Pretreatment Of Resveratrol Research Articles

Amelioration of endothelial integrity by 3,5,4′-trihydroxy-trans-stilbene against high-fat-diet-induced obesity and -associated vasculopathy and myocardial infarction in rats, targeting TLR4/MyD88/NF-κB/iNOS signaling cascade

Exacerbated expression of TLR4 protein (foremost pattern recognition receptor) during obesity could trigger NF-κB/iNOS signaling through linker protein (MyD88), predisposed to an indispensable inflammatory response. The induction of this detrimental cascade leads to myocardial and vascular abnormalities. Molecular docking was studied for protein-ligand interaction between these potential targets and resveratrol. The pre-treatment of resveratrol (20 mg/kg/p.o/per day for ten weeks) was given to investigate the therapeutic effect against HFD-induced obesity and associated vascular endothelial dysfunction (VED) and myocardial infarction (MI) in Wistar rats. In addition to accessing the levels of serum biomarkers for VED and MI, oxidative stress, inflammatory cytokines, and histopathology of these tissues were investigated. Lipopolysaccharide (for receptor activation) and protein expression analysis were introduced to explore the mechanistic involvement of TLR4/MyD88/NF-κB/iNOS signaling. Assessment of in-silico analysis showed significant interaction between protein and ligand. The involvement of this proposed signaling (TLR4/MyD88/NF-κB/iNOS) was further endorsed by the impact of lipopolysaccharide and protein expression analysis in obese and treated rats. Moreover, resveratrol pre-treated rats showed significantly lowered cardio and vascular damage measured by the distinct down expression of the TLR4/MyD88/NF-κB/iNOS pathway by resveratrol treatment endorses its ameliorative effect against VED and MI.

Changes of LncRNAs during the Process of Antioxidants Antagonize Cadmium-Induced Oxidative Damage in Islet β Cells.

Long non-coding RNAs (LncRNAs) play important regulatory roles in oxidative damage. Resveratrol, curcumin, and cyanidin are phytogenic antioxidants widely existing in nature and they have been proved to antagonize certain heavy metal-induced oxidative damage in cells. However, can they antagonize oxidative damage induced by cadmium in islet β cells? Are their mechanisms of antagonizing oxidative damage related to LncRNAs? In this study, we first detected the cell viability of each group by CCK8 assay. Next, reactive oxygen species (ROS) were detected by the fluorescent probe. The contents of malondialdehyde (MDA) and the activities of superoxide dismutase (SOD) were detected according to the instructions of corresponding kits. At last, the levels of LncRNAs were detected by fluorescence quantitative real-time polymerase chain reaction (qPCR). The results showed that resveratrol, curcumin and cyanidin were able to reverse the reduction of cell viability induced by cadmium (CdSO4). Further determination revealed that SOD activities of the resveratrol+CdSO4, curcumin+CdSO4, and cyanidin+CdSO4 treatment groups increased significantly, and ROS levels and MDA contents dramatically decreased when compared with single CdSO4-treated group. More importantly, the levels of three CdSO4-elevated LncRNAs (NONMMUT029382, ENSMUST00000162103, ENSMUST00000117235) were all decreased and levels of three CdSO4-inhibited LncRNAs (NONMMUT036805, NONMMUT014565, NONMMUT065427) were increased after the pretreatment of resveratrol, curcumin and cyanidin. In summary, resveratrol, curcumin and cyanidin may effectly reverse the cadmium-induced oxidative damage and suggest that phytogenic antioxidants may prevent cells from cadmium-induced oxidative damage through changing the levels of LncRNAs.

Resveratrol attenuates methamphetamine-induced memory impairment via inhibition of oxidative stress and apoptosis in mice.

