The Effects of Grape/Grape Products on Inflammatory and Oxidative Stress Markers: Systematic Review and Meta-Analysis of Randomized Controlled Trials

Dehghani, Fereshteh; Soltani, Sepideh; Kolahdouz-Mohammadi, Roya; C. T. Clark, Cain; Abdollahi, Shima

doi:https://doi.org/10.1155/2024/5086541

Journal of Food Biochemistry

On this page

Abstract Introduction Methods Results Discussion Conclusion Data Availability Disclosure Conflicts of Interest Authors’ Contributions Acknowledgments Supplementary Materials References Copyright Related Articles

Review Article | Open Access

Volume 2024 | Article ID 5086541 | https://doi.org/10.1155/2024/5086541

The Effects of Grape/Grape Products on Inflammatory and Oxidative Stress Markers: Systematic Review and Meta-Analysis of Randomized Controlled Trials

Fereshteh Dehghani,¹Sepideh Soltani,²Roya Kolahdouz-Mohammadi,³Cain C. T. Clark,⁴and Shima Abdollahi⁵

Academic Editor: Rana Muhammad Aadil

Received19 Sept 2023

Revised24 Dec 2023

Accepted25 Mar 2024

Published16 Apr 2024

Abstract

Background. A growing body of evidence has demonstrated the multiple effects of the individual phenolic antioxidants of grapes. However, it is not clear whether grape and its derivatives exert anti-inflammatory effects. In this systematic review and meta-analysis, we sought to examine the effects of grape/grape products on inflammation and oxidative stress in adults. Methods. This study has been conducted based on the PRISMA checklist. A systematic literature search in PubMed, Scopus, ISI Web of Science, and the Cochrane Library was conducted, from inception until January 2022, to identify eligible trials. Mean differences and standard deviations were pooled using random-effects models. Results. Twenty-nine eligible trials were included. Grape and its products significantly increased the catalase activity (n = 3 studies, 64 participants; WMD = 5.49 U/mg protein, 95% CI: 4.76, 6.22; ; = 0%; P-heterogeneity = 0.98), oxygen radical absorbance capacity (n = 5 studies, 206 participants; WMD = 90.06 µmol/l TE, 95% CI: 35.97, 144.15; ; = 35.6%; P-heterogeneity = 0.18), and total antioxidant capacity (n = 4 studies, 224 participants; WMD = 62.48 µmol/l, 95% CI: 31.62, 93.33; ; = 55.2%; P-heterogeneity = 0.08) and decreased thiobarbituric acid reactive substances levels (n = 5 studies, 153 participants; WMD = −0.17 nmol/mg, 95% CI: −0.31, −0.03; ; = 34.2%; P-heterogeneity = 0.19). No significant change was observed for inflammatory markers. Conclusion. Although grape/grape products elicited increases in antioxidant agents, they had no significant effect on inflammatory factors. This may be related to the low levels of baseline inflammatory factors, as none of the included studies enrolled patients with acute inflammation. Further well-designed studies are warranted to examine grape’s efficacy on inflammation and oxidative stress.

1. Introduction

Reactive oxygen species (ROS) are produced in the cells in small quantities [1] as a consequence of physiological oxidative metabolism, mitochondrial bioenergetics, and immune function [2]. They act as a regulatory agent in the signaling pathways including gene expression, receptor activation, and signal transduction as well as cell differentiation, cell growth, metabolic adaptation, and immune responses [3]. The excess production of ROS in the cells which exceeds the ability of the antioxidant system to neutralize them is known as oxidative stress [4], which can damage cellular molecules including lipids, protein, and DNA [5]. Oxidative stress also activates various inflammatory processes, such as nuclear factor κB (NF-κB) and activating protein-1 (AP-1), leading to the synthesis and secretion of pro-inflammatory cytokines [6]. Oxidative stress and inflammation have been shown to be associated with, and implicated in, various diseases including, diabetes, cardiovascular diseases [5], cancer, neurodegenerative diseases, and arthritis [7].

The cumulative evidence shows that dietary polyphenols are able to exert antioxidant activity, ROS scavenging properties, and anti-inflammatory functions which can alter the expression of pro-inflammatory cytokines [8]. Therefore, a possible approach to reduce oxidative stress [9] and inflammation is to add polyphenol-rich foods, such as grape or its products, to the diet [6]. Grapes are the major source of phenolic acids, proanthocyanidins, anthocyanins, flavonoids, and stilbenes [10]. The most common grape-derived products include raisins, juices, and wines [6], which are also reported to have a high nutraceutical level and are on the market in the form of powders, dried, and concentrated extracts [6, 9]. It has been shown that grape and its product consumption can reduce the risk factors for cardiovascular and neurodegenerative disease, diabetes, cancer, and cognitive decline [11].

The results of the human randomized controlled trials (RCTs) investigating the effect of grape and its products on inflammation and oxidative markers are controversial. For instance, a few studies have shown improvement in some inflammatory and oxidative stress biomarkers [12–14], while others have reported unchanged levels [15–17]. It is worth mentioning that recent meta-analyses on the effects of grape products on inflammation and oxidative stress are also equivocal. Indeed, some meta-analysis studies have reported significant benefits of grape polyphenols, grape seed extract, or grape products on CRP levels, total antioxidant activity (TAC), malondialdehyde (MDA), oxidized low-density lipoprotein (ox-LDL), and hs-CRP levels [18–20]. However, no significant effect on interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), superoxide dismutase (SOD), oxygen radical absorbance capacity (ORAC), and glutathione peroxidase (GPx) has been observed [18, 19, 21].

A serious criticism of prior studies is that they did not examine the effects of whole grape fruit or its products. Moreover, grape derivatives such as extracted polyphenols or grape seed extract were included in the same analysis along with fresh grape. Therefore, ascertaining whether whole grape fruit and its products can be effective on inflammatory factors is still unanswered.

Therefore, we sought to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effect of whole grape/grape products on inflammatory and oxidative markers in adults.

2. Methods

The present systematic review and meta-analysis was conducted in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [22]. The protocol of the present study was registered at the International Prospective Register for Systematic Reviews (PROSPERO) database (ID of CRD42022349904).

2.1. Search Strategy and Study Selection

To identify relevant studies, a systematic search was conducted in PubMed, Scopus, ISI Web of Science, and the Cochrane Library, from database inception to January 2022, without any restrictions for language or publication date. A combination of MeSH and non-MeSH terms related to “grape” and “study design” was applied. Further details on the search strategy and PICO components are provided in Tables S1 and S2, respectively. In addition, reference lists of all included studies were screened manually in order to find additional eligible trials.

