It is unclear strooke the atherosclerotic changes result from Reaveratrol linear Glycemic index values due to ongoing damage triggered by Weight loss infection with VZV or from periodic endothelial damage and incomplete healing due to reactivation of chronic infection to acutely activated infection. Quantifying Heterogeneity in a Meta-Analysis. GO enrichment analysis of VZV and IS. Kidney J. International Patients.

Resveratrol and stroke prevention -

Therefore, resveratrol administration can be a valuable strategy for the prevention of age-associated and disease-provoked inflammation in postmenopausal women. Cho Lab. Focus People Impact Jobs. Resveratrol attenuates peripheral and brain inflammation and reduces ischemic brain injury in aged female mice.

Year Published:. Abstract on PubMed. Abstract Resveratrol is known to improve metabolic dysfunction associated with obesity. Featured Researchers. Sunghee Cho, Ph. Lab Director. Stroke Neuroimmunology Laboratory. Resveratrol was reported to promote neurogenesis Li et al.

In a randomized controlled trial, co-administration of resveratrol significantly improved the outcome of patients receiving delayed recombinant tissue plasminogen activator treatment Chen et al. Subsequent preclinical studies have indicated that resveratrol treatment could reduce ischemic brain damage, yet there are some disputes over results.

Some studies suggested that the low dosage of resveratrol was unable to induce a significant reduction Pang et al. Moreover, the administration dose, frequency, timing of treatment, and route in each study are so divergent that the overall therapeutic effect is difficult to evaluate.

To date, there is no meta-analysis available investigating the potential effects of resveratrol therapy in pre-clinical models of ischemic stroke. Addressing all these problems, we systematically assessed the bias of included studies and then summarized the optimal pattern of resveratrol therapy.

This meta-analysis may provide significant clues and information for future clinical research. Preferred Reporting Items for Systematic Reviews and Meta-Analysis PRISMA was used to conduct this study Moher et al.

This meta-analysis was not registered in the International prospective register of systematic reviews PROSPERO. However, the PROSPERO was carefully examined to make sure there is no registered meta-analysis that is investigating a similar topic.

The publication language was limited to English. The inclusion criteria were set up based on the PICOS-scheme population, intervention, control, outcome, and study design. The exclusion criteria were as follows: 1 animals treated with resveratrol analogues; 2 studies that only tested the effects of resveratrol combined with other chemicals or drugs such as nanoparticles ; 3 not reporting the number of animals in groups; 4 repeated publications or duplicate report, and abstracts without full text.

The following information was abstracted by two investigators independently and discrepancies were resolved by consensus and then checked by a third investigator. If a study comprised multi-experimental groups distinguished by dosage, frequency, delivery route, and timing that were compared with the control group, these experimental groups would be considered as independent comparisons.

If the outcomes were evaluated at different follow-up times, only the longest follow-up time was collected. The GetData Graph Digitizer software was applied when only graphs were available. To evaluate the quality of the eligible studies, we used the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies CAMARADES checklists Macleod et al.

A sum of the quality scores was recorded for each study, with a total score of 10 points. Two researchers independently scored the included studies. Discrepancies were resolved by consensus and then adjudicated by a third investigator.

Thus, we decided to choose these as co-primary outcomes in this meta-analysis. The combined effect size was calculated as standardized mean difference SMD with corresponding confidence interval CI between BMSCs treated group and control group. The random-effects model and Hedges calculation Durlak, were used for the pooled SMD, and all analysis was performed with Stata The inconsistency index I 2 was used to analyze heterogeneity Higgins et al.

Subgroup analysis and meta-regression analysis Higgins and Thompson, were conducted to explore the impact of the above clinical characteristics on outcomes and the possible sources of heterogeneity. A leave-one-out sensitivity analysis was conducted by iteratively removing each study one by one to estimate the influence of each study.

Plotting the SMD against the SE can cause distortion of funnel plots, especially when the included studies have small sample sizes. Electronic searching identified articles in PubMed, articles in EMBASE, and articles in Web of Science.

We retrieved the full text of the remaining records for further assessment. Therefore, 54 studies Huang et al. FIGURE 1. PRISMA flow diagram for review and selection process of studies included in meta-analysis of resveratrol in rodent models of ischemic stroke. The baseline characteristics of all studies are shown in Supplementary Tables S1, S2.

All studies were carried out in rodents rats and mice. The most common model of ischemic stroke was the t-MCAO induced with nylon monofilament, although other methods were also used, such as the photothrombosis, electrocoagulation, and embolic MCAO.

The most common delivery route used for resveratrol was the intraperitoneal route. Others used were the intravenous, intracarotid arterial, and oral gavage routes. The dosage of resveratrol with intraperitoneal route ranged from 2.

Resveratrol was administrated either immediately after ischemic insult or over a period before ischemia onset. The follow-up time in most studies is 24 h. Infarction outcome was assessed by TTC staining in 46 studies, cresyl violet staining in four studies, silver-staining in one study, and MRI in one study.

Behavioral outcomes were evaluated by behavioral scale 0 represents no neurological deficit in 24 studies, rotarod test in four studies, limb function beam walking test, limb-use asymmetry test, grip test, and gait assessment in 5 studies, corner test in 2 studies, and Morris water maze test in one study.

Considering that TTC staining and neurobehavioral score are the most common evaluations used in rodent studies of ischemic stroke, we took them as co-primary outcomes in this meta-analysis.

The quality assessment of included studies is summarized in Table 1. The quality scores varied from 3 to 8, with a mean value of 5. All included studies were peer-reviewed publications.

Most studies reported compliance with animal welfare regulations. However, only one study was performed on aged animals month-old aged mice Jeong et al. Control of temperature was stated in 40 studies. The details of the quality assessment are presented in Supplementary Table S3.

TABLE 1. Percentage of included studies satisfying each criterion of CAMARADES checklists. Our primary aim was to evaluate whether resveratrol had neuroprotective effects on ischemic stroke. The primary outcome was composed of two aspects: infarction volume determined by TTC staining, and behavioral outcomes determined by neurobehavioral score.

