Resveratrol's Protective Effects Research Articles

Investigation of Possible Protective Effects of Resveratrol on Oxidative Stress and Ferroptosis in PFOA Exposure in HepG-2 Cells

Aim: Exposure to perfluorooctanoic acid (PFOA) is linked to adverse health effects, including cancer and hepatic diseases. PFOA induces reactive oxygen species generation in human hepatic cells, causing oxidative stress and cell death. Resveratrol (RSV) has garnered attention for its protective effects against xenobiotic-induced damage, yet its impact on PFOA-induced oxidative stress and ferroptosis in the liver remains understudied. This study investigates RSV's protective mechanisms against oxidative stress and ferroptosis in HepG2 cells exposed to PFOA. Method: HepG2 cells were cultured in DMEM with 10% FBS and 1% penicillin/streptomycin in a 5% CO2 incubator at 37°C. PFOA was added to the cells at concentrations ranging from 0 to 450 µM and incubated at 37°C for 24 hours. The IC50 was determined to be 457 μM. To examine RSV's protective effects, cells were treated with 60 μM RSV. Following treatment with PFOA, RSV, and the combination of PFOA+RSV, cell lysates were prepared for analysis. Oxidative stress and ferroptosis parameters were measured spectrophotometrically using ELISA. Results: In the PFOA+RSV group, antioxidant capacity increased, and ferroptosis was suppressed compared to the control. Conversely, the PFOA group showed decreased antioxidant capacity, increased oxidant capacity, and induced ferroptosis compared to the control and RSV-treated groups. Conclusion: PFOA exposure heightens oxidative stress and ferroptosis, whereas RSV treatment significantly reduces hepatic oxidative stress and protects against ferroptosis during PFOA exposure.

Protective effects of resveratrol against fumonisin B1-induced liver toxicity in mice.

The aim of this study was to investigate the effects of resveratrol against fumonisin B1 (FB1)-induced liver toxicity, as, to the best of our knowledge, these effects have not been investigated yet, even though the toxic effects and mechanisms of FB1 and the antioxidative effects of resveratrol are well known. 40 BALB/c mice were divided into control, FB1, resveratrol, and FB1+resveratrol groups. Control received saline for 14 days. The FB1 group received 2.25 mg/kg FB1 every other day for 14 days. The resveratrol group received 10 mg/kg resveratrol for 14 days. The FB1+resveratrol group received 2.25 mg/kg FB1 every other day and 10 mg/kg resveratrol every day for 14 days. All administrations were peritoneal. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total sialic acid (TSA) levels were analysed in serum samples, while total antioxidant status (TAS) and total oxidant status (TOS) were measured in the liver. Additionally, the liver tissue was examined for histopathological changes. AST, ALT, and TSA were significantly higher in the FB1 group than control. Resveratrol countered FB1 effects for all parameters, including TOS and TAS. Liver histology showed FB1-induced hyperaemia, infiltrations, and megalokaryosis in some hepatocytes. No pathological findings were detected in the control, resveratrol, or FB1+resveratrol group. Our findings confirm resveratrol's protective effect against liver damage and oxidative stress caused by FB1. In addition, they suggest that increased serum TSA levels can be used as a biomarker of FB1-induced hepatotoxicity.

Resveratrol, Endocrine Disrupting Chemicals, Neurodegenerative Diseases and Depression: Genes, Transcription Factors, microRNAs, and Sponges Involved.

