Proanthocyanidins prevent tau protein aggregation and disintegrate tau filaments

Occurrence of neurofibrillary tangles of the tau protein is a hallmark of tau-related neurodegenerative diseases, i.e. Alzheimer's disease(AD) and frontotemporal dementia. The pathological mechanism underlying AD remains poorly understood, and effective treatments are still unavailable to mitigate the disease.Inhibiting of tau aggregation and disrupting the existing fibrils are key targets in drug discovery towards preventing or curing AD. In this study, grape seed proanthocyanidins(GSPs) was found to effectively inhibit the repeat domain of tau(tau-RD) aggregation and disaggregate tau-RD fibrils in a concentrationdependent manner by inhibiting β-sheet formation of tau-RD. In cells, GSPs relieved cytotoxicity induced by tau-RD aggregates. Molecular dynamics simulations indicated that strong hydrogen bonding,hydrophobic interaction and π-π stacking between GSPs and tau-RD protein were major reasons why GSPs had high inhibitory activity on tau-RD fibrillogenesis. These results provide preliminary data to develop GSPs into medicines, foodstuffs or nutritional supplements for AD patients, suggesting that GSPs could be a candidate molecule in the drug design for AD therapeutics.

Neuroprotection by resveratrol-glucuronide and quercetin-glucuronide via binding to polyphenol-and glycosaminoglycan-binding sites in the laminin receptor

The dietary polyphenolic compounds resveratrol and quercetin prevent neurodegenerative diseases in experimental models;however, they reach the brain only in nanomolar concentrations in the glucuronidated and sulfated forms, and not as the aglycone parent form(Pasinetti et al.,2015).

Neuroprotective effects of resveratrol on retinal ganglion cells in glaucoma in rodents:A narrative review

Glaucoma,an irreversible optic neuropathy,primarily affects retinal ganglion cells(RGC)and causes vision loss and blindness.The damage to RGCs in glaucoma occurs by various mechanisms,including elevated intraocular pressure,oxidative stress,inflammation,and other neurodegenerative processes.As the disease progresses,the loss of RGCs leads to vision loss.Therefore,protecting RGCs from damage and promoting their survival are important goals in managing glaucoma.In this regard,resveratrol(RES),a polyphenolic phytoalexin,exerts antioxidant effects and slows down the evolution and progression of glaucoma.The present review shows that RES plays a protective role in RGCs in cases of ischemic injury and hypoxia as well as in ErbB2 protein expression in the retina.Additionally,RES plays protective roles in RGCs by promoting cell growth,reducing apoptosis,and decreasing oxidative stress in H_(2)O_(2)-exposed RGCs.RES was also found to inhibit oxidative stress damage in RGCs and suppress the activation of mitogen-activated protein kinase signaling pathways.RES could alleviate retinal function impairment by suppressing the hypoxia-i nducible factor-1 alpha/vascular endothelial growth factor and p38/p53 axes while stimulating the PI3K/Akt pathway.Therefore,RES might exert potential therapeutic effects for managing glaucoma by protecting RGCs from damage and promoting their survival.

Resveratrol combats chronic diseases through enhancing mitochondrial quality

Resveratrol(RSV),as a functional food component extracted from natural plants,has been widely studied and recognized in preventing and treating various diseases,with major mechanisms including executing anti-inflammation and anti-oxidation functions,and improving mitochondrial quality.Chronic diseases as non-communicable diseases are mainly caused by multiple factors,such as physiological decline and dysfunction in the body,and have become a significant challenge on public health worldwide.It is worth noting that chronic diseases such as Alzheimer's disease(AD),Parkinson's disease(PD),muscle atrophy,cardiovascular disease,obesity,and cancer are accompanied by abnormal mitochondrial function.Therefore,targeted regulation of mitochondria may be a meaningful way to prevent and treat chronic diseases.Increasing evidence has confirmed that RSV is actively involved in regulating mitochondria,and it has become an essential consideration to prevent and treat chronic diseases through targeting mitochondria and improving corresponding functions.In this article,current studies on RSV to optimize mitochondrial quality for preventing and alleviating chronic disease are systematically summarized,which can provide a theoretical reference for the development of functional foods or drugs to combat chronic diseases.