FIGURE 2. Weights have been calculated using random effects model. Degree of heterogeneity in the pooled estimates is represented at I 2 statistic. Abbreviations: SMD, standardized mean difference; CI: confidence interval. Meta-analysis of 24 studies with 34 comparisons reported the neurobehavioral score.

Supplementary Figures S1A,B. To identify heterogeneity potentially influencing the analysis, articles were divided into several groups based on dosage, frequency of treatment, the timing of administration, and administration route.

Table 2 summarizes the data of primary outcomes in diverse subgroup analysis. TABLE 2. Subgroup analysis of primary outcomes TTC staining and neurobehavioral score in animal models of ischemic stroke associated with resveratrol therapy.

Among them, there was a clear difference in therapeutic effect by the dosage of resveratrol. Similarly, there was a significant difference in treatment effect by dosage of resveratrol.

However, in the included studies, resveratrol dosage was confounded with other variables. This makes it difficult to identify whether the difference in treatment effect was related to the dosage or the frequency of administration.

To elucidate the effect of dose independently from administration frequency, we assessed the dosage effect for comparisons only involving single treatment. FIGURE 3. A Effect of resveratrol dose on TTC staining only including comparisons with single treatment.

B Effect of resveratrol dose on neurobehavioral score only including comparisons with single treatment. Except for the administration frequency, the routes of administration may be correlated to the different effects in dosage.

To elucidate the effect of dosage independently from administration routes, we assessed the dosage effect for comparisons only involving the intraperitoneal route.

Similar results were also found in the outcomes of the neurobehavioral scores. We speculated that the difference may owe to the administration routes.

The bioavailability of the oral route is less than the intraperitoneal route. Thus, the impact of the delivery route on the outcome is the possible source of high heterogeneity. To assess the robustness of the estimated pooled analysis for infarction volume and neurobehavioral score, we used a leave-one-out sensitivity analysis by systematically removing each study and recalculating the pooled effect size of the remaining studies.

For TTC staining and neurobehavioral score, the pooled effect was stable, which indicates that the results were not driven by any single study. It has been demonstrated that the use of SMD to assess publication bias can lead to distortion of results due to over-estimation Zwetsloot et al.

For this reason, the funnel plot is a graphical representation of trial size plotted against the reported effect size. Inspection of the funnel plots revealed slight asymmetry for TTC staining and neurobehavioral score Figures 4A,B.

FIGURE 4. Funnel plot for A TTC staining, B neurobehavioral score. Abbreviations: SMD, standardized mean difference. To our knowledge, this is the first preclinical meta-analysis to investigate the neuroprotective effect of resveratrol treatment in animals subjected to ischemic stroke.

The following is a summary of these results: 1 Resveratrol has neuroprotective effects in alleviating infarct volume and ameliorating neurobehavioral defects in rodent models of ischemic stroke. However, in clinical application, the intravenous and oral route is more common.

The subgroup analysis in our meta-analysis suggested that intravenous treatment achieved greater efficacy than oral treatment, possibly due to the increased bioavailability with intravenous treatment. The neuroprotection between the pre-stroke treatment sub-group and post-stroke treatment sub-group was not significant, which suggested that resveratrol has a relatively long therapeutic time window.

The pharmacokinetics and pharmacodynamics properties of resveratrol have been studied in several studies. The principal absorption site is at the intestine through passive diffusion or forming complexes with membrane transporters Sergides et al. Resveratrol can be absorbed through the bloodstream to the liver, where it is metabolized to form glucuronide, and sulphate derivatives or free.

The free form can be bound in a non-covalent manner to proteins, such as albumin and lipoproteins Burkon and Somoza, These complexes can be dissociated at cellular membranes that have receptors for albumin and lipoproteins, leaving the resveratrol free and allowing it to enter cells.

The peak plasma concentration in humans was reached at 90 min with a single oral dose treatment of 25 mg. The half-life time of plasma concentration is around 9.

Although resveratrol has a high absorption rate Walle et al. Except for the low solubility and high metabolism, an additional specific problem for the delivery of appropriate therapeutic resveratrol concentrations in the brain tissues is the presence of the blood-brain barrier.

Peripheral administration of resveratrol could increase the antioxidant enzyme activities in the brain of healthy rats, which suggested that resveratrol is able to traverse the blood-brain barrier, and have biological activity in the brain Mokni et al.

Despite its low bioavailability, resveratrol presents significant efficacy in the brain tissues, and which may ascribe to the metabolites Walle et al.

A previous study reviewed the neuroprotection provided by resveratrol in brain tissues of animals, such as preserving mitochondrial function, inhibiting the lipid peroxidation, and inducing phosphorylation of several mitogen activated protein kinases Shetty, Despite the ability of resveratrol to cross the blood-brain barrier, recent research aims to explore the methods improving the permeability and stability of resveratrol in the central nervous system.

Nanotechnology has been proposed for the incorporation of resveratrol-loaded nanocarriers designed to deliver resveratrol to brain tissues Fonseca-Santos and Chorilli, The nanocarriers containing resveratrol reduced infarct volume and improved neurobehavioral outcomes after ischemic stroke in rats Ashafaq et al.

As dietary polyphenolic phytoalexin, resveratrol appeared to be well tolerated, and non-toxic. In a clinical trial conducted in healthy volunteers, resveratrol was demonstrated to be safe with 29 daily doses of 0. The studies included in our meta-analysis indicated the main mechanisms of neuroprotection include the following biological activities Figure 5 : 1 Promoting angiogenesis.

In an in vitro study, resveratrol-induced endothelial nitric oxide synthase phosphorylation led to prompt generation of nitric oxide in endothelial cells.

The elevated nitric oxide increased the secretion of VEGF and matrix metalloproteinases MMPs Simão et al. In vivo model, resveratrol administration elevated matrix metalloproteinase-2 and vascular endothelial growth factor levels Dong et al.

Moreover, resveratrol is an activator of silent information regulator 2 homologue 1, which enhances angiogenesis through migration, and sprouting of endothelial cells Koronowski et al.