We aimed to examine the molecular basis of the positive effect of resveratrol against amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), cognitive impairment (CI), and depression induced by a mixture of bisphenol A (BPA), BPS, and BPF. The CTD, GeneMania, Metascape, SwissADME, Cytoscape, MIENTURNET, miRNAsong, and Autodock Vina were the fundamental tools for analysis. Resveratrol exerts its protective effects on selected diseases induced by a mixture of BPA, BPS, and BPF through the following genes: PTGS2 and GSR for ALS; INS, IL6, BDNF, and SOD1 for PD; BDNF, CASP3, TNF, INS, IGF1, IL1B for CI; and BDNF, PTGS2, and IL6 for depression. Detoxification was noted as the most important for ALS, dopamine metabolism for PD, apoptosis for CI, and the selenium micronutrient network for depression. hsa-miR-377-3p, hsa-miR-1-3p, hsa-miR-128-3p, and hsa-miR-204-5p were highlighted. We created and tested in silico sponges that inhibited these miRNAs. NFE2L2, BACH1, PPARG, and NR4A3 were listed as the key transcription factors implicated in resveratrol's protective effect against harmful studied chemicals. Furthermore, resveratrol's physicochemical properties and pharmacokinetics are consistent with its therapeutic benefits in ALS, PD, CI, and depression, owing to its high gastrointestinal absorption, drug-likeness, non-P-glycoprotein substrate, and capacity to penetrate the blood-brain barrier.

Resveratrol Mitigates Oxygen and Glucose Deprivation-Induced Inflammation, NLRP3 Inflammasome, and Oxidative Stress in 3D Neuronal Culture.

Oxygen glucose deprivation (OGD) can produce hypoxia-induced neurotoxicity and is a mature in vitro model of hypoxic cell damage. Activated AMP-activated protein kinase (AMPK) regulates a downstream pathway that substantially increases bioenergy production, which may be a key player in physiological energy and has also been shown to play a role in regulating neuroprotective processes. Resveratrol is an effective activator of AMPK, indicating that it may have therapeutic potential as a neuroprotective agent. However, the mechanism by which resveratrol achieves these beneficial effects in SH-SY5Y cells exposed to OGD-induced inflammation and oxidative stress in a 3D gelatin scaffold remains unclear. Therefore, in the present study, we investigated the effect of resveratrol in 3D gelatin scaffold cells to understand its neuroprotective effects on NF-κB signaling, NLRP3 inflammasome, and oxidative stress under OGD conditions. Here, we show that resveratrol improves the expression levels of cell viability, inflammatory cytokines (TNF-α, IL-1β, and IL-18), NF-κB signaling, and NLRP3 inflammasome, that OGD increases. In addition, resveratrol rescued oxidative stress, nuclear factor-erythroid 2 related factor 2 (Nrf2), and Nrf2 downstream antioxidant target genes (e.g., SOD, Gpx GSH, catalase, and HO-1). Treatment with resveratrol can significantly normalize OGD-induced changes in SH-SY5Y cell inflammation, oxidative stress, and oxidative defense gene expression; however, these resveratrol protective effects are affected by AMPK antagonists (Compounds C) blocking. These findings improve our understanding of the mechanism of the AMPK-dependent protective effect of resveratrol under 3D OGD-induced inflammation and oxidative stress-mediated cerebral ischemic stroke conditions.

Autophagy modulation in resveratrol protective effects on steroidogenesis in high-fat diet-fed mice and H2O2-challenged TM3 cells.

Autophagy dysregulation and oxidative stress play critical pathophysiological roles in developing obesity-related metabolic health disorders. This study aims to investigate how autophagy modulationis related to resveratrol (RSV) antioxidant activities and preventive effects on steroidogenesis decline associated with a high-fat diet (HFD) and oxidative damage. Eight-week-old C57BL/6J male mice were fed with HFD with or without supplement RSV (400mg/kg/day) by gavage for 16weeks. The control group was fed with a standard diet with no RSV or the same amount of RSV. Mouse Leydig cell line TM3 cell was used for in vitro studies. Oxidative stress was induced in TM3 cells with H2O2, followed by RSV treatment plus autophagy activator rapamycin or autophagy inhibitor 3-methyladenine, respectively. RSV supplement could upregulate proteins level of StAR and mitochondrial proteins COX4 and mtTFA, indicating the amelioration of steroidogenesis decline and mitochondrial dysfunction caused by HFD. Antioxidants such as GPx4 and SOD2 were improved by RSV as well. The observation of autophagosomes and the changes in expressions of LC3II/I, Beclin1, and Atg7 indicated that RSV could reverse the autophagy defect associated with HFD. 3-methyladenine inhibition of autophagy partially abolished RSV protection on mitochondrial function and steroidogenesis in H2O2-challenged TM3 cells. However, the combination use of rapamycin and RSV did not improve protection on Leydig cells against oxidative damage. The stimulation of autophagy by RSV is closely linked to its antioxidant actions and positive impact on steroidogenesis in HFD mice. The findings suggest RSV is protective against obesity-related Leydig cell impairment.

