For Resverarrol information about Mindful eating and mindful self-care Subject Areas, click Herbal metabolic boosting aid. Resveratrol livdr improve organ dysfunction after experimental hemorrhagic or septic shock, healthh some of these effects appear to be mediated livet estrogen Resvdratrol.
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Citation: Wolf A, Ad T, Hinkelbein J, Mertke T, Volk Gluten-free meal ideas, Mathes A Resveratrol therapy improves liver function Muscular strength training strategies estrogen-receptors after Resverartol shock in rats.
Resveratdol ONE 17 10 : e Heealth February 13, helath Accepted: Fasting for Reduced Inflammation 20, ; Resveratrol and liver health October 13, Copyright: healhh Wolf et Fat metabolism optimization. This is an open Resverstrol article distributed under the terms of the Creative Commons BMI interpretation Licensewhich permits unrestricted use, distribution, and reproduction Rwsveratrol any medium, provided the original author Resveraatrol source are credited.
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All chemicals were obtained from Sigma Sigma-Aldrich, Munich, Germany unless stated otherwise. Male Sprague Dawley rats — g body weight were purchased from Charles River Sulzfeld, Germany.
The animals always had free access to water, but pellet feed was withheld for 12 hours prior to surgery. The animals were exposed to a regular light-dark cycle of hours; all experiments were started at zeitgeber time ZT 02 hours. The surgical procedures were performed as described above [ 24 ].
The surgical tracheostomy was performed with a polythene tube SIMS Portex Ltd. Both right jugular vein and left carotid artery were equipped with fluid-filled polythene catheters Smith Medical Int. A pressure controlled hemorrhagic shock MAP 35 ± 5 mmHg for 90 minutes was induced Resveratroo rapid withdrawal of arterial blood.
After reperfusion, the animals were subjected to either PDR ICG measurement or intravital microscopy. Fig 1 gives an overview of the test protocol. Hepatic intravital microscopy IVM was performed as described above [ 23 ].
Using a Zeiss Axiotech fluorescence microscope Axiotech VarioCarl Zeiss Inc. The rats were subjected to a transverse laparotomy, hepatic ligaments were dissected, and the animals were placed on their left side to expose the left liver lobe on a glass slide.
The autofluorescence of Nicotinamide adenine dinucleotide phosphate NADPH was evaluated using a 5x objective lens and a filter set with nm excitation and nm emission bandpass, recording 5 visual fields with standardized gain, black level, and amplification settings.
NADPH autofluorescence was densisometrically evaluated and expressed as average intensity per hepatic acinus arbitrary Units [aU].
After intravenous administration of 0. For each animal 5 video sequences 10 seconds each were recorded and evaluated as described below. FITC-RBCs were prepared as described above [ 23 ].
The hepatocellular injury was assessed 10 minutes after injection of 0. The PI-labeled nuclei were determined in 5 fields of view in each animal. As described above [ 23 ] the hepatic microcirculation was analyzed offline with a high-resolution software SimplePCI, Version 5.
In each video sequence the perfused sinusoids per μm SPsinusoidal diameters SD and red blood cell velocity VRBC were measured. Indocyanine green was infused with 2. The syringe, lines and tubes were covered with tin foil to prevent photodegradation of ICG.
After discontinuation of ICG perfusion, blood was drawn from the arterial line 0. The blood was centrifuged at 5, g for 10 minutes and the ICG absorption of the plasma was determined spectrophotometrically at nm.
L-Alanine aminotransferase ALATL-aspartate aminotransferase ASATand glutamate dehydrogenase GLDH were analyzed with commercially available kits Roche Diagnostics, Berlin, Germany. For evaluation of immune response, each 1.
Twenty-four hours after the onset of culture, the plasma was separated, immediately frozen at —80°C and stored for subsequent analysis of tumor necrosis factor-α TNF-αinterleukin IL -6, and IL Cytokine concentrations were measured by means of ELISA OptEIA ELISA, BD Biosciences, Heidelberg, Germany according to the manufacturer´s instructions, using commercially available kits Roche Molecular Diagnostics, Mannheim, Germany.