2.2. Eligibility Criteria

Original randomized clinical trials with parallel or crossover design investigating the effects of grape or its products in comparison with a control/placebo group were eligible for inclusion in this study if they were conducted on an adult population (age >18 years), lasted for a 2-week intervention or more, and reported at least one of our key outcomes (including serum levels of oxidative stress (ox-LDL; MDA, SOD, ORAC, GPX, nitric oxide (NO), advanced oxidation protein products (AOPPs), thiobarbituric acid reactive substances (TBARSs), catalase (CAT), and Trolox equivalent antioxidant capacity (TEAC)) and inflammatory markers (TNF-α, hs/CRP, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1), and C3 protein) as mean ± standard deviation (SD) (or other statistics that can be converted to mean ± SD)), before/after or change during the study.

The exclusion criteria were as follows: (1) trials that administered grape seed, resveratrol, or any individual ingredient of grape; (2) trials conducted on pregnant or lactating women; and (3) trials that administered multiple intervention components that independent effect of grape/grape products could not be determined.

The initial abstract and full-text screening of all retrieved studies were executed independently by two authors (SS and RKM) according to inclusion and exclusion criteria, and disagreements were resolved by consensus with the third author (SA).

2.3. Data Extraction

Two authors (FD and SS) extracted the following data from eligible studies: (1) study characteristics including first author’s name, publication year, study location, study design, sample size, follow-up duration, type of intervention (grape, raisin, grape juice or powder), placebo, and dosage of intervention; (2) participant characteristics including sex, age, and health status; and (3) mean/SD or other convertible data of antioxidants and inflammatory markers before/after intervention or mean changes/SD during the follow-up period. Disagreements were resolved by consensus with the third author (SA). The dose of grape products was converted to cup equivalent unit using Food Patterns Equivalents Database (FPED) [23], to make the dose data of grape products comparable between trials.

PlotDigitizer software (https://plotdigitizer.sourceforge.net/) was used for extracting data only obtainable in graphical formats. The units of antioxidants and inflammatory markers were unified before analysis. For studies that administered multiple dosages or follow-up durations, the higher dosage or duration was included in the analysis.

2.4. Quality Assessment

The Cochrane risk of the bias tool for RCTs was used to assess the risk of bias based on the following six parameters: selection bias, performance bias, detection bias, attrition bias, reporting bias, and bias due to problems not covered elsewhere [24]. The eligible studies were classified as low risk, high risk, and unclear. Studies with low risk of bias for all criteria were judged as good quality, studies with one criterion not met or two criteria unclear were judged as fair quality, and studies with high risk of bias for two or more criteria were judged as poor quality.

2.5. Quality of Meta-Evidence

The quality of meta-evidence was assessed by applying the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach [25, 26]. Data from RCTs were initially considered high quality and might be downgraded considering the following domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. The quality of evidence for each outcome was classified as high, moderate, low, or very low. Two authors (RKM and SS) independently assessed the quality of evidence, and disagreements were resolved by consensus with the third author (SA).

2.6. Statistical Analysis

The effect of grape products on the change in the outcomes of inflammation (hs-CRP, TNF-α, IL-6, IL-10, and monocyte chemoattractant protein-1 (MCP-1)) and oxidative stress (ox-LDL), ORAC, thiobarbituric acid reactive substances (TBARSs), TAC, carbonyl, MDA, catalase (CAT), and SOD were examined. We applied analysis for the outcomes, when three studies or more reported data. The mean differences (MDs) and their corresponding 95% confidence interval (CI) between intervention and control groups were used to calculate the effect size. For studies that did not report change values, SDs were calculated according to the formulas suggested by the Cochrane Handbook of Systematic Review [27]. For all inflammatory and oxidative stress markers, we used a correlation coefficient of 0.5, with the exception of MDA, which was 0.48. Weighted mean differences (WMDs) and their SDs were calculated by using the DerSimonian and Laird random-effects model [28]. Due to the small number of included studies for each outcome, a modified method for random‐effects meta‐analysis (the Hartung–Knapp–Sidik–Jonkman method) was used to reduce the error rate [29].

To evaluate the statistical heterogeneity between the studies, Cochran’s Q test and statistic () were used [30]. In order to detect the sources of heterogeneity, predefined subgroup analyses were conducted for potential factors including sex (male, female, both), participants’ health status (healthy, metabolic syndrome, cardiovascular disease, and hemodialysis), study type (parallel, crossover), duration of intervention (≤12 wk, >12 wk), intervention type (fresh grape, dried grape (including pomace, raisin, powder), and grape extract (including juice, concentrate, extract)), dosage (<150 gr, ≥150 gr), study location (Asia, Europe, USA, and south USA), and quality of studies (unclear, low, and high). Sensitivity analysis was conducted by the leave-one-out method to determine whether a single trial affects the overall effect size [31]. For outcomes with at least 10 trials, publication bias was evaluated by the visual inspection of the funnel plot and assessed statistically by Begg’s adjusted rank correlation and Egger’s regression asymmetry tests [32]. In addition, meta‐regression analysis was conducted to explain the between-study variation based on the dose and duration of the intervention. The effect of other variables could not be assessed, due to the incomplete data. Statistical analyses were performed using STATA version 17 (StataCorp). Two-sided values <0.05 were considered statistically significant.

3. Results

3.1. Study Selection and Characteristics

Our primary search identified 8610 potentially relevant references. After excluding duplicates (n = 3426) and initial screening, 100 records remained for the full-text screening. Finally, 29 articles were considered eligible for inclusion in the analyses and reported the following outcomes: hs-CRP (n = 15), TNF-α (n = 10), IL-6 (n = 10), MCP-1 (n = 3), ox-LDL (n = 10), ORAC (n = 5), TBARS (n = 5), TAC (n = 4), Carbonyl (n = 3), MDA (n = 4), CAT (n = 3), and SOD (n = 3) (Figure 1). The reviewers’ agreement for including studies was high at the abstract screening (Cohen’s kappa = 0.76) and full-text screening (Cohen’s kappa = 0.81) phases.

Excluded studies, along with the reasons for exclusion, are shown in Supplemental Table 3.