Resveratrol Prevents Right Ventricle Dysfunction, Calcium Mishandling, and Energetic Failure via SIRT3 Stimulation in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vessel remodeling; however, its severity and impact on survival depend on right ventricular (RV) failure. Resveratrol (RES), a polyphenol found in red wine, exhibits cardioprotective effects on RV dysfunction in PAH. However, most literature has focused on RES protective effect on lung vasculature; recent finding indicates that RES has a cardioprotective effect independent of pulmonary arterial pressure on RV dysfunction, although the underlying mechanism in RV has not been determined. Therefore, this study is aimed at evaluating sirtuin-3 (SIRT3) modulation by RES in RV using a monocrotaline- (MC-) induced PAH rat model. Myocyte function was evaluated by confocal microscopy as cell contractility, calcium signaling, and mitochondrial membrane potential (ΔΨm); cell energetics was assessed by high-resolution respirometry, and western blot and immunoprecipitation evaluated posttranslational modifications. PAH significantly affects mitochondrial function in RV; PAH is prone to mitochondrial permeability transition pore (mPTP) opening, thus decreasing the mitochondrial membrane potential. The compromised cellular energetics affects cardiomyocyte function by decreasing sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) activity and delaying myofilament unbinding, disrupting cell relaxation. RES partially protects mitochondrial integrity by deacetylating cyclophilin-D, a critical component of the mPTP, increasing SIRT3 expression and activity and preventing mPTP opening. The preserved energetic capability rescues cell relaxation by maintaining SERCA activity. Avoiding Ca2+ transient and cell contractility mismatch by preserving mitochondrial function describes, for the first time, impairment in excitation-contraction-energetics coupling in RV failure. These results highlight the importance of mitochondrial energetics and mPTP in PAH.

The antidepressant- and anxiolytic-like effects of resveratrol: Involvement of phosphodiesterase-4D inhibition

Resveratrol is a natural non-flavonoid polyphenol found in red wine, which has numerous pharmacological properties including anti-stress and antidepressant-like abilities. However, whether the antidepressant- and anxiolytic-like effects of resveratrol are related to the inhibition of phosphodiesterase 4 (PDE4) and its subtypes remains unknown. The same holds true for the subsequent cAMP-dependent pathway. The first set of studies investigated whether resveratrol exhibited neuroprotective effects against corticosterone-induced cell lesion as well as its underlying mechanism. We found that 100 μM corticosterone induced PDE2A, PDE3B, PDE4A, PDE4D, PDE10 and PDE11 expression in HT-22 cells, which results in significant cell lesion. However, treatment with resveratrol increased cell viability in a dose- and time-dependent manner. These effects seem related to the inhibition of PDE4D, as evidenced by resveratrol dose-dependently decreasing PDE4D expression. In addition, the PKA inhibitor H89 reversed resveratrol's effects on cell viability. Resveratrol prevented corticosterone-induced reduction in cAMP, pVASP(s157), pCREB, and BDNF levels, indicating that cAMP signaling is involved in resveratrol-induced neuroprotective effects. Not to mention, PDE4D knockdown by PDE4D siRNA potentiated the effect of low dose of resveratrol on cAMP, pVASP, pCREB, and BDNF expression, while PDE4D overexpression reversed the effect of high dose of resveratrol on the expression of the above proteins. Finally, the subsequent in vivo data supports the in vitro findings, suggesting that resveratrol-induced antidepressant- and anxiolytic-like effects are mediated by PDE4D. Overall, these findings support the hypothesis that PDE4D-mediated cAMP signaling plays an important role in resveratrol's protective effects on stress-induced depression- and anxiety-like behavior.

