Topics: Animals; Antineoplastic Agents, Phytogenic; Catalase; Glucosephosphate Dehydrogenase; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Hepatic Artery; Liver; Liver Circulation; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Superoxide Dismutase; Vasodilator Agents

The objective was a comprehensive investigation of the mechanisms and sites of resveratrol cardioprotection during and following ischemia-reperfusion (I-R) injury, and to determine whether direct preservation of cardiomyocytes is an important site of cardioprotection. We now provide the first definitive evidence that resveratrol specifically protects cardiomyocytes from I-R injury via a combination of suppression of superoxide levels and activation of potassium channels. This protection is apparent whether resveratrol is present for the full duration of the insult or only on recovery. In addition, resveratrol improved postischemic recovery of left ventricular contractile function, attenuated myocardial injury, and increased myocardial activation of the survival kinase Akt in the intact heart. Furthermore, resveratrol elicited direct concentration-dependent protective actions on the vasculature (vasorelaxation, superoxide suppression) and enhanced endothelium-dependent vasodilatation. Resveratrol thus targets a number of consequences of myocardial I-R, including release of reactive oxygen species, loss of recovery of contractile function, and impaired endothelium-dependent vasodilatation. Previous evidence indicates that resveratrol elicits potent preconditioning in the heart. Given that myocardial ischemic events are often unpredictable in humans, the findings that resveratrol protection is also evident when administered during and/or after the insult adds new dimensions to the clinical potential of resveratrol.

Topics: Animals; Antioxidants; Carotid Arteries; Dose-Response Relationship, Drug; Endothelial Cells; Heart; Humans; Hypoxia; In Vitro Techniques; Male; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes

Topics: Angiogenesis Inhibitors; Animals; Brain; Brain Ischemia; Humans; Models, Cardiovascular; Models, Neurological; Neovascularization, Physiologic; Reperfusion Injury; Resveratrol; Stilbenes

Ischemic - reperfusion (IR) injury is a multifactorial process that leads to tissue damage and rejection in composite tissue allotransplantation (CTA). Antioxidant or free radical scavenger may reduce IR injury, so the effects of resveratrol, a natural antioxidant, on amelioration of leukocyte - endothelial cell adhesive interaction and prevention of transplant rejection in CTA were investigated.. In a microcirculatory study, resveratrol significantly reduced the number of IR-induced leukocytes rolling, adhering, and transmigrating in the postcapillary venules of the cremaster muscle. In the CTA study using groin skin flap allotransplantation across the MHC barrier 8-11-week-old Brown Norway donors (RT1(n)) and 10-11-week-old Lewis recipients (RT1(l)) rats were randomized into 4 groups: isograft control, allograft control, and 2 groups that received different doses of resveratrol (0.1 or 0.5 mg/kg) for 7 days. Allograft control animals rejected their allograft between 5 and 7 days postoperatively, whereas resveratrol-treated recipients had a moderate survival prolongation compared with the allograft control group. Consistent with these observations, histology results also showed reduction of lymphocytic infiltration and necrosis in resveratrol-treated subjects.. Resveratrol treatment prolonged groin skin flap allotransplant survival in the recipient and ameliorated the leukocyte - endothelial cell adhesive interactions that may lead to attenuated and delayed rejection in CTA.

Topics: Animals; Cell Adhesion; Endothelial Cells; Endothelium, Vascular; Graft Survival; Histocompatibility; Leukocyte Rolling; Leukocytes; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Skin Transplantation; Stilbenes; Transplantation, Homologous; Venules

Topics: Animals; Antioxidants; Brain Ischemia; DNA, Mitochondrial; Flavonoids; Humans; Hypoxia; Mice; Mitochondria; Models, Biological; Phenols; Polyphenols; Reactive Oxygen Species; Reperfusion Injury; Resveratrol; Stilbenes; Stroke

The periods of ischemia and reperfusion represent different characteristics by lack of oxygen and reoxygenation. The aim of this experimental spinal cord injury model was to investigate whether resveratrol has protective effects during ischemia or reperfusion and the mechanism of the protection by using N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase. Rabbits were divided into seven groups according to the time of administration of resveratrol or L-NAME (RI and RR, resveratrol during ischemia or reperfusion; IL and RL, L-NAME during ischemia or reperfusion; RILR, resveratrol during ischemia and L-NAME during reperfusion; LIRR, L-NAME during ischemia and resveratrol during reperfusion; control group). After neurologic evaluation at the twenty-fourth hour of reperfusion, lumbar spinal cords were removed for electron microscopic evaluation, immunohistochemical staining for apoptosis, and malondialdehyde (MDA) and myeloperoxidase (MPO) measurements. The RILR group had the best functional recovery, with a mean 3.6 Tarlov score (P < 0.05), and showed near normal electron microscopic findings (scores of 7.6 +/- 0.9 for the control group and 3.9 +/- 2.9 for the RILR group, P < 0.05). MPO and MDA levels were decreased in all groups compared with the control group, but only the decrement in the RILR group reached statistical significance. Immunohistochemical analysis showed that the groups including resveratrol and L-NAME together had the best staining for apoptosis. Resveratrol exhibits important protection by means of neurologic outcome, histopathologic analysis, and biochemical analysis, especially when used in during ischemia followed by L-NAME administration during reperfusion. Also, resveratrol protects against apoptosis, especially when combined with L-NAME.

Topics: Analysis of Variance; Animals; Antioxidants; Apoptosis; Disease Models, Animal; Enzyme Inhibitors; Hindlimb; Immunohistochemistry; Ischemic Preconditioning; Lumbar Vertebrae; Malondialdehyde; Microscopy, Electron; Movement; NG-Nitroarginine Methyl Ester; Nitrates; Nitrites; Peroxidase; Rabbits; Recovery of Function; Reperfusion; Reperfusion Injury; Resveratrol; Spinal Cord Injuries; Stilbenes; Time Factors; Treatment Outcome

Resveratrol, a polyphenol found in grape and red wine, was previously shown to have free radical scavenging and antioxidant properties in various tissues. In this study, the effects of resveratrol were investigated in muscle tissue concerning the ischemia reperfusion (I/R) injury of rat hindlimb.. Arterial circulation of right hindlimbs of 24 Sprague-Dawley rats was ceased by a tourniquet applied for four hours (h). The tourniquet was released at the end of 4th hours and rats were divided into four groups of six rats. Then, extremity was reperfused for 4h in group I and for 8h in group II. Resveratrol in 0.5% ethyl alcohol was administered with a dose of 10 mg/kg in the treatment groups (group I and group II) intraperitoneally. Only 0.5% ethyl alcohol were administered in the control groups (group III and group IV) intraperitoneally. Gastrocnemius muscle was used for histological assessments and the anterior tibial muscle was used for measurement of malondialdehyde (MDA) levels.. MN infiltration, edema, changes in diameters of muscle fibers and segmental necrosis were less prominent in rats treated with resveratrol compared with control groups (p<0.05). The MDA levels was significantly lower in treatment groups (p<0.05).. The results suggest that resveratrol may protect the skeletal muscles against I/R injury with its potent antioxidant properties.