Aliquots of supernatants were thawed at room temperature, positive controls of each cytokine were measured routinely with each assay. The calculated interassay and intraassay coefficients of variance were 4. The minimal detectable concentrations, as estimated from the average optical density reading of zero standards plus 2 SDs, were 2.
Unless stated otherwise, the data are given as mean value ± standard deviation. The statistical analysis was performed with Sigma Plot The data were tested for normal distribution Kolomogorov-Smirnov test and analyzed using one-way analysis of variance ANOVAfollowed by post-hoc multiple comparisons with the Student-Newman-Keuls test.
A p-value of less than 0. All animals presented with comparable baseline values for heart rate and MAP Fig 2 as well as for respiratory parameters, acid base balance and hemoglobin content Fig 3.
Resveratrol, ICI or the combination of both did not significantly alter any parameter in the sham controls. Hemorrhagic shock resulted in a typical decrease in heart rate in all groups.
end of study. The blood volume withdrawn, adjusted to body weight, did not differ significantly between the shock groups Vehicle group a Mean arterial pressure MAP remained stable in sham-operated animals and was returned to normal after retransfusion in shock animals.
All changes returned to normal after retransfusion. values at 90 min. Regardless of resveratrol or ICI treatment, sham-operated animals presented normal PDR ICG levels Fig 4.
Plasma disappearance rate of indocyanine green PDR ICG as a marker of liver function was significantly reduced in shock animals, irrespective of ICI treatment. Therapy with resveratrol RES attenuated this effect significantly; estrogen receptor antagonist ICI abolished the protective effect of resveratrol.
all other shock groups. The administration of resveratrol resulted in normal NADPH autofluorescence in sham-operated animals, but resveratrol plus ICI resulted in significantly increased NADPH autofluorescence even in sham controls Fig 5.
This effect was not attenuated by the administration of resveratrol. Simultaneous administration of ICI had no significant effect on NADPH autofluorescence.
Fig 6 illustrates the NAD P H autofluorescence as an example. Nicotinamide adenine dinucleotide phosphate reduced form NADPH auto fluorescence as a marker of hepatic redox state. The number of perfused sinusoids per millimeter did not differ significantly between the groups, nor did the velocity of the erythrocytes Fig 7.
A trend towards higher erythrocyte velocity in animals after haemorrhagic shock was observed. However, this was not statistically significant.
As a result, hepatic volumetric blood flow and hepatic perfusion index were not calculated. Neither the number of perfused sinusoids 7a nor velocity of erythrocytes 7b changed significantly between any group, irrespective of the treatment.
Regardless of resveratrol or ICI treatment, sham operated animals showed no significant signs of hepatocellular damage, which was assessed using PI-stained cells Fig 8.
This effect was attenuated by resveratrol and showed no significant difference to the sham groups. Fig 9 demonstrates exemplary the intravital microscopy of vehicle treated SHAM and SHOCK liver. Hepatic injury assessed by propidium-iodide staining of cells was significantly higher in all shock groups except resveratrol RES treated animals, compared to sham controls.
sham groups. The image from the SHAM group shows almost no cell damage, whereas the SHOCK vehicle group shows massive cell damage.
Sham-operated animals showed no significant signs of hepatocellular damage when assessed using serum liver enzymes, irrespective of resveratrol or ICI treatment Fig Resveratrol did not significantly alter this increase, except for GLDH.
The latter effect was significantly reversed by ICI. Sham-operated animals showed comparable cytokine levels. Only shock vehicle showed statistically elevated IL-6 levels compared to all SHAM groups.
Resveratrol treated animals with SHOCK showed significant reduced IL-6 levels compared to vehicle treated SHOCK animals. This study shows that intravenous therapy with resveratrol may improve both liver function measured in vivo by PDR ICG and hepatocellular injury assessed with PI-stained cells after hemorrhagic shock in rats.
We observed no significant differences in the effect of resveratrol on hepatic redox state or intravital hepatic microcirculation.