Resveratrol inhibits pancreatic cancer proliferation and metastasis by depleting senescent tumor-associated fibroblasts

BACKGROUND Pancreatic cancer,a formidable gastrointestinal neoplasm,is characterized by its insidious onset,rapid progression,and resistance to treatment,which often lead to a grim prognosis.While the complex pathogenesis of pancreatic cancer is well recognized,recent attention has focused on the oncogenic roles of senescent tumor-associated fibroblasts.However,their precise role in pancreatic cancer remains unknown.Resveratrol is a natural polyphenol known for its multifaceted biological actions,including antioxidative and neuroprotective properties,as well as its potential to inhibit tumor proliferation and migration.Our current investigation builds on prior research and reveals the remarkable ability of resveratrol to inhibit pancreatic cancer proliferation and metastasis.AIM To explore the potential of resveratrol in inhibiting pancreatic cancer by targeting senescent tumor-associated fibroblasts.METHODS Immunofluorescence staining of pancreatic cancer tissues revealed prominent coexpression ofα-SMA and p16.HP-1 expression was determined using immunohistochemistry.Cells were treated with the senescence-inducing factors known as 3CKs.Long-term growth assays confirmed that 3CKs significantly decreased the CAF growth rate.Western blotting was conducted to assess the expression levels of p16 and p21.Immunofluorescence was performed to assess LaminB1 expression.Quantitative real-time polymerase chain reaction was used to measure the levels of several senescence-associated secretory phenotype factors,including IL-4,IL-6,IL-8,IL-13,MMP-2,MMP-9,CXCL1,and CXCL12.A scratch assay was used to assess the migratory capacity of the cells,whereas Transwell assays were used to evaluate their invasive potential.RESULTS Specifically,we identified the presence of senescent tumor-associated fibroblasts within pancreatic cancer tissues,linking their abundance to cancer progression.Intriguingly,Resveratrol effectively eradicated these fibroblasts and hindered their senescence,which consequently impeded pancreatic cancer progression.CONCLUSION This groundbreaking discovery reinforces Resveratrol's stature as a potential antitumor agent and positions senescent tumor-associated fibroblasts as pivotal contenders in future therapeutic strategies against pancreatic cancer.

Identification of anti-gastric cancer effects and molecular mechanisms of resveratrol: From network pharmacology and bioinformatics to experimental validation

BACKGROUND Gastric cancer(GC)is one of the most aggressive malignancies with limited therapeutic options and a poor prognosis.Resveratrol,a non-flavonoid poly-phenolic compound found in a variety of Chinese medicinal materials,has shown excellent anti-GC effect.However,its exact mechanisms of action in GC have not been clarified.AIM To identify the effects of resveratrol on GC progression and explore the related molecular mechanisms.METHODS Action targets of resveratrol and GC-related targets were screened from public databases.The overlapping targets between the two were confirmed using a Venn diagram,and a“Resveratrol-Target-GC”network was constructed using Cyto-scape software version 3.9.1.The protein-protein interaction(PPI)network was constructed using STRING database and core targets were identified by PPI network analysis.The Database for Annotation,Visualization and Integrated A total of 378 resveratrol action targets and 2154 GC disease targets were obtained from public databases,and 181 intersection targets between the two were screened by Venn diagram.The top 20 core targets were identified by PPI network analysis of the overlapping targets.GO function analysis mainly involved protein binding,identical protein binding,cytoplasm,nucleus,negative regulation of apoptotic process and response to xenobiotic stimulus.KEGG enrichment analysis suggested that the involved signaling pathways mainly included PI3K-AKT signaling pathway,MAPK signaling pathway,IL-17 signaling pathway,TNF signaling pathway,ErbB signaling pathway,etc.FBJ murine osteosarcoma viral oncogene homolog(FOS)and matrix metallopeptidase 9(MMP9)were selected by differential expression analysis,and they were closely associated with immune infiltration.Molecular docking results showed that resveratrol docked well with these two targets.Resveratrol treatment arrested the cell cycle at the S phase,induced apoptosis,and weakened viability,migration and invasion in a dose-dependent manner.Furthermore,resveratrol could exhibit anti-GC effect by regulating FOS and MMP9 expression.CONCLUSION The anti-GC effects of resveratrol are related to the inhibition of cell proliferation,migration,invasion and induction of cell cycle arrest and apoptosis by targeting FOS and MMP9.