The general characteristics of the included studies are summarized in Table 1. Studies were conducted in the USA [14, 16, 17, 34, 38, 39, 42, 47, 49, 50], Spain [12, 35, 36, 46, 52, 55], Greece [13, 43, 44], Brazil [15, 37, 41, 53], Iran [48, 51], France [45], Turkey [33], Canada [40], and Israel [54]. Nineteen studies had a parallel design [12, 13, 15, 33, 35–37, 40, 42–44, 47, 48, 50–55], and 10 had a crossover design [14, 16, 17, 34, 38, 39, 41, 45, 46, 49]. The duration of the intervention ranged from 2 to 52 weeks. The included studies administered grape (n = 1) [48], grape powder (n = 6) [14, 16, 17, 34, 39, 54], grape extract (n = 4) [40, 45, 52, 55], grape juice (n = 11) [12, 15, 35–38, 41, 42, 45, 50, 53], raisin (n = 5) [43, 44, 47, 49, 51], currants (n = 1) [13], and grape pomace (n = 1) [46]. All the included studies were conducted in both sexes, except for three studies that were exclusively conducted on women [14, 37] and men [34]. Fourteen studies enrolled healthy participants [14, 16, 17, 33, 37, 41, 42, 44, 45, 47, 49, 50, 53, 55], and others recruited patients with metabolic syndrome [34, 39, 46], hemodialysis [12, 35, 36], prediabetes /diabetes [40, 43], hypertension [38, 54], hyperlipidemia [48, 51], nonalcoholic fatty liver disease (NAFLD) [13], Parkinson [15], and stable coronary artery disease [52]. One study also reported the results in postmenopause and premenopause women separately; the effect sizes of both were included in the analysis [14].

3.2. Quality Assessment

The methodological quality of the included studies was assessed using the Cochrane collaboration tool. We found eight studies to have a good quality design [37, 40, 41, 44, 45, 50, 52, 54]: one study had fair quality [38] and the remaining had poor quality [12–17, 33–36, 39, 42, 43, 46–49, 51, 53, 55]. The most contributing factors were random sequence generation and allocation concealment, details of the process of which were not explained (Table S4).

The GRADE assessment system showed that the quality of evidence was very low for the effect of grape products on carbonyl, ox-LDL, MDA, SOD, total antioxidant capacity (TAC), TNF-α, and MCP-1 and low for the remaining outcomes (catalase, ORAC, TBARS, hs-CRP, and IL-6) (Table S5).

4. Meta-Analysis

4.1. The Effect of Grape/Grape Products on Inflammatory Markers

Our results showed that grape/whole grape products had no significant effect on hs-CRP (n = 15 studies, 659 participants; WMD = −0.01 mg/L, 95% CI: −0.14, 0.11; ; = 0%, 95% CI: 0, 52; P-heterogeneity = 0.59) (Figure 2(a)), IL-6 (n = 10 studies, 310 participants; WMD = −0.04 pg/ml, 95% CI: −0.44, 0.36; ; = 0%, 95% CI: 0, 60; P-heterogeneity = 0.99) (Figure 2(b)), TNF-α (n = 10 studies, 310 participants; WMD = −0.04 pg/ml, 95% CI: −0.25, 0.17; ; = 70.8%, 95% CI: 46, 84; P-heterogeneity <0.001) (Figure 2(c)), and MCP-1 (n = 3 studies, 55 participants; WMD = −4.96 pg/ml, 95% CI: −14.04, 4.13; ; = 0%, 95% CI: 0, 90; P-heterogeneity = 0.50) (Figure 2(d)).

(a)

(b)

(c)

(d)

The results of the subgroup analysis are presented in Tables S6–S8. The subgroup analysis revealed a significant reduction in hs-CRP levels following grape extract supplementation (n = 5 studies, 192 participants; WMD = −0.52 mg/L, 95% CI: −0.99, −0.04; ; = 0%; P-heterogeneity = 0.74) (Table S6). Moreover, TNF-α levels reduced in RCTs with crossover design (n = 6 studies, 140 participants; WMD = −0.17 pg/ml, 95% CI: −0.32, −0.02; ; = 0%; P-heterogeneity = 0.76), when intervention lasted for less than 12 weeks (n = 7 studies, 200 participants; WMD = −0.16 pg/ml, 95% CI: −0.24, −0.09; ; = 0%; P-heterogeneity = 0.84), when grape extract was used (n = 2 studies, 110 participants; WMD = −0.16 pg/ml, 95% CI: −0.25, −0.07; ; = 0%; P-heterogeneity = 0.61), in studies that were conducted in the USA (n = 6 studies, 188 participants; WMD = −0.16 pg/ml, 95% CI: −0.31, −0.01; ; = 0%; P-heterogeneity = 0.75), and when studies enrolled healthy subjects (n = 5 studies, 157 participants; WMD = −0.16 pg/ml, 95% CI: −0.24, −0.09; ; = 0%; P-heterogeneity = 0.99) (Table S7).

4.2. The Effect of Grape/Grape Products on Oxidative Stress Markers

Grape/grape products showed a significant increase in levels of catalase (n = 3 studies, 64 participants; WMD = 5.49 U CAT/mg protein, 95% CI: 4.76, 6.22; ; = 0%, 95% CI: 0, 90; P-heterogeneity = 0.98) (Figure 3(a)), ORAC (n = 5 studies, 206 participants; WMD = 90.06 µmol/l TE, 95% CI: 35.97, 144.15; ; = 35.6%, 95% CI: 0, 76; P-heterogeneity = 0.18) (Figure 3(b)), and TAC (n = 4 studies, 224 participants; WMD = 62.48 µmol/l, 95% CI: 31.62, 93.33; ; = 55.2%, 95% CI: 0, 85; P-heterogeneity = 0.08) (Figure 3(c)), while they showed a significant reduction in TBARSs (n = 5 studies, 153 participants; WMD = −0.17 nmol/mg, 95% CI: −0.31, −0.03; ; = 34.2%, 95% CI: 0, 75; P-heterogeneity = 0.19) (Figure 3(d)).

(a)

(b)

(c)

(d)

The overall analysis showed no significant effect of grape products on carbonyl (n = 3 studies, 64 participants; WMD = −3.27 nmol/mg, 95% CI: −18.30, 11.77; ; = 87%, 95% CI: 63, 95; P-heterogeneity < 0.001) (Figure 4(a)), ox-LDL (n = 10 studies, 385 participants; WMD = −3.19 U/L, 95% CI: −6.64, 0.25; ; = 63.7%, 95% CI: 28, 82; P-heterogeneity = 0.003) (Figure 4(b)), MDA (n = 4 studies, 193 participants; WMD = −0.09 µmol/l, 95% CI: −0.50, 0.33; ; = 56.5%, 95% CI: 0, 86; P-heterogeneity = 0.07) (Figure 4(c)), and SOD (n = 3 studies, 64 participants; WMD = 4.95 U SOD/mg of protein, 95% CI: −0.14, 10.04; ; = 93.5%, 95% CI: 84, 97; P-heterogeneity < 0.001) (Figure 4(d)).