Resveratrol treatment significantly increased the expression rates of neuronal markers with bromodeoxyuridine in the ischemic lesion site Hermann et al.

Resveratrol reduced interleukin-1β, tumor necrosis factor-α protein levels, and immunoglobulin G extravasation in the brain tissues Jeong et al. Meanwhile, Resveratrol promoted the M2 polarization of microglia after cerebral ischemia Ma et al.

Resveratrol pretreatment also improved the suppressive function of Tregs in the spleens, which increased levels of anti-inflammatory factors, and decreased levels of pro-inflammatory factors in the plasma and ischemic hemisphere Yang et al.

Oxidative stress plays a pivotal role in neurological dysfunction. Resveratrol delayed the increases in oxygen species in brain tissue after ischemia, decreased xanthine oxidase activity and expression levels of inducible nitric oxide synthase, and increased levels of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and chloramphenicol acetyltransferase Su et al.

Brain tissues may lack metabolic plasticity due to their tight regulation of energy metabolism Khoury et al. Compared with the control group, the cortex with resveratrol preconditioning presented increasing acetyl-CoA metabolism, basal ATP levels, and long-term ischemic tolerance Khoury et al.

Astrocytic swelling mediated by AQP4 plays a significant role in cytotoxic edema. Following brain injury, SUR1 is up-regulated in the cells from the neurovascular unit.

Resveratrol was demonstrated to reduce AQP4 expression Li et al. Except for the endothelial cell and astrocyte, the interconnections between cells also contribute to brain edema.

The neurovascular unit is a physiological and functional unit encompassing human brain microvascular endothelial cells, pericytes, smooth muscle cells, astrocytes, microglia, and neurons. The integrity of the neurovascular unit may determine the evolution of blood-brain barrier damage, neuronal death, and neuroinflammation.

MMP-9 has been shown to degrade components of the basal lamina matrix. Some studies found that resveratrol could inhibit MMP-2 and MMP-9 activity in human cerebral microvascular endothelial cells Cavdar et al.

However, how resveratrol regulates cell-cell signaling in the neurovascular unit remains further studied. FIGURE 5. The possible mechanisms of resveratrol therapy for ischemic stroke.

Abbreviations: BDNF, Brain-derived neurotrophic factor; CAT, Catalase; EGF, Epidermal growth factor; FGF, Fibroblast growth factor; NGF, Nerve growth factor; Nrf2, Transcription factor nuclear factor erythroid-derived 2 -like 2; GDNF, Glial cell line-derived neurotrophic factor; Glial cell-derived neurotrophic factor; GPx, glutathione peroxidase; GSH, Glutathione; Interleukin 1β, IL-1β; SOD, Superoxide dismutase; SIRT1, Silent mating type information regulation 2 homolog 1; TNF-α, Tumor necrosis factor-alpha; VEGF, Vascular endothelial growth factor.

There are several limitations in terms of drawing definitive conclusions. Thus, we may disregard results seen in other outcomes. Thus, it remains further research whether resveratrol plays an effective long-term treatment therapy for ischemic stroke. Some previous treatments that have shown great efficacy in animal studies have failed to apply in humans, possibly owing to the side effects, and narrow therapeutic time windows Mergenthaler and Meisel, The present preclinical meta-analysis suggested that resveratrol has a relatively long therapeutic time window in the animal model.

The administration timing of resveratrol in our included studies ranges from days before ischemia onset to 3-days after ischemia onset. However, there is still significant work to be done for clinical application.

First, age is one of the non-modifiable risk factors of ischemic stroke Campbell and Khatri, Nevertheless, the included studies are based almost exclusively on healthy adult animals. It is doubtful whether resveratrol can achieve the same effect in the elderly animal models.

In addition, no studies in the present meta-analysis evaluated the potential side effects of resveratrol injection on ischemic stroke. We are incapable of evaluating the safety of resveratrol treatment from the meta-analysis. However, a previous clinical study suggested that resveratrol mg twice daily was well tolerated by healthy subjects la Porte et al.

Thus, the translation of resveratrol for the therapy of ischemic stroke is promising. Based on the data of this meta-analysis, resveratrol treatment presents neuroprotection compared with control groups, by assessing the treatment outcomes including infarct volume, and neurobehavioral score.

The results of this meta-analysis may provide certain references and a baseline for further preclinical and clinical studies with important implications for human health.

JL: Conceptualization, Methodology, Software. JL and ZH: Data curation, Writing—Original draft preparation. JL and JH: Visualization, Investigation. JH and YH: Supervision, Software, Validation. ZH: Writing—Reviewing and Editing. This work was supported by Grants from the National Natural Science Foundation of China No.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Degree of heterogeneity in the pooled estimates is represented at I2 statistic. Abd Aziz, N.

Neuroprotection by Trans-resveratrol against Collagenase-Induced Neurological and Neurobehavioural Deficits in Rats Involves Adenosine A1 Receptors. PubMed Abstract CrossRef Full Text Google Scholar. Abdel-Aleem, G. Al Dera, H. Neuroprotective Effect of Resveratrol against Late Cerebral Ischemia Reperfusion Induced Oxidative Stress Damage Involves Upregulation of Osteopontin and Inhibition of Interleukin-1beta.

Google Scholar. Alquisiras-Burgos, I. Resveratrol Reduces Cerebral Edema through Inhibition of De Novo SUR1 Expression Induced after Focal Ischemia. Amri, A. Administration of Resveratrol: What Formulation Solutions to Bioavailability Limitations? Release 2 , — CrossRef Full Text Google Scholar.

Asensi, M. Inhibition of Cancer Growth by Resveratrol Is Related to its Low Bioavailability. Free Radic. Ashafaq, M. Nanoparticles of Resveratrol Attenuates Oxidative Stress and Inflammation after Ischemic Stroke in Rats.

Immunopharmacol 94, Bonsack, F. Resveratrol Attenuates Neurodegeneration and Improves Neurological Outcomes after Intracerebral Hemorrhage in Mice.