Resveratrol protects photoreceptors by blocking caspase- and PARP-dependent cell death pathways

Retinal degeneration is a major cause of severe vision loss and irreversible blindness and is characterized by progressive damage to retinal photoreceptor cells. Resveratrol (RSV) serves as an activator of the histone deacetylase, Sirt1, and has been shown to exert anti-oxidative properties. In this study, we mimicked retinal degeneration by subjecting photoreceptors (661 W cells) to glucose deprivation (GD) or light exposure. Under these conditions, we investigated the mechanisms underlying GD- or light exposure-induced cell death and the protective effect of RSV. We found that GD and light exposure resulted in mitochondrial dysfunction, oxidative stress, and cell death. Treatment of injured cells with RSV decreased the production of reactive oxygen species (ROS), improved the ratio of reduced/oxidized glutathione (GSH/GSSG), mitochondrial membrane potential and morphology, and reduced apoptosis. We used the caspase inhibitor, z-VAD-fmk, and a lentiviral-mediated shRNA knockdown of PARP-1 to reveal that GD and light exposure-induced cell death have different underlying mechanisms; GD triggered a caspase-dependent cell death pathway, whereas light exposure triggered a PARP-dependent cell death pathway. The level of caspase-9 and caspase-3, upregulated following GD, were reduced by treatment with RSV. Similarly, the level of PARP-1 and AIF, upregulated following light exposure, were decreased by treatment with RSV. Additionally, treatment with RSV elevated the protein expression and enzymatic activity of Sirt1 and a Sirt1 inhibitor reduced the protective effect of RSV against insult-induced cellular injuries, indicating that RSV's protective effect may involve Sirt1 activation. Finally, we investigated the neuroprotection of RSV in vivo. Administration of RSV to mice under extreme light exposure led to a suppression of the light-induced thinning of the outer nuclear layer (ONL) detected by hematoxylin and eosin (H&E) staining and restored retinal function evaluated by electroretinography (ERG). Taken together, our findings provide evidence that treatment with RSV has neuroprotective effects on both GD and light exposure-induced cell death pathways in photoreceptor cells.

Resveratrol Delays Retinal Ganglion Cell Loss and Attenuates Gliosis-Related Inflammation From Ischemia-Reperfusion Injury.

Resveratrol has been shown to enhance the survival of retinal ganglion cells (RGCs) following ischemia-reperfusion (I/R) injury for glaucoma. However, the precise mechanisms for resveratrol's protective effects are still unclear. The aim of this study is to determine whether resveratrol can inhibit RGC apoptosis, retinal gliosis, and inflammation, all of which are critical events in retinal degeneration following I/R injury. Right retinal ischemia was induced in adult male Sprague Dawley rats by increasing intraocular pressure to 110 mm Hg for 60 minutes, and the left eyes maintained at normal pressure serve as the control. Intraperitoneal injection of resveratrol or control buffer was performed continuously for 3 days from pre- to post-I/R injury and the protective effects were evaluated and compared. RGCs were retrogradely labeled with Fluoro-Gold by injection into superior colliculi. Apoptosis was detected by TUNEL staining. Western blotting and immunostaining for Bax, Bcl-2, and Caspase-3 were used to explore the Bax-associated apoptotic pathway. Gliosis was assessed by western blotting and immunostaining of retinal cross sections with anti-glial fibrillary acidic protein (GFAP) antibodies. In this study, resveratrol treatment significantly reduced retinal damage and RGC loss as demonstrated by the relatively intact tissue structure in hematoxylin and eosin staining at day 7 and increased Fluoro-Gold labeling of RGCs at day 14, respectively. We found that resveratrol exhibited an anti-apoptotic effect as assessed by reduced TUNEL staining, inhibition of the early upregulated expression of the apoptosis-related protein Bax, and decreased subsequently cleaved caspase-3. However, it did not affect Bcl-2 levels. Moreover, in our I/R injury model, the combined response of reactive gliosis and related inflammation, which were demonstrated by an early induction of pro-inflammatory mediators and subsequently increased GFAP level, were significantly attenuated after resveratrol treatment. These results demonstrate that resveratrol can prevent RGC death by blocking the Bax-caspase-3-dependent apoptotic pathway and suppressed gliosis-related inflammation in the retina after I/R injury. Together these results support the use of resveratrol as a possible therapeutic strategy for glaucoma.