Topics: Animals; Antioxidants; Hindlimb; Injections, Intraperitoneal; Male; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes

To investigate the protective effects of resveratrol on inflammatory process induced by focal cerebral ischemia-reperfusion in rats.. Rats were pretreated with resvreratrol at the dose of 10, 20, 40 mg kg(-1) for 7 days and then subjected to cerebral ischemia/reperfusion induced by a middle cerebral artery occlusion (MCAO). The infarct volume and the neurological deficit were determined by the method of TTC (2, 3, 5-triphenylterazolium chloride) staining and Longa's score. The permeability of blood-brain barrier (BBB) was evaluated by measurement of the evans blue (EB) content in the brain with spectrophotometer. The content of interleukin-lbeta, interleukin-6 (IL-6, IL-1beta) in serum and tumor necrosis factor-alpha (TNF-alpha), myeloperoxidase (MPO) in brain were determined by radio-immunoassay and ELISA assay.. Resveratrol reduced infarct volume, ameliorated the neurological deficit and the permeability of BBB, the content of IL-6, IL-1beta in serum and TNF-alpha, MPO activity in brain tissue also were significantly decreased.. These results showed that resveratrol had protective effects on cerebral injury by inhibiting the releasing of the inflammatory mediators after ischemia/reperfusion injury.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Ischemia; Infarction, Middle Cerebral Artery; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Male; Neuroprotective Agents; Peroxidase; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Tumor Necrosis Factor-alpha

Nitric oxide (NO), synthesized from L-arginine by the enzyme nitric oxide synthase (NOS), seems to play an ambiguous role during tissue ischemia-reperfusion (I/R) injury. This study was designed to investigate the effects of resveratrol, a polyphenolic phytoalexin, in renal ischemia reperfusion (RIR) injury in rats.. Forty-eight rats were randomized into six groups. Group 1: sham operated (C); group 2: right nephrectomy (UNI); group 3: UNI + 45 min of ischemia and 24 h of reperfusion in the contralateral kidney; group 4: UNI + RIR + L-NAME (10 mg/kg, i.p.); group 5: UNI + RIR + resveratrol (5 mg/kg, p.o.); group 6: UNI + RIR + resveratrol + L-NAME. At the end of the reperfusion period, rats were sacrificed. Thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) levels, catalase (CAT), and superoxide dismutase (SOD) activities were determined in renal tissue. Serum creatinine and blood urea nitrogen (BUN) were measured for the evaluation of renal function. Tissue and urine nitrite levels were measured to assess total nitric oxide levels.. Ischemic control animals demonstrated severe deterioration of renal function, altered renal morphology, reduced total nitric oxide levels and a marked renal oxidative stress.. Pretreatment of animals with resveratrol markedly attenuated renal dysfunction, morphological alterations, improved nitric oxide levels, reduced elevated TBARS levels and restored the depleted renal antioxidant enzymes, However, treatment with L-NAME attenuated this protection afforded by resveratrol indicating that resveratrol exerts its protective effect through NO release.

Topics: Angiogenesis Inhibitors; Animals; Enzyme Inhibitors; Kidney; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; Stilbenes

Tomato (Lycopersicon esculentum) is a vegetable rich in antioxidants, such as lycopene, lutein, and zeaxanthin. Their presence is responsible for the characteristic ability of this product to inhibit the formation of reactive oxygen species, including singlet oxygen. The grapes and wines derived from grapes also contain powerful antioxidants. The antioxidant effect is derived from the polyphenols such as resveratrol and proanthocyanidin. Resveratrol is phytoalexin that is synthesized via the activation of the gene, stilbene synthase (STS). We decided to determine if the introduction of this gene into Lycopersicon esculentum Mill could modify its antioxidant activity. Using Electronic Paramagnetic Resonance (EPR) spectroscopy, which permits the detection of antiradical activity, especially *OH (hydroxyl radical), we showed that the antioxidant activity of the products, into which the gene STS had been introduced, was almost double than that of natural products and that their activity was especially pronounced due to ripening. Moreover, resveratrol concentrations in modified tomatoes were much higher than that found in the individual fruit. In the isolated hearts subjected to ischemia/reperfusion, the rats fed with modified tomato exhibited better cardiac performance, reduced myocardial infarct size and decreased number of apoptotic cardiomyocytes, and reduced oxidative stress compared to unmodified tomato or resveratrol alone indicating superior cardioprotective abilities of modified tomatoes.

Topics: Acyltransferases; Animals; Antioxidants; Apoptosis; Diet; Electron Spin Resonance Spectroscopy; Free Radicals; Lipid Peroxidation; Male; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Oxidative Stress; Plants, Genetically Modified; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Solanum lycopersicum; Stilbenes

Stroke is one of the leading causes of mortality; however, its treatment remains obscure and largely empirical. Since matrix metalloproteinase 9 (MMP-9) has been postulated to be the major contributor of neuronal injury during reperfusion, inhibition of MMP-9 could be a potential approach in maintaining the viability of neurons. Trans-resveratrol (resveratrol), a polyphenolic compound has recently been shown to have neuroprotective activity against cerebral ischemia. Therefore, the aim of the present study was to evaluate the effect of resveratrol on MMP-9 induced by cerebral ischemia-reperfusion in vivo. Male Balb/C mice were treated with resveratrol for 7 days (50 mg/kg, gavage). Thereafter, middle cerebral artery occlusion (MCAo) was performed for 2 h with the help of intraluminal thread. Drug-treated mice showed improvement in necrotic changes in cortex and basal ganglia. Detection of MMP-9 activity and gene expression was performed at various time points after MCAo. The elevated levels of MMP-9 were significantly attenuated in the resveratrol-treated mice as compared to the vehicle MCAo mice. The study suggests that resveratrol has protective effects against acute ischemic stroke, which could be attributed to its property against MMP-9. Thus, resveratrol may be a potential agent for the treatment of neuronal injury associated with stroke.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cerebral Cortex; Disease Models, Animal; Gene Expression; Ischemic Attack, Transient; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Neuroprotective Agents; Reperfusion Injury; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Stroke

Resveratrol is as an antioxidant with free radical-scavenging activity and finds its clinical application in the prevention of postischemic tissue injury following solid organ transplantation. This study investigates the effect of Resveratrol on spleen and ileum tissues subjected to hepatic ischemia-reperfusion (I/R) in rats. Twenty-four rats were recruited in the study as follows: group A: I/R (n = 8), group B: I/R + Resveratrol (n = 8), and group C: sham operation (n = 8). After intraperitonealy pretreatment of eight rats with resveratrol (15 mg/kg/d) for 5 days, 16 rats were subjected to 45 minutes of hepatic ischemia followed by 30 minutes reperfusion period. Resveratrol was given 15 minutes prior to ischemia and just before the reperfusion in rats. After reperfusion period all rats were sacrificed. Spleen and ileum tissues were examined spectrophotometrically to measure malondialdehyde (MDA), glutathione (GSH), and total nitrite, nitrate as an end product of nitric oxide (NO) levels. Concerning the spleen, statistically significant decrease of GSH and increase of MDA and NO levels were found group A when compared to groups B and C (P = .040, P = .004, and P = .001 group A vs group B; P = .05, P = .003, and P = .001 group A vs group C, respectively). Parallel results were obtained in ileum. A statistically significant decrease in GSH and an increase in MDA and NO levels in group A in respect to group B and group C was obtained (P = .048, P = .034, and P = .001 group A vs group B; P = .004, P = .001, and P = .003 group A vs group C, respectively). The result of this study shows that resveratrol has a protective effect on spleen and ileal mitochondrial oxidative stress in rats subjected to I/R.