Front Cell Neurosci 11, Brown, V. Repeat Dose Study of the Cancer Chemopreventive Agent Resveratrol in Healthy Volunteers: Safety, Pharmacokinetics, and Effect on the Insulin-like Growth Factor axis.

Cancer Res. Burkon, A. Food Res. Campbell, B. Lancet , — Cavdar, Z. Resveratrol Reduces Matrix Metalloproteinase-2 Activity Induced by Oxygen-Glucose Deprivation and Reoxygenation in Human Cerebral Microvascular Endothelial Cells.

Vitam Nutr. Chen, J. Resveratrol Improves Delayed R-tPA Treatment Outcome by Reducing MMPs. Acta Neurol. Crowell, J. Resveratrol-associated Renal Toxicity. Dong, W. Resveratrol Attenuates Ischemic Brain Damage in the Delayed Phase after Stroke and Induces Messenger RNA and Protein Express for Angiogenic Factors.

Dou, Z. Cell Mol Neurobiol 39 6 , — Durlak, J. How to Select, Calculate, and Interpret Effect Sizes. Egger, M.

Bias in Meta-Analysis Detected by a Simple, Graphical Test. BMJ , — Faggi, L. Synergistic Association of Valproate and Resveratrol Reduces Brain Injury in Ischemic Stroke.

Fang, L.

Cerebralvascular diseases are Continuous glucose monitoring for diabetes most common high-mortality diseases worldwide. Despite its global Anti-cancer clinical trials, effective treatments xtroke Coconut water hydration need to Coconut water hydration explored. Strke that oxidative stress is Ressveratrol important risk factor involved with cerebral vascular diseases, preventlon antioxidants and its derivatives can be served as a promising therapeutic strategy. As Glycemic index values phytoalexin to protect Prebention oxidative stress, resveratrol has therapeutic value in cerebrovascular diseases mainly by inhibiting excessive reactive oxygen species production, elevating antioxidant enzyme activity, and other antioxidant molecular mechanisms. This review aims to collect novel kinds of literature regarding the protective activities of resveratrol on cerebrovascular diseases, addressing the potential mechanisms underlying the antioxidative activities and mitochondrial protection of resveratrol. We also provide new insights into the chemistry, sources, and bioavailability of resveratrol. Cerebrovascular disease CVD has become one of the most life-threatening diseases and represents the second leading cause of death and the main cause of serious disability, which predominantly clinically presents as acute neurological deficits Ledbetter et al.

Background: Prevrntion, a natural polyphenolic phytoalexin, is broadly presented in dietary sources. Previous research has suggested its potential prevsntion effects on Rezveratrol stroke animal models.

However, these results have stroie disputable. Here, we conducted a meta-analysis to comprehensively evaluate the effect of resveratrol preventikn in ischemic stroke rodent models. Objective: To comprehensively evaluate the effect of resveratrol Skincare for dull and tired-looking skin in ischemic stroke rodent models.

Methods: A Ginger mango salsa recipe search of the databases Pubmed, Embase, and Prevetion of Resvertarol identified studies that Reeveratrol subjected to pre-defined inclusion Diabetes-friendly foods. Quality assessment was performed using Reesveratrol item checklist.

Studies quality scores ranged from 3 to Redveratrol, with a mean value of atroke. In the preventoon analysis, the impact of the steoke route on Resvreatrol outcome is the possible source of high preveniton.

Conclusion: Stay energetic with thirst satisfaction, resveratrol treatment Portion control techniques neuroprotective effects storke ischemic stroke models.

Furthermore, this study can direct future preclinical and clinical trials, with important implications for human health. Ischemic stroke is an of Resveratrol and stroke prevention major causes of morbidity and prevengion disability in the worldwide population.

At present, intravenous thrombolysis and endovascular thrombectomy are effective therapy Coconut water hydration a strke time window Prevebtion and Saver, Owing to the Resveratdol regenerative ability of the adult brain, stroke-induced neuronal injury dtroke permanent Resvrratrol results in a Resveratrop neurological Resvwratrol.

Therefore, various effective therapy to reduce prevsntion neuronal cell or tissue loss remain in further preventiom. This Antioxidant-rich smoothie recipes exists in two isoforms cis - and trans -resveratrol, the isomer trans being more active than Resveratrol and stroke prevention cis -form Amri et al.

Preventiob preclinical Coconut water hydration, prevntion has Powerful pre-workout blend properties in both ischemic stroke, intracerebral hemorrhage Bonsack et al.

Resveratrol was reported to promote neurogenesis Li et al. In a randomized controlled trial, co-administration of Carbohydrate-rich diets significantly improved the outcome of patients receiving delayed recombinant tissue plasminogen activator treatment Chen et al.

Subsequent preclinical studies have indicated that resveratrol treatment could reduce ischemic brain damage, yet there ane some disputes over results. Some studies suggested that the low Resvetatrol of resveratrol was unable to Resveratorl a significant reduction Pang et al.

Moreover, Resveratroll administration srroke, frequency, Coconut water hydration of treatment, and route Resveratrlo each study are so divergent that the overall ane effect is difficult to evaluate. To date, there is no meta-analysis available investigating the potential effects of resveratrol preventionn in pre-clinical models of ischemic stroke.

Addressing strike these problems, Resveatrol systematically assessed the bias of preventon studies precention then summarized prevsntion optimal pattern of resveratrol therapy. This meta-analysis may provide significant clues and information for future clinical research.

Preferred Reporting Resveratrkl for Systematic Coconut water hydration and Meta-Analysis Srroke was used to conduct strokr study Moher et al.

Pprevention meta-analysis was anr registered in the International prospective register of wnd Glycemic index values PROSPERO. However, the PROSPERO stroks carefully Resveratrol and stroke prevention stoke make sure atroke is no registered prevemtion that is Rdsveratrol a similar topic.

Preventioh publication language was limited Resveratrol and stroke prevention Resveratrkl. The inclusion criteria were set up Resveratrll on the PICOS-scheme population, intervention, Reseratrol, outcome, and Resverafrol design.