Immunomodulatory and chemopreventive effects of resveratrol on the digestive system cancers

Resveratrol(RSV),the primary polyphenol found in grapes,has been revealed to have anti-inflammatory properties by reducing the capacity of the peripheral blood mononuclear cells to produce pro-inflammatory cytokines,including IL-1β,IL-6,IL-1ra and TNFα.Considering the close association between chronic inflammation and cancer development,RSV’s immunomodulatory properties are one way by which the polyphenol may inhibit cancer initiation,proliferation,neovascularization,and migration.Resveratrol influences the generation of microtumor environment which is one of the key factors in cancer progress.In addition to immunomodulation,RSV inhibits cancer development by expressing anti-oxidant effects,causing cell cycle arrest,stimulating the function of certain enzymes,and activating cell signaling pathways.The end outcome is one of the various forms of cell death,including apoptosis,pyroptosis,necroptosis,and more,as it has been observed in vitro.RSV has been shown to act against cancer in practically every organ,while its effects on colon cancer have been documented more frequently.It is remarkable that longer-term clinical studies that may have established the potential for this natural substance to serve as a therapeutic adjuvant to traditional anti-cancer medications were not prompted by the encouraging outcomes seen with cancer cells treated with non-toxic doses of resveratrol.The current review aims to assess the recent findings about the immunological and anti-cancer characteristics of RSV,with a particular emphasis on cancers of the digestive tract,as a challenge for future clinical research that may contribute to the better prognosis of cancer.

Protective effect of ginkgo proanthocyanidins against cerebral ischemia/reperfusion injury associated with its antioxidant effects

Proanthocyanidins have been shown to effectively protect ischemic neurons, but its mechanism remains poorly understood. Ginkgo proan-thocyanidins （20, 40, 80 mg/kg） were intraperitoneally administered 1, 24, 48 and 72 hours before reperfusion. Results showed that ginkgo proanthocyanidins could effectively mitigate neurological disorders, shorten infarct volume, increase superoxide dismutase activity, and de-crease malondialdehyde and nitric oxide contents. Simultaneously, the study on grape seed proanthocyanidins （40 mg/kg） confirmed that different sources of proanthocyanidins have a similar effect. The neurological outcomes of ginkgo proanthocyanidins were similar to that of nimodipine in the treatmen＇t of cerebral ischemia/reperfusion injury. （Sur results suggestthat-ginkgo proanthocyanidins can effectively lessen cerebral ischemia/reperfusion injury and protect ischemic brain tissue and these effects are associated with antioxidant properties.

Protective effects of proanthocyanidins on beta-amyloid peptide (25-35)-induced PC12 cell apoptosis by blocking S-phase and increasing p53 gene expression

