• Chemopreventive
• Hepatocellular carcinoma
• Liver cancer
• Natural products
• Signaling pathways
• Therapeutic targets

Balanced nutrition and appropriate dietary interventions are fundamental in the prevention and management of viral infections. Additionally, accurate modulation of the inflammatory response is necessary to achieve an adequate antiviral immune response. Many studies, both in vitro with mammalian cells and in vivo with small animal models, have highlighted the antiviral properties of resveratrol, rapamycin and metformin. The current review outlines the mechanisms of action of these three important compounds on the cellular pathways involved with viral replication and the mechanisms of virus-related diseases, as well as the current status of their clinical use.

• antiviral
• dietary supplement
• metformin
• rapamycin
• resveratrol

• Animals
• Antiviral Agents/pharmacology
• Host-Pathogen Interactions
• Humans
• Metformin/pharmacology
• Resveratrol/pharmacology
• Signal Transduction/drug effects
• Sirolimus/pharmacology
• Virus Diseases/drug therapy
• Virus Diseases/virology
• Virus Replication/drug effects

The characterization of bioactive resveratrol oligomers extracted from Vitis vinifera canes has been recently reported. Here, we screened six of these compounds (ampelopsin A, trans-ε-viniferin, hopeaphenol, isohopeaphenol, R2-viniferin, and R-viniferin) for their cytotoxic activity to human hepatocellular carcinoma (HCC) cell lines p53 wild-type HepG2 and p53-null Hep3B. The cytotoxic efficacy depended on the cell line. R2-viniferin was the most toxic stilbene in HepG2, with inhibitory concentration 50 (IC₅₀) of 9.7 ± 0.4 µM at 72 h, 3-fold lower than for resveratrol, while Hep3B was less sensitive (IC₅₀ of 47.8 ± 2.8 µM). By contrast, hopeaphenol (IC₅₀ of 13.1 ± 4.1 µM) and isohopeaphenol (IC₅₀ of 26.0 ± 3.0 µM) were more toxic to Hep3B. Due to these results, and because it did not exert a large cytotoxicity in HH4 non-transformed hepatocytes, R2-viniferin was selected to investigate its mechanism of action in HepG2. The stilbene tended to arrest cell cycle at G2/M, and it also increased intracellular reactive oxygen species (ROS), caspase 3 activity, and the ratio of Bax/Bcl-2 proteins, indicative of apoptosis. The distinctive toxicity of R2-viniferin on HepG2 encourages research into the underlying mechanism to develop the oligostilbene as a therapeutic agent against HCC with a particular genetic background.

• HepG2 cells
• anticancer activity
• natural product
• polyphenol
• resveratrol oligomers
• stilbene

• approach strategies
• cancer
• innovative formulations
• mechanisms
• prevention
• resveratrol

• Animals
• Antineoplastic Agents, Phytogenic/chemistry
• Antineoplastic Agents, Phytogenic/pharmacology
• Antineoplastic Agents, Phytogenic/therapeutic use
• Chemoprevention
• Clinical Studies as Topic
• Disease Management
• Disease Susceptibility
• Drug Discovery
• Drug Evaluation, Preclinical
• Humans
• Neoplasms/diagnosis
• Neoplasms/etiology
• Neoplasms/metabolism
• Neoplasms/prevention & control
• Resveratrol/chemistry
• Resveratrol/pharmacology
• Resveratrol/therapeutic use
• Signal Transduction/drug effects

Liver failure after resection for liver cancer is associated with increased patient mortality. This study aimed to investigate the mechanism of the protective effects of resveratrol, a natural plant-derived compound, on liver injury in a rat model of partial hepatectomy.