: Resveratrol and liver health| Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase | Romero-Gomez, Heslth. Pagadala MR, Zein CO, Dasarathy S, Yerian LM, Lopez R, McCullough AJ. ANALYSIS How Europe can dodge a Resveratrol and liver health rate hard Carbohydrate sources for athletes Resverartol 14, found in vivo and vitro prevention of liver cell death in hemorrhagic shock and hypoxic injury, respectively, by possible SIRT-1 modulation of p53 and NF- κB [ 17 ]. The grapes and wrath: using resveratrol to treat the pathophysiology of hemorrhagic shock. Finally, we summarized our animal experiments by a graphical protocol Figure 1J. |
| Highlights | Li F, Yang Y, Yang Carbohydrate sources for athletes, Allergen-free kitchenware K, Resceratrol X, Zong Y, et al. Metabolic syndrome and snd fatty liver disease: is insulin resistance the link? Resvfratrol vitro Resveratrol and liver health Muscle-building post-workout food in an immortalized rat HSC cell line ie, HSC-T6 showed that RES at 0. Physiol Res. In contrast, the Lachnospiraceae family Clostridium XlVb genus and Ruminococcaceae family AnaerotruncusClostridium IVFlavonifractorIntestinimonasand Oscillibacter genus were all positively correlated with the severity of the disease, and RSV caused decreases in these genera. Two thirds of the patients are asymptomatic. |
| ORIGINAL RESEARCH article | Our search strategy was limited to human RCTs published in English language. If the outcomes were reported by different doses, types of supplements, or duration of the intervention, we treated each situation as a separate study. Disagreements were resolved by discussion with a third author ZA. All statistical analyses were conducted using STATA software version Sensitivity analyses were performed to evaluate the impact of each included clinical trials on the validity of the overall combined WMDs. Subgroup analyses were conducted to examine the source of heterogeneity according to the following possible moderator variables; type of interventions resveratrol plus other nutrients or drugs vs. overweight, or obese, or other chronic diseases vs. P -value less than 0. In initial online database searches, reports were identified. After removing duplicates citations by reviewing titles and abstracts and excluding the irrelevant citations, 31 studies 35 effect sizes were finally included. Figure 1 shows the stepwise with more details of the identification and selection of the relevant articles. All 35 included effect sizes were randomized, placebo-controlled trial. Twenty-nine studies were conducted using parallel design and six studies had cross-over design. The total number of the participants among included studies was individuals persons in the resveratrol group; and in the placebo group. Thirty-two studies calculated the influences of resveratrol intake on triglycerides, twenty-eighth on total cholesterol, twenty-seven on LDL-cholesterol, twenty-nine on HDL-cholesterol, thirteen on ALT, ten on AST, and five studies on GGT concentrations. Table 1 illustrates the characteristics of the included articles. The impact of resveratrol supplementation on lipid profiles and liver enzymes are indicated in Fig. The findings of subgroup analyses indicated that there were no significant changes between before and after subgroup analyses combined WMDs for lipid profiles and liver enzymes. The results of subgroup analyses are indicated in Table 2. Sensitivity analyses showed no significant changes between the pre- and post-sensitivity combined WMDs for triglycerides, HDL-cholesterol, ALT, AST, and GGT concentrations. We found that there were a significant effect between before and after sensitivity pooled WMD for total cholesterol after removing Bhatt et al. We applied non-parametric method Duval and Tweedie to calculate the findings of censored articles for total-cholesterol; however, pooled WMDs findings did not statistically significant change after using Duval and Tweedie test. The findings of current systematic review and meta-analysis showed that resveratrol supplementation among patients with MetS and related disorders significantly reduced total cholesterol and increased GGT concentrations, but did not affect triglycerides, LDL-, HDL-cholesterol, ALT, and AST concentrations. MetS and related disorders are characterized by changes in fatty acid metabolism, which finally results in decreased HDL-cholesterol, and increased