Topics: Animals; Disease Models, Animal; Glutathione; Ileum; Malondialdehyde; Nitric Oxide; Oxidative Stress; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; Spleen; Stilbenes; Vasodilator Agents

2,3,5,4'-tetra-hydroxystilbene-2-O-glucoside (THSG), the water-soluble active components extracted from dried tuber root of Polygonum multiflorum (Polygonaceae), can promote the release of nitric oxide (NO) from vascular endothelial cells and has strong antioxidation. The postconditioning's protection of THSG on cardiac ischemia-reperfusion injury and the mechanism were investigated. After reperfusion for 3 h following occlusion of rat left anterior descending coronary artery (LAD) for 30 min, SalphaT recovery speed, arrhythmia and cardiac infarct size were observed. The ischemic size and infarct size was identified by using Evans blue and TTC staining methods respectively. The results showed that the infarct size in THSG 7. 5 mg/kg postconditioning group was significantly decreased from 43.6% +/- 9.1% in mode group to 16.5% +/- 6.5% (P < 0.01). SalphaT recovery was quicker and the incidence of arrhythmia (55.6% vs 100%, P < 0.05) was significantly lower than in control group. The infarct size in THSG+glybenclamide group was greater than in THSG group, but equivalent to that in control group (46.8% +/- 9.8% vs 43.6% +/- 9.1%, P > 0.05), SalphaT recovery speed slower and the incidence of arrhythmia also lower (33.3% vs 100%, P < 0.01), suggesting that glybenclamide could abolish the effects of THSG postconditioning reducing the cardiac infart size. It was concluded that THSG administration before reperfusion could effectively alleviate the cardiac reperfusion injury and possessed the postconditioning effects of reducing cardiac infarct size, which might be related with the K(ATP) channel opening.

Topics: Animals; Antioxidants; Female; Glucosides; Ischemic Preconditioning, Myocardial; Male; Polygonum; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Stilbenes

Previous studies have demonstrated that polydatin, a crystal component extracted from the root stem of the perennial herbage Polygonum Cuspidatum Sieb.et Zucc, exerts a neuroprotective effect on cerebral injury induced by ischemia/reperfusion. To investigate the possible mechanism of this action, we determined the effects of polydatin on the expression of cell adhesion molecules (CAMs) after ischemia-induced cerebral injury. Rats were treated with polydatin (i.v.) immediately after the operation of middle cerebral artery occlusion (MCAO) for 1 h. It was found that polydatin improved neurological deficits and reduced the volume of brain infarction. In addition, polydatin decreased the levels of CAMs relative to the control (MCAO alone); these included intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, L-selectin and Integrins. These results suggest that polydatin exerts protective effects likely via inhibition of the expression of various CAMs; polydatin may be a potential agent for treatment of brain injury associated with stroke.

Topics: Analysis of Variance; Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression; Glucosides; Immunohistochemistry; Intercellular Adhesion Molecule-1; Male; Neural Cell Adhesion Molecules; Neurologic Examination; Neuroprotective Agents; Oligonucleotide Array Sequence Analysis; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Stilbenes; Vascular Cell Adhesion Molecule-1

The present study aimed to investigate the possible beneficial activities of resveratrol (3,5,4'-trans-trihydroxystilbene), a natural phytoalexin, on contractility and oxidant damage after ischemia/reperfusion (I/R) of the rat urinary bladder.. The abdominal aorta of Sprague-Dawley rats was occluded for 60 min to induce ischemia and then allowed 60 min of reperfusion. Resveratrol (10 mg/kg) or saline was administered intraperitoneally 15 min before ischemia and immediately before reperfusion. In the sham-operated group, the abdominal aorta was left intact and the animals were treated with resveratrol or saline. The bladder samples were either used for functional studies or stored for biochemical assays.. In the I/R group, the isometric contractile responses of the bladder strips to carbachol (CCh; 10(-8)-10(-4) mol/l) were lower than those of the control group and were reversed by treatment with resveratrol. Histological evaluation revealed loss of urothelial cells, detachment and loss of urothelial cells and local ulcerated areas and severe inflammatory cell infiltration in the untreated I/R group, and regeneration of luminal mucosa and a significant decrease in the density of the inflammatory cell population in the resveratrol-treated I/R group. Lipid peroxidation and the myeloperoxidase activity of the bladder tissues in the I/R group were higher than in the sham-operated group. Resveratrol treatment in the I/R group decreased these parameters compared with I/R alone. Similarly, the significant decrease in tissue glutathione level in the I/R group compared with controls was also prevented by resveratrol.. Treatment with resveratrol almost completely reversed the low contractile responses of the rat urinary bladder to CCh and prevented oxidative tissue damage following I/R.

Topics: Animals; Female; Glutathione; In Vitro Techniques; Lipid Peroxidation; Male; Muscle Contraction; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Urinary Bladder

The present study was designed to examine whether resveratrol, a potent antioxidant, protects against renal ischemia-reperfusion (I/R) injury.. Wistar albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 6 h of reperfusion. Resveratrol (RVT, 30 mg/kg, i.p.) or vehicle was administered twice, at 30 min prior to ischemia and immediately before the reperfusion period. At the end of the reperfusion period, rats were decapitated and kidney samples were taken for histological examination or determination of levels of renal malondialdehyde (MDA), an end product of lipid peroxidation; glutathione (GSH), a key antioxidant; and myeloperoxidase (MPO) activity, an index of tissue neutrophil infiltration. Formation of reactive oxygen species in hepatic tissue samples was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes. Renal tissue collagen content as a fibrosis marker was also determined, while serum creatinine and urea concentrations were measured for the evaluation of renal function. Tumor necrosis factor-alpha (TNF-alpha ) and lactate dehydrogenase (LDH) were also assayed in serum samples.. Ischemia/reperfusion caused a significant decrease in tissue GSH level, which was accompanied by significant increases in the renal luminol and lucigenin CL values, MDA level, MPO activity and collagen content. Similarly, serum creatinine and BUN levels, as well as LDH and TNF-alpha, were elevated in the I/R group as compared to control group. On the other hand, resveratrol treatment reversed all these biochemical indices, as well as histopathological alterations that were induced by I/R.. Findings of the present study suggest that resveratrol exerts renoprotective effects via its radical scavenging and antioxidant activities, which appear to involve the inhibition of tissue neutrophil infiltration.

Topics: Acridines; Animals; Antioxidants; Blood Urea Nitrogen; Creatine; Glutathione; Kidney Diseases; L-Lactate Dehydrogenase; Luminol; Male; Malondialdehyde; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; Stilbenes

Topics: Animals; Blood Pressure; Disease Models, Animal; Ischemic Preconditioning; Rabbits; Reperfusion Injury; Resveratrol; Spinal Cord Ischemia; Stilbenes; Swine; Vasodilator Agents

Ischemia and reperfusion injury of the skeletal muscle is a common and serious condition observed in patients admitting to peripheral vascular surgery, interventional radiology and cardiology departments. Resveratrol (RVT) being a strong natural antioxidant is found in deal of red wine and Mediterranean diet. In the present study, male Spraque-Dawley rats were randomized into two groups of equal size. The first group was the control group, and these rats were administered with tap water with a gastric tube for fourteen consecutive days once daily. According to the same protocol, the rats in the second group were treated with tap water containing 20 mg/kg RVT. All the rats in the two groups were subjected to acute hind limb ischemia through clamping of the abdominal aorta for 120 min. Following this procedure, 60 minutes of reperfusion was applied by reestablishing blood flow in both iliac arteries. Ischemic damage in the skeletal muscle tissue was assessed by measuring myoglobin, lactate dehydrogenase, creatinine phosphokinase, aspartate transaminase enzymes in venous blood samples obtained at the end of the reperfusion period. Oxidative stress caused by reperfusion was determined by measuring MDA, carbonyl and protein sulphydryl levels in quadriceps muscle tissue retrieved at the end of the experiment. In Group II rats, all the measured ischemic enzymes and the markers of oxidative stress reflected robust anti-ischemic properties obtained by RVT administration. The data from both groups revealed statistically significant protection against acute skeletal muscle ischemia and reperfusion injury in Group II rats, compared to Group I. As a major dietary flavonoid RVT can protect the skeletal muscle tissue against global ischemia and reperfusion injury because of its strong antioxidant and cytoprotective properties.