BACKGROUND： Current studies related to the effects of proanthocyanidins on Alzheimer＇s disease have focused primarily on the signal transduction pathway of cellular apoptosis. However, the influence of p53 gene expression on cell cycle regulation, with regard to the protective mechanisms of proanthocyanidins, has not been reported. OBJECTIVE： To observe the effect of proanthocyanidins on cell cycle distribution, cellular apoptosis and p53 gene expression in β-amyloid peptide （25-35） （Aβ25-35）-induced PC12 cells cultured in serum-free media, and to investigate the molecular neuroprotective mechanisms of proanthocyanidins with regard to cell cycle regulation. DESIGN, TIME AND SETTING： A parallel, controlled, at the Institute of Biochemistry and Molecular Biology cellular, and molecular study was performed Guangdong Medical College from July 2006 to July 2008. MATERIALS： Proanthocyanidins were provided by Nanjing Xuezi Medical and Chemical Research Center, China; Aβ25-35 was provided by Sigma, USA; PC12 cells were provided by the Institute of Basic Medical Science, Academy of Military Medical Sciences; and rabbit anti-p53 polyclonal antibody was provided by Santa Cruz Biotechnology, USA. METHODS： PC12 cells were cultured in serum-free media for 24 hours. Cells from the model group were treated with 25 μmol/L Aβ25-35 for 24 hours. Cells in the drug protection group were pre-treated with 30 mg/L proanthocyanidins for 1 hour and then treated with 25 μmol/LAβ2^-35 for 24 hours. The control group was not treated. MAIN OUTCOME MEASURES： Flow cytometry was used to detect cell cycle distribution and rate of apoptosis; reverse-transcriptase polymerase chain reaction was used to detect p53 mRNA expression; and Western blot was used to detect p53 protein expression. RESULTS： After treating with 25 μmol/LAβ25-35 for 24 hours, the rate of apoptosis and the percentage of cells in S phase were significantly increased （P 〈 0.01 ）, and p53 mRNA and protein expressions were decreased. Pretreatment with proanthocyanidins for 1 hour blocked the increase in apoptosis and the percentage of cells in S phase in Aβ25-35-induced PC12 cells （P 〈 0.01 ） and increased p53 mRNA and protein expressions. CONCLUSION： Proanthocyanidins blocked apoptosis and S-phase arrest in Aβ25-35-induced PC12 cells cultured in serum-free media. The protective mechanism could be related to increased p53 mRNA and protein expressions.

Comparative Analysis of Proanthocyanidins and Polysaccharides on Wild Lycium ruthenicum

[Objectives] To compare content of proanthocyanidins and polysaccharides in wild Lycium ruthenicum. [Methods] The wild L. ruthenicum collected from different regions such as Qinghai, Inner Mongolia, Ningxia and Gansu Province were taken as the research objects. The conventional indicators such as proanthocyanidins and polysaccharides of the experimental materials were determined, and the proanthocyanidins and polysaccharides of the experimental materials in different regions were compared and analyzed. The difference in content and correlation, and the cluster analysis method were used to divide clusters of the experimental materials. [Results] The absorbance of proanthocyanidins in the fruit of wild L. ruthenicum was No.4>No.1>No.5>No.6>No.3>No.2, among which the absorbance of anthocyanin(2.43) of wild L. ruthenicum variety No.4 was significantly higher than other experimental materials(P<0.05), and proanthocyanidin of No.2 had the lowest absorbance value of 1.35. There was no significant difference between No.3 and No.6(P>0.05), and there were significant differences among other experimental materials(P<0.05). The content of polysaccharides was: No.3>No.7>No.2>No.4>No.5>No.6>No.1; there was no significant difference between No.3 and No.7(P>0.05), but significantly higher than other materials(P<0.05). Besides, proanthocyanidins and polysaccharides showed significant variability, but there was no consistency in the correlation between them. [Conclusions] In terms of the absorbance of proanthocyanidins, the experimental materials No.1 and No.4 can be classified into a cluster; experimental materials No.2, No.3, No.5 and No.6 can be classified into another cluster. This can provide a theoretical basis for the introduction and breeding of fine varieties.

Biological function of resveratrol and its application in animal production:a review

With the prohibition of antibiotics in feed,plant functional substances have been widely studied as feed additives.Resveratrol,a natural stilbene,and a non-flavonoid polyphenol found in plants,possesses antioxidant,anti-inflammatory,and metabolic regulatory features.Resveratrol generated intense scientific and public interest,primarily due to its widely reported ability to prevent cancer,delay aging and alleviate related metabolic diseases.Recently,resveratrol has been studied and applied as a feed additive in animal production.This review focuses on the outline of the absorption and metabolism and biological functions of resveratrol and summarizes the application of dietary resveratrol in animal production up to the present,including pigs,poultry,and ruminants.In pigs,dietary resveratrol improved intestinal health,mitochondrial function,meat quality,and more.In poultry,studies have shown that dietary resveratrol improves growth performance and meat and egg quality and alleviates heat stress induced adverse effects.There are few studies on dietary resveratrol in ruminants;however previous studies have indicated that dietary resveratrol increases nutrient digestibility and reduces methane emissions in sheep.It is hoped that this review could provide a specific theoretical basis and research ideas for the research and application of resveratrol.