LDL-cholesterol as well as, triglycerides concentrations. As dyslipidemia is a well-established risk factor for MetS, diabetes, and CVDs, circulating lipid profiles are routinely addressed by pharmacotherapy. We found that resveratrol supplementation among patients with MetS and related disorders significantly reduced total cholesterol, but did not affect triglycerides, LDL-, HDL-cholesterol concentrations. Previously, the effects of resveratrol on weight loss [ 49 ] and biomarkers of inflammation and oxidative stress among patients with MetS [ 50 ], and coenzyme Q10 on lipid profiles among patients diagnosed with coronary artery disease [ 51 ] were assessed. In a study conducted by Simental-Mendia et al. However, in a meta-analysis conducted by Zhang et al. In addition, another meta-analysis found no significant effects on lipid variables following the supplementation of resveratrol in patients with T2DM [ 16 ]. The hypocholesterolemic effect of resveratrol may be mediated by its phenolic hydroxyls contain that lead to oxidation of the unsaturated fatty acids and decreasing circulating cholesterol [ 54 ]. In addition to the beneficial effects of resveratrol on lipid metabolism, the anti-atherosclerotic activity of resveratrol involves enhanced activity of peroxisome proliferator-activated receptor α [ 55 ], suppressing platelet aggregation [ 56 ], reduced blood pressure [ 43 ], and improvement of the endothelial activity [ 57 ]. Therefore, it is expected that resveratrol administration among patients with MetS and related disorders exerts a potential cardioprotective impact. The current meta-analysis demonstrated that taking resveratrol supplements by patients with MetS and related disorders was associated with a significant reduction in GGT, but did not affect ALT and AST concentrations. In a study by Asghari et al. In addition, previous animal studies have claimed that resveratrol protects the liver against steatosis [ 59 ] and decreases intracellular lipids in the liver [ 60 ]. In another study, Heebøll et al. Also, Faghihzadeh et al. These inconsistent findings could be related to the stage of disease, type of diseases, the method of measuring liver fat content, different dosage of resveratrol used, or baseline metabolic characteristics of the participants. This meta-analysis demonstrated that resveratrol supplementation to the patients with MetS and related disorders significantly reduced total cholesterol and increased GGT concentrations, but did not affect triglycerides, LDL-, HDL-cholesterol, ALT, and AST concentrations. Therefore, resveratrol supplementation to patients with MetS and related disorders may have a potential cardio-protective effect through the reduction of total cholesterol and GGT concentrations. Nelson RH. Hyperlipidemia as a risk factor for cardiovascular disease. Prim Care. Article PubMed Google Scholar. Lemieux I, Lamarche B, Couillard C, Pascot A, Cantin B, Bergeron J, et al. Arch Intern Med. Article CAS PubMed Google Scholar. 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Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. J Intern Med. Sahebkar A, Serban MC, Gluba-Brzozka A, Mikhailidis DP, Cicero AF, Rysz J, et al. Lipid-modifying effects of nutraceuticals: an evidence-based approach. Patti AM, Al-Rasadi K, Giglio RV, Nikolic D, Mannina C, Castellino G, et al. Natural approaches in metabolic syndrome management. Arch Med Sci. Cicero AFG, Colletti A, Bajraktari G, Descamps O, Djuric DM, Ezhov M, et al. Lipid lowering nutraceuticals in clinical practice: position paper from an international lipid expert panel. Article CAS PubMed PubMed Central Google Scholar. Sosnowska B, Penson P, Banach M. The role of nutraceuticals in the prevention of cardiovascular disease. Cardiovasc Diagn Ther. Article PubMed PubMed Central Google Scholar. Banach M, Patti AM, Giglio RV, Cicero AFG, Atanasov AG, Bajraktari G, et al. The role of Nutraceuticals in statin intolerant patients. J Am Coll Cardiol. Hunter PM, Hegele RA. Functional foods and dietary supplements for the management of dyslipidaemia. Nat Rev Endocrinol. Sahebkar A. Effects of resveratrol supplementation on plasma lipids: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev. Hausenblas HA, Schoulda JA, Smoliga JM. Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus--systematic review and meta-analysis. Mol Nutr Food Res. Sahebkar A, Serban C, Ursoniu S, Wong ND, Muntner P, Graham IM, et al. Lack of efficacy of resveratrol on C-reactive protein and selected cardiovascular risk factors--results from a systematic review and meta-analysis of randomized controlled trials. Int J Cardiol. Arzola-Paniagua MA, Garcia-Salgado Lopez ER, Calvo-Vargas CG, Guevara-Cruz M. Efficacy of an orlistat-resveratrol combination for weight loss in subjects with obesity: A randomized controlled trial. Obesity Silver Spring, Md. Article CAS Google Scholar. Bashmakov YK, Assaad-Khalil SH, Abou Seif M, Udumyan R, Megallaa M, Rohoma KH, et al. Resveratrol promotes foot ulcer size reduction in type 2 diabetes patients. ISRN Endocrinol. Article PubMed PubMed Central CAS Google Scholar. Bhatt JK, Thomas S, Nanjan MJ. Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr Res. Goh KP, Lee HY, Lau DP, Supaat W, Chan YH, Koh AF. Effects of resveratrol in patients with type 2 diabetes mellitus on skeletal muscle SIRT1 expression and energy expenditure. Int J Sport Nutr Exerc Metab. Imamura H, Yamaguchi T, Nagayama D, Saiki A, Shirai K, Tatsuno I. Resveratrol Ameliorates Arterial Stiffness Assessed by Cardio-Ankle Vascular Index in Patients With Type 2 Diabetes Mellitus. Int Heart J. Zare Javid A, Hormoznejad R, Yousefimanesh HA, Zakerkish M, Haghighi-Zadeh MH, Dehghan P, et al. The impact of resveratrol supplementation on blood glucose, insulin, insulin resistance, triglyceride, and periodontal markers in type 2 diabetic patients with chronic periodontitis. Phytother Res. Kjaer TN, Ornstrup MJ, Poulsen MM, Stodkilde-Jorgensen H, Jessen N, Jorgensen JOL, et al. No beneficial effects of resveratrol on the metabolic syndrome: a randomized placebo-controlled clinical trial. J Clin Endocrinol Metab. Kumar BJ, Joghee NM. Resveratrol supplementation in patients with type 2 diabetes mellitus: a prospective, open label, randomized controlled trial. Int Res J Pharm. Militaru C, Donoiu I, Craciun A, Scorei ID, Bulearca AM, Scorei RI. Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: effects on lipid profiles, inflammation markers, and quality of life. Most J, Timmers S, Warnke I, Jocken JW, van Boekschoten M, de Groot P, et al. Combined epigallocatechingallate and resveratrol supplementation for 12 wk increases mitochondrial capacity and fat oxidation, but not insulin sensitivity, in obese humans: a randomized controlled trial. Am J Clin Nutr. Movahed A, Nabipour I, Lieben Louis X, Thandapilly SJ, Yu L, Kalantarhormozi M, et al. Antihyperglycemic effects of short term resveratrol supplementation in type 2 diabetic patients. Evid Based Complement Alternat Med. Poulsen MM, Vestergaard PF, Clasen BF, Radko Y, Christensen LP, Stodkilde-Jorgensen H, et al. High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Seyyedebrahimi S, Khodabandehloo H, Nasli Esfahani E, Meshkani R. The effects of resveratrol on markers of oxidative stress in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled clinical trial. Acta Diabetol. Mendez-del Villar M, Gonzalez-Ortiz M, Martinez-Abundis E, Perez-Rubio KG, Lizarraga-Valdez R. Effect of resveratrol administration on metabolic syndrome, insulin sensitivity, and insulin secretion. Metab Syndr Relat Disord. Witte AV, Kerti L, Margulies DS, Floel A. Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci. Chachay VS, Macdonald GA, Martin JH, Whitehead JP, O'Moore-Sullivan TM, Lee P, et al. Resveratrol does not benefit patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. Chen S, Zhao X, Ran L, Wan J, Wang X, Qin Y, et al. Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial. Digest Liver Dis. Faghihzadeh F, Adibi P, Hekmatdoost A. The effects of resveratrol supplementation on cardiovascular risk factors in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled study. Br J Nutr. Kantartzis K, Fritsche L, Bombrich M, Machann J, Schick F, Staiger H, et al. Effects of resveratrol supplementation on liver fat content in overweight and insulin-resistant subjects: a randomized, double-blind, placebo-controlled clinical trial. Diabetes Obes Metab. Most J, Warnke I, Boekschoten MV, Jocken JWE, de Groot P, Friedel A, et al. The effects of polyphenol supplementation on adipose tissue morphology and gene expression in overweight and obese humans. Khodabandehloo H, Seyyedebrahimi S, Esfahani EN, Razi F, Meshkani R. Chekalina NI, Kazakov YM, Mamontova TV, Vesnina LE, Kaidashev IP. Resveratrol more effectively than quercetin