PMID: 

Pharmacol Res. 2019 Dec ;150:104476. Epub 2019 Oct 9. PMID: 31605783

Abstract Title: 

Resveratrol in experimental Alzheimer's disease models: A systematic review of preclinical studies.

Abstract: 

Alzheimer's disease (AD) is a progressive dementia caused by degeneration of the central nervous system with a high incidence in the elderly. Resveratrol is a natural compound contained in a wide range of plant species, including grapes. Recent studies have shown positive effects of resveratrol in animal models of AD; however, whether these results justify clinical trials is uncertain. Furthermore, there are multiple theories about the mechanism(s) by which resveratrol works and knowing how it works can suggest targets for future drug development. So far, systematic evaluation of both of these aspects is lacking. In this study, we selected 19 studies describing the efficacy of resveratrol in rodent AD models by electronic and manual retrieval. The method quality of the study were analyzed by the SYRCLE's risk of bias tool and the experimental data were retrieved and meta-analyzed using forest plot. Analysis of these studies demonstrates the consistent neuroprotective effects of resveratrol in AD models and offers insights into the possible pharmacological mechanisms. This information eliminates the bias of each study, providing supporting evidence for the implementation of clinical trials. However, the limits of studies were also noticed: low method quality, lack of sample size calculation and high risks of bias.

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PMID: 

Infect Agent Cancer. 2019 ;14:27. Epub 2019 Oct 18. PMID: 31636696

Abstract Title: 

Resveratrol induces immunogenic cell death of human and murine ovarian carcinoma cells.

Abstract: 

Purpose: This study aimed to clarify whether immunogenic cell death (ICD) contributed to the anti-tumor action of resveratrol against ovarian carcinoma.Methods: Resveratrol suppressed cell proliferation and induced apoptosis in ovarian carcinoma cells. In addition, resveratrol treatment stimulated cell surface exposure of calreticulin, HMGB1 secretion and ATP release.Results: Vaccination with resveratrol-pretreated ID8 cells significantly inhibited growth of subsequent inoculated xenograft tumor. Direct administration with resveratrol suppressed tumor progression accompanied with compromised cell proliferation and enhanced cell apoptosis. We further characterized increases of both mature dendritic cells and cytotoxic T cells in xenograft tumor in response to resveratrol treatment, which also inhibited TGF-β production and stimulated both IL12p7 and IFN-γ secretion. Most importantly, we demonstrated that combination with PD-1 antibody greatly inhibited tumor growth, while depletion of CD8+ T cells by neutralizing antibody restored xenograft progression.Conclusion: Our data suggested resveratrol exerted anti-tumor action against ovarian cancer via both apoptosis and ICD pathways.

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PMID: 

Eur Rev Med Pharmacol Sci. 2019 Oct ;23(20):9117-9125. PMID: 31696503

Abstract Title: 

Resveratrol ameliorates high-fat diet-induced insulin resistance and fatty acid oxidation via ATM-AMPK axis in skeletal muscle.

Abstract: 

OBJECTIVE: Resveratrol (RSV) is a polyphenolic phytoalexin that exhibits diverse pharmacological actions, including its effect on the insulin resistance. However, the mechanism through which RSV improves insulin resistance is not fully understood yet. The aim of this study was to determine the mechanism through which RSV ameliorates insulin resistance in skeletal muscle of high-fat diet (HFD)-induced mouse model, as well as palmitic acid (PA) treated L6 cells, with a specific focus on the response of RSV on fatty acid oxidation.MATERIALS AND METHODS: Male C57BL6/J mice were randomly divided into three groups: normal diet-fed mice (ND), the high-fat diet-fed mice (HFD), HFD supplemented with RSV (100 mg/kg body weight [BW]/day orally; n = 10). Fasting plasma glucose, insulin, total cholesterol, triglyceride (TG), and free fatty acid levels were determined. The intraperitoneal glucose tolerance test was used to measure blood glucose and area under the curve. The quantitative insulin sensitivity index was calculated to assess insulin resistance. Skeletal muscles were collected for histology study and protein expression measurement. L6 cells were cultured with PA and the glucose concentration in the culture medium, and the intracellular TG levels were tested. RSV, chloroquine, palmitoyltransferase and Ku-55933 were administered to differentiate L6 cells.RESULTS: The HFD fed mice showed increased BW, hyperglycemia, and hyperlipidemia. The expressions of ataxia telangiectasia mutated (ATM), 5' adenosine monophosphate-activated protein kinase (AMPK), carnitine palmitoyltransferase 1, cytochrome oxidase subunit IV protein were significantly decreased in the skeletal muscles of HFD fed mice and PA-treated L6 cells. All these effects induced by HFD and PA were reversed by RSV treatment.CONCLUSIONS: ATM is a key factor to improve HFD-induced lipid metabolism and insulin resistance in skeletal muscles. The effects of RSV on ameliorating HFD-induced abnormal lipid metabolism and insulin resistance mediated through ATM-AMPK pathway may due to its improvement in fatty acid oxidation efficiency and sequential reduction in ROS production in skeletal muscle. These results provide important theoretical evidence for the application of RSV in the prevention and treatment of diabetes mellitus and related metabolic diseases.

