Effect of Dietary Berry Supplementation on Antioxidant Biomarkers in Adults with Cardiometabolic Risks: A Systematic Review of Clinical Trials

Cardiometabolic conditions are closely associated with inflammation and oxidative stress. Dietary berries may serve as a beneficial nutrition intervention to address the features of cardiometabolic dysfunction and associated oxidative stress. The high antioxidant status of dietary berries may increase antioxidant capacity and reduce biomarkers of oxidative stress. This systematic review was conducted to investigate these effects of dietary berries. The search was conducted using PubMed, Cochrane Library, Web of Science, and citation searching. Through this search we identified 6309 articles and 54 were included in the review. Each study’s risk of bias was assessed using the 2019 Cochrane Methods’ Risk of Bias 2 tool. Antioxidant and oxidative stress outcomes were evaluated, and the magnitude of effect was calculated using Cohen’s d. A range of effectiveness was reported in the included studies and the quality of the studies differed between the parallel and crossover trials. Considering the inconsistency in reported effectiveness, future investigations are warranted to determine the acute and sustained reductions of oxidative stress biomarkers from dietary berry intake (PROSPERO registration# CRD42022374654).


Introduction
Cardiometabolic diseases represent four of the ten leading causes of death in the United States [1]. Between 1990 and 2017, cardiometabolic diseases accounted for nearly 5 million deaths of working-age adults [2]. A cluster of pathologies typify cardiovascular and metabolic diseases, including hypertension, insulin resistance, dyslipidemia, and visceral adiposity [3]. This cluster of pathologies is associated with inflammation due to the causality between active immune system and metabolic impairments [4]. Cardiometabolic risk factors can promote inflammation and be an outcome of exacerbated inflammatory processes. Hypertension increases the circulation of cytotoxic T cells, creating a pro-inflammatory physiological state [5]. Visceral adiposity is also a pro-inflammatory state that stimulates the immune system production of cytokines [6]. Inflammation disrupts insulin action and secretion [4], potentially contributing to insulin resistance. Similarly, cytokine inflammatory markers contribute to the accumulation of cholesterol seen in dyslipidemia [7].
Oxidative stress plays a major role in the pathology of inflammation and associated cardiometabolic diseases. While it is a complex cascade of physiological processes, oxidative stress can simply be explained as an imbalance of reactive oxygen species and         This search yielded 6299 articles from databases, and after removing duplicates, 2586 articles were screened. An additional 2687 articles were identified through citation searching. In total, 54 studies (~2040 participants) were included in this review ( Figure 1). All included studies were randomized controlled trials-30 used a parallel design and 24 used a crossover designed. Overall, 37 studies measured the effects of berries in adults with features of MetS   (Table 1) and 17 studies measured these same effects in adults with obesity or overweight [64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] (Table 2).

Quality Assessment
Using the Risk of Bias 2 tool, we assessed all of the study's assignment to the intervention. Studies were assessed based on study design as parallel (Table 3) or crossover (Table 4) trials. Both the parallel and crossover studies had some concerns with randomization and the crossover studies had some concern with period and carryover effects. Overall, the majority (61%) of assessed studies had a low risk of bias, 19% had a high risk of bias, and 20% had some concerns.     [33,49,63].
Out of the studies assessing oxidative stress biomarkers, 15 studies reported statistically significant changes in the outcomes [30,31,36,38,43,45,48,50,51,53,54,56,[58][59][60][61]. Across the studies, the most common oxidative stress biomarker was oxidized products, in particular oxidized LDL-C. Intake of freeze-dried strawberry powder [59], Korean blackberry [30], freeze-dried blueberry powder [56], cranberry juice [61], and black raspberry [45] reduced levels of oxidized LDL-C, with acute freeze-dried strawberry powder consumption (10 g with a high-fat meal) having the largest effect (d = 4.97). These berry interventions reduced plasma-oxidized LDL-C by 9 to 34% from baseline. In addition to oxidized LDL-C, freezedried blueberry powder also significantly reduced oxidized purines in blood mononuclear cells with a moderate effect (d = 0.60) [53]. Cranberry juice also significantly reduced levels of lipid peroxidation and protein oxidation, however the magnitude of effect cannot be determined due to omitted data from the study [54]. Due to the heterogeneity of the interventions, dose-response relationships between berry intake and oxidized products reductions are challenging to infer.