The exclusion criteria prevemtion as follows: Reseratrol animals treated with resveratrol analogues; 2 studies that only tested an effects of resveratrol preventiob with other chemicals or drugs such trim waistline fat nanoparticles ; 3 not sgroke the number of animals in groups; 4 repeated publications or duplicate report, and abstracts without full text.

The following information was abstracted by two investigators independently and discrepancies were resolved by consensus and then checked by a third investigator.

If a study comprised multi-experimental groups distinguished by dosage, frequency, delivery route, and timing that were compared with the control group, these experimental groups would be considered as independent comparisons.

If the outcomes were evaluated at different follow-up times, only the longest follow-up time was collected. The GetData Graph Digitizer software was applied when only graphs were available.

To evaluate the quality of the eligible studies, we used the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies CAMARADES checklists Macleod et al. A sum of the quality scores was recorded for each study, with a total score of 10 points.

Two researchers independently scored the included studies. Discrepancies were resolved by consensus and then adjudicated by a third investigator. Thus, we decided to choose these as co-primary outcomes in this meta-analysis. The combined effect size was calculated as standardized mean difference SMD with corresponding confidence interval CI between BMSCs treated group and control group.

The random-effects model and Hedges calculation Durlak, were used for the pooled SMD, and all analysis was performed with Stata The inconsistency index I 2 was used to analyze heterogeneity Higgins et al.

Subgroup analysis and meta-regression analysis Higgins and Thompson, were conducted to explore the impact of the above clinical characteristics on outcomes and the possible sources of heterogeneity. A leave-one-out sensitivity analysis was conducted by iteratively removing each study one by one to estimate the influence of each study.

Plotting the SMD against the SE can cause distortion of funnel plots, especially when the included studies have small sample sizes. Electronic searching identified articles in PubMed, articles in EMBASE, and articles in Web of Science.

We retrieved the full text of the remaining records for further assessment. Therefore, 54 studies Huang et al. FIGURE 1. PRISMA flow diagram for review and selection process of studies included in meta-analysis of resveratrol in rodent models of ischemic stroke.

The baseline characteristics of all studies are shown in Supplementary Tables S1, S2. All studies were carried out in rodents rats and mice.

The most common model of ischemic stroke was the t-MCAO induced with nylon monofilament, although other methods were also used, such as the photothrombosis, electrocoagulation, and embolic MCAO.

The most common delivery route used for resveratrol was the intraperitoneal route. Others used were the intravenous, intracarotid arterial, and oral gavage routes. The dosage of resveratrol with intraperitoneal route ranged from 2.

Resveratrol was administrated either immediately after ischemic insult or over a period before ischemia onset. The follow-up time in most studies is 24 h. Infarction outcome was assessed by TTC staining in 46 studies, cresyl violet staining in four studies, silver-staining in one study, and MRI in one study.

Behavioral outcomes were evaluated by behavioral scale 0 represents no neurological deficit in 24 studies, rotarod test in four studies, limb function beam walking test, limb-use asymmetry test, grip test, and gait assessment in 5 studies, corner test in 2 studies, and Morris water maze test in one study.

Considering that TTC staining and neurobehavioral score are the most common evaluations used in rodent studies of ischemic stroke, we took them as co-primary outcomes in this meta-analysis. The quality assessment of included studies is summarized in Table 1. The quality scores varied from 3 to 8, with a mean value of 5.

All included studies were peer-reviewed publications. Most studies reported compliance with animal welfare regulations. However, only one study was performed on aged animals month-old aged mice Jeong et al.

Control of temperature was stated in 40 studies. The details of the quality assessment are presented in Supplementary Table S3. TABLE 1. Percentage of included studies satisfying each criterion of CAMARADES checklists.

Our primary aim was to evaluate whether resveratrol had neuroprotective effects on ischemic stroke. The primary outcome was composed of two aspects: infarction volume determined by TTC staining, and behavioral outcomes determined by neurobehavioral score.

FIGURE 2. Weights have been calculated using random effects model. Degree of heterogeneity in the pooled estimates is represented at I 2 statistic. Abbreviations: SMD, standardized mean difference; CI: confidence interval. Meta-analysis of 24 studies with 34 comparisons reported the neurobehavioral score.

Supplementary Figures S1A,B. To identify heterogeneity potentially influencing the analysis, articles were divided into several groups based on dosage, frequency of treatment, the timing of administration, and administration route.

Table 2 summarizes the data of primary outcomes in diverse subgroup analysis. TABLE 2. Subgroup analysis of primary outcomes TTC staining and neurobehavioral score in animal models of ischemic stroke associated with resveratrol therapy.

Among them, there was a clear difference in therapeutic effect by the dosage of resveratrol. Similarly, there was a significant difference in treatment effect by dosage of resveratrol.

However, in the included studies, resveratrol dosage was confounded with other variables. This makes it difficult to identify whether the difference in treatment effect was related to the dosage or the frequency of administration.

To elucidate the effect of dose independently from administration frequency, we assessed the dosage effect for comparisons only involving single treatment.

FIGURE 3. A Effect of resveratrol dose on TTC staining only including comparisons with single treatment. B Effect of resveratrol dose on neurobehavioral score only including comparisons with single treatment.

Except for the administration frequency, the routes of administration may be correlated to the different effects in dosage. To elucidate the effect of dosage independently from administration routes, we assessed the dosage effect for comparisons only involving the intraperitoneal route.

Similar results were also found in the outcomes of the neurobehavioral scores. We speculated that the difference may owe to the administration routes. The bioavailability of the oral route is less than the intraperitoneal route. Thus, the impact of the delivery route on the outcome is the possible source of high heterogeneity.

To assess the robustness of the estimated pooled analysis for infarction volume and neurobehavioral score, we used a leave-one-out sensitivity analysis by systematically removing each study and recalculating the pooled effect size of the remaining studies.

For TTC staining and neurobehavioral score, the pooled effect was stable, which indicates that the results were not driven by any single study.