Methamphetamine (METH) abuse produces serious neurotoxicity to the central nervous system along with long-term cognitive dysfunction. Resveratrol, a natural polyphenol, has broad application prospects in the treatment of neurodegenerative diseases. Therefore, this study was conducted to investigate whether resveratrol might alleviate METH-induced memory deficits in vivo. We found that multiple exposures to METH significantly impaired cognitive functions and caused long-lasting memory deficits (p<.05). Pretreatment of resveratrol (10 or 100mg/kg) remarkably attenuated METH-induced memory impairment in mice (p<.05). Bioinformatics analysis results showed that resveratrol might alleviate memory deficits by inhibiting METH-induced oxidative damage and apoptosis. Molecular docking showed that resveratrol had hydrogen bonding interactions with Kelch-like ECH associated protein 1 (Keap1), a repressor protein of the classic antioxidant Keap1-Nrf2 pathway. Further results validated oxidative stress parameters, apoptosis, and expression of Keap1 were significantly increased, while the translocation and activation of nuclear factor erythroid 2-related factor 2 (Nrf2) into the nucleus and expression of its downstream proteins were greatly decreased in the hippocampus after METH exposure (p<.05). These changes caused by METH could be prevented by resveratrol (p<.05). Therefore, these findings suggested that the prevention of resveratrol on memory dysfunction induced by METH was possibly related to the activation of the Keap1-Nrf2 pathway and reduction of apoptosis. Supplementation of resveratrol could be a potential treatment for preventing the neurotoxicity of METH in the future. PRACTICAL APPLICATIONS: As one of the worst commonly abused psychostimulants, methamphetamine (METH) addiction produces serious complications including cognitive impairment and memory deficits. Resveratrol is a natural polyphenol that has important nutritional supplements and protective effects in the treatment of many neurodegenerative diseases. In this study, the results of bioinformatics prediction and experimental validation showed that resveratrol might effectively prevent memory impairment via the interaction with Keap1, activation of the Keap1-Nrf2 pathway, and inhibition of DNA damage and apoptotic responses post METH exposure. Therefore, these findings provide new ideas and insights into the application of resveratrol in the treatment of nervous system damage caused by METH.

Potential of resveratrol in enrichment of neural progenitor-like cell induction of human stem cells from apical papilla

IntroductionStem cell transplantation of exogenous neural progenitor cells (NPCs) derived from mesenchymal stem cells (MSCs) has emerged as a promising approach for neurodegenerative disease. Human stem cells from apical papilla (hSCAPs) are derived from migratory neural crest stem cells and exhibit a potential of neuronal differentiation. However, their neuronal differentiation is low and unpredictable. Resveratrol has been described as a sirtuin 1 (SIRT1) activator which plays an important role in enhancing neuronal differentiation. In this study, we investigate the potential of resveratrol as an enhancer on neuronal differentiation through NPCs induction of hSCAPs.MethodsStem cells were isolated from human apical papilla and characterized as MSCs. The cellular toxicity of resveratrol treatment to the characterized hSCAPs was investigated by MTT assay. The non-cellular toxicity concentrations of resveratrol were assessed with various pre-treatment times to select the optimal condition that highly expressed the neural progenitor gene, NES. Consequently, the optimal condition of resveratrol pre-treatment was synergistically performed with a neuronal induction medium to trigger neuronal differentiation. The differentiated cells were visualized, the genes profiling was quantified, and the percentage of neuronal differentiation was calculated. Moreover, the intracellular calcium oscillation was demonstrated.ResultsThe cellular toxicity of resveratrol was not observed for up to 50 μM for 12 h. Interestingly, hSCAPs pre-treated with 10 μM resveratrol for 12 h (RSV-hSCAPs) significantly expressed NES, which is determined as the optimal condition. Under neuronal induction, both of hSCAPs and RSV-hSCAPs were differentiated (d-hSCAPs and RSV-d-hSCAPs) as they exhibited neuronal-like appearances with Nissl substance staining. The highest expression of NES and SOX1 was observed in RSV-d-hSCAPs. Additionally, the percentage of neuronal differentiation of RSV-d-hSCAPs was significantly higher than d-hSCAPs for 4 times. Importantly, the neuronal-like cells exhibited slightly increasing pattern of calcium intensity.ConclusionThis study demonstrated that pre-treatment of resveratrol strongly induces neural progenitor marker gene expression which synergistically enhances neural progenitor-like cells’ induction with neuronal induction medium.

