OBJECTIVE: This study investigated how the natural phytophenol and potent SIRT1 activator resveratrol (RSV) regulate necroptosis during Vibrio vulnificus (V. vulnificus)-induced sepsis and the potential mechanism. METHODS: The effect of RSV on V. vulnificus cytolysin (VVC)-induced necroptosis was analyzed in vitro using CCK-8 and Western blot assays. Enzyme-linked immunosorbent assays and quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry and survival analyses were performed to elucidate the effect and mechanism of RSV on necroptosis in a V. vulnificus-induced sepsis mouse model. RESULTS: RSV relieved necroptosis induced by VVC in RAW264.7 and MLE12 cells. RSV also inhibited the inflammatory response, had a protective effect on histopathological changes, and reduced the expression level of the necroptosis indicator pMLKL in peritoneal macrophages, lung, spleen, and liver tissues of V. vulnificus-induced septic mice in vivo. Pretreatment with RSV downregulated the mRNA of the necroptosis indicator and protein expression in peritoneal macrophages and tissues of V. vulnificus-induced septic mice. RSV also improved the survival of V. vulnificus-induced septic mice. CONCLUSION Our findings collectively demonstrate that RSV prevented V. vulnificus-induced sepsis by attenuating necroptosis, highlighting its potency in the clinical management of V. vulnificus-induced sepsis.
Animals ; Mice ; Necroptosis ; Resveratrol/therapeutic use* ; Vibrio vulnificus ; Sepsis/drug therapy* ; Blotting, Western

OBJECTIVE: To investigate the therapeutic mechanism of resveratrol (RES) for Alzheimer's disease (AD) in light of network pharmacology. METHODS: We searched PubChem, BATMAN-TCM, Genecards, AD, TTD, String 11.0, AlzData, SwissTargetPrediction, Metascape and other databases for the therapeutic targets of RES and human AD-related targets. The intersection was determined using Venny 2.1 to obtain the therapeutic targets of RES for AD. The protein-protein interaction (PPI) network was constructed, the gene ontology (GO) was enriched and the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG pathway) were analyzed. Cytoscape 3.7.1 software was used to construct a target-signaling pathway network of RES in the treatment of AD. Molecular docking verification was carried out on SwissDock (http://www.swissdock.ch/docking). We examined a 293Tau cell model of AD for changes in protein levels of pS396, pS199, Tau5, CDK5, glycogen synthase kinase 3β (GSK3β) and p-GSK3β in response to RES treatment using Western blotting. RESULTS: We obtained 182 targets of RES, 525 targets related to AD, and 36 targets of RES for AD treatment, among which 34.6% of the targets were protein-modifying enzymes, 27.7% were metabolite invertase, 13.8% were gene-specific transcriptional regulators, and 10.3% were transporters. The core key targets of RES in the treatment of AD included INS, APP, ESR1, MMP9, IGF1R, CACNA1C, MAPT (microtubule- associated protein Tau), MMP2, TGFB1 and GSK3B. Enrichment analysis of GO biological process suggested that the biological function of RES in AD treatment mainly involved the response to β-amyloid protein, positive regulation of transferase activity, the transmembrane receptor protein tyrosine kinase signaling pathway, regulation of behavior, learning or memory, aging, and transmembrane transport. KEGG pathway enrichment analysis showed that the most significantly enriched signaling pathways were AD pathway, PI3K-AKT signaling pathway, cGMP-PKG signaling pathway, and MAPK signaling pathway. Molecular docking results showed that RES had strong binding with ESR1, GSK3B, MMP9, IGF1R, APP and INS. In the cell model of AD, treatment with 50 μmol/L RES for 12 h significantly reduced the levels of pS396 and pS199 by regulating CDK5 and GSK3β activity ( CONCLUSIONS RES produces therapeutic effects on AD by acting on multiple targets and affecting multiple signaling pathways and improves AD-associated pathologies