Resveratrol alleviates oxidative stress induced by oxidized soybean oil and improves gut function via changing gut microbiota in weaned piglets

Background Oxidized soybean oil(OSO)has been shown to impair growth and exacerbate inflammation,leading to intestinal barrier injury in animals.Recent evidence suggests important roles for resveratrol(RES)in the promoting growth performance,antioxidant capacity,anti-inflammatory,and regulate intestinal barriers in animals.Therefore,The objectives of this study are to investigate the effects of dietary RES(purity 98%)supplementation on the growth performance,antioxidant capacity,inflammatory state,and intestinal function of weaned piglets challenged with OSO.Methods A total of 28 castrated weaned male piglets with a similar body weight of 10.197 replications per treatment and±0.10 kg were randomly assigned to 4 dietary treatments for 28-d feeding trial with 1 piglet per replicate.Treatments were arranged as a 2×2 factorial with oil type[3%fresh soybean oil(FSO)vs.3%OSO]and dietary RES(0vs.300 mg/kg).Results The results showed that relative to the FSO group,OSO stress tended to decrease the average daily feed intake(ADFI),and decreased the activity levels of lipase,villus/crypt ratio(VCR),the mRNA expression of FABP1,SOD2,IL-10 and ZO-1 in the jejunum,and SOD2,GPX1,occludin and ZO-1 in the colon,the levels of acetic acid in the colonic digesta,whereas up-regulated the mRNA expression of IL-1βand TNF-αin the jejunum(P<0.05).Moreover,dietary supplementation with RES increased ether extract(EE),the activity levels of sucrase,lipase,α-amylase,villus height(VH)and VCR,the mRNA expression of FABP1,SOD2,IL-10 and occludin in the jejunum,and FABP1,PPAR-γ,GPX1,occludin and ZO-1 in the colon,and the abundance of Firmicutes,acetic and propionic acid,but decreased the levels of D-lactic acid in the plasma,the abundance of Bacteroidetes in the colonic digesta of weaned piglets compared to the non-RES group(P<0.05).Meanwhile,in the interaction effect analysis,relative to the OSO group,dietary RES supplementation in the diets supplemented with OSO increased the activity levels of trypsin,VH in the jejunum,the abundance of Actinobacteria,the levels of butyric acid of weaned piglets,but failed to influence the activity levels of trypsin and VH,Actinobacteria abundance,the levels of butyric acid when diets were supplemented with FSO(interaction,P<0.05).Relative to the OSO group,dietary RES supplementation in the diets supplemented with OSO decreased the activity levels of DAO in the plasma of weaned piglets but failed to influence the activity levels of DAO when diets were supplemented with FSO(interaction,P<0.05).Relative to the FSO group,dietary RES supplementation in the diets supplemented with FSO decreased the level of propionic acid,whereas RES supplementation failed to influence the level of propionic acid when the diet was supplemented with OSO(interaction,P<0.01).Conclusions Inclusion of OSO intensified inflammatory states and impaired the intestinal health characteristics of weaned piglets.Dietary RES supplementation improved the antioxidant capacity,anti-inflammatory activity,and intestinal morphology.Further studies showed that the protective effects of RES on gut health could be linked to the decreased abundance of Prevotella_1,Clostridium_sensu_stricto_6,and Prevotellaceae_UCG003 and increased levels of acetic and propionic acid.