In addition to oxidized products, biomarkers of oxidative damage were significantly reduced by freeze-dried strawberry powder [50], dried whortleberry [51], and freeze-dried blueberry powder [56]. A low (25 g) and high (50 g) dose of freeze-dried strawberry powder reduced combined malondialdehyde and 4-hydroxy-2-nonenal by approximately 33% from baseline with a very large between group effect (d = 2.62 and 7.20, respectively) [50]. A dosage of 500 mg of dried whortleberry reduced malondialdehyde by 12% from baseline with a moderate between group effect (d = 0.57) [51]. Because of omitted baseline values, the magnitude of effect of freeze-dried blueberry powder on malondialdehyde and 4-hydroxy-2-nonenal cannot be determined [56]. As a biomarker of lipid peroxidation, concentrations of 8-isoprostanes were statistically significantly reduced from baseline by 31% and 4% by acaí pulp [36] and cranberry powder [31], respectively. Both of these interventions had a modest effect between groups (d = 0.33 and 0.42 respectively). Similarly, strawberries [60] and aronia extract [58] reduced thiobarbituric acid reactive substances, a measurement of lipid peroxidation, with a large effect (d = 1.36 and 1.25, respectively). With respect to oxidative damage in deoxyribonucleic acid, freeze-dried blueberries reduced hydrogen peroxide damage by 2%, as measured by percent of deoxyribonucleic acid in tail [53]. The blueberry powder had a medium effect on the damage reduction (d = 0.85) [53]. These data suggest that strawberry intake has the greatest effect of reducing peroxidation in cells and blueberry intake has protective effects on nucleic acid oxidative damage.
Antioxidant enzymatic activity was also assessed to determine the effect of dietary berries in neutralizing reactive oxygen species. Intake of 100 mg of aronia extract for two months significantly increased serum superoxide dismutase (29% from baseline) and decreased serum catalase (18% from baseline) [58]. The intervention had a very large between group effect on superoxide dismutase (d = 2.18) and a large effect on catalase (d = 1.33) [58]. Freeze-dried blueberry powder for two months also increased serum superoxide dismutase by 138%, however the study did not provide between group statistical analysis and thus the magnitude of effect cannot be calculated [48]. Interestingly, serum superoxide dismutase also increased by 113% in the group of participants receiving the macronutrient-matched placebo powder [48]. The statistically significant increase within the intervention and comparison groups suggests the increase in enzymatic activity may not be related to the berry intervention. Whole blood and monocyte superoxide dismutase production rates, on the other hand, statistically significantly reduced with consumption of freeze-dried blueberries [38]. Wolfberry extract also reduced erythrocyte superoxide dismutase and increased erythrocyte catalase activities [43]. The magnitude of effect from the freeze-dried blueberry [38] or wolfberry [43] interventions cannot be calculated due to data omitted in each study. Based on these findings, aronia extract appears to have the greatest effect on serum oxidative stress enzymatic activity but quantifying enzymatic activity in blood cells is a challenge.
Similar to the studies that exclusively assessed oxidative stress, the studies that assessed biomarkers in both categories of outcomes predominately measured oxidized products and oxidative damage in addition to antioxidant capacity. Eight weeks of cranberry juice consumption reduced oxidized LDL-C by 33%, combined malondialdehyde and 4-hydroxy-2-nonenal by 50%, and increased plasma antioxidant capacity by 47% from baseline [55]. Compared to the placebo group, the intervention had a moderate to very large effect on each of these outcomes (d between 0.67 to 2.06) [55]. Acute consumption of freeze-dried strawberry powder also statistically significantly reduced oxidized LDL-C but did not have an impact on total antioxidant capacity quantified by oxygen radical absorbance capacity [47]. These data suggest that cranberries may have a more comprehensive effect on protecting against oxidative stress by reducing oxidized products and increasing antioxidant capacity.