Alzheimer Disease/genetics* ; Drugs, Chinese Herbal/therapeutic use* ; Humans ; Molecular Docking Simulation ; Phosphatidylinositol 3-Kinases ; Resveratrol/pharmacology*

OBJECTIVE: To explore the effect of resveratrol on the cognition of Alzheimer's mice (AD) and its mechanism, and to assess its action on the reproduction system. METHODS: According to the results of step-down test, 84 Kunming female mice were randomly divided into 6 groups: Group A [sham operated+1% CMC-Na (0.01 mL/g)], Group B [ovariectomy+D-galactose+1% CMC-Na (0.01 mL/g)], Group C [ovariectomy+D-galactose+0.05 mg/(kg.d) Diethylstilbestrol], Group D [ovariectomy+D-galactose+15 mg/(kg.d) Res], and Group E [ovariectomy+D-galactose injected+45 mg/(kg.d) Res], and Group F [ovariectomy+D-galactose +135 mg/(kg.d) Res]. Experimental cycle was 60 days. RESULTS: Resveratrol of every dosage could improve the performance records of behavior tests in AD mice,could inhibit the SOD vitality and the MDA level both in the serum and in the brain, and could suppress the acetylcholinesterase vitality and the bax expression. Resveratrol has no endometrial hyperplasia effect. CONCLUSION Resveratrol can improve the cognitive ability of AD mice, which may contribute to the resveratrol's antioxidation and antiapoptosis, and can modulate acetylcholinesterase. Resveratrol has no side-effect of endometrial hyperplasia on AD mice.
Alzheimer Disease ; drug therapy ; psychology ; Animals ; Antioxidants ; therapeutic use ; Cognition ; drug effects ; Female ; Galactose ; Mice ; Ovariectomy ; Random Allocation ; Resveratrol ; Stilbenes ; therapeutic use

OBJECTIVE: To explore the anti-radiation protective effect of resveratrol (RES). METHODS: (60)Co-γ irradiated injury model was established. A total of 200 Kunming mice were randomly divided into 4 groups (50 in each group): Group I, II, III, and IV. Each group was sub-divided into 5 groups: a normal control (n=10), an irradiated model control group (n=10) and 3 treatment groups of RES (50, 100, and 300 mg/kg RES treatment groups, 10 in each group). RES was orally administered daily for 30 d in the RES treatment groups and 1% sodium carboxymethylcellulose was orally administered in the normal control and irradiated model group. Thereafter, except the normal control group, the mice in other groups were exposed to different dosages of (60)Co-γ once, and the gavage was continued until the end of different experimental periods. Peripheral leucocytes, nucleated bone marrow cells were counted; superoxide dismutase (SOD) activity and hemolysin in the serum were determined at different time. RESULTS: Under the different dosages of (60)Co-γ irradiation and the provisions of the experimental conditions, the leucocyte count was (1.69±0.82)× 10(9) and (1.61±0.51)× 10(9)/L in the 100 and 300 mg/kg RES treatment groups, which was significantly increased, when compared with the irradiated model control group [(0.73±0.69)× 10(9)/L] ( P<0.05, P<0.01 respectively). The number of nucleated bone marrow cells was (17.5±4.8) and (17.1±4.7)× 10(5)/mL in the 100 and 300 mg/kg RES treatment groups respectively, which significantly increased when compared with the irradiated model control group [(7.3±2.2)× 10(5)/mL ] ( P<0.01 ). The SOD activity was (110.41±17.04) U/ mL in the 100 mg/kg RES treatment group, which was significantly increased when compared with the irradiated model control group [(95.80±10.42) U/mL ] ( P<0.05 ). There was no significant difference in the serum hemolysin in all RES treatment groups (all P>0.05). CONCLUSION At 100 and 300 mg/kg, RES has good anti-radiation effect.