Topics: Animals; Disease Models, Animal; Lower Extremity; Male; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Treatment Outcome; Vasodilator Agents

Recent studies have suggested that an ischemia/reperfusion (I/R) injury enhances the expression of costimulatory adhesion molecules on the vascular endothelium. In the present study, we investigated the protective effects of resveratrol, a phenolic product, on the renal function and expression of CD86 in rat kidneys with I/R injury. Wistar rats were divided into four groups; 1) an I/R group with right nephrectomy and 1-hour clamping of the left renal pedicle; 2) a vehicle group, I/R plus 10% ethanol (0.1 ml/kg/day) administered by intra-peritoneal injection from day -1 through to 7; 3) a resveratrol group, I/R plus 4 mg/kg/day of resveratrol; and 4) a sham group. Blood samples were obtained via the tail vein at 1 day before, and 1, 3, and 7 days after the operation (day 0) for the measurement of serum creatinine (Scr) levels. The expression of CD86 protein was analyzed by immunofluorescence staining, and the level of CD86 messenger RNA (mRNA) was evaluated quantitatively by a real-time reverse transcription-polymerase chain reaction (RT-PCR) in the renal cortex at day 3. Scr levels of the resveratrol group were significantly lower than those of the I/R and vehicle groups on days 1 and 3 after the operation. From the immunohistochemical study, the expression of CD86 in the glomerular endothelium and peritubular vessels was found to be attenuated in the resveratrol group compared with the I/R or vehicle group. In the resveratrol group, the CD86 mRNA level was significantly lower than that in the I/R or vehicle group, and it was significantly decreased by about one fifth of that in the sham group. Our results suggest that resveratrol markedly reduces renal dysfunction and attenuates the mRNA and protein expression of CD86 following I/R injury.

Topics: Animals; Antigens, CD; B7-2 Antigen; Creatinine; Endothelium, Vascular; Ischemia; Kidney; Kidney Cortex; Kidney Function Tests; Kidney Glomerulus; Membrane Glycoproteins; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; RNA, Messenger; Stilbenes

The aim of the study was to evaluate the effects of resveratrol on testicular ischemia reperfusion injury. Forty Wistar albino rats were divided into 4 groups. Torsions (ischemia) were created by rotating the right testis 720 degrees in a clockwise direction for 4 hours in all groups except the control group. In the torsion group after 4 hours' ischemia bilateral orchiectomy was performed. In the detorsion group, saline was injected by an intraperitoneal route, 30 min before detorsion (reperfusion). In the resveratrol group, 30 mg/kg resveratrol was injected by an intraperitoneal route, 30 min before detorsion. In the detorsion and resveratrol groups, the bilateral testes were removed after 20 hours of detorsion. In all groups, the tissue levels of malondialdehyde (MDA) and glutathione (GSH) and histological changes were determined. In rats treated with resveratrol, MDA levels (138 +/- 25 nmol/mg protein) were significantly decreased compared with torsion (426 +/- 178 nmol/mg protein) and detorsion (370 +/- 76 nmol/mg protein) groups (p < 0.05). GSH levels (6.54 +/- 0.8 micromol/g wet tissue) were significantly increased compared with torsion (4.61 +/- 0.4 micromol/g wet tissue) and detorsion groups (5.24 +/- 0.9 micromol/g wet tissue) (p < 0.05). The mean testicular tissue injury score in the resveratrol group was significantly lower than in torsion and detorsion groups (p < 0.05). The present study demonstrates that intraperitoneal administration of resveratrol in rats may protect testis against injury associated with reperfusion.

Topics: Animals; Antioxidants; Male; Models, Animal; Rats; Reperfusion Injury; Resveratrol; Spermatic Cord Torsion; Stilbenes; Vasodilator Agents

Severe neurologic injury still represents one of the most devastating complications after surgical repair of thoracoabdominal aneurysms. We therefore aimed to investigate the protective effect of resveratrol, a natural polyphenol antioxidant present in grapes and wine, in an experimental model of spinal cord ischemia-reperfusion injury.. Sixteen rabbits were assigned either to group A (n = 8; receiving resveratrol, treated group) or group B (n = 8; control group, nontreated group) and underwent a 30-minutes period of spinal cord ischemia by clamping the abdominal aorta between the left renal artery and the aortic bifurcation. Fifteen minutes before clamping, rabbits received either intravenous resveratrol (100 microg/kg; group A) or normal saline (group B). Functional assessment with Tarlov score at 8, 16, and 24 hours postoperatively, histopathologic assessment of the spinal cord, measurements of malondialdehyde levels, and myeloperoxidase activity in the spinal cord were performed.. Neurologic impairment (Tavlov score for group A = 4.38 +/- 1.19 and for group B = 0.38 +/- 0.74, p < 0.001), malondialdehyde levels (47.71 +/- 7.81 nmol/g versus 86.56 +/- 11.39 nmol/g, p < 0.001), and myeloperoxidase activity (2.13 +/- 0.72 nm/min versus 3.75 +/- 0.78 nm/min, p = 0.002) were significantly lower in the resveratrol-treated animals. Additionally, pathologically assessed outcomes were better in the resveratrol-treated group. The total number of motor neurons in the gray matter was significantly lower in the nontreated group than in the resveratrol-treated group (14.26 +/- 2.94 versus 29.12 +/- 3.64, p = 0.003).. Prophylactic use of resveratrol reduced neurologic injury and provided clinical improvement by attenuating the inflammatory milieu in the rabbit spinal cord ischemia/reperfusion model.

Topics: Animals; Male; Phenols; Rabbits; Reperfusion Injury; Resveratrol; Spinal Cord Injuries; Stilbenes; Wine

Topics: Animals; Phenols; Rabbits; Reperfusion Injury; Resveratrol; Spinal Cord Injuries; Stilbenes; Wine