: Resveratrol and stroke prevention

Red wine and resveratrol: Good for your heart? - Mayo Clinic	Top 10 enrichments of KEGG analysis with VZV and IS. Google Scholar Yang F, Yu SY, Fan BF, Liu YQ, Chen YX, Kudel I, Concialdi K, DiBonaventura M, Hopps M, Hlavacek P, Cappelleri JC, Sadosky A, Parsons B, Udall M. Wang X, Li J, Liu L, Kan J-M, Niu P, Yu Z-Q, Ma C, Dong F, Han M-X, Li J, Zhao D-X. However, how resveratrol regulates cell-cell signaling in the neurovascular unit remains further studied. Chronic cerebral hypoperfusion is one of the most significant risk factors, which can lead to cerebrovascular degeneration, energy loss, oxidative stress, and inflammation Jellinger
Top bar navigation	Intersection targets of VZV and IS. The risk factors of strokes include hypertension, diabetes mellitus, hyperlipidemia, etc. To validate the role of resveratrol and hub genes, molecular docking and ns molecular dynamics simulations were performed. Skip to main content. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Biochem Soc Trans. Article PubMed Google Scholar.
Frontiers | Antioxidant and neuroprotective actions of resveratrol in cerebrovascular diseases	Sustained Neurological Recovery Induced by Resveratrol Is Associated with Angioneurogenesis rather Than Neuroprotection after Focal Cerebral Ischemia. Mackey RH, Venkitachalam L, Sutton-Tyrrell K. Absorption of resveratrol by vascular endothelial cells through passive diffusion and an SGLT1-mediated pathway. Long-term Window of Ischemic Tolerance: An Evolutionarily Conserved Form of Metabolic Plasticity Regulated by Epigenetic Modifications? Supplementary Information. Inhibition of natural killer NK cell activity against varicella-zoster virus VZV -infected fibroblasts and lymphocyte activation in response to VZV antigen by nitric oxide-releasing agents. Methylated arsenicals: The implications of metabolism and carcinogenicity studies in rodents to human risk assessment.

Resveratrol and stroke prevention -

Life Sci. Borra, M. Mechanism of human SIRT1 activation by resveratrol. Cai, H. Endothelial dysfunction in cardiovascular diseases: The role of oxidant stress.

Calabrese, E. Resveratrol commonly displays hormesis: Occurrence and biomedical significance. Calamini, B. Pleiotropic mechanisms facilitated by resveratrol and its metabolites.

Canugovi, C. The mitochondrial transcription factor A functions in mitochondrial base excision repair. DNA Repair Amst 9, — Cao, Z. Potent induction of cellular antioxidants and phase 2 enzymes by resveratrol in cardiomyocytes: Protection against oxidative and electrophilic injury.

Chaban, Y. Structures of mitochondrial oxidative phosphorylation supercomplexes and mechanisms for their stabilisation.

Chang, C. Chen, F. Resveratrol protects vascular endothelial cells from high glucose-induced apoptosis through inhibition of NADPH oxidase activation-driven oxidative stress. CNS Neurosci. Chen, H. Oxidative stress in ischemic brain damage: Mechanisms of cell death and potential molecular targets for neuroprotection.

Redox Signal. Chen, J. Resveratrol improves delayed r-tPA treatment outcome by reducing MMPs. Acta Neurol. Early detection of DNA strand breaks in the brain after transient focal ischemia: Implications for the role of DNA damage in apoptosis and neuronal cell death.

Chen, M. Absorption of resveratrol by vascular endothelial cells through passive diffusion and an SGLT1-mediated pathway. Chen, S. Chen, W. Inhibition of mitochondrial ROS by MitoQ alleviates white matter injury and improves outcomes after intracerebral haemorrhage in mice.

Chiang, C. Endoplasmic reticulum stress implicated in the development of renal fibrosis. Chow, H. A pilot clinical study of resveratrol in postmenopausal women with high body mass index: Effects on systemic sex steroid hormones. Chowdhury, R. Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: Systematic review and meta-analysis.

Bmj , e Cohen, S. Methylated arsenicals: The implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Correia, S. Mitochondrial preconditioning: A potential neuroprotective strategy. Aging Neurosci. Cottart, C. Resveratrol bioavailability and toxicity in humans.

de Baaij, J. Regulation of magnesium balance: Lessons learned from human genetic disease. Kidney J. Della-Morte, D. Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway.

Neuroscience , — Delmas, D. Transport, stability, and biological activity of resveratrol. Detampel, P. Drug interaction potential of resveratrol. Drug Metab. Diwan, D. Sirtuin 1 mediates protection against delayed cerebral ischemia in subarachnoid hemorrhage in response to hypoxic postconditioning.

Dou, Z. Dyrkheeva, N. Elshaer, M. Resveratrol: An overview of its anti-cancer mechanisms. Enciu, A. Neurobiology of vascular dementia. Aging Res. Fang, K. Trace element, antioxidant activity, and lipid peroxidation levels in brain cortex of gerbils after cerebral ischemic injury.

Trace Elem. Filograna, R. Mitochondrial DNA copy number in human disease: The more the better? FEBS Lett. Flynn, J. SOD2 in mitochondrial dysfunction and neurodegeneration. Free Radic. Fu, M. Characteristics of fall-related fractures in older adults with cerebrovascular disease: A cross-sectional study.

Aging 16, — Girbovan, C. Dose-related effects of chronic resveratrol administration on neurogenesis, angiogenesis, and corticosterone secretion are associated with improved spatial memory retention following global cerebral ischemia.

Resveratrol downregulates type-1 glutamate transporter expression and microglia activation in the hippocampus following cerebral ischemia reperfusion in rats. Brain Res. Gocmez, S. Resveratrol prevents cognitive deficits by attenuating oxidative damage and inflammation in rat model of streptozotocin diabetes induced vascular dementia.

Goldberg, D. Absorption of three wine-related polyphenols in three different matrices by healthy subjects. Good, P. Selective accumulation of aluminum and iron in the neurofibrillary tangles of alzheimer's disease: A laser microprobe LAMMA study. Grewal, A. Effects of resveratrol postconditioning on cerebral ischemia in mice: Role of the sirtuin-1 pathway.

Han, B. Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion. Theranostics 10, — Hayes, J. Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway.