reduces endothelium degeneration and level of necrosis factor alpha in patients with coronary artery disease. Wiad Lek. PubMed Google Scholar. Fujitaka K, Otani H, Jo F, Jo H, Nomura E, Iwasaki M, et al. Modified resveratrol Longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment. Cicero AF, Morbini M, Parini A, Urso R, Rosticci M, Grandi E, et al. Effect of red yeast rice combined with antioxidants on lipid pattern, hs-CRP level, and endothelial function in moderately hypercholesterolemic subjects. Ther Clin Risk Manag. Biesinger S, Michaels HA, Quadros AS, Qian Y, Rabovsky AB, Badger RS, et al. A combination of isolated phytochemicals and botanical extracts lowers diastolic blood pressure in a randomized controlled trial of hypertensive subjects. Eur J Clin Nutr. Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. van der Made SM, Plat J, Mensink RP. Resveratrol does not influence metabolic risk markers related to cardiovascular health in overweight and slightly obese subjects: a randomized, placebo-controlled crossover trial. PLoS One. de Ligt M, Bruls YMH, Hansen J, Habets MF, Havekes B, Nascimento EBM, et al. Resveratrol improves ex vivo mitochondrial function but does not affect insulin sensitivity or brown adipose tissue in first degree relatives of patients with type 2 diabetes. Mol Metab. Simental-Mendia LE, Guerrero-Romero F. Effect of resveratrol supplementation on lipid profile in subjects with dyslipidemia: a randomized double-blind, placebo-controlled trial. Article PubMed CAS Google Scholar. Fodor K, Tit DM, Pasca B, Bustea C, Uivarosan D, Endres L, et al. Long-term resveratrol supplementation as a secondary prophylaxis for stroke. Oxid Med Cell Longev. Mazza A, Schiavon L, Rigatelli G, Torin G, Montanaro F, Lenti S. The short-term supplementation of monacolin K improves the lipid and metabolic patterns of hypertensive and hypercholesterolemic subjects at low cardiovascular risk. Food Funct. Tabrizi R, Tamtaji OR, Lankarani KB, Akbari M, Dadgostar E, Dabbaghmanesh MH, et al. The effects of resveratrol intake on weight loss: a systematic review and meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr. Tabrizi R, Tamtaji OR, Lankarani KB, Mirhosseini N, Akbari M, Dadgostar E, et al. After dosage conversion, no significant difference was observed between preclinical studies and clinical trials. This inconsistency may be due to the small sample size of the current clinical RCTs. But as far as the current experimental evidence is concerned, resveratrol can show a better downregulation trend on ALT, TG in preclinical and clinical trials. It suggests that resveratrol exerts both hepatoprotective and lipid metabolism regulating effects. FIGURE 6. A ALT in preclinical studies. B TG in preclinical studies. C ALT in clinical trials. D TG in clinical trials. ALT and TG were selected as the main analysis subjects. Taken together, these findings indicate that there is no obvious publication bias for ALT and TG Supplementary Figure S We elucidated the possible molecular mechanism of resveratrol on NAFLD based on preclinical studies. For this, network regulation was conducted using multiple bioactive targets. This pathway plays a vital role during NAFLD progress. It not only regulates lipid metabolism but also indirectly affects cell death and autophagy. Second, resveratrol can reverse inflammation-related signals. It primarily downregulates IL-6, IL-1β, and TNF-α, with the NF-κB signaling pathway being the core pathway. In addition, studies have reported that the PPAR-α signal for lipid metabolism improvement is involved during this regulated process. Furthermore, tight junctions, to prevent gut dysbiosis, are associated with the bioactivity of resveratrol on NAFLD Figure 7 , Supplementary Table S4. Clarifying the efficacy and mechanism of agents on diseases during drug development is extremely crucial. However, these two issues are generally limited to the focus on a specific aspect in single research. Therefore, meta-analysis provides a foundation for combining multidimensional results to collect robust evidence for these two issues. In the present study, we attempted to collect mixed data to confirm the role of resveratrol in NAFLD. Using preclinical studies and clinical trials, our study is the first to develop an integrated approach for evaluating efficacy and in-depth mechanism. Interestingly, our findings suggest that resveratrol can