Animals ; Cobalt Radioisotopes ; Gamma Rays ; Mice ; Plant Extracts ; therapeutic use ; Radiation Injuries, Experimental ; drug therapy ; metabolism ; prevention & control ; Radiation-Protective Agents ; therapeutic use ; Resveratrol ; Stilbenes ; therapeutic use ; Superoxide Dismutase ; metabolism

OBJECTIVES: To explore the effect of resveratrol (Res) on Kawasaki disease (KD)-induced myocardial injury and to evaluate its effect on apoptosis and autophagy. METHODS: Forty-eight juvenile male Sprague Dawley rats were randomly divided into a control group, a Res group, a lactobacillus casei cell wall extract (LCWE)-induced Kawasaki disease group (KD group), and a LCWE-induced Kawasaki disease + Res treatment group (Res+KD group). The control group was intraperitoneally injected with saline. The Res group was intraperitoneally injected with resveratrol (100 mg/kg). The KD group was intraperitoneally injected with 0.5 mL LCWE (1 mg/mL). The Res+KD group was intraperitoneally injected with 0.5 mL LCWE (1 mg/mL) and resveratrol (100 mg/kg). After 4 weeks, the left ventricular ejection fraction (LVEF) and short axis shortening rate (LVFS) were detected by echocardiography. The apoptotic rate was detected by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) staining. The levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), microtubule-associated protein 1 light chain 3β (LC3B), Beclin-1, autophagy related 5 (Atg5) and sequestosome-1 (p62) were detected by Western blotting. The formation of autophagosome was observed under transmission electron microscope. RESULTS: There was no significant difference in the above-mentioned indexes between the control group and the Res group (all CONCLUSIONS Res can attenuate the KD-induced myocardial injury via inhibiting the apoptosis and autophagy.
Animals ; Apoptosis ; Autophagy ; Male ; Mucocutaneous Lymph Node Syndrome/drug therapy* ; Rats ; Rats, Sprague-Dawley ; Resveratrol/therapeutic use* ; Stroke Volume ; Ventricular Function, Left

High-fat diets affect male reproduction and sexual function. Therefore, we evaluated the effects of prolonged resveratrol administration on the metabolic, sperm, and testicular parameters of rats fed a cafeteria diet. Male Wistar rats were divided at weaning into control (C, n = 20) and cafeteria (CAF, n = 16) groups. At 3 months, half of them were given daily supplementations of resveratrol (C-R, n = 10; CAF-R, n = 8) at a dosage of 30 mg kg^-1 body mass for 2 months. Animals were killed at 5 months of age, and blood, spermatozoa, and testes were collected for further analysis. Data were analyzed by one-way ANOVA, and P < 0.05 was considered statistically significant. The CAF diet promoted hyperglycemia (P < 0.0001), and treatment with resveratrol reversed this condition (P < 0.0001). The CAF diet reduced sperm viability and motility, while resveratrol improved these parameters (P < 0.05). Regarding testicular morphology, the height of the seminiferous epithelium was reduced in the CAF group compared with that of the C group (P = 0.0007). Spermatogenic cell proliferation was also reduced in the CAF group compared with that of the C group. However, the CAF-R showed an increase in cell proliferation rate compared with that of the untreated CAF group (P = 0.0024). Although it did not modify body mass, the consumption of a CAF diet promoted hyperglycemia, adverse testicular morphology remodeling, and abnormal sperm, which were attenuated by treatment with resveratrol, thus suggesting a protective effect of this antioxidant on spermatogenesis.