Synergistic effects of resveratrol (free and inclusion complex) and sulfamethoxazole-trimetropim treatment on pathology, oxidant/antioxidant status and behavior of mice infected with Toxoplasma gondii

This study aimed to investigate the synergistic effects of resveratrol and sulfamethoxazole-trimethoprim (ST) on the treatment of mice experimentally infected by Toxoplasma gondii during the chronic phase of the disease considering infection, behavior, and oxidative/antioxidants profile aspects. For the study, 60 mice were initially divided into two groups: uninfected (n = 24) and infected by T. gondii (n = 36). These two groups were later subdivided into other groups and treated with resveratrol (free and inclusion complex containing resveratrol) alone and co-administered with ST: groups A to D were composed by healthy mice and groups E to J were consisted of animals infected by T. gondii (VEG strain). Treatments began 20 days post-infection for 10 consecutive days with oral doses of 0.5 mg kg−1 of ST (groups B and F), 100 mg kg−1 of free resveratrol (groups C and G) and inclusion complex of resveratrol (nanoparticles containing resveratrol) (groups D and H), and lastly an co-administration of both drugs (groups I and J). Behavioral tests (memory, anxiety and locomotion) were performed after treatment. Liver and brain fragments were collected to evaluate pathological changes, brain cysts counts, as well as oxidant and antioxidant levels. A reduction on the number of cysts in the brain of animals treated with both drugs combined was observed; there was also reduced number of lesions on both organs. This drug combined effect was also able to reduce oxidative and increase antioxidant levels in infected mice, which might be interpreted as a resveratrol protective effect. In addition, the combination of ST and resveratrol was able to prevent behavioral changes in infected mice. Therefore, the use of co-administration drugs enhances the therapeutic effect acting on a synergic way, reducing the oxidizing effects of the chemical treatment for toxoplasmosis. In addition, resveratrol in inclusion complex when co-administered with ST showed an improved therapeutic effect of ST reducing oxidative damage, liver damage and the number of cysts in the brain of T. gondii infected mice.

Resveratrol Protects against Titanium Particle-Induced Aseptic Loosening Through Reduction of Oxidative Stress and Inactivation of NF-κB.

Aseptic implant loosening is closely associated with chronic inflammation induced by implant wear debris, and reactive oxygen species (ROS) play an important role in this process. Resveratrol, a plant compound, has been reported to act as an antioxidant in many inflammatory conditions; however, its protective effect and mechanism against wear particle-induced oxidative stress remain unknown. In this study, we evaluated resveratrol's protective effects against wear particle-induced oxidative stress in RAW 264.7 macrophages. At non-toxic concentrations, resveratrol showed dose-dependent inhibition of nitric oxide (NO) production, ROS generation, and lipid peroxidation. It also downregulated the gene expression of oxidative enzymes, including inducible nitric oxide synthase (iNOS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-1 and NOX-2, and promoted the gene expression and activities of antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), and glutathione peroxidase (GPx). This protective effect against wear particle-induced oxidative stress was accompanied by a reduction of gene expression and release of tumor necrosis factor-α (TNF-α), and decreased gene expression and phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). These findings demonstrate that resveratrol can inhibit wear particle-induced oxidative stress in macrophages, and may exert its antioxidant effect and protect against aseptic implant loosening.