(a)

(b)

(c)

(d)

In the subgroup analysis, we found that ox-LDL levels were reduced significantly in hemodialysis patients (n = 2 studies, 54 participants; WMD = −10.25 U/L, 95% CI: −15.42, −5.07; ; = 0%; P-heterogeneity = 0.89), in studies that were conducted in European countries (n = 7 studies, 281 participants; WMD = −6.43 U/L, 95% CI: −7.32, −5.54; ; = 0%; P-heterogeneity = 0.53), and in studies with parallel design (n = 7 studies, 281 participants; WMD = −6.42 U/L, 95% CI: −7.31, −5.54; ; = 0%; P-heterogeneity = 0.56). Additionally, grape extract supplementation significantly reduced ox-LDL (n = 6 studies, 209 participants; WMD = −6.46 U/L, 95% CI: −7.35, −5.57; ; = 0%; P-heterogeneity = 0.51) (Table S9).

4.3. The Qualitative Systematic Review

4.3.1. Advanced Oxidation Protein Products (AOPPs)

Three studies reported the effect of raisin [44], black current [56], and freeze-dried grape [39] on AOPP levels. The data from the articles could not be analyzed because the unit reported in one of the articles could not be converted and equated. No significant effect was observed in all three studies.

4.3.2. Paraoxonase (PON1)

The effect of the freeze-dried grape extract on the PON1 activity has been investigated in adults with metabolic syndrome. The results showed that grape supplementation did not significantly change the PON1-arylesterase activity and PON1-lactonase activity compared with placebo [57].

4.3.3. Homocysteine (Hcy)

In healthy adults, a traditional fermented grape-based drink “hardaliye” in two different dosages (250 and 500 mL) significantly reduced the serum Hcy concentrations () [33].

4.3.4. GPx

The grape extract and powder supplementation (400 mg/day) could not significantly change GPx levels in elite athletes [45] and hemodialysis patients [58], respectively. Grape juice consumption (400 ml/day) in patients with Parkinson’s disease for 4 weeks significantly reduced GPx levels compared to the placebo group [15]. The data of the articles could not be analyzed because the unit reported in one of the articles could not be converted and equated.

4.3.5. Nitric Oxide

In one study, raisin consumption showed no significant effect on nitric oxide in healthy smokers [44].

4.3.6. Complement Component 3-Protein (C3)

One study reported the effect of dietary supplementation with concentrated red grape juice on C3 in hemodialysis patients, which had no significant differences between the intervention and control groups [35].

4.3.7. IL-1β

Two trials examined the effects of dietary grape powder and grape on IL-1β in obese and healthy subjects, respectively. Zunino et al. reported no significant difference in IL-1β concentrations between groups [17]. In Ammollo’s study, grape intake did not show any significant change in the plasma levels of IL-1β in intervention and control groups, while a significant reduction in the release of IL-1β by lipopolysaccharide (LPS-) stimulated blood cells was observed in the intervention group compared with the control group [59].

4.3.8. IL-18

One study showed a significant reduction in IL-18 after grape consumption for one year in patients receiving primary CVD prevention, but it was not significant in comparison with the control group [60].

4.3.9. IL-6/IL-10

Two studies explored the effects of grape extract supplementation in patients with stable coronary artery disease [52] and those on primary CVD prevention [60]. In both studies, grape extract supplementation did not change the IL-6/L-10 ratio significantly.

4.3.10. IL-8

Two trials evaluated the effect of the grape powder supplement on plasma concentration and LPS-stimulated monocytes’ production of IL-8 in obese [17] and men with metabolic syndrome [34]. Grape powder supplementation did not significantly alter the IL-8 levels between the intervention and control groups in both studies.

4.3.11. IL-10

The effect of the grape extract and grape powder on IL-10 was investigated in three trials. However, a contradictory result was reached. A study showed that grape consumption increased IL-10 levels in patients with metabolic syndrome [34], while another study revealed no significant change in patients with stable coronary artery disease [52] and patients undergoing primary prevention of cardiovascular disease [60].

4.4. Sensitivity Analysis, Publication Bias, and Hartung–Knapp–Sidik–Jonkman Method-Based Analysis

To assess the robustness of the overall effect, a leave-one-out sensitivity analysis was performed, and the results were stable for IL-6, hs-CRP, and TNF-α. However, excluding the study by Bradagjy et al. [16] changed the results to a significant reduction in the ox-LDL levels (WMD = −4.45 U/L, 95% CI: −7.60, −1.30; ; I² = 39.03%; P-heterogeneity = 0.11).

Publication bias was assessed for the effect of grape products on levels of hs-CRP, TNF-α, IL-6, and ox-LDL. The visual inspection of the funnel plots revealed no sign of asymmetry, which was also confirmed by Egger’s and Begg’s tests.

The Hartung–Knapp–Sidik–Jonkman method meta-analysis changed the results to a significant reduction for ox-LDL levels (WMD = −3.28 U/L, 95% CI: −6.47, −0.09; ; P-heterogeneity = 0.0.03) and a significant increase for SOD levels (WMD = 5.02 U SOD/mg of protein, 95% CI: 1.1, 8.94; ; I² = 88.75%; P-heterogeneity = 0.0) (Table S10).

4.5. Meta-Regression

No significant associations were found between LFDs compared with HFDs on CRP, TNF, LDL-ox, and IL-6 and dose or duration of the intervention in meta-regression analysis (Supplementary Table 11).

5. Discussion

In the present meta-analysis, we pooled data from RCTs examining the effect of grape products on inflammation and oxidative stress markers in adults. Our main results showed that grape products significantly increased the catalase activity, ORAC, TAC, and decreased TBARS levels. We also found the grape extract may have more beneficial effects on inflammatory markers, including CRP, ox-LDL, and TNF-α, as compared to the other types of intervention (fresh grape or dried grape).

There are bidirectional communications between oxidative stress and inflammation; indeed, both are able to activate and aggravate each other in a direct or indirect manner [61]. Frequent exposure to ROS leads to cell damage and consequently induces proinflammatory pathways. Oxidative damage can induce the release of TNF-α from the cells, which binds to its cell surface receptors, leading to NF-𝜅B inflammasome activation [61]. As a result of NF-𝜅B signaling activation, other proinflammatory cytokines, such as IL-1𝛽, IL-6, and TNF-α, are produced [61–63]. Grapes are known as one of the main sources of antioxidants due to their high polyphenol content [64]. Polyphenols are capable of enhancing antioxidant enzyme activities directly or indirectly through the activation of Keap1/Nrf2/ARE and sirtuin 1 (Sirt1) signaling pathways, which can enhance the expression of antioxidant genes [65]. Moreover, polyphenols can suppress the NF-κB pathway, toll-like receptor (TLR), and expression of inflammatory genes, consequently [66].