Toxicity evaluation of CdSe nanorods on macrophages and the protective effect of resveratrol

Cadmium selenide (CdSe) nanomaterials (NMs) easily access to organism due to the applications in photocatalysis, gene therapy, and cell labeling, while the increasing environmental release and accumulating in lungs tend to pose threat to humans and the incidence of cytotoxicity largely compromises their application. Resveratrol is recognized as antioxidant and has protective effects on oxidative stress, depending on its special structure of scavenging free radicals. Herein, we demonstrated that CdSe nanorods induced apoptosis to macrophages and resveratrol exhibited an excellent ability to prevent cells from damage. CdSe nanorods with the average length of 70–100 nm caused an increasing reactive oxygen species (ROS) and disrupted the cellular antioxidant system. The cellular organelles including mitochondria, endoplasmic reticulum, and nuclei were both interfered by the oxidative stress. Notably, pretreatment of resveratrol could largely alleviate the apoptosis. Macrophages recovered the normal morphology and reinforced antioxidant system in the presence of resveratrol, which showed a selective protection towards the changes of mitochondrial function.

Resveratrol influences platinum pharmacokinetics: A novel mechanism in protection against cisplatin-induced nephrotoxicity

Cisplatin (CP) is a widely used drug in treatment of solid tumors. However, the use of CP was hampered by its serious side effects especially nephrotoxicity. This study aims to investigate the effect of resveratrol (RES) on CP-induced nephrotoxicity, particularly, the effect of RES on CP pharmacokinetics (PKs). Male white albino rats were divided to four group’s six rats each. The first group received (1%) tween 80 in normal saline and served as control. The second group received RES (30 mg kg−1) per day for 14 consecutive day’s i.p. The third and fourth groups were given a single i.p. injection of CP (6 mg kg−1) with or without pre-treatment of RES (30 mg kg−1per day for 14 consecutive days), respectively. Following administration of CP, plasma, urine and kidney platinum concentration were monitored to study PKs of CP. Five days after the CP injection, rats were killed; blood samples were collected; kidneys were dissected; and biochemical, immunohistochemical, and histological examinations were performed. Our results revealed that CP treatment significantly deteriorated kidney functions with subsequent alteration in redox balance of the kidney. On the other hand, RES successfully ameliorated CP-induced kidney injury and recovered normal kidney tissue redox status. Importantly, while RES pre-treatment did not significantly alter the plasma CP level, it dramatically decreased the urine concentration of CP and lowered its accumulation into the kidneys. Moreover, it increased CP plasma half-life (t1/2) with subsequent decrease in its elimination rate constant, indicating an important role of PKs modulation in RES protection against CP-induced renal damage. Taken together, RES may protect the kidney tissue from the deleterious effects of CP through constringe of CP renal accumulation and enhancement of CP-induced oxidative stress.

Resveratrol Improves Tube Formation in AGE-Induced Late Endothelial Progenitor Cells by Suppressing Syndecan-4 Shedding.

Dysfunction of endothelial progenitor cells (EPCs) contributes to cardiovascular complications in diabetes, and resveratrol has been shown to improve EPC functions. Syndecan-4 (Synd4), a cell surface heparin sulfate proteoglycan, has been shown to promote neovascularization. Thus, the present study was performed to determine whether resveratrol promoted angiogenesis of EPCs by regulating Synd4. Late EPCs were isolated from human peripheral blood and stimulated with AGEs. Western blot showed that AGEs induced Synd4 shedding in a dose- and time-dependent manner. AGE-induced Synd4 shedding was partly reversed by NAC or resveratrol, along with normalized ROS production. Overexpression of Synd4 or pretreatment of resveratrol reversed AGE-impaired tube formation of EPCs and regulated the Akt/eNOS pathway. Furthermore, resveratrol suppressed Synd4 shedding via the inhibition of oxidative stress and improved tube formation of late EPCs via the regulation of the Synd4/Akt/eNOS pathway.