Protective effect of resveratrol against cadmium-induced toxicity on ovine oocyte in vitro maturation and fertilization

Background:Heavy metal cadmium(Cd)is a widespread environmental contaminant with a potential toxicity that might negatively affect female reproduction and fertility.It has been reported that Cd exposure impaired the quality of oocytes and led to a defective maturation and fertilization,through oxidative stress induction.Resveratrol(Res)is a natural polyphenol with strong antioxidant properties that exhibited protective role in preventing oocyte redox homeostasis disruption and quality decline.Here,we explored whether the addition of Res to in vitro maturation(IVM)medium might act as a protection against Cd-induced toxicity on ovine oocyte maturation and fertilization.Firstly,we evaluated the effect of supplementing IVM medium with two different Res concentrations(1and 2μmol/L)on nuclear maturation and fertilization of oocytes matured under CdCl2(2μmol/L)exposure.Therefore,the concentration of 1μmol/L Res was selected to analyse the effects of this compound on intracellular ROS levels,mitochondrial(mt)distribution and activity,chromatin configuration,cytoskeleton morphology,cortical granules(CGs)distribution and mRNA expression of genes associated with cellular response to oxidative stress(i.e.SIRT1,SOD 1,GPX1,GSR,CAT)in Cd-exposed in vitro matured oocytes.Results:We found that 1μmol/L Res restored the reduced oocyte meiotic competence induced by Cd exposure as well as,Res sustained oocyte ability to be normally fertilized and decreased polyspermic fertilization at both tested concentrations.Moreover,we demonstrated that 1μmol/L Res mitigated Cd-induced alterations of oocyte cytoplasmic maturation by reducing reactive oxygen species(ROS)accumulation,preventing mt dysfunction,maintaining the correct meiotic spindle and cortical F-actin assembly and the normal cortical granule distribution as well as up-regulating SIRT1,SOD1 and GPX1 genes.Conclusions:Taken together,our findings highlighted the beneficial influence exerted by Res in preventing Cdinduced disturbance of nuclear and cytoplasmic maturation and subsequent fertilization in ovine oocytes.Res treatment may help to establish defence strategies counteracting Cd-induced toxicity on the female gamete.

Antioxidant activity of proanthocyanidins from adansonia digitata fruit

Besides（-）-epicatechin,epicatechin-（4β-8 ）-epicatechin（procyanidin B2）,epicatechin-（4β-6 ）-epicatechin （procyanidin B5）,epicatechin-（4β-8,2β-O-7）-epicatechin（proanthocyanidin A2） and epicatechin- （4β-8）-epicatechin-（4β-8）-epicatechin（procyanidin C1）,which were isolated before from Adansonia digitata, in this work an A-type proanthocyanidin trimer,i.e.epicatechin-（4β-8）-epicatechin-（4β-8,2β-0-7）- epicatechin,tetrameric procyanidin D1,i.e.epicatechin-（4β-8）-epicatechin-（4β-8）-epicatechin-（4β-8）- epicatechin and a polymeric compound were isolated from the pericarp（fruit wall） of the fruits for the first time from this plant.The antioxidant activity of different fractions and pure compounds was experimentally evaluated in the DPPH- assay.The ethyl acetate fraction,and most of the isolated compounds displayed a high activity(IC50 2.40-9.60μg/ml) compared with the reference antioxidant Trolox(IC50 12.18μg/ml) as a standard.