Although we found no significant effect of grape and its products on inflammatory markers in the overall analysis, it seems grape extracts can reduce inflammatory markers. It may be associated with the higher dose of antioxidant in the grape extract compared to fresh grape. On the other hand, none of the included studies investigated patients with pre-existing acute inflammation, so the low level of inflammatory factors was not affected by the short-term intervention. In line with our results, a meta-analysis of eight studies regarding grape polyphenols did not show any significant effect on hs-CRP, IL-6, and TNF-α [21]. In another meta-analysis, grape products had no significant effect on IL-6 and TNF-α, while they showed a significant effect on CRP levels [18]. However, two meta-analyses showed grape seed extract supplementation [20] and grape products containing polyphenols significantly reduced the CRP levels [19]. The inconclusive findings in the extant literature may be related to the different eligibility criteria used by the studies. For example, in the meta-analysis of grape products containing polyphenols, red wine and resveratrol interventions were also included in the analysis, which might distort our understanding of the actual effect of grape and its derivatives.

We also found that grape supplementation significantly increased catalase, ORAC, and TAC and decreased the TBARS levels. However, no significant changes were observed regarding carbonyl, ox-LDL, MDA, and SOD levels. The results of recent meta-analyses are also equivocal. In one study, grape products had no significant effect on TAC and MDA levels [18]. In another study, grape products containing polyphenols showed a significant increase in TAC, whereas they did not have any significant effect on SOD, MDA, ORAC, and GPx levels [19]. Moreover, grape seed extract supplementation significantly decreased MDA and ox-LDL along with eliciting an increase in TAC levels [20].

In the subgroup analysis, grape and its products significantly reduced the ox-LDL levels in hemodialysis patients. Hemodialysis patients exhibit oxidative stress throughout dialysis due to the accumulation of oxidative products (such as ox-LDL) and insufficient antioxidant ability [67]. Grape polyphenols are able to reduce lipid levels through pancreatic lipase inhibition, lipoprotein synthesis reduction in hepatocytes, and increasing fatty acid metabolism [68].

The present study has several strengths that should be acknowledged. To the best of our knowledge, this is the largest and most comprehensive meta-analysis to have examined the effects of grape/whole grape products on circulating levels of inflammatory and oxidative markers in adults. In addition, only RCTs were included in our study, permitting causal statements to be made. Previous meta-analyses regarding the effect of grape/grape products on oxidative and inflammatory markers have some limitations such as including grape seed and grape products containing polyphenols, which failed to show the real effect of grape and whole grape products on these factors. Furthermore, our search was more comprehensive, and we included all the studies with grape intervention without any missing publications. Moreover, it has been reported that has not enough power to show heterogeneity in meta-analysis with small number of studies [69], so the CI for has been reported in our study to avoid misconceptions.

However, despite the strengths outlined above, there are some potential limitations worth noting. First, the number of included studies for most outcomes (except for hs-CRP, IL-6, TNF, and ox-LDL) was small, which could affect the results’ validity. Second, several factors including sex, age, environmental factors, diet, and genetics might affect the bioavailability of polyphenols and physiological responses to oxidative stress [64], and we were unable to include all these variables in our subgroup analysis. Third, although all the eligible studies administered grape and its products, there was a wide variety of the interventions or grapes, which might affect the products’ antioxidant content due to different processing methods. This is probably the reason for the observed significant result regarding the geographical location for TNF-α and ox-LDL. It is suggested that future studies focus on the composition of nutrients of grapes depending on the geographical location of plant growth and their health effects. Fourth, based on the CI of , there was a considerable heterogeneity between studies for all outcomes, which we could not find the source of it. Fifth, some of the included studies used untreated group and some others used placebo as the control group. Although in dietary intervention studies, the criteria of a placebo group may not be possible to achieve, untreated groups are accepted as a control group in these studies. However, blinding in these studies may not be possible, but it may not matter for objective outcomes. Nevertheless, a subgroup analysis was performed and no significant differences between placebo- and untreated control studies were found (data not shown). Sixth, the methodological quality of most of the included studies was poor, and the certainty of evidence was low and very low for all the outcomes, mainly due to the small sample size for each outcome that did not reach the optimal information size, which means the observed results may change when further studies are added to the present analyses. Lastly, the compliance rate for most included studies was not mentioned, which might affect the results.

6. Conclusion

In conclusion, grape products can significantly improve some biomarkers of oxidative stress, although appear to have no significant effect on reducing inflammation in an adult population. Low certainty of evidence emphasizes the need to further good quality of randomized clinical trials to clarify the actual effect of grape and its derivatives on oxidative stress and inflammation.

Data Availability

The raw data required to reproduce these findings are available from the corresponding author.

Disclosure

The financial source had no role in the implementation, writing, or submitting the manuscript.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

SA and SS designed the review; RKM and SS conducted the major database search according to search strategy; FD and SS did data extraction; SS performed the analysis; FD, CC, and SA wrote the manuscript’s draft; and all authors have read and evaluated the final version of the manuscript precisely and approved it and agree with its submission to the Journal of Food Biochemistry.

Acknowledgments

The authors thank the North Khorasan University of Medical Sciences (Grant No. 4010162) for the financial support.

Supplementary Materials

Table S1: Literature search strategy terms. Table S2: PICO criteria for inclusion and exclusion of trials. Table S3: References of the excluded studies with reasons for exclusion. Table S4: Risk of bias assessment according to the Cochrane criteria for the studies regarding the effect of grape/grape products on inflammation and oxidative stress markers. Table S5: Assessing the quality of evidence regarding the effect of grape/whole grape products on oxidative stress and inflammatory markers by the GRADE system. Table S6: Subgroup analysis to assess the effect of grape/whole grape products on high-sensitivity C-reactive protein (hs-CRP) levels. Table S7: Subgroup analysis to assess the effect of grape/whole grape products on tumor necrosis factor alpha (TNF-α) levels. Table S8: Subgroup analysis to assess the effect of grape/whole grape products on interleukin 6 (IL-6) levels. Table S9: Subgroup analysis to assess the effect of grape/whole grape products on oxidized low-density lipoprotein (Ox-LDL) levels. Table S10: Subgroup analysis to assess the effect of grape/whole grape products on inflammatory and oxidative stress markers using DerSimonian–Laird and Hartung–Knapp–Sidik–Jonkman methods. Table S11: Meta-regression analysis of the potential source of heterogeneity. (Supplementary Materials)