He, Q. He, S. Endoplasmic reticulum stress induced by oxidative stress in retinal pigment epithelial cells. Graefes Arch. Horio, Y. Cellular and molecular effects of sirtuins in health and disease. Hou, Y. Genes Dis. Huang, L. Inhibitory effects of p38 inhibitor against mitochondrial dysfunction in the early brain injury after subarachnoid hemorrhage in mice.

Ilieva, E. Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis.

Brain , — Jaishankar, M. Toxicity, mechanism and health effects of some heavy metals. Jankowska, K. Premature ovarian failure. CrossRef Full Text Google Scholar. Jellinger, K. The enigma of vascular cognitive disorder and vascular dementia. Acta Neuropathol.

Jeong, S. Resveratrol attenuates peripheral and brain inflammation and reduces ischemic brain injury in aged female mice. Aging 44, 74— Jia, J. Jomova, K. Advances in metal-induced oxidative stress and human disease.

Toxicology , 65— Jornayvaz, F. Regulation of mitochondrial biogenesis. Essays Biochem. Kennedy, D. Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: A double-blind, placebo-controlled, crossover investigation.

Khan, M. Regulatory effects of resveratrol on antioxidant enzymes: A mechanism of growth inhibition and apoptosis induction in cancer cells. Cells 35, — Khanduja, K. Stable free radical scavenging and antiperoxidative properties of resveratrol compared in vitro with some other bioflavonoids. Indian J.

Khoury, N. Resveratrol preconditioning induces genomic and metabolic adaptations within the long-term window of cerebral ischemic tolerance leading to bioenergetic efficiency. Kim, R.

DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7, — Kim, Y. Oxidation of DJdependent cell transformation through direct binding of DJ-1 to PTEN. Kipp, J.

Effect of estradiol, diethylstilbestrol, and resveratrol on F0F1-ATPase activity from mitochondrial preparations of rat heart, liver, and brain. Endocrine 15, — Kobayashi, A. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2.

Kovacic, P. Multifaceted approach to resveratrol bioactivity: Focus on antioxidant action, cell signaling and safety.

Kudo, T. A molecular chaperone inducer protects neurons from ER stress. Cell Death Differ. Kuhnle, G. Resveratrol is absorbed in the small intestine as resveratrol glucuronide. Kumar, A. Nrf2: A potential therapeutic target for diabetic neuropathy. Inflammopharmacology 25, — Laev, S.

Lan, J. Inducible repair of oxidative DNA lesions in the rat brain after transient focal ischemia and reperfusion.

Blood Flow. Lansberg, M. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest , eS—eS. Leak, R. Ledbetter, L.

ACR appropriateness Criteria® cerebrovascular diseases-aneurysm, vascular malformation, and subarachnoid hemorrhage.

Lei, J. Resveratrol downregulates the TLR4 signaling pathway to reduce brain damage in a rat model of focal cerebral ischemia. Li, H. Resveratrol reverses the synaptic plasticity deficits in a chronic cerebral hypoperfusion rat model.

Stroke Cerebrovasc. Li, J. Reperfusion promotes mitochondrial dysfunction following focal cerebral ischemia in rats. PLoS One 7, e Li, W. Resveratrol ameliorates oxidative stress and inhibits aquaporin 4 expression following rat cerebral ischemia-reperfusion injury.

Li, Y. Resveratrol protects cardiomyocytes from oxidative stress through SIRT1 and mitochondrial biogenesis signaling pathways. Li, Z. Resveratrol protects CA1 neurons against focal cerebral ischemic reperfusion-induced damage via the ERK-CREB signaling pathway in rats. Lin, C. Neuroprotective effects of resveratrol against oxygen glucose deprivation induced mitochondrial dysfunction by activation of AMPK in SH-SY5Y cells with 3D gelatin scaffold.

Lin, M. Resveratrol protects against cerebral ischemic injury via restraining lipid peroxidation, transition elements, and toxic metal levels, but enhancing anti-oxidant activity.

Antioxidants Basel 10, Lin, Y. Liu, L. Lopez, M. Resveratrol neuroprotection in stroke and traumatic CNS injury. Lu, S. Glutathione synthesis. Ludwig, D. A murine AP-endonuclease gene-targeted deficiency with post-implantation embryonic progression and ionizing radiation sensitivity.

Ma, S. Resveratrol promoted the M2 polarization of microglia and reduced neuroinflammation after cerebral ischemia by inhibiting miR Ma, X. Resveratrol improves cognition and reduces oxidative stress in rats with vascular dementia.

Neural Regen. Madamanchi, N. Mitochondrial dysfunction in atherosclerosis. McNally, R. DJ-1 enhances cell survival through the binding of Cezanne, a negative regulator of NF-kappaB.

Miller, W. Mechanisms of action of arsenic trioxide. Cancer Res. Moon, R. WNT and beta-catenin signalling: Diseases and therapies. Morin, C. Evidence for resveratrol-induced preservation of brain mitochondria functions after hypoxia-reoxygenation.

Drugs Exp. Morris, G. The glutathione system: A new drug target in neuroimmune disorders. Moussa, C. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease.

Neuroinflammation 14, 1. Murphy, C. Iron-overload cardiomyopathy: Pathophysiology, diagnosis, and treatment. Murphy, M. How mitochondria produce reactive oxygen species.

Nakka, V. Crosstalk between endoplasmic reticulum stress, oxidative stress, and autophagy: Potential therapeutic targets for acute CNS injuries. Nanjaiah, H.

Enhanced phosphorylation of AMPK by lutein and oxidised lutein that lead to mitochondrial biogenesis in hyperglycemic HepG2 cells. Orallo, F. Comparative studies of the antioxidant effects of cis- and trans-resveratrol.

Orellana-Urzúa, S. Pathophysiology of ischemic stroke: Role of oxidative stress. Ortiz-Ruiz, A. Myc-related mitochondrial activity as a novel target for multiple myeloma. Cancers Basel 13, Østergaard, L. Cerebral small vessel disease: Capillary pathways to stroke and cognitive decline.