Protective effects of resveratrol and its analogs on age-related macular degeneration in vitro.

Damage of retinal pigment epithelial (RPE) cells by A2E may be critical for age-related macular degeneration (AMD) management. Accumulation and photooxidation of A2E are known to be one of the critical causes in AMD. Here, we evaluated the protective effect of resveratrol (RES), piceatannol (PIC) and RES glycones on blue-light-induced RPE cell death caused by A2E photooxidation. A2E treatment followed by blue light exposure caused significant damages on human RPE cells (ARPE-19). But the damages were attenuated by post- and pre-treatment of RES and PIC in our in vitro models. The results of cell free system and FAB-MS analysis clearly showed that the reduction of A2E by blue light exposure was significantly rescued, and that oxidized forms of A2E were significantly reduced by RES or PIC treatment. Besides, RES or PIC inhibited the intracellular accumulation of A2E. Not only RES and PIC but RES glycones showed protection of ARPE-19 cells against A2E and blue-light-induced photo-damage. These findings demonstrate that RES and its analogs may have protective effects against A2E and blue-light-induced ARPE-19 cell death through regulation of A2E accumulation as well as photooxidation of A2E. Thus RES and its analogs may be beneficial for AMD treatment.

Resveratrol attenuates neuropathic pain through balancing pro-inflammatory and anti-inflammatory cytokines release in mice

Anti-inflammatory activity of resveratrol has been widely studied, while its beneficial effect on the management of neuropathic pain, a refractory chronic syndrome with pro-inflammation implicated in, is very little investigated. In the present study, the effects of different doses and various time window of administration of resveratrol were explored in a neuropathic mouse model of chronic constriction injury (CCI) of the sciatic nerve. It was demonstrated that pretreatment of resveratrol (5, 10, 20 and 40mg/kg) for 7 consecutive days before CCI did not alleviate neuropathic pain, while it clearly relieved the pain when administrated after CCI and such pain relief effect was more pronounced when administrated right after the peak of pain symptom at day 7 after CCI, as evidenced by the alleviation of thermal hyperalgesia and mechanical allodynia. Such a beneficial effect of resveratrol was in a dose-dependent manner. Mechanistic study showed that resveratrol repressed the expression of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, and promoted the expression of anti-inflammatory cytokine IL-10 at the same time, which was further confirmed in a cell model of microglia. It was also shown that neuropathic pain inversely correlated with pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, but not with anti-inflammatory cytokine IL-10 in all experimental mice from Spearman correlation coefficient. Our study reveals that resveratrol displays a significant neuropathic pain relief effect and paved a way for novel treatment of chronic pain.

Protective effects of resveratrol on the inhibition of hippocampal neurogenesis induced by ethanol during early postnatal life

Ethanol (EtOH) exposure during early postnatal life triggers obvious neurotoxic effects on the developing hippocampus and results in long-term effects on hippocampal neurogenesis. Resveratrol (RSV) has been demonstrated to exert potential neuroprotective effects by promoting hippocampal neurogenesis. However, the effects of RSV on the EtOH-mediated impairment of hippocampal neurogenesis remain undetermined. Thus, mice were pretreated with RSV and were later exposed to EtOH to evaluate its protective effects on EtOH-mediated toxicity during hippocampal development. The results indicated that a brief exposure of EtOH on postnatal day 7 resulted in a significant impairment in hippocampal neurogenesis and a depletion of hippocampal neural precursor cells (NPCs). This effect was attenuated by pretreatment with RSV. Furthermore, EtOH exposure resulted in a reduction in spine density on the granular neurons of the dentate gyrus (DG), and the spines exhibited a less mature morphological phenotype characterized by a higher proportion of stubby spines and a lower proportion of mushroom spines. However, RSV treatment effectively reversed these responses. We further confirmed that RSV treatment reversed the EtOH-induced down-regulation of hippocampal pERK and Hes1 protein levels, which may be related to the proliferation and maintenance of NPCs. Furthermore, EtOH exposure in the C17.2 NPCs also diminished cell proliferation and activated apoptosis, which could be reversed by pretreatment of RSV. Overall, our results suggest that RSV pretreatment protects against EtOH-induced defects in neurogenesis in postnatal mice and may thus play a critical role in preventing EtOH-mediated toxicity in the developing hippocampus.