References

M. Y. Ansari, N. Ahmad, and T. M. Haqqi, “Oxidative stress and inflammation in osteoarthritis pathogenesis: role of polyphenols,” Biomedicine & Pharmacotherapy, vol. 129, Article ID 110452, 2020.
View at: Publisher Site | Google Scholar
B. L. Tan, M. E. Norhaizan, and W.-P.-P. Liew, “Nutrients and oxidative stress: friend or foe?” Oxidative Medicine and Cellular Longevity, vol. 2018, Article ID 9719584, 24 pages, 2018.
View at: Publisher Site | Google Scholar
C. R. Reczek and N. S. Chandel, “ROS-dependent signal transduction,” Current Opinion in Cell Biology, vol. 33, pp. 8–13, 2015.
View at: Publisher Site | Google Scholar
A. Charlton, J. Garzarella, K. A. Jandeleit-Dahm, and J. C. Jha, “Oxidative stress and inflammation in renal and cardiovascular complications of diabetes,” Biology, vol. 10, no. 1, p. 18, 2020.
View at: Publisher Site | Google Scholar
T. Hussain, B. Tan, Y. Yin, F. Blachier, M. C. Tossou, and N. Rahu, “Oxidative stress and inflammation: what polyphenols can do for us?” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 7432797, 9 pages, 2016.
View at: Publisher Site | Google Scholar
C.-C. Chuang and M. K. McIntosh, “Potential mechanisms by which polyphenol-rich grapes prevent obesity-mediated inflammation and metabolic diseases,” Annual Review of Nutrition, vol. 31, no. 1, pp. 155–176, 2011.
View at: Publisher Site | Google Scholar
L. Zuo, E. R. Prather, M. Stetskiv et al., “Inflammaging and oxidative stress in human diseases: from molecular mechanisms to novel treatments,” International Journal of Molecular Sciences, vol. 20, no. 18, p. 4472, 2019.
View at: Publisher Site | Google Scholar
T. Magrone, M. Magrone, M. A. Russo, and E. Jirillo, “Recent advances on the anti-inflammatory and antioxidant properties of red grape polyphenols: in vitro and in vivo studies,” Antioxidants, vol. 9, no. 1, p. 35, 2019.
View at: Publisher Site | Google Scholar
V. Georgiev, A. Ananga, and V. Tsolova, “Recent advances and uses of grape flavonoids as nutraceuticals,” Nutrients, vol. 6, no. 1, pp. 391–415, 2014.
View at: Publisher Site | Google Scholar
A. Sabra, T. Netticadan, and C. Wijekoon, “Grape bioactive molecules, and the potential health benefits in reducing the risk of heart diseases,” Food Chemistry X, vol. 12, Article ID 100149, 2021.
View at: Publisher Site | Google Scholar
L. M. Vislocky and M. L. Fernandez, “Biomedical effects of grape products,” Nutrition Reviews, vol. 68, no. 11, pp. 656–670, 2010.
View at: Publisher Site | Google Scholar
P. Castilla, R. Echarri, A. Dávalos et al., “Concentrated red grape juice exerts antioxidant, hypolipidemic, and antiinflammatory effects in both hemodialysis patients and healthy subjects,” American Journal of Clinical Nutrition, vol. 84, no. 1, pp. 252–262, 2006.
View at: Publisher Site | Google Scholar
A. C. Kaliora, A. Kokkinos, A. Diolintzi et al., “The effect of minimal dietary changes with raisins in NAFLD patients with non-significant fibrosis: a randomized controlled intervention,” Food & Function, vol. 7, no. 11, pp. 4533–4544, 2016.
View at: Publisher Site | Google Scholar
T. L. Zern, R. J. Wood, C. Greene et al., “Grape polyphenols exert a cardioprotective effect in pre-and postmenopausal women by lowering plasma lipids and reducing oxidative stress,” Journal of Nutrition, vol. 135, no. 8, pp. 1911–1917, 2005.
View at: Publisher Site | Google Scholar
G. S. De Oliveira, G. S. Pinheiro, I. C. Proença et al., “Aquatic exercise associated or not with grape juice consumption-modulated oxidative parameters in Parkinson disease patients: a randomized intervention study,” Heliyon, vol. 7, no. 2, Article ID e06185, 2021.
View at: Publisher Site | Google Scholar
A. S. Bardagjy, Q. Hu, K. A. Giebler, A. Ford, and F. M. Steinberg, “Effects of grape consumption on biomarkers of inflammation, endothelial function, and PBMC gene expression in obese subjects,” Archives of Biochemistry and Biophysics, vol. 646, pp. 145–152, 2018.
View at: Publisher Site | Google Scholar
S. J. Zunino, J. M. Peerson, T. L. Freytag et al., “Dietary grape powder increases IL-1β and IL-6 production by lipopolysaccharide-activated monocytes and reduces plasma concentrations of large LDL and large LDL-cholesterol particles in obese humans,” The British Journal of Nutrition, vol. 112, no. 3, pp. 369–380, 2014.
View at: Publisher Site | Google Scholar
S. S. Ghalishourani, F. Farzollahpour, M. Shirinbakhshmasoleh et al., “Effects of grape products on inflammation and oxidative stress: a systematic review and meta‐analysis of randomized controlled trials,” Phytotherapy Research, vol. 35, no. 9, pp. 4898–4912, 2021.
View at: Publisher Site | Google Scholar
S. Sarkhosh-Khorasani, Z. S. Sangsefidi, and M. Hosseinzadeh, “The effect of grape products containing polyphenols on oxidative stress: a systematic review and meta-analysis of randomized clinical trials,” Nutrition Journal, vol. 20, no. 1, pp. 25–18, 2021.
View at: Publisher Site | Google Scholar
S. Foshati, M. H. Rouhani, and R. Amani, “The effect of grape seed extract supplementation on oxidative stress and inflammation: a systematic review and meta‐analysis of controlled trials,” International Journal of Clinical Practice, vol. 75, no. 11, Article ID e14469, 2021.
View at: Publisher Site | Google Scholar
F. Haghighatdoost, A. Gholami, and M. Hariri, “Effect of grape polyphenols on selected inflammatory mediators: a systematic review and meta-analysis randomized clinical trials,” EXCLI journal, vol. 19, pp. 251–267, 2020.
View at: Publisher Site | Google Scholar
M. J. Page, J. E. McKenzie, P. M. Bossuyt et al., “The prisma 2020 statement: an updated guideline for reporting systematic reviews,” Systematic Reviews, vol. 10, no. 1, pp. 1–11, 2021.
View at: Google Scholar
S. A. Bowman, “Added sugars: definition and estimation in the USDA food Patterns equivalents databases,” Journal of Food Composition and Analysis, vol. 64, pp. 64–67, 2017.
View at: Publisher Site | Google Scholar
J. P. Higgins, D. G. Altman, P. C. Gotzsche et al., “The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials,” BMJ, vol. 343, no. 2, p. d5928, 2011.