In addition to antioxidant capacity, three studies also measured enzymatic activity related to oxidative stress [27,39,46]. Low dose (25 g) and high dose (50 g) of freeze-dried strawberry powder consumed for 12 weeks statistically significantly increased plasma antioxidant capacity with an immense effect (d = 4.33 and 7.60, respectively) [46]. The doses resulted in an 81% and 72% increase in antioxidant capacity from baseline, respectively [46]. Both doses of the intervention also immensely increased serum whole blood glutathione reductase (d = 4.61 and 10.75, respectively), while only the low dose had a significant impact on serum catalase (76% increase) with a large effect (d = 2.07) [46]. Freeze-dried strawberry powder at a low dose (13 g) and high dose (32 g) consumed for four weeks also statistically significantly increased serum antioxidant capacity [27]. Interestingly, these doses had lower antioxidant capacity increases from baseline (25% and 40%, respectively) and only had a moderate effect on the outcome (d = 0.37 and 0.62, respectively) [27]. These results suggest that longer exposure to the intervention amplifies the improvements in serum antioxidant capacity. These doses of freeze-dried strawberry powder also increased serum superoxide dismutase by 100% and 200%, respectively [27]. The 32 g dose had a larger effect on this outcome (d = 1.00 versus 0.51) [27]. Erythrocyte superoxide dismutase, on the other hand, statistically significantly decreased with consumption of goji berries [39]. Consumption of goji berries also reduced erythrocyte catalase and increased serum antioxidant capacity and blood reduced glutathione [39]. The magnitude of effect of the goji berries, however, cannot be calculated based on the data provided in the study [39].
Two studies assessed the effects of different species of blueberries on oxidative stress in nucleic acids in addition to antioxidant biomarkers [35,42]. A 22 g blend of highbush and Rubel blueberries had an immense effect (d = 4.54) on reducing 8-hydroxy-2deoxyguanosine (13% reduction from baseline), however the reduction was not sustained from week four to week eight [42]. This blend of blueberries did not have any statistically significant impact on serum glutathione reductase [42]. Andean blueberries, on the other hand, only had a moderate effect on reducing 8-hydroxy-2 -deoxyguanosine (d = 0.54) but did increase antioxidant capacity as measured using the 2,2-diphenyl-1-picrylhydazyl method [35]. The Andean blueberry effect on antioxidant capacity was small (d = 0.31). The findings from these two studies suggest that consuming these species of blueberries for increasing antioxidant capacity may have limited practical meaningfulness.
Finally, neither chokeberry [62] nor bilberry [57] juice improved biomarkers of lipid peroxidation, but both did increase plasma availability of antioxidants. Chokeberry juice increased concentration of vitamin A with a large effect (d = 0.94) [62] and bilberry juice increased plasma quercetin and p-coumaric acid [57]. The magnitude of the bilberry juice's effect cannot be calculated due to omitted data in the study. Of the studies that only assessed antioxidant outcomes, none reported statistically significant findings.
Among the studies assessing both categories of biomarkers, three reported significant changes in the outcomes [64,73,78]. A 250 mg and 500 mg dosage of Indian gooseberry increased serum glutathione from baseline by 24% and 53%, respectively, after 12 weeks of supplementation [64]. Between groups, the 250 mg intervention had a large effect on plasma glutathione (d = 0.99) and the 500 mg intervention had a very large effect (d = 2.79). Similarly, 500 mg of raspberry ketone supplementation for 12 weeks yielded a 26% increase in serum glutathione from baseline [73]. The raspberry ketones had a large effect this increase (d = 1.37) in between group analysis [73]. Both Indian gooseberries and raspberry ketones also yielded a statistically significant decrease in serum malondialdehyde. The 250 mg dosage of Indian gooseberries decreased serum malondialdehyde by 21% with a large effect (d = 1.69) and the 500 mg dosage decreased the biomarker by 31% with a very large effect (d = 2.90) [64]. The 500 mg of raspberry ketones decreased the biomarker by 43%; however, the intervention only had a medium effect (d = 0.42) [73]. These results suggest similar effectiveness between Indian gooseberry and raspberry ketones on serum glutathione and malondialdehyde after 12 weeks in adults with overweight [64] and obesity [73]. The third study measured plasma F 2 -isoprostanes, lipid hydroperoxides, and total plasma antioxidant potential after three weeks of consuming 250 mg of blueberries [78]. This dosage of blueberries decreased plasma concentration of lipid hydroperoxides by 50% from baseline [78]. The article omitted necessary data to determine between group change or effect size.