Smilax China root extract detoxifies nicotine by reducing reactive oxygen species and inducing CYP2A6.

Resveratrol has a beneficial effect of lowering reactive oxygen species (ROS) and reduces cellular oxidative stress. We hypothesized that ethanol extract of Smilax china root (EESC) rich in resveratrol (RES) and oxyresveratrol (OXY) could reduce ROS caused by nicotine and promoting nicotine turnover by induction of CYP2A6. The amount of cotinine converted from nicotine was quantified by the direct barbiturate assay method. Expression of CYP2A6 was unregulated by RES, OXY, or EESC, respectively. Pretreatment of RES (50, 100, and 250 μM), OXY (50, 100, and 250 μM), and RES+OXY (50 and 100 μM) inhibited cytotoxicity and ROS production caused by nicotine in a dose-dependent manner. EESC pretreatment (1.8 mg/mL) increased cell viability by 1.5-fold higher than the control (nicotine only), and lowered cellular ROS levels. A significant amount of the conversion of nicotine to cotinine was observed in EESC pretreatment by CYP2A6 induction in HepG2 cells. These results suggested that hepatic induction of CYP2A6 and ROS reduction by EESC activate nicotine metabolism and reduce cellular oxidative stress. Nicotine exposure due to smoking is very concerning because it is the major factor for lung diseases and cardiovascular disorders. It is necessary to examine natural ingredients that can detoxify from nicotine to cotinine as well as neutralize free radicals induced from nicotine. Results from the current study suggest potential applications of Smilax china root for detoxification of nicotine in the food industry.

Resveratrol Inhibits Glycine Receptor-Mediated Ion Currents

Resveratrol is found in grapes, red wine, and berries. Resveratrol has been known to have many beneficial health effects, such as anti-cancer, neuroprotective, anti-nociceptive, and life-prolonging effects. However, the single cellular mechanisms by which resveratrol acts are relatively unknown, especially in terms of possible regulation of receptors involved in synaptic transmission. The glycine receptor is an inhibitory ligand-gated ion channel involved in fast synaptic transmission in spinal cord. In the present study, we investigated the effect of resveratrol on human glycine receptor channel activity. Glycine α1 receptors were expressed in Xenopus oocytes and glycine receptor channel activity was measured using a two-electrode voltage clamp technique. Treatment with resveratrol alone had no effect on oocytes injected with H2O or on oocytes injected with glycine α1 receptor cRNA. In the oocytes injected with glycine α1 receptor cRNA, co- or pre-treatment of resveratrol with glycine inhibited the glycine-induced inward peak current (IGly) in a reversible manner. The inhibitory effect of resveratrol on IGly was also concentration dependent, voltage independent, and non-competitive. These results indicate that resveratrol regulates glycine receptor channel activity and that resveratrol-mediated regulation of glycine receptor channel activity is one of several cellular action mechanisms of resveratrol for pain regulation.

Neurotoxic effect of cypermethrin and protective role of resveratrol in Wistar rats