View at: Publisher Site | Google Scholar
G. H. Guyatt, A. D. Oxman, H. J. Schünemann, P. Tugwell, and A. Knottnerus, “GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology,” Journal of Clinical Epidemiology, vol. 64, no. 4, pp. 380–382, 2011.
View at: Publisher Site | Google Scholar
G. H. Guyatt, A. D. Oxman, R. Kunz et al., “Going from evidence to recommendations,” BMJ, vol. 336, no. 7652, pp. 1049–1051, 2008.
View at: Publisher Site | Google Scholar
I. Shemilt, M. Mugford, S. Byford et al., “15 Incorporating economics evidence,” Cochrane handbook for systematic reviews of interventions, vol. 12, p. 449, 2008.
View at: Google Scholar
R. DerSimonian and N. Laird, “Meta-analysis in clinical trials,” Controlled Clinical Trials, vol. 7, no. 3, pp. 177–188, 1986.
View at: Publisher Site | Google Scholar
J. IntHout, J. P. Ioannidis, and G. F. Borm, “The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method,” BMC Medical Research Methodology, vol. 14, pp. 25–12, 2014.
View at: Publisher Site | Google Scholar
J. P. Higgins, S. G. Thompson, J. J. Deeks, and D. G. Altman, “Measuring inconsistency in meta-analyses,” BMJ, vol. 327, no. 7414, pp. 557–560, 2003.
View at: Publisher Site | Google Scholar
M. Egger, J. P. Higgins, and G. D. Smith, Systematic Reviews in Health Research: Meta-Analysis in Context, John Wiley & Sons, Hoboken, NY, USA, 2022.
M. Egger, G. D. Smith, M. Schneider, and C. Minder, “Bias in meta-analysis detected by a simple, graphical test,” BMJ, vol. 315, no. 7109, pp. 629–634, 1997.
View at: Publisher Site | Google Scholar
B. Amoutzopoulos, G. B. Löker, G. Samur et al., “Effects of a traditional fermented grape-based drink 'hardaliye' on antioxidant status of healthy adults: a randomized controlled clinical trial,” Journal of the Science of Food and Agriculture, vol. 93, no. 14, pp. 3604–3610, 2013.
View at: Publisher Site | Google Scholar
J. Barona, C. N. Blesso, C. J. Andersen, Y. Park, J. Lee, and M. L. Fernandez, “Grape consumption increases anti-inflammatory markers and upregulates peripheral nitric oxide synthase in the absence of dyslipidemias in men with metabolic syndrome,” Nutrients, vol. 4, no. 12, pp. 1945–1957, 2012.
View at: Publisher Site | Google Scholar
P. Castilla, A. Dávalos, J. L. Teruel et al., “Comparative effects of dietary supplementation with red grape juice and vitamin E on production of superoxide by circulating neutrophil NADPH oxidase in hemodialysis patients,” The American Journal of Clinical Nutrition, vol. 87, no. 4, pp. 1053–1061, 2008.
View at: Publisher Site | Google Scholar
Z. Corredor, L. Rodríguez-Ribera, E. Coll et al., “Unfermented grape juice reduce genomic damage on patients undergoing hemodialysis,” Food and Chemical Toxicology, vol. 92, pp. 1–7, 2016.
View at: Publisher Site | Google Scholar
C. Dani, K. M. Dias, L. Trevizol et al., “The impact of red grape juice (Vitis labrusca)consumption associated with physical training on oxidative stress, inflammatory and epigenetic modulation in healthy elderly women,” Physiology & Behavior, vol. 229, Article ID 113215, 2021.
View at: Publisher Site | Google Scholar
M. M. Dohadwala, N. M. Hamburg, M. Holbrook et al., “Effects of Concord grape juice on ambulatory blood pressure in prehypertension and stage 1 hypertension,” American Journal of Clinical Nutrition, vol. 92, no. 5, pp. 1052–1059, 2010.
View at: Publisher Site | Google Scholar
Q. Duclos, “Effects of a Standardized, Freeze-Dried Grape Powder in Adults with Metabolic Syndrome,” Master's thesis, University of Connecticut, Storrs, CT, USA, 2017, https://digitalcommons.lib.uconn.edu/gs_theses/1121/.
View at: Google Scholar
M. Evans, D. Wilson, and N. Guthrie, “A randomized, double-blind, placebo-controlled, pilot study to evaluate the effect of whole grape extract on antioxidant status and lipid profile,” Journal of Functional Foods, vol. 7, pp. 680–691, 2014.
View at: Publisher Site | Google Scholar
M. Goulart, D. S. Pisamiglio, G. B. Möller et al., “Effects of grape juice consumption on muscle fatigue and oxidative stress in judo athletes: a randomized clinical trial,” Anais da Academia Brasileira de Ciencias, vol. 92, no. 4, Article ID e20191551, 2020.
View at: Publisher Site | Google Scholar
J. H. Hollis, J. A. Houchins, J. B. Blumberg, and R. D. Mattes, “Effects of concord grape juice on appetite, diet, body weight, lipid profile, and antioxidant status of adults,” Journal of the American College of Nutrition, vol. 28, no. 5, pp. 574–582, 2009.
View at: Publisher Site | Google Scholar
P. T. Kanellos, A. C. Kaliora, N. K. Tentolouris et al., “A pilot, randomized controlled trial to examine the health outcomes of raisin consumption in patients with diabetes,” Nutrition, vol. 30, no. 3, pp. 358–364, 2014.
View at: Publisher Site | Google Scholar
P. T. Kanellos, A. C. Kaliora, A. D. Protogerou, N. Tentolouris, D. N. Perrea, and V. T. Karathanos, “The effect of raisins on biomarkers of endothelial function and oxidant damage; an open-label and randomized controlled intervention,” Food Research International, vol. 102, pp. 674–680, 2017.
View at: Publisher Site | Google Scholar
S. Lafay, C. Jan, K. Nardon et al., “Grape extract improves antioxidant status and physical performance in elite male athletes,” Journal of Sports Science and Medicine, vol. 8, no. 3, pp. 468–480, 2009.
View at: Google Scholar
D. Martínez-Maqueda, B. Zapatera, A. Gallego-Narbón, M. P. Vaquero, F. Saura-Calixto, and J. Pérez-Jiménez, “A 6-week supplementation with grape pomace to subjects at cardiometabolic risk ameliorates insulin sensitivity, without affecting other metabolic syndrome markers,” Food & Function, vol. 9, no. 11, pp. 6010–6019, 2018.
View at: Publisher Site | Google Scholar
M. J. Puglisi, U. Vaishnav, S. Shrestha et al., “Raisins and additional walking have distinct effects on plasma lipids and inflammatory cytokines,” Lipids in Health and Disease, vol. 7, no. 1, pp. 14–19, 2008.
View at: Publisher Site | Google Scholar