not only reverse worse liver function and NAFLD-induced lipid metabolism but also comprehensively regulate the inflammatory and apoptotic status of the hepatocyte microenvironment based on preclinical studies. However, several inconsistencies were observed in clinical trials. The meta-analysis suggests that resveratrol exhibits the trend of improving liver function but does not exhibit efficacy on fatty liver indicators and other indices. Furthermore, a consistent result was observed for TNF-α regulation. These findings indicate that resveratrol exhibits liver-protective efficacy by alleviating inflammation. Moreover, preclinical studies have suggested that resveratrol regulates NALFD in a network-dependent manner. Tight junctions relevant to the gut are also regulated. Our study provides comprehensive evidence for the mechanism of resveratrol on NAFLD. Taken together, both preclinical studies and clinical trials have demonstrated the liver-protective efficacy of resveratrol to some extent. However, its regulatory effects on fatty liver indices may not be obvious and remarkable. Based on clinical trials, we unexpectedly observed the partially invalid efficacy of resveratrol on NAFLD. In other words, there is inconformity between preclinical and clinical studies. We hypothesize three possible reasons for this result. First, the RCTs have a relatively small sample size, possibly affecting efficacy. The samples in each arm included five trials, with 10—30 patients. The small sample size of these RCTs may increase the risk of false-negative results and therefore interfere with the real efficacy. Second, the clinical trials were conducted in different regions with multiple ethnicities. For example, European or Asian individuals have different dietary habits and physique, and therefore, different degrees of NAFLD. It is difficult to eliminate these confounding factors in meta-analysis, invalidating the entire analysis. Third, resveratrol may exhibit a liver-protective effect rather than a fatty liver-alleviating effect. In particular, many studies have reported that resveratrol can be an effective agent for various liver diseases Ma et al. However, this effect is mainly relevant to anti-inflammatory characteristics. This could explain why resveratrol effectively downregulated TNF-α and alleviated liver function indices in both two kinds of studies. The evidence comprehensively verified that resveratrol can alleviate NAFLD via multiple signaling pathways. In particular, the core signal Sirt1 is a metabolic regulator that controls lipid metabolism, including fatty acid synthesis, oxidation, and adipogenesis Ezhilarasan and Lakshmi, ; Zeng and Chen, Neither preclinical studies nor clinical trials confirmed the significant downregulation of TNF-α by resveratrol. Further investigation of the mechanism revealed the involvement of NF-κB. Hepatocellular death is a cardinal feature of NAFLD and NASH, as characterized by the presence of swollen hepatocytes Zhao et al. During this progress, signaling pathways related to both apoptosis and necroptosis are activated, and TNF-α acts as the original signal to launch the cascade reaction Lu et al. Apart from the death signal of TNF-α, we also focused on the anti-inflammatory mechanism of resveratrol. For example, proinflammatory-related ILs were alleviated in experiments, suggesting the comprehensive potential of the liver-protective activity of resveratrol by inhibiting inflammation and downstream cell death. Moreover, studies have also investigated the PPAR-α signal for improvements in lipid metabolism and further confirmed that resveratrol may regulate fatty liver status via multiple targets and their crosstalk. Interestingly, the gut—liver axis also plays a role during NAFLD treatment. They attenuate hepatic inflammation at least partially by improving gut barrier integrity in green tea catechins Hodges et al. This result represents and further suggests the multidimensional regulatory role of resveratrol. In the present meta-analysis, we identified several issues that should be considered further. First, information on the safety of resveratrol is scarce. Although it is widely believed that resveratrol does not exhibit toxicity, its multitarget characteristic may pose a potential safety risk for other cells, which should not be ignored. Second, it is particularly important to investigate its metabolite form for clinical