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PMID: 

Mol Med Rep. 2019 Nov ;20(5):4587-4593. Epub 2019 Oct 2. PMID: 31702039

Abstract Title: 

Effects of resveratrol on learning and memory in rats with vascular dementia.

Abstract: 

The purpose of the present study was to study the effects of resveratrol on cognitive function in rats with vascular dementia and to investigate the molecular mechanisms of its neuroprotective effects. Forty‑five SD rats were randomly divided into 3 groups: The control group (Con group, n=15), the model group (VD group, n=15) and the resveratrol‑treated VD group (Res group, n=15). The VD rats (the VD group and the Res group) were generated by bilateral common carotid artery occlusion. The rats in the Res group received daily resveratrol treatment intraperitoneally for 4 weeks. Cognitive function was tested using the Morris water maze test. The levels of SOD and MDA (oxidative stress indicators) were detected by ELISA kits. The protein expression of Bax, Bcl‑2 and caspase‑3 was detected bywestern blotting. Compared with the rats in the Con group, the rats in the VD group exhibited decreased cognitive function, significantly increased hippocampal content of MDA, Bax and caspase‑3 (P

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PMID: 

Int J Biochem Cell Biol. 2019 Nov 9 ;118:105644. Epub 2019 Nov 9. PMID: 31712163

Abstract Title: 

Resveratrol induces depletion of TRAF6 and suppresses prostate cancer cell proliferation and migration.

Abstract: 

Although the early diagnosis of prostate cancer (PCa) enhances life expectancy with a 5-year survival rate of 100 %, metastasized-PCa is the fundamental reason for death by PCa, hence requires an advanced and target-directed treatment strategy. Metastasis is considered to be initiated with the epithelial-mesenchymal transition (EMT) event in which tumor cells change their epithelial characteristics into mesenchymal form and exacerbates the cancer progression. Herein, we investigated the effect and mechanism of resveratrol function in PCa cell proliferation and migration and reported that TNF-receptor associated factor 6 (TRAF6), an unconventional E3 ligase, is a key mediator of resveratrol function to inhibit PCa cell growth and proliferation and targeted for lysosomal degradation by resveratrol. MTT and cell counting demonstrated that resveratrol inhibited the viability and proliferation in DU145 and PC3 cells. Resveratrol (50μM) mediated the degradation of TRAF6 which in turn facilitated repression of the NF-κB pathway. Also, wound healing and transwell migration assays and level of EMT-related proteins showed that resveratrol used TRAF6, at least in part to inhibit cell migration. Overexpression of TRAF6 augmented EMT in PCa by upregulating the expression of transcription factor SLUG. Moreover, TRAF6 overexpression was closely associated with EMT process through the NF-κB pathway. Our exploration exhibited that resveratrol may inhibit EMT through the TRAF6/NF-κB/SLUG axis. Altogether, this study represents that TRAF6 acts as an intermediary of resveratrol action to suppress PCa cell proliferation and migration, and concerns future attention to obtain as a therapeutic target for the treatment of PCa.