Adult male Sprague-Dawley (SD) rats (n=60) were divided into the sham group (n=20), the liver resection group (n=20), and the liver resection plus resveratrol-treated group (n=20). Liver resection removed 2/3 of the liver resection; resveratrol was given at a dose of 30 mg/kg/day from one week before surgery until death. Liver injury was assessed by serum liver function tests, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl-transferase (γ-GT) and total bilirubin, histological examination of the rat liver, and liver cell apoptosis using the TUNEL assay. High mobility group box 1 (HMGB1) expression was measured by enzyme-linked immunoassay (ELISA). Sirtuin 1 (SIRT1) and acetylated HMGB1 (Ac-HMGB1) expression were detected by Western blot. Normal human liver cells and HepG2 liver cancer cells were incubated with acetylated HMGB1, and albumin production and ammonia elimination assays were performed.

Resveratrol reduced postoperative liver injury as shown by reduced ALT, AST, γ-GT, and total bilirubin levels, maintained liver structure, and reduced cell apoptosis. Resveratrol treatment reduced the expression and acetylation levels of HMGB1 via the SIRT1 signaling pathway. Resveratrol reversed Ac-HMGB1 induced dysfunction in liver cells cultured in vitro.

Resveratrol reduced liver damage after liver resection in a rat model by upregulating SIRT1 and reducing the acetylation of HMGB1.

Resveratrol (trans-3, 4’, 5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits, has anti-inflammatory and anti-oxidant effects. Its anti-carcinogenic effects are closely associated with its antioxidant activity; thus, the use of resveratrol as a possible cancer chemo-preventive is considered to be an important area of investigation. In this study we have examined the inhibitory effects of resveratrol in nicotine induced proliferation of pancreatic cancer cells.

Cultured AR42J cells were incubated with 100 μM nicotine for 3 min and with 100 μM resveratrol for 30 min, either alone or in combination. Proliferation assays were conducted for a period of 0 to 96 h in serum media, incubated with nicotine and resveratrol, and evaluated by MTT assay. Protein was measured in lysed cells and activation of MAPK signals was measured by western blot using purified p-ERK antibody. Co-localization of activated ERK signals was confirmed by FITC conjugated ERK antibody using immunofluorescence assay and confocal microscopy. Biomarker of lipid peroxidation was determined in cell lysates by malondialdehyde (MDA) bioassay.

Resveratrol significantly suppressed the nicotine-induced proliferation of acinar cells compared to untreated controls (p<0.05). Mitogen activated protein kinase (MAPK) analysis revealed up-regulation of p-ERK expression by nicotine (p<0.05) that was suppressed significantly by resveratrol (p<0.05). Co-localization of activated ERK signals was confirmed by FITC conjugated ERK antibody, and this response was reduced significantly by resveratrol. Nicotine-induced malondialdehyde formation was also suppressed by resveratrol (p<0.05).

The data suggest that resveratrol suppressed nicotine-induced AR42J cell proliferation. The proliferation of AR42J cells by nicotine is associated with activation of MAPK signals and induction of protein oxidation. Resveratrol suppressed lipid peroxidation and P-ERK activated signals induced by nicotine. We conclude that resveratrol acts as an effective antioxidant in reversing the nicotine induced pancreatic cancer cell proliferation.

• AR42J cell
• MAPK signaling
• oxidative stress
• resveratrol

• aging
• caloric restriction
• caloric restriction mimetics
• cancer
• epigenetics/genetics
• gene expression

• Acetaminophen
• Inflammation
• Liver injury
• Mitochondria
• Natural products
• Oxidative stress