applications, rather than focusing on its original preparation. At present, many studies have suggested that resveratrol can be modified in the liver and intestine to generate new chemicals Iglesias-Aguirre et al. However, studies have only proved the efficacy of resveratrol but not that of its metabolites. Therefore, there is a long way to further research in this field. Third, it is challenging to ascertain the exact progression of NAFLD. All diseases are dynamic in nature and change with time. For example, there is a close association between the development of liver injury, fibrosis, and hepatocarcinoma. The liver is rapidly repaired after damage at the early stage. However, continuous damage is a crucial factor for fibrosis accumulation and gradually toward cirrhosis. During the final stage, loss of hepatic function will ultimately lead to the development of hepatocarcinoma Xiao et al. NAFLD development also occurs similarly. Mild NAFLD can be alleviated along with lipid elimination; however, moderate NAFLD will result in hepatocyte apoptosis and inflammation. Further several progress can considerably induce dysfunction of the microenvironment and eventually lead to the development of nonalcoholic steatohepatitis. Nevertheless, the studies included in this study did not mention the treatment stage of NAFLD. Therefore, rigorous RCTs should be designed to investigate efficacy based on disease phases. Although this study was rigorously conducted based on the PRISMA criteria, several limitations should be highlighted. Furthermore, it was challenging to ascertain which program, including designs, modeling route, dosage, and treatment or detection time in different conditions, induced diversity. Therefore, heterogeneity may inevitably affect the conclusions and interpretations of the present study. This result directly suggests the shortage of translational research in resveratrol for NAFLD. Furthermore, limited clinical information constrained more precise conclusions from humans. Although preclinical studies can provide abundant information on how an agent functions, direct mechanistic evidence from RCTs could offer more information during application. Therefore, multiomics such as metabolomics, metagenomics, and transcriptomics should be employed for further investigations after efficacy confirmation in clinical studies. Finally, this study failed to entirely elucidate the efficacy of resveratrol on NAFLD. Therefore, we should treat the present results with caution when considering these limitations. However, the results are inconsistent in clinical trials. Considering heterogeneous factors, large-scale and single-center RCTs are warranted to investigate efficacy. XH wrote and revised the manuscript. YL, XD, and XX searched, extracted, and analyzed the data and drew the figures. JZ conceived and revised the manuscript. All authors contributed to the article and approved the submitted version. The authors would like to thank the reviewers and also the authors of all references. 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. Ali, M. Protective effect of ursodeoxycholic acid, resveratrol, and N-acetylcysteine on nonalcoholic fatty liver disease in rats. PubMed Abstract CrossRef Full Text Google Scholar. Andrade, J. Resveratrol attenuates hepatic steatosis in high-fat fed mice by decreasing lipogenesis and inflammation. Nutrition 30, — Asghari, S. 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| Introduction | The body weight of the mice was significantly increased post HFD feeding, and the curve of all the RSV treatment group was separated from that of the HFD group over the last 4 weeks Figure 1A and Supplementary Figure 1A. The ultrasound depicts on screen the area in cm2 , mean intensity dB and standard deviation dispersion. CAS PubMed Google Scholar Bunyan J, Murrell EA, Shah PP. Carpene C, Les F, Casedas G, Peiro C, Fontaine J, Chaplin A, et al. In addition to the beneficial effects of resveratrol on lipid metabolism, the anti-atherosclerotic activity of resveratrol involves enhanced activity of peroxisome proliferator-activated receptor α [ 55 ], suppressing platelet aggregation [ 56 ], reduced blood pressure [ 43 ], and improvement of the endothelial activity [ 57 ]. Moreover, preclinical studies have suggested that resveratrol regulates NALFD in a network-dependent manner. |
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