Effect of resveratrol in gestational diabetes mellitus and its complications

The incidence rate of diabetes in pregnancy is about 20%,and diabetes in pregnancy will have a long-term impact on the metabolic health of mothers and their offspring.Mothers may have elevated blood glucose,which may lead to blood pressure disease,kidney disease,decreased resistance and secondary infection during pregnancy.The offspring may suffer from abnormal embryonic development,intrauterine growth restriction,obesity,autism,and other adverse consequences.Resveratrol(RSV)is a natural polyphenol compound,which is found in more than 70 plant species and their products,such as Polygonum cuspidatum,seeds of grapes,peanuts,blueberries,bilberries,and cranberries.Previous studies have shown that RSV has a potential beneficial effect on complex pregnancy,including improving the indicators of diabetes and pregnancy diabetes syndrome.This article has reviewed the molecular targets and signaling pathways of RSV,including AMP-activated protein kinase,mitogen-activated protein kinases,silent information regulator sirtuin 1,miR-23a-3p,reactive oxygen species,potassium channels and CX3C chemokine ligand 1,and the effect of RSV on gestational diabetes mellitus(GDM)and its complications.RSV improves the indicators of GDM by improving glucose metabolism and insulin tolerance,regulating blood lipids and plasma adipokines,and modulating embryonic oxidative stress and apoptosis.Furthermore,RSV can ameliorate the GDM complications by reducing oxidative stress,reducing the effects on placentation,reducing the adverse effects on embryonic development,reducing offspring's healthy risk,and so on.Thus,this review is of great significance for providing more options and possibilities for further research on medication of gestational diabetes.

Resveratrol Prevents Vibrio vulnificus-Induced Sepsis by Attenuating Necroptosis

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.vulnificusinduced 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.

One-year outcomes of resveratrol supplement with aflibercept versus aflibercept monotherapy in wet agerelated macular degeneration

AIM:To determine the one-year outcomes of resveratrol oral supplement in patients suffering from wet age-related macular degeneration(AMD).METHODS:Fifty naïve and previously untreated patients suffering from wet AMD,were randomly assigned in two subgroups of 25 patients each.All the participants were treated with 3 monthly intravitreal injections of 2.0 mg aflibercept(IAIs)followed by injections“according to need”,while in one group the patients also received daily two tablets of resveratrol oral supplement.Prior to treatment initiation,a complete ophthalmological examination,including best corrected visual acuity(BCVA)and contrast sensitivity evaluation,optical coherence tomography(OCT)scans,fundus autofluorescence(FAF),fluorescein angiography,indocyanine green angiography,and OCT angiography(OCTA),was performed to every participant,while all of them completed the Hospital Anxiety and Depression Scale(HADS)questionnaire,in order to assess their quality of life(QoL)status.The patients were assessed monthly for 1y with FAF,and OCT or OCTA;the main endpoints were the number IAIs,the changes in BCVA,in contrast sensitivity,and in patients’QoL status.RESULTS:No significant differences were present between the groups regarding the baseline demographic and clinical data.Over the 12-month period,a similar number of IAIs was applied in both groups(4.52±1.00 vs 4.28±0.90,P=0.38),while the rest of the clinical data also did not differ significantly after the completion of the study period.However,for HADS Depression(11.88±2.51 vs 8.28±1.54,P<0.001)and HADS Anxiety(11.92±2.52 vs 7.76±1.51,P<0.001)questionnaires values,the score was significantly better in patients who received resveratrol supplements.Moreover,a statistically significant difference was detected in the mean change from baseline values of contrast sensitivity(0.17±0.19 vs 0.35±0.24,P=0.005),HADS Depression(0.08±1.38 vs-3.88±1.48,P<0.001),and HADS Anxiety(0.36±1.98 vs-5.12±2.70,P<0.001)scores,in favour of the patients treated with resveratrol supplements.CONCLUSION:The resveratrol oral supplement is a complementary treatment in cases of wet AMD,highlighting its effectiveness in improving patients’QoL status.

Effect of grape seed proanthocyanidins on tumor vasculogenic mimicry in liver cancer xenograft model