Resveratrol is reported to possess chemotherapeutic properties in several cancers. In this study, we wanted to investigate the molecular mechanisms of resveratrol-induced cell cycle arrest and apoptosis as well as the impact of resveratrol on NAMPT and SIRT1 protein function and asked whether there are differences in hepatocarcinoma cells (HepG2, Hep3B cells) and non-cancerous primary human hepatocytes. We found a lower basal NAMPT mRNA and protein expression in hepatocarcinoma cells compared to primary hepatocytes. In contrast, SIRT1 was significantly higher expressed in hepatocarcinoma cells than in primary hepatocytes. Resveratrol induced cell cycle arrest in the S- and G2/M- phase and apoptosis was mediated by activation of p53 and caspase-3 in HepG2 cells. In contrast to primary hepatocytes, resveratrol treated HepG2 cells showed a reduction of NAMPT enzymatic activity and increased p53 acetylation (K382). Resveratrol induced NAMPT release from HepG2 cells which was associated with increased NAMPT mRNA expression. This effect was absent in primary hepatocytes where resveratrol was shown to function as NAMPT and SIRT1 activator. SIRT1 inhibition by EX527 resembled resveratrol effects on HepG2 cells. Furthermore, a SIRT1 overexpression significantly decreased both p53 hyperacetylation and resveratrol-induced NAMPT release as well as S-phase arrest in HepG2 cells. We could show that NAMPT and SIRT1 are differentially regulated by resveratrol in hepatocarcinoma cells and primary hepatocytes and that resveratrol did not act as a SIRT1 activator in hepatocarcinoma cells.

• Antineoplastic Agents, Phytogenic/pharmacology
• Apoptosis/drug effects
• Cell Line, Tumor
• Cytokines/genetics
• Cytokines/metabolism
• G2 Phase Cell Cycle Checkpoints/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Hepatocytes/cytology
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Humans
• Nicotinamide Phosphoribosyltransferase/genetics
• Nicotinamide Phosphoribosyltransferase/metabolism
• Organ Specificity
• Primary Cell Culture
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Resveratrol
• S Phase Cell Cycle Checkpoints/drug effects
• Signal Transduction
• Sirtuin 1/genetics
• Sirtuin 1/metabolism
• Stilbenes/pharmacology
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

Resveratrol is a polyphenol that plays a potentially important role in many disorders and has been studied in different diseases. The research on this chemical started through the “French paradox,” which describes improved cardiovascular outcomes despite a high-fat diet in French people. Since then, resveratrol has been broadly studied and shown to have antioxidant, anti-inflammatory, anti-proliferative, and anti-angiogenic effects, with those on oxidative stress possibly being most important and underlying some of the others, but many signaling pathways are among the molecular targets of resveratrol. In concert they may be beneficial in many disorders, particularly in diseases where oxidative stress plays an important role. The main focus of this review will be the pathways affected by resveratrol. Based on these mechanistic considerations, the involvement of resveratrol especially in cardiovascular diseases, cancer, neurodegenerative diseases, and possibly in longevity will be is addressed.

• cancer
• cardiovascular diseases
• resveratrol
• signal transduction

Resveratrol is a plant-derived polyphenol that extends lifespan and healthspan in model organism. Despite extensive investigation, the biological processes mediating resveratrol's effects have yet to be elucidated. Because repression of translation shares many of resveratrol's beneficial effects, we hypothesized that resveratrol was a modulator of protein synthesis. We studied the effect of the drug on the H4-II-E rat hepatoma cell line. Initial studies showed that resveratrol inhibited global protein synthesis. Given the role of the mammalian Target of Rapamycin (mTOR) in regulating protein synthesis, we examined the effect of resveratrol on mTOR signaling. Resveratrol inhibited mTOR self-phosphorylation and the phosphorylation of mTOR targets S6K1 and eIF4E-BP1. It attenuated the formation of the translation initiation complex eIF4F and increased the phosphorylation of eIF2α. The latter event, also a mechanism for translation inhibition, was not recapitulated by mTOR inhibitors. The effects on mTOR signaling were independent of effects on AMP-activated kinase or AKT. We conclude that resveratrol is an inhibitor of global protein synthesis, and that this effect is mediated through modulation of mTOR-dependent and independent signaling.