Of the studies assessing only antioxidant biomarkers, five reported statistically significant changes in the outcomes [70,74,77,79,80]. Indeed, 10, 20, and 40 g of freeze-dried strawberry powder yielded statistically significant increases in peak plasma anthocyanin concentration [74]. Pelargonidin-O-glucuronide increased by 93, 167, and 226 nmol/L, respectively, with exceptionally large effect sizes (d = 6.74, d = 4.66 d = 12.02, respectively). The reported 11, 13, and 16 nmol/L increase in pelargonidin-3-O-glucoside did not statistically differ between 10, 20, and 40 g of supplementation. Similarly, the reported 4 and 5 nmol/L increase in cyanidin-3-O-glucoside from 10 and 20 g supplementation, respectively, did not statistically differ from one another, but the 40 g supplementation yielded a statistically significant increase of 7 nmol/L with a large effect (d = 3.87). A second study reported similar results with 34 g of freeze-dried strawberry powder statistically significantly increasing plasma pelargonidin sulfate and pelagonidin-3-O-glucoside by approximately 15% and 86% compared to the comparison group [77]. The study omitted data necessary to calculate effect size of the intervention. A third study also reported statistically significant increases in plasma phenolic compounds after fresh strawberry consumption [79]. The magnitude of change and effect of the intervention compared to the comparison group cannot be calculated due to omitted data in the article. That said, these three studies suggest a high bioavailability of fresh and freeze-dried strawberries that result in increased plasma antioxidant biomarkers in individuals with obesity and overweight.
The other two studies that assessed only antioxidant biomarkers reported statistically significant changes in antioxidant capacity using multiple methods (2,2-diphenyl-1-picrylhydrazyl scavenging capacity [74], ferric reducing ability of plasma [74,80], and oxygen radical absorbance capacity [80]). A beverage with 240 g of fresh strawberries increased oxygen radical absorbance capacity and ferric reducing ability of plasma by 12% and 10%, respectively, compared to a control beverage four hours after consumption [80]. The intervention had a moderate effect on the increase in oxygen radical absorbance capacity and ferric reducing ability of plasma (d = 0.84 and d = 0.61, respectively). Ferric reducing ability of plasma and non-urate ferric reducing ability of plasma also statistically significant increased after seven-day consumption of 500 g of fresh strawberries [80]. Compared to fasting values, non-urate ferric reducing ability of plasma increased by 26% after strawberry consumption [80]. The strawberry consumption also yielded a statistically significant decrease in 2,2-diphenyl-1-picryl-hydrazyl scavenging capacity on the eleventh and fourteenth day of consumption compared to baseline (44% and 40%, respectively) [80]. Data to determine effect size differences between groups was not provided. Although effect of the intervention could not be calculated for both studies, these results suggest increased antioxidant capacity from the consumption of fresh strawberries in overweight adults.
An additional study that assessed plasma antioxidant outcomes did not provide statistical analysis of results but reported concentration of anthocyanins and phenolic acids across 24 h after consumption of 25 g freeze-dried strawberries [67]. Zhong et al. reported peonidin glycosides having the highest fractional bioavailability, vanillic acid glucuronide having the highest concentration, and a biphasic response of anthocyanin glucuronide metabolites [67].
In the studies assessing only oxidative stress outcomes, two reported statistically significant decreases in the related biomarkers [66,72]. Consumption of 50 g of freezedried strawberry powder reduced serum 4-hydroxynonenal-2-nonenal-modified proteins, however data are not available to calculate the magnitude of effect [66]. The second study reported reductions in oxidized LDL-C and urinary F 2 -isoprostanes compared to baseline after consumption of 150 mg maqui berry extract [72]. Similar to the previously mentioned study, data are not available to calculate the magnitude of effect. Both of these studies suggest protective implications from berry consumption on oxidative stress, but the strength of the relationship cannot be determined based on the available data.