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that causes progressive paralysis and death due to degeneration of motoneurons in spinal cord, brainstem and motor cortex. Nowadays, there is no effective therapy and patients die 2-5 years after diagnosis. Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural polyphenol found in grapes, with promising neuroprotective effects since it induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of resveratrol administration on SOD1(G93A) ALS mice. We determined the onset of symptoms by rotarod test and evaluated upper and lower motoneuron function using electrophysiological tests. We assessed the survival of the animals and determined the number of spinal motoneurons. Finally, we further investigated resveratrol mechanism of action by means of western blot and immunohistochemical analysis. Resveratrol treatment from 8 weeks of age significantly delayed disease onset and preserved lower and upper motoneuron function in female and male animals. Moreover, resveratrol significantly extended SOD1(G93A) mice lifespan and promoted survival of spinal motoneurons. Delayed resveratrol administration from 12 weeks of age also improved spinal motoneuron function preservation and survival. Further experiments revealed that resveratrol protective effects were associated with increased expression and activation of Sirtuin 1 and AMPK in the ventral spinal cord. Both mediators promoted normalization of the autophagic flux and, more importantly, increased mitochondrial biogenesis in the SOD1(G93A) spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS.

The Combined Therapy with Resveratrol and Hypothermia Prevents Apoptosis in a Neonatal Rat Model of Global Hypoxic-Ischemic Encephalopathy

Birth asphyxia and newborn prematurity are the two major causes of perinatal mortality resulting in central nervous system (CNS) injury by hypoxia and ischemia. Hypoxia and ischemia produce massive brain damage following a typical pattern which is defined by selective vulnerability of the brain regions.The main objective of this study was to test the possible protective effect of resveratrol and hypothermia in hypoxic-ischemic encephalopathy in newborn rats. The changes in terms of histology and apoptosis were determined in brain so as to assess the local damages induced by hypoxic ishemia. The experiment was performed on 17 newborn Wistar rats that were given resveratrol in a dose of 20 mg/kg/day for seven days as premedication. At the end of this period the animals were exposed to hypobaric hypoxia (9% O+2 for 90 minutes) and ischemia (by clamping the right carotid artery). In global hypoxic-ischemic encephalopathy the resveratrol at a dose of 20 mg/kg/day as premedication offers neuroprotection by reducing the number of cells expressing apoptosis in CA1, CA2, CA3 and dentate gyrus of the hippocampus under the conditions of conjugation with post-injury hypothermia. In the cerebral cortex the resveratrol protective effects were not hypothermia dependent. No protective effect of resveratrol was observed in thalamus after global hypoxic-ischemic encephalopathy. The results of this study prove that resveratrol offers neuroprotection in hypobaric hypoxic brain injuries, but the protection is conditioned in most of the brain regions (excepting cerebral cortex) by conjugation of the protective therapy with post-injury hypothermia treatment

Neuroprotective effect of resveratrol against scopolamine-induced cognitive impairment and oxidative stress in rats