• AMP-Activated Protein Kinases
• Animals
• Carcinoma, Hepatocellular/enzymology
• Carcinoma, Hepatocellular/pathology
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Enzyme Activation/drug effects
• Eukaryotic Initiation Factor-2/metabolism
• Eukaryotic Initiation Factor-4F/metabolism
• Liver/drug effects
• Liver/enzymology
• Liver/metabolism
• Liver Neoplasms/enzymology
• Liver Neoplasms/pathology
• Phosphorylation/drug effects
• Protein Biosynthesis/drug effects
• Protein Kinase Inhibitors/pharmacology
• Protein Stability/drug effects
• Proto-Oncogene Proteins c-akt/metabolism
• Rats
• Resveratrol
• Signal Transduction/drug effects
• Sirolimus/pharmacology
• Stilbenes/pharmacology
• TOR Serine-Threonine Kinases/antagonists & inhibitors
• TOR Serine-Threonine Kinases/metabolism
• Transcription Factors/metabolism

• R01 AG024360 NIA NIH HHS
• R01 HD024455 NICHD NIH HHS
• R01HD24455 NICHD NIH HHS
• R01AG024360 NIA NIH HHS

• Chemoprevention
• Hepatocellular carcinoma
• Phytochemicals

• Annexin A5/metabolism
• Anticarcinogenic Agents/pharmacology
• Apoptosis/drug effects
• Carcinoma, Hepatocellular/pathology
• Cell Cycle/drug effects
• Cell Nucleus Size/drug effects
• DNA Fragmentation/drug effects
• Dose-Response Relationship, Drug
• Flow Cytometry
• HL-60 Cells
• Humans
• Leukemia, Promyelocytic, Acute/pathology
• Liver Neoplasms/pathology
• Resveratrol
• Stilbenes/pharmacology
• Thymidine/pharmacokinetics
• Tritium

AIM: To study the antitumor and immunomodulatory activity of resveratrol on experimentally implanted tumor of H22 in Balb/c mice

METHODS: The cytotoxicity of peritoneal macrophages (MΦ) against H22 cells was measured by the radioactivity of [³H]TdR assay, mice with H22 tumor were injected with different concentrations of resveratrol, and the inhibitory rates were calculated and IgG contents were determined by single immunodiffusion method. the plaque forming cell (PFC) was measured by improved Cunningham method, the levels of serum tumor necrosis factor-α (TNF-α) were measured by cytotoxic assay against L929 cells.

RESULTS: Resveratrol 2.5 mg•l^-1, 5.0 mg•l^-1, 10.0 mg•l^-1, 20.0 mg•l^-1 (E:T = 10:1, 20:1) promoted the cytotoxicity of MΦagainst H22 cells. Resveratrol ip 500 mg•kg^-1, 1000 mg•kg^-1 and 1500 mg•kg^-1 could curb the growth of the implanted tumor of H22 in mice. The inhibitory rates were 31.5%, 45.6% and 48.7%, respectively (P < 0.05), which could raise the level of serum IgG and PFC response to sheep red blood cell. Resveratrol 1000 mg•kg^-1 and 1500 mg•kg^-1 and BCG 200 mg•kg^-1 ip could increase the production of serum TNF-α in mice H22 tumor. However, the effect of resveratrol was insignificant (P > 0.05).

CONCLUSION: Resveratrol could inhibit the growth of H22 tumor in Balb/c mice. The antitumor effect of resveratrol might be related to directly inhibiting the growth of H22 cells and indirectly inhibiting its potential effect on nonspecific host immunomodulatory activity.

• Adjuvants, Immunologic/pharmacology
• Animals
• Antibody-Producing Cells/drug effects
• Antineoplastic Agents, Phytogenic/pharmacology
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/immunology
• Erythrocytes
• Immunoglobulin G/blood
• Liver Neoplasms, Experimental/drug therapy
• Liver Neoplasms, Experimental/immunology
• Macrophages, Peritoneal/immunology
• Mice
• Mice, Inbred BALB C
• Neoplasm Transplantation
• Resveratrol
• Sheep
• Stilbenes/pharmacology
• Tumor Necrosis Factor-alpha/metabolism