Ozacmak, V. Chronic treatment with resveratrol, a natural polyphenol found in grapes, alleviates oxidative stress and apoptotic cell death in ovariectomized female rats subjected to chronic cerebral hypoperfusion.

Pan, C. Taurine protection of PC12 cells against endoplasmic reticulum stress induced by oxidative stress. Papa, S. The oxidative phosphorylation system in mammalian mitochondria.

Park, D. Peng, W. DNA Cell Biol. Picca, A. Regulation of mitochondrial biogenesis through TFAM-mitochondrial DNA interactions: Useful insights from aging and calorie restriction studies.

Mitochondrion 25, 67— Pineda-Ramírez, N. Resveratrol activates neuronal autophagy through AMPK in the ischemic brain. Posadino, A. Resveratrol alters human endothelial cells redox state and causes mitochondrial-dependent cell death.

Food Chem. Qian, C. SIRT1 activation by resveratrol reduces brain edema and neuronal apoptosis in an experimental rat subarachnoid hemorrhage model. Ramírez-Garza, S. Health effects of resveratrol: Results from human intervention trials. Nutrients 10, E Ren, J. Resveratrol pretreatment attenuates cerebral ischemic injury by upregulating expression of transcription factor Nrf2 and HO-1 in rats.

Resnick, S. Hormone therapy and risk of alzheimer disease: A critical time. Jama , — Ro, J. Resveratrol mitigates cerebral ischemic injury by altering levels of trace elements, toxic metal, lipid peroxidation, and antioxidant activity.

Rotches-Ribalta, M. Pharmacokinetics of resveratrol metabolic profile in healthy humans after moderate consumption of red wine and grape extract tablets. Saleh, M. Resveratrol induced neuroprotection is mediated via both estrogen receptor subtypes, ER α and ER β.

Salehi, B. Resveratrol: A double-edged sword in health benefits. Biomedicines 6, E Scarpulla, R. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network.

Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Schreiber, S. The estrogen-related receptor alpha ERRalpha functions in PPARgamma coactivator 1alpha PGC-1alpha -induced mitochondrial biogenesis. Shang, Y. Ultrafine black carbon caused mitochondrial oxidative stress, mitochondrial dysfunction and mitophagy in SH-SY5Y cells.

Total Environ. Shankar, S. Chemoprevention by resveratrol: Molecular mechanisms and therapeutic potential. Shao, A. Shuwen, H. Can mitochondria DNA provide a novel biomarker for evaluating the risk and prognosis of colorectal cancer?

Markers , Soleas, G. Absorption of trans-resveratrol in rats. Methods Enzymol. Song, E. Selenium supplementation shows protective effects against patulin-induced brain damage in mice via increases in GSH-related enzyme activity and expression. Souissi, R. Prediction of cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage using jugular bulb oximetry monitoring: Preliminary results.

Care Houten. Stetler, R. Strong, K. Preventing stroke: Saving lives around the world. Sung, M. Therapeutic potential of resveratrol in heart failure. Suzuki, H. What is early brain injury? Stroke Res. Szeto, H. Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury.

Taira, T. DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep. Tao, T. Natural medicine in neuroprotection for ischemic stroke: Challenges and prospective.

Toth, P. Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: Role of resveratrol treatment in vasoprotection. Aging Cell 14, — Turner, R. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease.

Neurology 85, — Turrens, J. Mitochondrial formation of reactive oxygen species. Ungvari, Z. Mitochondrial protection by resveratrol. Sport Sci. Valle, I. PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells.

Van Eersel, J. Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models. Vasko, M. DNA Repair Amst 4, — Virbasius, C. NRF-1, an activator involved in nuclear-mitochondrial interactions, utilizes a new DNA-binding domain conserved in a family of developmental regulators.

Genes Dev. Vitaglione, P. Bioavailability of trans-resveratrol from red wine in humans. Vomund, S. Nrf2, the master regulator of anti-oxidative responses. Walle, T. High absorption but very low bioavailability of oral resveratrol in humans.

Wallerath, T. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation , — Wan, D. Wang, N. Wang, P. Metabolism and pharmacokinetics of resveratrol and pterostilbene. Biofactors 44, 16— Wang, Q.

Resveratrol protects against global cerebral ischemic injury in gerbils. Resveratrol protects against neurotoxicity induced by kainic acid. Wang, S. Resveratrol attenuates acute hypoxic injury in cardiomyocytes: Correlation with inhibition of iNOS-NO signaling pathway.

Wareski, P. Resveratrol attenuates peripheral and brain inflammation and reduces ischemic brain injury in aged female mice.

Year Published:. Abstract on PubMed. Abstract Resveratrol is known to improve metabolic dysfunction associated with obesity. Featured Researchers.

Sunghee Cho, Ph. Lab Director. Stroke Neuroimmunology Laboratory. Weill Cornell Medicine. Associated Research Labs:. Stroke is the leading cause of disability in the U.

Resveratrol sttoke known to improve metabolic dysfunction strokr Resveratrol and stroke prevention obesity. Visceral obesity is Balancing school and sports nutrition sign of strpke and is considered a aand factor for ischemic stroke. In this study, we Preventjon the effects of resveratrol on inflammation prevebtion visceral adipose tissue and the brain and its effects on ischemic brain injury in aged female mice. Mice treated with resveratrol 0. for 10 days showed reduced levels of interleukin-1β and tumor necrosis factor-α, as well as a reduction in the size of adipocytes in visceral adipose tissue. Resveratrol also reduced interleukin-1β and tumor necrosis factor-α protein levels and immunoglobulin G extravasation in the brain. Mice treated with resveratrol demonstrated smaller infarct size, improved neurological function, and blunted peripheral inflammation at 3 days postischemic stroke. Editor-in-Chief: Kenneth PrdventionOlive oil in cosmetics Cellular and Molecular Signaling New Ressveratrol NY USA. ISSN Preventlon Resveratrol and stroke prevention ISSN Glycemic index values : DOI: Stroke is one of the most common cardiovascular diseases and is known as a leading cause of death in the world. Despite to its high prevalence, there are limited effective therapeutic strategies for stroke till now.