Background: Cypermethrin is a synthetic pyrethroid commonly used in agriculture, veterinary, and household insects/pests management. Resveratrol a polyphenolic phytoalexin abundantly found in grapes and red wine is a potent antioxidant and cytoprotective agent. Objectives: Neurotoxicity of cypermethrin is well-known. The aim of this study was to evaluate neurotoxic effects of cypermethrin and protective role of resveratrol in Wistar rats. Materials and Methods: Thirty male Wistar rats were divided into five groups. Group A served as control. Rats of Group B were treated with cypermethrin at the dose of 3.83 mg/kg body weight (bw) for 7 days. Group C and D were post- and pretreatment of resveratrol (20 mg/kg bw) along with cypermethrin exposure. In Group E, resveratrol served as control. Results: Cypermethrin treated group showed elevation in lipid peroxidation (LPO 83.99%) and inhibition in glutathione (GSH 12.81%), superoxide dismutase (SOD 17.08%), catalase (CAT 11.51%), glutathione-S-transferase (GST 12.12%), glutathione reductase (GR 77.55%), glutathione peroxidase (GPX 23.78 %), total protein (42.95%), and acetylcholinesterase (AChE) activity (47.64%) in rat brain. Posttreatment, pretreatment, and treatment with resveratrol reversed the toxic effect induced by cypermethrin. Conclusion: Our findings strongly suggest that cypermethrin-induced neurotoxicity may be mediated through free radical formation, reduced antioxidant defense mechanism, and inhibition of acetylcholinestrase (AChE) activity. Cypermethrin may be showing AChE inhibitory activity by interacting with the anionic substrate binding site. Administration of resveratrol increased AChE activity and ameliorated cypermethrin-induced brain damage in Wistar rats.

Resveratrol Inhibited Hydroquinone-Induced Cytotoxicity in Mouse Primary Hepatocytes

Hydroquinone (1,4-benzenediol) has been widely used in clinical situations and the cosmetic industry because of its depigmenting effects. Most skin-lightening hydroquinone creams contain 4%–5% hydroquinone. We have investigated the role of resveratrol in prevention of hydroquinone induced cytotoxicity in mouse primary hepatocytes. We found that 400 µM hydroquinone exposure alone induced apoptosis of the cells and also resulted in a significant drop of cell viability compared with the control, and pretreatment of resveratrol to a final concentration of 0.5 mM 1 h before hydroquinone exposure did not show a significant improvement in the survival rate of the hepatocytes, however, relatively higher concentrations of resveratrol (≥1 mM) inhibited apoptosis of the mouse primary hepatocytes and increased cell viability in a dose-dependent manner, and in particular the survival rate of the hepatocytes was recovered from 28% to near 100% by 5 mM resveratrol. Interestingly, pretreatment with resveratrol for longer time (24 h), even in very low concentrations (50 µM, 100 µM), blocked the damage of hydroquinone to the cells. We also observed that resveratrol pretreatment suppressed hydroquinone-induced expression of cytochrome P450 2E1 mRNA dose-dependently. The present study suggests that resveratrol protected the cells against hydroquinone-induced toxicity through its antioxidant function and possibly suppressive effect on the expression of cytochrome P450 2E1.

Resveratrol Modulates MED28 (Magicin/EG-1) Expression and Inhibits Epidermal Growth Factor (EGF)-Induced Migration in MDA-MB-231 Human Breast Cancer Cells

Resveratrol and pterostilbene exhibit diverse biological activities. MED28, a subunit of the mammalian Mediator complex for transcription, was also identified as magicin, an actin cytoskeleton Grb2-associated protein, and as endothelial-derived gene (EG-1). Several tumors exhibit aberrant MED28 expression, whereas the underlying mechanism is unclear. Triple-negative breast cancers, often expressing epidermal growth factor (EGF) receptor (EGFR), are associated with metastasis and poor survival. The objective of this study is to compare the effect of resveratrol and pterostilbene and to investigate the role of MED28 in EGFR-overexpressing MDA-MB-231 breast cancer cells. Pretreatment of resveratrol, but not pterostlbene, suppressed EGF-mediated migration and expression of MED28 and matrix metalloproteinase (MMP)-9 in MDA-MB-231 cells. Moreover, overexpression of MED28 increased migration, and the addition of EGF further enhanced migration. Our data indicate that resveratrol modulates the effect of MED28 on cellular migration, presumably through the EGFR/phosphatidylinositol 3-kinase (PI3K) signaling pathway, in breast cancer cells.