Ischemia-reperfusion is a critical event in the development of primary graft dysfunctions after liver transplantations. Ischemia-reperfusion causes cell injuries which are related to the successive cold preservation-warm reperfusion (CPWR) periods required by the graft. Recent evidences suggest that oxidative stress plays an important role in the development of these injuries and that mitochondrial dysfunctions are involved. The purpose of this study was to investigate the effect of the natural phytoalexin resveratrol on the prevention of liver injuries induced by 40-h cold preservation followed by a warm reperfusion. CPWR induced liver mitochondrial and cellular damages as attested by the increase in lipid peroxidation of liver membranes, the alteration of oxidative phosphorylation parameters, mitochondrial swelling and the activation of the cellular markers of necrosis and apoptosis, i.e., lactate dehydrogenase (LDH) leakage, mitochondrial cytochrome c release and caspase activation. Resveratrol inhibits lipid peroxidation and protects mitochondrial functions. It improves respiratory chain activity and prevents opening of the permeability transition pore, allowing better recovery of ATP energetic charge. Resveratrol also limits the activation of the cellular markers of necrosis and apoptosis. These protective effects could be related to the antioxidant properties of the drug but also to its membrane-stabilizing activity. Indeed, further experiments demonstrate that resveratrol is able to prevent the release of cytochrome c caused by oxygen deprivation in isolated liver mitochondria. These data demonstrate that resveratrol ameliorates the liver injury induced by CPWR and appears as a promising drug to improve the primary function of the grafted liver after transplantation.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Apoptosis; Caspases; Cold Temperature; Cytochromes c; Dose-Response Relationship, Drug; In Vitro Techniques; L-Lactate Dehydrogenase; Lipid Peroxidation; Liver; Male; Mitochondria, Liver; Mitochondrial Membranes; Mitochondrial Swelling; Necrosis; Oxidative Phosphorylation; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury; Resveratrol; Stilbenes; Time Factors

The aim of this study is to investigate the effects of resveratrol on histopathological changes, antioxidant status and lipid peroxidation, in torsion-detorsion injury in rat ovaries.. To determine whether ischemia followed by reperfusion can induce ovarian oxidative damage, we created a model of adnexal ischemia-reperfusion by using rats. Ischemia was induced by unilateral occlusion of the tubo-ovarian vessels for 3 h. Reperfusion was achieved by releasing the occlusion and restoring the circulation for 3 h. Thirty-two adult female albino rats were divided equally into 4 groups: sham operation, torsion, saline/detorsion and resveratrol/detorsion. Rats in the torsion group were killed after 360 degrees clockwise adnexal torsion for 3 h. Resveratrol was injected intraperitoneally 30 min before detorsion in the resveratrol/detorsion group, and saline was administered in the saline/detorsion group. After 3 h of adnexal detorsion in both of these groups, the rats were killed and adnexa were removed. The tissue levels of malondialdehyde, reduced glutathione and xanthine oxidase activity were measured.. Malondialdehyde and xanthine oxidase levels in the saline/detorsion group were increased significantly when compared to the torsion and sham operation groups (p < 0.001). Malondialdehyde levels in the resveratrol group were lower than in the saline/detorsion group, and differences between the two groups were statistically significant (p < 0.001). Xanthine oxidase levels in the resveratrol group were lower than in the saline/detorsion and torsion groups, and differences between these groups were statistically significant (p < 0.001). Reduced glutathione levels in the saline/detorsion group were decreased significantly when compared to the torsion and sham operation groups. Reduced glutathione levels in the resveratrol group were significantly higher than in the saline/detorsion group (p < 0.006). Histological examination showed a significant improvement in ovarian morphology in the resveratrol-treated rats compared with the ischemia and ischemia-reperfusion groups.. Our results demonstrated that intraperitoneal resveratrol administration reduced the lipid peroxidation products of ischemic rats and ovarian damage was reduced as indicated by histological examination.

Topics: Animals; Antioxidants; Female; Flavonoids; Ovarian Diseases; Ovary; Phenols; Phytotherapy; Polyphenols; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; Stilbenes; Torsion Abnormality; Vitis; Wine

The cardioprotective effect of red wine has been attributed to resveratrol. The resveratrol-induced protection against ischemia-reperfusion (I/R) injury has been documented in heart, kidney, and brain. Resveratrol scavenges free O(2) radicals and upregulates nitric oxide (NO). However, the presence of resveratrol-induced spinal cord protection against I/R injury has not been reported in the literature. The objective of this study was to evaluate the effects of resveratrol on neurologic functions, histopathologic changes, and NO metabolism following temporary spinal cord ischemia (SCI) in rabbits. Material and methods SCI was induced with occlusion of the infrarenal aorta in rabbits. In addition to the sham group (group S, n = 7), group C (n = 7) received vehicle 30 minutes before ischemia. Group R1 (n = 7) and R10 (n = 7) received 1 mg/kg and 10 mg/kg resveratrol instead of vehicle, respectively. Blood samples were taken to obtain nitrite/nitrate levels during the surgical procedure. After neurologic evaluation at the 48th hour of reperfusion, lumbar spinal cords were removed for histopathologic examination and malondialdehyde measurement as a marker of oxidative stress.. Five animals in group C had paraplegia while 5 in group R10 had normal neurologic functions. The average Tarlov score of group R10 was significantly higher than that the score of group C (4.1 +/- 1.2, vs 1.2 +/- 2.2; P =.014). Histopathologic examination revealed higher neuronal viability index in group R10 compared with that of group C (0.82 +/- 0.24 vs. 0.46 +/- 0.34; P =.018). Nitrite/nitrate levels decreased in group C (from 357 +/- 20.15 micromol/L to 281 +/- 47.9 micromol/L; P <.01) whereas they increased both in group R1 and group R10 (from 287+/-28 micromol/L to 310 +/- 33.9 micromol/L and from 296 +/- 106 micromol/L to 339 +/- 87 micromol/L, respectively) during SCI. Malondialdehyde levels of group R10 was lower than those of group C (55 +/- 12.9 nmol/mg protein vs 83.9 +/- 15.1 nmol/mg protein; P =.001, respectively).. In this model of SCI, resveratrol decreased oxidative stress, increased NO release, and protected spinal cord from I/R injury. Resveratrol-induced neuroprotection is probably mediated by its antioxidant and NO promoting properties. Before considering the clinical use of this natural antioxidant, further research is warranted about its mechanism of effects, timing, and optimum dose.. Paraplegia that results from spinal cord ischemia is a catastrophic complication of thoracic and thoracoabdominal aorta surgical procedures. Despite several surgical modifications and pharmacologic approaches, paraplegia has not been totally eliminated. On clinical grounds, the efficiency of currently used pharmacologic agents to prevent spinal cord injury during thoracic and thoracoabdominal aorta surgery is very limited and their benefit is controversial. Preischemic infusion of resveratrol protects the spinal cord from ischemia reperfusion injury in rabbits. Following clarification of the underlying protective mechanism, optimal dose, and timing, resveratrol may used in humans as an adjunct to eliminate this catastrophic complication.

Topics: Animals; Antioxidants; Flavonoids; Free Radical Scavengers; Male; Neuroprotective Agents; Nitric Oxide; Oxidative Stress; Paraplegia; Phenols; Polyphenols; Rabbits; Reperfusion Injury; Resveratrol; Spinal Cord; Spinal Cord Ischemia; Stilbenes; Wine

Epithelial injury and repair are central consequences of ischemia and reperfusion of the gut. Intestinal mucosal wounds are repaired in part by epithelial restitution. However, the signaling mechanisms regulating restitution remain poorly understood, and few therapies to enhance restitution have been described. Previously we demonstrated that alpha-melanocyte-stimulating hormone (alpha-MSH) protected against postischemic gut injury in the rat. In this report, we tested the effects and mechanisms of alpha-MSH on wound restitution of rat small intestine (IEC-6) cells subjected to H2O2 stress with or without scrape wounding. H2O2 treatment resulted in tyrosine phosphorylation of Syk kinase and its downstream target IkappaBalpha, with subsequent NF-kappaB activation. Alpha-MSH and the Syk kinase inhibitor piceatannol blocked these processes. In scrape-wounded cells, H2O2 inhibited wound restitution, and this was partially restored by cotreatment with alpha-MSH or piceatannol. In contrast, overexpression of NF-kappaB p65 or Syk kinase, but not a dominant-negative mutant of Syk kinase, aggravated H2O2 inhibition of wound restitution, and inhibitors of c-Src tyrosine kinase or phosphatidylinositol-3 kinase were without effect. The results indicate an important role for Syk tyrosine kinase and the NF-kappaB pathway in the response to oxidant stress and the impairment of epithelial restitution in IEC-6 cells. The data also disclose that the beneficial effects of alpha-MSH on gut ischemia/reperfusion injury may relate to its acceleration of epithelial restitution.