Animals ; Antioxidants/therapeutic use* ; Blood Glucose ; Cell Proliferation/drug effects* ; Diet, High-Fat ; Hyperglycemia/metabolism* ; Lipids/blood* ; Male ; Rats ; Rats, Wistar ; Resveratrol/therapeutic use* ; Sperm Motility/drug effects* ; Spermatozoa/metabolism* ; Testis/metabolism*

This study aimed to explore the mechanism of resveratrol(RES) pretreatment in improving mitochondrial function and alleviating myocardial ischemia-reperfusion(IR) injury by inhibiting stromal interaction molecule 2(STIM2) through microRNA-20 b-5 p(miR-20 b-5 p). Ninety rats were randomly assigned into sham group, IR group, IR+RES(50 mg·kg~(-1) RES) group, IR+RES+antagomir NC(50 mg·kg~(-1) RES+80 mg·kg~(-1) antagomir NC) group, and IR+RES+miR-20 b-5 p antagomir(50 mg·kg~(-1) RES+80 mg·kg~(-1) miR-20 b-5 p antagomir) group, with 18 rats/group. The IR rat model was established by ligation of the left anterior descending coronary artery. Two weeks before the operation, rats in the IR+RES group were intraperitoneally injected with 50 mg·kg~(-1) RES, and those in the sham and IR groups were injected with the same dose of normal saline, once a day. Ultrasonic instrument was used to detect the left ventricular internal diameter at end-diastole(LVIDd) and left ventricular internal diameter at end-systole(LVIDs) of rats in each group. The 2,3,5-triphenyte-trazoliumchloride(TTC) method and hematoxylin-eosin(HE) staining were employed to detect the myocardial infarction area and histopathology, respectively. Real-time quantitative PCR(qRT-PCR) was carried out to detect the expression of miR-20 b-5 p in myocardial tissue. Oxygen glucose deprivation/reoxygenation(OGD/R) was performed to establish an OGD/R model of H9 c2 cardiomyocytes. CCK-8 assay was employed to detect H9 c2 cell viability. H9 c2 cells were assigned into the control group, OGD/R group, OGD/R+RES group(25 μmol·L~(-1)), OGD/R+RES+inhibitor NC group, OGD/R+RES+miR-20 b-5 p inhibitor group, mimic NC group, miR-20 b-5 p mimic group, inhibitor NC group, and miR-20 b-5 p inhibitor group. Flow cytometry was employed to detect cell apoptosis. Western blot was employed to detect the expression of B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), cleaved-cysteine proteinase 3(cleaved-caspase-3), and STIM2 in cells. The mitochondrial membrane potential(MMP) assay kit, reactive oxygen species(ROS) assay kit, and adenosine triphosphate(ATP) assay kit were used to detect the MMP, ROS, and ATP levels, respectively. Dual luciferase reporter gene assay was adopted to verify the targeting relationship between miR-20 b-5 p and STIM2. Compared with the sham group, the modeling of IR increased the myocardial infarction area, LVIDd, LVIDs, and myocardial pathology and down-regulated the expression of miR-20 b-5 p(P<0.05). These changes were alleviated in the IR+RES group(P<0.05). The IR+RES+miR-20 b-5 p antagomir group had higher myocardial infarction area, LVIDd, LVIDs, and myocardial pathology and lower expression of miR-20 b-5 p than the IR+RES group(P<0.05). The OGD/R group had lower viability of H9 c2 cells than the control group(P<0.05) and the OGD/R+RES groups(25, 50, and 100 μmol·L~(-1))(P<0.05). Additionally, the OGD/R group had higher H9 c2 cell apoptosis rate, protein levels of Bax and cleaved caspase-3, and ROS level and lower Bcl-2 protein, MMP, and ATP levels than the control group(P<0.05) and the OGD/R+RES group(P<0.05). The OGD/R+RES+miR-20 b-5 p inhibitor group had higher H9 c2 cell apoptosis rate, protein levels of Bax and cleaved-caspase 3, and ROS level and lower Bcl-2 protein, MMP, and ATP levels than the OGD/R+RES group(P<0.05). miR-20 b-5 p had a targeting relationship with STIM2. The expression of STIM2 was lower in the miR-20 b-5 p mimic group than in the mimic NC group(P<0.05) and lower in the inhibitor NC group than in the miR-20 b-5 p inhibitor group(P<0.05). RES pretreatment can inhibit the expression of STIM2 by promoting the expression of miR-20 b-5 p, thereby improving the function of mitochondria and alleviating myocardial IR damage.
Animals ; Rats ; Adenosine Triphosphate ; Antagomirs/metabolism* ; bcl-2-Associated X Protein/metabolism* ; Caspase 3/metabolism* ; Glucose/metabolism* ; MicroRNAs/metabolism* ; Mitochondria, Heart/drug effects* ; Myocardial Infarction/drug therapy* ; Myocardial Reperfusion Injury/drug therapy* ; Myocytes, Cardiac ; Oxygen/metabolism* ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism* ; Resveratrol/therapeutic use* ; Stromal Interaction Molecule 2/metabolism*