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PMID: 

Wounds. 2019 Nov ;31(11):279-284. Epub 2019 Sep 15. PMID: 31730508

Abstract Title: 

Resveratrol Exerts Therapeutic Effects on Mice With Atopic Dermatitis.

Abstract: 

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a high prevalence in children worldwide. Resveratrol exerts various pharmacologic effects, and application of resveratrol has been suggested as an alternative treatment for microorganism infection and skin pathologies.OBJECTIVE: The present study examines the effect of resveratrol on AD using an in vivo murine model.MATERIALS AND METHODS: Atopic dermatitis was induced in 30 BALB/c mice by topical application of 2,4-dinitrochlorobenzene (DNCB) prior to treatment with 0 mg/kg, 5 mg/kg, or 25 mg/kg resveratrol. Histologic data changes were evaluated, and the levels of thymus- and activation-regulated chemokine; type 2 helper T cytokines interleukin (IL) 4, IL-5, and IL-13; and type 1 helper T cytokines IL-12 and interferonγ were examined by enzyme-linked immunosorbent assay. Messenger ribonucleic acid expression was evaluated with quantitative polymerase chain reaction. Filaggrin (FLG), envoplakin (EVPL), transglutaminase (TG), and kallikrein 7 (KLK7) protein expression were evaluated with Western blot.RESULTS: Resveratrol ameliorated the onset of AD-like skin lesions and significantly improved the DNCB-induced dermal destruction in mice. In addition, resveratrol reduced the levels of the above chemokines, downregulated the expression of the proinflammatory cytokine KLK7, and upregulated the expression of several cytokines, such as EVPL, FLG, and TG.CONCLUSIONS: These results suggest resveratrol has therapeutic effects in the treatment of AD.

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PMID: 

J Mater Chem B. 2019 Nov 20. Epub 2019 Nov 20. PMID: 31746932

Abstract Title: 

Anti-breast cancer activity of resveratrol encapsulated in liposomes.

Abstract: 

Resveratrol (RES) is a naturally occurring and effective drug for tumor prevention and treatment. However, its low levels of aqueous solubility, stability, and poor bioavailability limit its application, especially when used as a free drug. In this study, RES was loaded into peptide and sucrose liposomes (PSL) to enhance the physico-chemical properties of RES and exploit RES delivery mediated by liposomes to effectively treat breast cancer. RES loaded PSL (the complex: PSL@RES) were stable, had a good RES encapsulation efficiency, and prolonged RES-release in vitro. PSL@RES was exceptionally efficient for inhibiting the growth of cancer cells, as the IC50 of PSL@RES in MCF-7 cells was found to be only 20.89μmol L-1. The therapeutic efficacy of PSL@RES was evaluated in mice bearing breast cancer. The results showed that PSL@RES at a dosage of 5 mg kg-1 was more effective than 10 mg kg-1 free RES, and PSL@RES inhibited tumor growth completely at a dosage of 10 mg kg-1. PSL@RES induced apoptosis in breast tumor by upregulation of p53 expression. This then downregulated Bcl-2 and upregulated Bax, thereby inducing Caspase-3 activation. More importantly, encapsulation of RES within peptide liposomes greatly reduced the toxicity of free RES to mice. Overall, the simple formulation of liposomal nanocarriers of RES developed in this study produces satisfactory outcomes to encourage further applications of liposomal carriers for the treatment of breast cancer.

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PMID: 

J Biochem Mol Toxicol. 2019 Nov 20:e22420. Epub 2019 Nov 20. PMID: 31746523

Abstract Title: 

Resveratrol delay the cataract formation against naphthalene-induced experimental cataract in the albino rats.