Resveratrol Enhances 5-Hydroxytryptamine Type 3A Receptor-Mediated Ion Currents: The Role of Arginine 222 Residue in Pre-transmembrane Domain I

Resveratrol, which is found in grapes, red wine, and berries, has many beneficial health effects, such as anti-cancer, neuro-protective, anti-inflammatory, and life-prolonging effects. However, the cellular mechanisms by which resveratrol acts are relatively unknown, especially in terms of possible regulation of receptors involved in synaptic transmission. 5-Hydroxytryptamine type 3A (5-HT(3A)) receptor is one of several ligand-gated ion channels involved in fast synaptic transmission. In the present study, we investigated the effect of resveratrol on mouse 5-HT(3A) receptor channel activity. 5-HT(3A) receptor was expressed in Xenopus oocytes, and the current was measured using a two-electrode voltage clamp technique. Treatment of resveratrol itself had no effect on the oocytes injected with H(2)O as well as on the oocytes injected with 5-HT(3A) receptor cRNA. In the oocytes injected with 5-HT(3A) receptor cRNA, co- or pre-treatment of resveratrol with 5-HT potentiated 5-HT-induced inward peak current (I(5-HT)) with concentration-, reversible, and voltage-independent manners. The EC(50) of resveratrol was 28.0±2.4 µM. The presence of resveratrol caused a leftward shift of 5-HT concentration-response curve. Protein kinase C (PKC) activator or inhibitor had no effect on resveratrol action on I(5-HT). Site-directed mutations of pre-transmembrane domain 1 (pre-TM1) such as R222A, R222D, R222E, R222K, and R222T abolished or attenuated resveratrol-induced enhancement of I(5-HT), indicating that resveratrol might interact with pre-TM1 of 5-HT(3A) receptor. These results indicate that resveratrol might regulate 5-HT(3A) receptor channel activity via interaction with the N-terminal domain and these results further show that resveratrol-mediated regulation of 5-HT(3A) receptor channel activity might be one of cellular mechanisms of resveratrol action.

Effects of resveratrol on H2O2‐induced apoptosis and expression of SIRTs in H9c2 cells

Resveratrol, a polyphenol found in fruits, has been demonstrated to activate Sir2. Though many studies have demonstrated that resveratrol can activate SIRT1, whether it has effect on other sirtuins (SIRT2-7) are unknown. The present study shows that exposure of H9c2 cells to 50 microM H(2)O(2) for 6 h caused a significant increase in apoptosis, as evaluated by TUNEL and flow cytometry (FCM), but pretreatment of resveratrol (20 microM) eliminated H(2)O(2)-induced apoptosis. Resveratrol also prevented H(2)O(2)-induced caspase-3 activation. Exposure of cells to resveratrol caused rapid activation of SIRT1,3,4,7. Sirtuin inhibitor, nicotinamide (20 mM) attenuated resveratrol's inhibitory effect on cell apoptosis and caspase-3 activity. These results suggest that resveratrol protects cardiomyocytes from H(2)O(2)-induced apoptosis by activating SIRT1,3,4,7.

Protective effects of resveratrol on UVB-irradiated HaCaT cells through attenuation of the caspase pathway

Resveratrol, a polyphenol present in grapes and red wine, exerts wide biological properties including antioxidant, chemoprevention and cardioprotective effects. It was recently reported that resveratrol attenuates the oxidative DNA damage in neuronal cells. However, whether resveratrol attenuates the UVB-induced cell death in skin still remains largely unknown. In this study, to confirm the photoprotection properties of resveratrol, we investigated the effect of the pretreatment of resveratrol on UVB-treated HaCaT cells and molecular mechanisms concerning apoptotic pathways. Our data showed that HaCaT cells markedly decreased cell proliferation rates after UVB irradiation. Notably, the pretreatment of resveratrol on UVB irradiation resulted in an increase in cell survival which concomitantly reduced the reactive oxygen species production. Furthermore, the activation of caspase-3 and -8 was partially decreased in resveratrol-pretreated HaCaT cells, implying that the attenuation of caspase-3 and -8 activation is involved in cell survival after UVB irradiation. Thus, our data indicate that resveratrol may be a promising photoprotection agent, used in sunscreen products, to reduce cell death in UV-damaged skin.

Chemoprevention of skin cancer by grape constituent resveratrol: relevance to human disease?