Secondary Outcomes
In addition to biomarkers of antioxidant status and oxidative stress, some studies assessed features of the MetS (i.e., triglycerides, blood pressure, blood glucose, waist circumference, and high-density lipoprotein cholesterol). One study reported the prevalence of MetS after the intervention, and daily consumption of agraz nectar resulted in 22.5% fewer women having at least three MetS criteria after four weeks; thus, they no longer had MetS [35]. This study, however, did not report specificity on the metabolic features that were reduced in the women who no longer had MetS after the intervention [35].
Whortleberry [51], chokeberry [62], aronia extract [58], and gooseberry [64] reduced triglyceride concentrations by 18.5 mg/dL [64] to 49.6 mg/dL [51]. Gooseberry yielded a dose-dependent reduction with the larger dosage (500 mg versus 250 mg) resulting in a 76% greater reduction [64]. Similarly, chokeberry [62] and aronia extract [58] reduced diastolic and systolic blood pressure by 5-7 mmHg and 11.5-13.5 mmHg, respectively. Freeze-dried blueberry powder yielded a similar reduction in diastolic blood pressure [48], but a lesser reduction in systolic blood pressure (7 mmHg) [48,56]. Chokeberry consumption also reduced serum glucose by 7.7 mg/dL [62]. Of the final two criteria for MetS, waist circumference was reduced by goji berry [39], raspberry ketones [73], and cranberry juice [63] by 6 cm, 4 cm, and 2 cm, respectively. Cranberry juice [63] and aronia extract [58] both increased high-density lipoprotein cholesterol by approximately 1.5 mg/dL. The increase from the aronia extract, however, was not great enough to surpass 40 mg/dL which is the minimum concentration of high-density lipoprotein cholesterol to not meet MetS features. Even though not all the studies assessed each criterion of MetS, these results suggest that chokeberry may be the most effective in modulating features of MetS.

Discussion
The results of our systematic review documented a range of effectiveness of berry interventions in addressing oxidative stress and antioxidant biomarkers in adults. In individuals with features of MetS and in individuals with overweight or obesity, the percentage of reported significant improvements were similar (62% and 58% of studies). Consumption of 50 g of freeze-dried strawberries for 12 weeks had the largest effect on these outcomes, specifically increasing antioxidant capacity (d = 7.60) and whole blood glutathione reductase (d = 10.75), in adults with obesity and elevated serum lipids [46]. This dosage of freeze-dried strawberries also had large effects on decreasing combined levels of malondialdehyde and 4-hydroxynonenal (d = 7.20) in hyperlipidemic adults [50]. Multiple interventions also significantly reduced oxidized LDL in adults with features of MetS (within and between group analysis); however, due to omitted data the magnitude of effect could not be calculated. In overweight adults, 12-week supplementation of 1000 mg of Indian gooseberry largely increased levels of glutathione (d = 2.79) and decreased levels of malondialdehyde (d = 2.90) [64]. Various doses of freeze-dried strawberry powder also substantially increased antioxidant activity as measured by phenolic compounds in adults with obesity (d between 3.06 and 12.02) [74]. Collectively, the berry interventions in adults with overweight or obesity had less significant effects on oxidative stress biomarkers.
Each of the features of MetS-hypertension, hyperglycemia, dyslipidemia, and abdominal obesity [81]-have some relationship with oxidative stress. Animal models have demonstrated a causal relationship between nitrogen oxides and hypertension induced by angiotensin II [82]. In mice deficient of nicotinamide adenine dinucleotide oxidase 1, vascular superoxide production and gradual blood pressure increase were stunted in the aorta after infusion of angiotensin II [83]. In wild type mice, however, this infusion increased blood pressure and vascular superoxide production [83]. A similarly designed study also produced these results in addition to reduced media hypertrophy [84], supporting the relationship between nicotinamide adenine dinucleotide oxidase-generating reactive oxygen species and induced hypertension. Increased and dysregulated blood glucose levels increase biomarkers of oxidative stress through various pathways such as mitochondrial mechanisms, cellular antioxidant systems, and lipid peroxidation [85]. Hyperglycemia glycates metabolic end products in the extracellular matrix which bind with certain receptors to increase the production of reactive oxygen species [86]. In addition, glycation effects enzymatic activity which is demonstrated in reduced activity of catalase and superoxide dismutase in diabetic rats compared to control rats [87]. Finally, visceral adiposity is positively associated with dyslipidemia due to increased plasma free fatty acids [88,89]. Both of these features increase oxidative stress by activating reduced nicoti-namide adenine dinucleotide phosphate, and animal models have indicated induction of this pathway by white adipose tissue [90].