A. R. Rahbar, M. M. Mahmoudabadi, and M. S. Islam, “Comparative effects of red and white grapes on oxidative markers and lipidemic parameters in adult hypercholesterolemic humans,” Food & Function, vol. 6, no. 6, pp. 1992–1998, 2015.
View at: Publisher Site | Google Scholar
J. Rankin, M. Andreae, C. Y. Oliver Chen, and S. O’keefe, “Effect of raisin consumption on oxidative stress and inflammation in obesity,” Diabetes, Obesity and Metabolism, vol. 10, no. 11, pp. 1086–1096, 2008.
View at: Publisher Site | Google Scholar
C. A. Rowe, M. P. Nantz, C. Nieves, R. L. West, and S. S. Percival, “Regular consumption of concord grape juice benefits human immunity,” Journal of Medicinal Food, vol. 14, no. 1-2, pp. 69–78, 2011.
View at: Publisher Site | Google Scholar
F. Shishehbor, P. Joola, A. S. Malehi, and M. A. Jalalifar, “The effect of black seed raisin on some cardiovascular risk factors, serum malondialdehyde, and total antioxidant capacity in hyperlipidemic patients: a randomized controlled trials,” Irish Journal of Medical Science, vol. 191, no. 1, pp. 195–204, 2022.
View at: Publisher Site | Google Scholar
J. Tomé-Carneiro, M. Gonzálvez, M. Larrosa et al., “Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: a triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease,” Cardiovascular Drugs and Therapy, vol. 27, no. 1, pp. 37–48, 2013.
View at: Publisher Site | Google Scholar
L. T. Toscano, A. S. Silva, L. T. Toscano et al., “Phenolics from purple grape juice increase serum antioxidant status and improve lipid profile and blood pressure in healthy adults under intense physical training,” Journal of Functional Foods, vol. 33, pp. 419–424, 2017.
View at: Publisher Site | Google Scholar
N. Vaisman and E. Niv, “Daily consumption of red grape cell powder in a dietary dose improves cardiovascular parameters: a double blind, placebo-controlled, randomized study,” International Journal of Food Sciences & Nutrition, vol. 66, no. 3, pp. 342–349, 2015.
View at: Publisher Site | Google Scholar
N. Yubero, M. Sanz-Buenhombre, A. Guadarrama et al., “LDL cholesterol-lowering effects of grape extract used as a dietary supplement on healthy volunteers,” International Journal of Food Sciences & Nutrition, vol. 64, no. 4, pp. 400–406, 2013.
View at: Publisher Site | Google Scholar
K. Yoshida, I. Ohguro, and H. Ohguro, “Black currant anthocyanins normalized abnormal levels of serum concentrations of endothelin-1 in patients with glaucoma,” Journal of Ocular Pharmacology and Therapeutics, vol. 29, no. 5, pp. 480–487, 2013.
View at: Publisher Site | Google Scholar
C. L. Millar, Q. Duclos, C. Garcia et al., “Effects of freeze-dried grape powder on high-density lipoprotein function in adults with metabolic syndrome: a randomized controlled pilot study,” Metabolic Syndrome and Related Disorders, vol. 16, no. 9, pp. 464–469, 2018.
View at: Publisher Site | Google Scholar
A. G. R. Janiques, V. O. Leal, M. B. Stockler-Pinto, N. X. Moreira, and D. Mafra, “Effects of grape powder supplementation on inflammatory and antioxidant markers in hemodialysis patients: a randomized double-blind study,” Jornal Brasileiro de Nefrologia, vol. 36, no. 4, pp. 496–501, 2014.
View at: Publisher Site | Google Scholar
C. T. Ammollo, F. Semeraro, R. A. Milella, D. Antonacci, N. Semeraro, and M. Colucci, “Grape intake reduces thrombin generation and enhances plasma fibrinolysis. Potential role of circulating procoagulant microparticles,” The Journal of Nutritional Biochemistry, vol. 50, pp. 66–73, 2017.
View at: Publisher Site | Google Scholar
J. Tomé-Carneiro, M. Gonzálvez, M. Larrosa et al., “One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease,” The American Journal of Cardiology, vol. 110, no. 3, pp. 356–363, 2012.
View at: Publisher Site | Google Scholar
K. Petersen and C. Smith, “Ageing-associated oxidative stress and inflammation are alleviated by products from grapes,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 6236309, 12 pages, 2016.
View at: Publisher Site | Google Scholar
K. Lambert, M. Coisy-Quivy, C. Bisbal et al., “Grape polyphenols supplementation reduces muscle atrophy in a mouse model of chronic inflammation,” Nutrition, vol. 31, no. 10, pp. 1275–1283, 2015.
View at: Publisher Site | Google Scholar
S. Abdollahi, F. Meshkini, C. C. Clark, J. Heshmati, and S. Soltani, “The effect of probiotics/synbiotics supplementation on renal and liver biomarkers in patients with type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials,” British Journal of Nutrition, vol. 128, no. 4, pp. 625–635, 2022.
View at: Publisher Site | Google Scholar
E. Elejalde, M. C. Villarán, and R. M. Alonso, “Grape polyphenols supplementation for exercise-induced oxidative stress,” Journal of the International Society of Sports Nutrition, vol. 18, no. 1, pp. 3–12, 2021.
View at: Publisher Site | Google Scholar
G. Annunziata, M. Jimenez-García, S. Tejada et al., “Grape polyphenols ameliorate muscle decline reducing oxidative stress and oxidative damage in aged rats,” Nutrients, vol. 12, no. 5, p. 1280, 2020.
View at: Publisher Site | Google Scholar
N. Yahfoufi, N. Alsadi, M. Jambi, and C. Matar, “The immunomodulatory and anti-inflammatory role of polyphenols,” Nutrients, vol. 10, no. 11, p. 1618, 2018.
View at: Publisher Site | Google Scholar
V. Liakopoulos, S. Roumeliotis, X. Gorny, E. Dounousi, and P. R. Mertens, “Oxidative stress in hemodialysis patients: a review of the literature,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 3081856, 22 pages, 2017.
View at: Publisher Site | Google Scholar
R. Lupoli, P. Ciciola, G. Costabile, R. Giacco, M. N. D. Di Minno, and B. Capaldo, “Impact of grape products on lipid profile: a meta-analysis of randomized controlled studies,” Journal of Clinical Medicine, vol. 9, no. 2, p. 313, 2020.
View at: Publisher Site | Google Scholar
T. B. Huedo-Medina, J. Sánchez-Meca, F. Marín-Martínez, and J. Botella, “Assessing heterogeneity in meta-analysis: Q statistic or I² index?” Psychological Methods, vol. 11, no. 2, pp. 193–206, 2006.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2024 Fereshteh Dehghani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

87

Downloads

46

Citations