Abstract: 

Oxidative stress-induced toxicity plays a major role in ocular diseases such as retinal degeneration, age-related cataract (ARC) formation and macular dystrophy. In this study, we explored the possible role of resveratrol (RSV) at the different dose levels (10, 20 and 40 mg/kg/day, ip) in an experimental model of naphthalene (1 g/kg/day, po)-induced age-related cataracts. Morphological changes in the eyes of the rats in two groups, the RSV and the ARC groups, were monitored weekly, and biochemical parameters in the lenses were assessed after completion of the experimental work. A comparison between the rats in the two groups showed that treatments at RSV doses of 20 and 40 mg/kg/day significantly retarded lenticular opacity, restored antioxidants (CAT, SOD, GPX, GSH), CaATPase function, and protein contents, and reduced lipid peroxidation in the lenses of the animals in the RSV group. The treatment with resveratrol at a dose of 10 mg/kg/day did not show any anti-cataractogenic effects. Based on the results of our investigation, we conclude that supplemental doses of resveratrol at 40 mg/kg/day effectively prevent cataract formation associated with the aging via increased soluble protein contents and Cahomeostasis, apart from the antioxidant restoration. The results demonstrate that RSV treatment may be considered as a promising preventive or supplemental measure for delaying and/or preventing the formation of ARCs.

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PMID: 

J Physiol Biochem. 2019 Nov 30. Epub 2019 Nov 30. PMID: 31786730

Abstract Title: 

Resveratrol pretreatment alleviates myocardial ischemia/reperfusion injury by inhibiting STIM1-mediated intracellular calcium accumulation.

Abstract: 

Previous studies have shown that stromal interaction molecule1 (STIM1)-mediated store-operated Caentry (SOCE) contributes to intracellular Caaccumulation in H9C2 cells subjected to hypoxia/reoxygenation(H/R) injury. The aim of the present study was to investigate the effect of resveratrol on STIM1-mediated intracellular Caaccumulation and subsequent cell death in the context of myocardial ischemia/reperfusion (I/R) injury. C57 BL/6 mice were fed with either saline or resveratrol (50 mg/kg daily for 2 weeks) and then subjected to myocardial I/R injury. TTC/Evans Blue staining and TUNEL assay were performed to quantify the infarct size and apoptosis index. The cardiac function was evaluated by echocardiography. Neonatal rat ventricular cardiomyocytes (NRVCs) underwent hypoxia/reoxygenation (H/R) to establish the in vitro model. To achieve over-expression, NRVCs were transfected with STIM1-adenovirus vector. Apoptosis was analyzed by TUNEL assay. Cell viability was measured using MTS assay and cell necrosis was determined by LDH release assay. Intracellular Caconcentration was detected by laser scanning confocal microscopy using a Fluo-3AM probe. Resveratrol significantly reduced apoptosis, decreased infarct size, and improved cardiac function in mice subjected to myocardial I/R injury. In NRVCs, resveratrol also downregulated STIM1 expression accompanied by decreased intracellular Caaccumulation elicited by H/R injury. In addition, resveratrol reduced cell apoptosis, upregulated the Bcl-2, decreased Bax, and cleaved caspase-3 expression. Furthermore, the effects of resveratrol on STIM1-mediated intracellular Caaccumulation, apoptotic proteins, and H/R-induced cell injury were exacerbated by STIM1 over-expression and were partly abolished by SOCE inhibitor SKF96365 in NRVCs in vitro. Our findings demonstrate that resveratrol exerts anti-apoptotic activity and improves cardiac functional recovery following myocardial I/R by inhibiting STIM1-induced intracellular Caaccumulation.

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PMID: 

Food Funct. 2019 Dec 3. Epub 2019 Dec 3. PMID: 31793596

Abstract Title: 

Xanthohumol inhibits tau protein aggregation and protects cells against tau aggregates.

Abstract: 

Alzheimer's disease (AD) is a neurodegenerative disease. The molecular mechanisms of AD are not yet clear, and no effective treatments are available to cure AD. Because of the huge number of patients and related costs, it is urgent to discover new medicines to prevent or cure AD. In this study, xanthohumol (XN), a natural botanic compound, is found to inhibit tau protein aggregation and disaggregate tau fibrils. XN directly interacts with tau protein at sites sporadically located in all four repeating domains with a Kd value of 52μM. Binding with XN does not alter the secondary structures of tau protein. Cellular experiments showed that XN exhibits little cytotoxicity and attenuates apoptosis induced by tau oligomers. The results provide preliminary experimental data to develop XN into medicines, food products, or nutritional supplements for AD. The findings also provide data for computational drug design.

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