According to the World Cancer Report, skin cancer constitutes approximately 30% of all newly diagnosed cancers in the world, and solar ultraviolet (UV) radiation (particularly, its UVB component; 290-320 nm) is an established cause of approximately 90% of skin cancers. The available options have proven to be inadequate for the management of skin cancers. Therefore, there is an urgent need to develop mechanism-based novel approaches for prevention/therapy of skin cancer. In this study, we evaluated the chemopreventive effects of resveratrol against UVB radiation-mediated skin tumorigenesis in the SKH-1 hairless mouse model. For our studies, we used a UVB initiation-promotion protocol in which the control mice were subjected to chronic UVB exposure (180 mJ/cm2, twice weekly, for 28 weeks). The experimental animals received either a pretreatment (30 min before each UVB) or post-treatment (5 min after UVB) of resveratrol (25 or 50 micro mole/0.2 ml acetone/mouse). The mice were followed for skin tumorigenesis and were killed at 24 h after the last UVB exposure, for further studies. The topical application of skin with resveratrol (both pre- and post- treatment) resulted in a highly significant 1) inhibition in tumor incidence, and 2) delay in the onset of tumorigenesis. Interestingly, the post-treatment of resveratrol was found to impart equal protection than the pretreatment; suggesting that resveratrol-mediated responses may not be sunscreen effects. Because Survivin is a critical regulator of survival/death of cells, and its overexpression has been implicated in several cancers, we evaluated its involvement in chemoprevention of UVB-mediated skin carcinogenesis by resveratrol. Our data demonstrated a significant 1) up-regulation of Survivin (both at protein- and mRNA- levels), 2) up-regulation of phospho-Survivin protein, and 3) down-regulation of proapoptotic Smac/DIABLO protein in skin tumors; whereas treatment with resveratrol resulted in the attenuation of these responses. Our study also suggests that resveratrol enhanced apoptosis in UVB-exposure-mediated skin tumors. Our study, for the first time, demonstrated that 1) resveratrol imparts strong chemopreventive effects against UVB exposure-mediated skin carcinogenesis (relevant to human skin cancers), and 2) the chemopreventive effects of resveratrol may, at least in part, be mediated via modulations in Survivin and other associated events. On the basis of our work, it is conceivable to design resveratrol-containing emollient or patch, as well as sunscreen and skin-care products for prevention of skin cancer and other conditions, which are believed to be caused by UV radiation.

신경교 세포에서 resveratrol이 amyloid-β에 의해 유도되는 Cdk inhibitor p21 및 Bax 발현의 감소 효과

Resveratrol (3,4',5-trihydroxy-trans-stilbene), a phytoalexin found in grape skins, peanuts, and red wine, has been reported to have a wide range of biological and pharmacological properties. Amyloid-β deposition and senile plaque-associated astrocytes are common neuropathological features of Alzheimer's disease. In this study, we have explored the effects of resveratrol on amyloid-β-peptide-mediated cytotoxicity in vitro and modulation of cell growth-regulatory gene products in astroglioma C6 cells to elucidate its possible mechanism for anti-cytotoxicity. Exposure of C6 cells to amyloid-β resulted in dose-dependent growth inhibition and morphological changes of C6 cells, which were recovered by pre-treatment with resveratrol. The anti-proliferative effect of amyloid-β was associated with the induction of tumor suppressor p53 and cyclin-dependent kinase (Cdk) inhibitor p21 (WAF1/CIP1) expression assessed by RT-PCR and Western blot analysis in time-dependent manner in C6 cells. In addition, the pro-apoptotic Bax expression was also up-regulated in amyloid-β-treated C6 cells without alteration of anti-apoptotic Bcl-2 and Bcl-XL expression. However, pre-treatment of resveratrol significantly inhibited amyloid-β-induced p53, p21 and Bax levels, suggesting that the modulation of p53, p21 and Bax levels could be one of the possible pathways by which resveratrol functions as anti-cytotoxic agent. Our results demonstrate that resveratrol may enhance the protection against amyloid-β-induced cytotoxicity by promoting the survival of glial cells.