Topics: alpha-MSH; Animals; Blotting, Western; Cell Line; Cells, Cultured; Epithelial Cells; Genes, Reporter; Hydrogen Peroxide; I-kappa B Proteins; Immunoprecipitation; NF-kappa B; NF-KappaB Inhibitor alpha; Oxidants; Phosphatidylinositol 3-Kinases; Phosphorylation; Plasmids; Rats; Reperfusion Injury; Signal Transduction; Stilbenes; Transfection; Tyrosine; Wound Healing

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

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

Increased oxidative stress has been implicated in the mechanisms of delayed neuronal cell death (DND) following cerebral ischemic insult. In this study, we investigated whether resveratrol, a polyphenolic antioxidant enriched in grape, may ameliorate ischemia-induced neuron cell death. Mongolian gerbils were divided into three groups, namely, sham control, ischemia and ischemia treated with resveratrol. Transient global cerebral ischemia was induced by occlusion of both common carotid arteries (CCA) for 5 min. Resveratrol was injected i.p. (30 mg/kg body weight), either during or shortly after CCA occlusion, and again at 24 h after ischemia. Cerebral blood flow was monitored before and during CCA occlusion using a laser Doppler flowmeter. Brain sections were immuno-stained for neurons, astrocytes and microglial cells. A time course study was also carried out to assess the bioavailability of resveratrol in serum, liver and brain using high performance liquid chromatography (HPLC). Morphometric measurements indicated extensive DND in the hippocampal CA1 region 4 days after ischemia and that neuron cell death was marked by the increase in reactive astrocytes and microglial cells. Administration of resveratrol, either during or after CCA occlusion, significantly (P<0.05) decreased DND as well as glial cell activation. Analysis of resveratrol after i.p. injection indicated its presence in serum, liver and brain with peak activity at 1, 4 and 4 h, respectively. This study demonstrated for the first time that resveratrol, a polyphenolic antioxidant, can cross the blood-brain barrier and exert protective effects against cerebral ischemic injury.

Topics: Animals; Brain Ischemia; Cell Death; Gerbillinae; Hippocampus; Male; Neuroglia; Neurons; Reperfusion Injury; Resveratrol; Stilbenes

1. Dietary antioxidants are thought to be beneficial in reducing the incidence of coronary heart disease. In this study, we compared resveratrol and analogues on their antioxidation and free radical scavenging activities to their protective effects on ischaemia-reperfusion induced injuries of rat hearts. 2. Astringinin (3,3',4',5-tetrahydroxystilbene) was shown to be a more potent inhibitor than other analogues against Cu(2+)-induced LDL (low-density lipoprotein) oxidation, as measured by the formation of conjugated diene and TBARS (thiobarbituric acid-reactive substance) and by the electrophoretic mobility of the oxidized LDL. 3. Resveratrol (trans-3,4',5-trihydroxystilbene) and astringinin scavenged the stable free radical DPPH (1,1-diphenyl-2-picryl-hydrazyl) with an IC(0.200) of 7.1 and 4.3 microM, respectively. 4. Astringinin has a superoxide anion scavenging activity about 160 fold more potent than resveratrol. 5. After a 30 min global ischemia followed by 2 h reperfusion, astringinin (10 microM) significantly reduced infarct size, superoxide anion production and increased functional recovery of the coronary flow in Langendorff-perfused rat hearts. 6. The result showed there is a positive correlation between the anti-oxidation and cardioprotective activities among these phenolic compounds. Our finding together with the fact that astringinin is more water-soluble than resveratrol suggest that astringinin could potentially be used as an anti-oxidant and cardioprotective agent in biological systems.

Topics: Animals; Biphenyl Compounds; Disease Models, Animal; Free Radical Scavengers; Humans; Lipoproteins, LDL; Male; Myocardial Ischemia; Oxidation-Reduction; Picrates; Protective Agents; Rats; Rats, Inbred WKY; Reperfusion Injury; Resveratrol; Stilbenes; Superoxides

Free radicals have been implicated in neuronal injury during ischemia reperfusion in stroke. Trans resveratrol, a potent antioxidant, polyphenolic compound found in grapes and wines has recently been shown to have neuroprotective activity against oxidative stress in in vitro studies. In the present study the effect of chronic treatment of trans resveratrol was evaluated in focal ischemia induced by middle cerebral artery [MCA] occlusion in rats. Male Wistar rats were pretreated with trans resveratrol 20 mg/kg i.p. for 21 days and were subjected to focal ischemia by occlusion of MCA using intraluminal thread. After two hours of MCA occlusion reperfusion was allowed by retracting the thread. Animals were assessed for motor performance after 24 hours and subsequently rats were sacrificed for estimation of markers of oxidative stress [malondialdehyde [MDA] and reduced glutathione] and for evaluation of volume of infarction. Control group received vehicle and similar protocol was followed. Significant motor impairment, with elevated levels of MDA and reduced glutathione was observed in the vehicle treated MCA occluded rats. Treatment with trans resveratrol prevented motor impairment, rise in levels of MDA and reduced glutathione and also significantly decreased the volume of infarct as compared to control. The study provides first evidence of effectiveness of trans resveratrol in focal ischemia most probably by virtue of its antioxidant property.

Topics: Animals; Brain; Disease Models, Animal; Drug Administration Schedule; Free Radicals; Hand Strength; Ischemic Attack, Transient; Male; Malondialdehyde; Middle Cerebral Artery; Motor Activity; Muscle, Skeletal; Oxidative Stress; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Reference Values; Reperfusion Injury; Resveratrol; Stilbenes; Stroke; Time Factors

Ischemia is an inciting factor in 50% of incidences of acute renal failure, and it increases the risk of organ rejection after renal transplantation. We have previously demonstrated that resveratrol (RSV) reduces ischemia-reperfusion (I/R) injury of rat kidney both by antioxidant and anti-inflammatory mechanisms. However, a clear morphological demonstration of this activity has not been made. To answer this question we have performed a new set of experiments following the experimental protocol reported below to investigate the effects of I/R injury and RSV pretreatment on kidney morphology by computerized morphometric analysis. Both renal arteries were clamped for 40 minutes in 40 male Wistar rats (b.w. 220 +/- 20 g); 20 rats were pretreated with RSV 1 microM e.v. 40 minutes before clamping. All animals were reperfused for 24 hours and then sacrificed. Histological examination showed tissue conservation in treated rats. I/R-induced glomerular collapse (as revealed by mean glomerular volume and glomerular shape factor) was significantly reduced by RSV pretreatment. Capillary tuft/Bowman's capsule area ratio was enhanced in the I/R group suggesting tubular hypertension. RSV pre-treatments significantly reduced this parameter to the control value. The number of platelet clots in the capillary tuft and tubular necrosis were also reduced by RSV versus I/R group. L-NAME administration worsened both functional and structural damage. Finally, cGMP urinary levels were markedly reduced from 12.1 +/- 8.4 nmol/day to 0.10 +/- 0.10 nmol/day in the I/R group. RSV provided cGMP (5.01 +/- 1.5 nmol/day, P < 0.05). As expected, L-NAME administration significantly reduced cGMP in urine (0.71 +/- 0.6 nmol/day). The present study confirms the protective effect of RSV pretreatment in I/R injury of rat kidney and suggests multiple mechanisms of action.