Objective: As a novel blood supply pattern, vasculogenic mimicry(VM) has attracted increasingly attention in recent years, which may partly compensate for the absence of feeding and facilitate tumor perfusion. However, anti-angiogenic drugs have little effect on VM. The grape seed proanthocyanidins(GSPs), a kind of promising bioactive phytochemical, has shown anti-carcinogenesis and anti-angiogenic in several tumor models. However, GSPs regulation of VM and its possible mechanisms in a H22 hepatoma carcinoma model remain not clear. The aim of this study was to examine the effects of GSPs on proliferation and VM in a H22 hepatoma carcinoma model and to investigate the underlying mechanism. Methods: Seventy-five mice were divided into the control group and experimental groups treated with different concentration of GSPs. CD34-PAS dual staining was employed to identify the VM structure. The immunohistochemical staining for investigating the expression of VEGF, Eph A2 and MMP-2 protein was performed. Results: Treatment of the H22 model with Endostar(4 mg/kg), 50, 100, 200 mg/kg of the GSPs resulted in 6.87%, 17.81%, 27.43%, 53.52% inhibition in tumor growth, respectively. The mean weight of tumors were significantly lower in GSPs(100 mg/kg) and GSPs(200 mg/kg) groups than in the control group(all P < 0.01). Similarly, compared with the control group, the number of VM channels were significantly reduced in GSPs(100 mg/kg) and GSPs(200 mg/kg) groups(all P < 0.01). Immunohistochemistry showed significant decreases in the expression levels of VEGF, Eph A2 and MMP-2 protein in GSPs(100 mg/kg) and GSPs(200 mg/kg) groups when compared with control group(all P < 0.001). Conclusion: This is the first report providing evidence that GSPs inhibit the VM structure by regulation of the VEGF/Eph A2/MMPs signaling pathway. Therefore, we concluded that GSPs has the potential of being a clinical anti-VM inhibitor.

Effect of grape proanthocyanidins on tumor growth and angiogenesis in H22 liver cancer xenograft model

Objective: The aim of this study was to investigate the effect of grape proanthocyanidins(GPC) on the growth and angiogenesis of hepatocellular carcinoma H22 cells xenograft in mice. Methods: The xenograft model was established using injected subcutaneously H22 cells into the right axilla of the mice. Each group was treated with different doses of GPC and Endostar. All these treatments were maintained for 10 days, and mice were sacrificed. The xenograft tumors in mice were measured. The proliferation activity level of H22 cells was determined by MTT assay, and the levels of vascular endothelial growth factor(VEGF) protein were examined by immunohistochemistry. Results: When treated with 50, 100 and 200 mg/kg of GPC and Endostar, the tumor inhibition rates were 13.17%, 23.37%, 36.15% and 14.71%, respectively. The tumor weight of xenograft was significantly lighter in high GPC group than the control group(P < 0.05). The ODs in GPC groups were 0.835, 0.666 and 0.519, respectively. The absorbances in middle and high GPC groups were statistically significant, compared with control group(P < 0.01). Immunohistochemical technique showed the expression of VEGF of the GPC groups was downregulated significantly compared with the control group(P < 0.01). Conclusion: GPC can inhibit the growth of hepatocellular carcinoma H22 cell xenograft in mice. The inhibition of angiogenesis by the down-regulation of VEGF expression may play a key role in the anti-neoplastic effect of GPC.

New N-acetyl-L-cysteine derivatives synthesized by the degradation of proanthocyanidins as high biological activity antioxidants

A novel degradation method was investigated to synthesize highly biologically active flavan-3-ol derivatives in the presence of N-acetyl-L-cysteine(NAC)as a nucleophile under acidic conditions for polymerized proanthocyanidins degradation.The reaction conditions were optimized by the combination of single-factor test and central composite experimental design(CCD).Grape seed proanthocyanidins were reacted with NAC at a ratio of 1:3 with 0.3 M methanolic HC1,a temperature of 55°C,and a reaction time of 50 mins.Most of the degradation products were separated and prepared by one-step high-speed countercurrent chromatography(HSCCC)and preparative high-performance liquid chromatography(prep-HPLC).Three monomeric pro anthocyanidins and four new N-acetyl-L-cysteine derivatives were isolated from degradation products with total degradation yield of 55.44%and high purity over 95%.Furthermore,the neuroprotective abilities of these compounds to H2O2-treated PC-12 neuroblastoma cells were evaluated.NAC derivatives showed better antioxidant activity than their corresponding underivatized monomers and NAC,indicating that they had a better performance in protecting PC-12 cells from oxidative stress damage.