The objective of this study was to examine the neuroprotective effect of resveratrol on cognitive impairment induced by scopolamine, a muscarinic antagonist, in rats. Memory impairment was induced by administration of sco- polamine (1 mg/kg) intraperitoneally. Cognitive functions were assessed using radial arm maze, an active avoidance paradigm. Oxidative stress parameters like malondialdehyde, catalase and superoxide dismutase were assessed and acetylcholinesterase activity was estimated. More working and reference memory errors in the radial arm maze test and fewer avoidances in the active avoidance test were observed with scopolamine in the 1 mg/kg i.p.-treated animals. This phenomenon is a clear indication of memory impairment. Oral administration of resveratrol (20 mg/kg) inhibited the occurrence of higher working, reference memory errors and prevented the incidence of less avoidances. Resveratrol appeared to have exerted memory-enhancing effects by inhibiting acetylcholinesterase activity and prevented the rise in malondialdehyde levels and loss of antioxidant enzymes catalase and superoxide dismutase, showing antioxidant po- tential. Based on the above results of behavioral and biochemical studies, it can be concluded that resveratrol protected against scopolamine-induced loss of cognition. The results also indicate that resveratrol is an antioxidant and an acetyl- cholinesterase inhibitor, and it is likely that resveratrol's protective effect is related to its antioxidant and cholinesterase inhibitory effects.

Resveratrol Prevention of Oxidative Stress Damage to Lens Epithelial Cell Cultures Is Mediated by Forkhead Box O Activity

To evaluate the potential role that FoxO transcription factors play in modulating resveratrol's protective effects against oxidative stress in lens epithelial cells. Primary human or porcine lens epithelial cells (LECs) were treated with resveratrol (RES) 25 μM and incubated under either physiologic (5%) or chronic hyperoxic (40%) oxygen conditions. Acute oxidative stress was applied using 600 μM H(2)O(2). Changes in expression of FoxO1A, FoxO3A, and FoxO4 were analyzed. The production of intracellular reactive oxygen species (iROS), SA-β-galactosidase (SA-β-gal) activity, and autofluorescence (AF) was assessed by flow cytometry. SiRNAs of FoxO1A, FoxO3A, and FoxO4 were used to study the roles that these transcription factors play in resveratrol's protective effects against cell death induced by oxidative stress. RES incubation under 40% oxygen increased the expression of FoxO1A, FoxO3A, and FoxO4. RES also increases mitochondrial membrane potential under 5% and/or 40% O(2) conditions and significantly decreased iROS, SA-β-gal, and AF normally induced by hyperoxic conditions. While RES had a mild pro-apoptotic effect in nonstressed cells, it significantly prevented apoptosis induced by H(2)O(2) stress. SiRNA inhibition of FoxO1A, FoxO3A, and FoxO4 not only led to loss of the anti-apoptotic effects of RES in stressed cells but actually exhibited a mild pro-apoptotic effect. RES exerts a protective effect against oxidative damage in LEC cultures. The levels of expression of FoxO1A, FoxO3A, and FoxO4 appear to play a central role in determining the pro- or anti-apoptotic effects of RES. This has implications for future studies on oxidative stress-related lenticular disorders such as cataract formation.

Mechanism for the protective effect of resveratrol against oxidative stress-induced neuronal death

Oxidative stress can induce cytotoxicity in neurons, which plays an important role in the etiology of neuronal damage and degeneration. This study sought to determine the cellular and biochemical mechanisms underlying resveratrol's protective effect against oxidative neuronal death. Cultured HT22 cells, an immortalized mouse hippocampal neuronal cell line, were used as an in vitro model, and oxidative stress and neurotoxicity were induced in these neuronal cells by exposure to high concentrations of glutamate. Resveratrol strongly protected HT22 cells from glutamate-induced oxidative cell death. Resveratrol's neuroprotective effect was independent of its direct radical scavenging property, but instead was dependent on its ability to selectively induce the expression of mitochondrial superoxide dismutase (SOD2) and, subsequently, reduce mitochondrial oxidative stress and damage. The induction of mitochondrial SOD2 by resveratrol was mediated through the activation of the PI3K/Akt and GSK-3β/β-catenin signaling pathways. Taken together, the results of this study show that up-regulation of mitochondrial SOD2 by resveratrol represents an important mechanism for its protection of neuronal cells against oxidative cytotoxicity resulting from mitochondrial oxidative stress.