Topics: Animals; Cyclic GMP; Dose-Response Relationship, Drug; Ischemia; Kidney Diseases; Kidney Glomerulus; Male; Rats; Rats, Wistar; Renal Circulation; Reperfusion Injury; Resveratrol; Stilbenes; Vitis; Wine

Reactive oxygen species have been implicated in the pathophysiology of renal ischemia reperfusion injury. Antioxidants including polyphenolics have been found to protect renal cells from the cellular injury induced by ischemia and reperfusion. Resveratrol, a stilbene polyphenol found in grapes and red wine, has recently been found to protect isolated rat heart from ischemia reperfusion injury. This study was sought to determine if resveratrol could also protect renal cells from ischemic injury. Male Wistar rats were treated with control, resveratrol (0.23 microg/kg), vehicle used to solubilize resveratrol, and resveratrol plus L-NAME (15 mg/kg body wt), a nitric oxide blocker. Our results demonstrated that resveratrol administration reduced the mortality of ischemic rats from 50% to 10% and renal damage was reduced as indicated by histologic examination and serum creatinine level. The short-term administration of resveratrol also inhibited renal lipid peroxidation induced by ischemia and reperfusion both in cortex and in medulla. Electron paramagnetic resonance detected an increased formation of nitric oxide in the resveratrol-treated kidney that was reduced to the baseline value after treating the rats with L-NAME in addition to resveratrol. The results suggest that resveratrol reduced the renal ischemia reperfusion injury through a nitric oxide-dependent mechanism.

Topics: Animals; Antioxidants; Ischemia; Kidney; Lipid Peroxidation; Male; Nitric Oxide; Rats; Rats, Wistar; Reperfusion Injury; Resveratrol; Stilbenes

Various organs, including heart, kidneys, liver or brain, respond to brief exposures to ischemia with an increased resistance to severe ischemia/reperfusion and this phenomenon is called "preconditioning". No study so far has been undertaken to check whether such short, repeated gastric ischemic episodes protect gastric mucosa against severe damage caused by subsequent prolonged ischemia/reperfusion and, if so, what could be the mechanism of this phenomenon. The ischemic preconditioning was induced by short episodes of gastric ischemia (occlusion of celiac artery from one to five times, for 5 min each) applied 30 min before prolonged (30 min) ischemia followed by 3 h of reperfusion or 30 min before topical application of strong mucosal irritants, such as 100% ethanol, 25% NaCl or 80 mM taurocholate. Exposure to regular 30-min ischemia, followed by 3-h reperfusion, produced numerous severe gastric lesions and significant fall in the gastric blood flow and prostaglandin E(2) generation. Short (5-min) ischemic episodes (1-5 times) by itself failed to cause any gastric lesions, but significantly attenuated those produced by ischemia/reperfusion. This protection was accompanied by a reversal of the fall in the gastric blood flow and prostaglandin E(2) generation and resembled that induced by classic gastric mild irritants. These protective and hyperemic effects of standard preconditioning were significantly attenuated by pretreatment with cyclooxygenase-2 and cyclooxygenase-1 inhibitors, such as indomethacin, Vioxx, resveratrol and nitric oxide (NO)-synthase inhibitor, N(G)-nitro-L-arginine (L-NNA). The protective and hyperemic effects of standard preconditioning were restored by addition of 16,16 dm prostaglandin E(2) or L-arginine, a substrate for NO synthase, respectively. Gastroprotective and hyperemic actions of standard ischemic preconditioning were abolished by pretreatment with capsaicin-inactivating sensory nerves, but restored by the administration of exogenous CGRP to capsaicin-treated animals. Gene and protein expression of cyclooxygenase-1, but not cyclooxygenase-2, were detected in intact gastric mucosa and in that exposed to ischemia/reperfusion with or without ischemic preconditioning, whereas cyclooxygenase-2 was overexpressed only in preconditioned mucosa. We conclude that: (1) gastric ischemic preconditioning represents one of the most powerful protective interventions against the mucosal damage induced by severe ischemia/reperfusion as well

Topics: Adenosine; Animals; Blotting, Western; Calcitonin Gene-Related Peptide; Capsaicin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Denervation; Digestive System; Dinoprostone; Enzyme Inhibitors; Gastric Mucosa; Gene Expression Regulation, Enzymologic; Indomethacin; Ischemic Preconditioning; Isoenzymes; Lactones; Male; Membrane Proteins; Neurons, Afferent; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Peptide Fragments; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Purinergic P1 Receptor Antagonists; Rats; Rats, Wistar; Receptors, Purinergic P1; Regional Blood Flow; Reperfusion Injury; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Sulfones; Theophylline; Time Factors

Resveratrol and trans-resveratrol are powerful phytoestrogens, present in the skins of grapes and other plant foods and wine, which demonstrate a broad spectrum of pharmacological and therapeutic health benefits. Phytoestrogens are naturally occurring plant-derived nonsteroidal compounds that are functionally and structurally similar to steroidal estrogens, such as estradiol, produced by the body. Various studies, reviewed herein, have demonstrated the health benefits of phytoestrogens in addressing climacteric syndrome including vasomotor symptoms and postmenopausal health risks, as well as their anticarcinogenic, neuroprotective and cardioprotective activities and prostate health and bone formation promoting properties. Conventional HRT drugs have been demonstrated to cause serious adverse effects including stroke and gallbladder disease, as well as endometrial, uterine and breast cancers. Recent research demonstrates that trans-resveratrol binds to human estrogen receptors and increases estrogenic activity in the body. We investigated the effects of protykin, a standardized extract of trans-resveratrol from Polygonum cuspidatum, on cardioprotective function, the incidence of reperfusion-induced arrhythmias and free radical production in isolated ischemic/reperfused rat hearts. The rats were orally treated with two different daily doses of protykin for 3 weeks. Coronary effluents were measured for oxygen free radical production by electron spin resonance (ESR) spectroscopy in treated and drug-free control groups. In rats treated with 50 and 100 mg/kg of protykin, the incidence of reperfusion-induced ventricular fibrillation was reduced from its control value of 83% to 75% (p < 0.05) and 33% (p < 0.05), respectively. Protykin was seen to possess cardioprotective effects against reperfusion-induced arrhythmias through its ability to reduce or remove the reactive oxygen species in ischemic/reperfused myocardium. Taken together, these data suggest that trans-resveratrol supplementation may be a potential alternative to conventional HRT for cardioprotection and osteoporosis prevention and may confer other potential health benefits in women.

Topics: Animals; Anthocyanins; Anticarcinogenic Agents; Antioxidants; Dose-Response Relationship, Drug; Estrogens, Non-Steroidal; Female; Free Radicals; Heart Diseases; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Proanthocyanidins; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Ventricular Fibrillation

Protykin is an all-natural, high potency standardized extract of trans-resveratrol (20%) and emodin (10%) derived from the dried rhizome of Polygonum cuspidatum. Previous studies have demonstrated free radical scavenging and anti-inflammatory activities of resveratrol. Since free radicals play a crucial role in the pathogenesis of myocardial ischemia/reperfusion injury, we examined whether Protykin could preserve the heart during ischemic arrest. Sprague-Dawley rats were divided into two groups: experimental group was gavaged Protykin (100 mg/kg body wt) dissolved in corn oil for three weeks, while the control group was gavaged corn oil alone. After three weeks, rats were sacrificed, isolated hearts perfused via working mode, were made globally ischemic for 30 min followed by 2 h of reperfusion. Left ventricular functions were continuously monitored and malonaldehyde (MDA) (presumptive marker for oxidative stress) formation were estimated. At the end of each experiment, myocardial infarct size was measured by TTC staining method. Peroxyl radical scavenging activity of Protykin was determined by examining its ability to remove peroxyl radical generated by 2,2'-azobis (2-amidinopropane) dihydrochloride, while hydroxy radical scavenging activity was tested with its ability to reduce 7-OH*-coumarin-3-carboxylic acid. The results of our study demonstrated that the Protykin group provided cardioprotection as evidenced by improved post-ischemic left ventricular functions (dp, dp/dt(max)) and aortic flow as compared to control group. This was further supported by the reduced infarct size in the Protykin group. Formation of MDA was also reduced by Protykin treatment. In vitro studies demonstrated that Protykin possessed potent peroxyl and hydroxyl radical scavenging activities. The results of this study indicate that Protykin can provide cardioprotection, presumably by virtue of its potent free radical scavenging activity.

Topics: Animals; Antioxidants; Blood Pressure; Coronary Vessels; Emodin; Fluoresceins; Free Radical Scavengers; Gamma Rays; Hydroxyl Radical; Male; Malondialdehyde; Myocardial Infarction; Myocardial Ischemia; Oxidative Stress; Peroxides; Polygonaceae; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes

Cardioprotective action of red wine was studied by preperfusing isolated rat hearts with ethanol-free red wine extract for 15 min before subjecting them to 30 min of global ischemia followed by 2 h of reperfusion. Four other group of rats were studied under identical conditions, of which one served as control; one was treated with 10 microM trans-resveratrol (RVT), one of the major antioxidants found in red wines; another, with 0.07% ethanol; and another, with 0.07% ethanol plus 10 microM RVT. The results of our study demonstrated that both red wine extract and RVT were equally cardioprotective, as evidenced by their abilities to improve postischemic ventricular functions including developed pressure and aortic flow. Developed pressure values at 60 min after reperfusion were 81.8 +/- 1.2 and 68.8 +/- 4.1 mm Hg for the red wine extract and RVT groups, respectively, versus 49.7 +/- 2.7 mm Hg for the control group. These compounds also reduced myocardial infarct size compared with the control hearts (20.1 +/- 0.5% and 10.5 +/- 0.3% for red wine extract and RVT groups, respectively, vs. 29.9 +/- 3.1% for the control group). The ethanol-treated group displayed slightly better functional recovery, which deteriorated sharply toward the end of the reperfusion period, and the extent of infarction was comparable to that of the control group (31.5 +/- 0.9%). In the ethanol plus RVT group, postischemic contractile function was significantly better than control, and infarct size also was reduced to 20.9 +/- 0.7%. The amount of malonaldehyde formation in the postischemic myocardium was reduced by red wine extract and RVT, indicating a reduction of oxidative stress developed in the ischemic reperfused myocardium. In vitro studies revealed that red wine extract is a potent antioxidant as evidenced by its ability to scavenge peroxyl radical in vitro. Taken together, the results of our study indicate that red wines are cardioprotective by their ability to function as an in vivo antioxidant.

Topics: Animals; Antioxidants; Blood Pressure; Drug Interactions; Ethanol; Free Radical Scavengers; Heart; In Vitro Techniques; Male; Malondialdehyde; Myocardial Contraction; Myocardial Infarction; Perfusion; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Resveratrol; Stilbenes; Time Factors; Wine

Resveratrol is a grape component with complex pharmacology related to its antioxidant activity. Little is known about the direct effects of resveratrol on the myocardium. We tested whether resveratrol administration before ischemia could attenuate ischemic/reperfusion damage. We examined how resveratrol affects high-energy phosphate metabolism (31P-nuclear magnetic resonance) and contractility of isolated Langendorff perfused rat hearts subjected to 20 min no-flow ischemia and 30 min reperfusion. During 10 min resveratrol infusion (10 microM) before ischemia, basal phosphorylation potential dropped by 40% (p < 0.05 vs. preinfusion value) without affecting contractility. The level of effluent adenosine was increased by 68%, parallel to a 50% increase in coronary flow. Resveratrol significantly improved postischemic recovery of rate-pressure product (62 +/- 5.2 vs. 23 +/- 8.1% of controls; p < 0.05). The metabolic pattern following resveratrol infusion was similar to that produced by ischemic preconditioning, suggesting that an increase in adenosine availability is involved in cardioprotection.

Topics: Adenosine; Animals; Antioxidants; Cardiovascular Physiological Phenomena; Heart; Ischemic Preconditioning, Myocardial; Male; Muscle Contraction; Myocardial Infarction; Myocardial Ischemia; Myocardium; Phosphates; Phosphorylation; Rats; Rats, Sprague-Dawley; Recovery of Function; Regional Blood Flow; Reperfusion Injury; Resveratrol; Stilbenes

In this study, ischemia-reperfusion produced in rats by clamping the celiac artery for 0.5 h followed by 1 h of reperfusion was used to develop a new model of superficial gastric erosions progressing to deeper ulcers. Ischemia alone resulted in an immediate fall in gastric blood flow but no gross mucosal lesions were observed. When ischemia was followed by reperfusion, gastric erosive lesions occurred, reached a maximum at 12 h and then declined after 24 h. These acute erosions progressed into deeper lesions 24 h after ischemia-reperfusion and reached a peak after 3 days. Gastric blood flow and the mucosal generation of prostaglandin E(2) were significantly suppressed immediately following ischemia-reperfusion, but with the healing of deeper gastric ulcers, both gastric blood flow and prostaglandin E(2) generation were gradually restored. Cyclooxygenase-1 mRNA was detected by reverse transcription-polymerase chain reaction in intact gastric mucosa and throughout the recovery of the mucosa from acute ischemia-reperfusion lesions, whereas cyclooxygenase-2 mRNA, was recorded only after ischemia-reperfusion. NS-398 and rofecoxib, selective inhibitors of cyclooxyganase-2, failed to affect prostaglandin E(2) generation in the non-ulcerated gastric mucosa but inhibited it significantly in the ulcer area. The two cyclooxygenase-2 inhibitors as well as resveratrol, a specific cyclooxygenase-1 inhibitor and indomethacin and meloxicam, non-specific inhibitors of cyclooxygenase, augmented acute gastric erosions induced by ischemia-reperfusion and delayed significantly the progression of these lesions into deeper ulcers at each time interval after ischemia-reperfusion. We conclude that prostaglandins generated by both cyclooxygenase-1 and cyclooxygenase-2 contribute to the healing of gastric lesions induced by ischemia-reperfusion.

Topics: Animals; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Gastric Mucosa; Gastrins; Gene Expression Regulation, Enzymologic; Indomethacin; Interleukin-1; Isoenzymes; Lactones; Meloxicam; Membrane Proteins; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Regional Blood Flow; Reperfusion Injury; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Stomach Ulcer; Sulfonamides; Sulfones; Thiazines; Thiazoles; Time Factors