In addition to the relationship between MetS and oxidative stress, MetS was also reported to decrease antioxidant status [91]. Thus, the findings of the present review may play an influential role in improving health outcomes in individuals with MetS. Glutathione reductase modulates reactive oxygen species by increasing antioxidant activity [92], malondialdehyde and 4-hydroxynonenal are both byproducts of lipid peroxidation [93], and oxidized LDL-C is atherogenic [94] and strongly associated with MetS [95][96][97]. Serum levels of glutathione are 30 to 60% less in individuals with MetS [91,95]. Thus, increasing glutathione reductase may modulate the decreased antioxidant status by increasing the supply of reduced glutathione. Improvements in antioxidant activity and reductions in lipid peroxidation byproducts may improve an individual's blood pressure, blood glucose levels, and lipid metabolism. In a longitudinal study, dietary antioxidant capacity was negatively correlated to hypertension and increases in capacity reduced risk of abdominal obesity by 38% [98]. Thus, the findings from this review provide meaningful mechanisms to address the decreased antioxidant status and increased oxidative stress found in individuals with features of MetS.
The reported results in individuals with overweight or obesity similarly reflect the relationship between adiposity and oxidative stress. Adiposity diminishes plasma redox status by nearly 50%, reduces serum levels of glutathione by 26%, and increases advanced glycated end products by 23% compared to healthy controls [91]. Animal models also confirm reduced antioxidant capacity in obesogenic conditions with 30% reduced total antioxidant status and reduced erythrocyte catalase and superoxide dismutase activity compared to control rats [99]. Similarly, plasma hydroperoxide levels are 48% higher in obese rats than in control rats. The findings from this review suggest promising interventions such as freeze-dried and fresh strawberries increasing plasma antioxidant compounds [74,79], raspberry ketones increasing glutathione levels [73], and modest increases in antioxidant capacity from fresh strawberries [80].
The certainty of evidence from this review is dependent on the study design. The parallel studies were more robust with limited missing outcome data and low concerns of measurement of outcomes and reported results. The findings from these studies represent the true treatment effects since the majority of studies had a low overall risk of bias. That said, the crossover studies had a higher risk of bias with concerns related to carryover effects, deviation from the intervention, and selection of reported results. The effects of the crossover studies should be interpreted with caution due to these concerns. For both study designs, more information from the authors about random sequence allocation and baseline participant data would have improved randomization-related bias. For the crossover trials, study designs could have been improved with justification of the time of the washout period, the inclusion of period effects in the analysis and reporting of all eligible results.
Although most studies had a low risk of bias and the parallel trials had a robust study design allowing for strong certainty of evidence, there are methodological limitations to the studies included in this review. The included studies do not address sustained improvements of oxidative stress and antioxidant biomarkers. The results may not be maintained after the exposure time or plateau. In addition, while all the participants had at least one cardiometabolic risk factor, the heterogeneity of characteristics limits the generalizability of the findings broadly to any cardiometabolic risk factor. The favorable effects reported in this review may be specifically linked to each group of participants' risk factors (e.g., dyslipidemia compared to obesity). The studies also had heterogeneity in berries used, dosage, and time of exposure. The difference in dosage and time of exposure challenges the ability to make meaningful dietary recommendations based on these findings. Despite these limitations, the present review followed the structured and focused search and selection processes as defined by the PRISMA 2020 statement, which strengthens the evaluation of the findings [23].

Conclusions
In conclusion, the effect of berry intake on oxidative stress and antioxidant status in individuals with cardiometabolic risk factors is promising, but inconsistent across berry type and exposure time. Based on the included studies, berries yield greater effects on oxidative stress biomarkers in individuals with features of MetS compared to those with only overweight or obesity (Figure 2). Berries did positively affect antioxidant capacity in both sets of participants. Due to the quality of study design, the evidence from the parallel trials is stronger than that of crossover trials, thus some results should be analyzed with caution. That said, clinical practice and public health nutrition approaches can still incorporate the findings of this review as the promotion of berry intake aligns with standard nutrition recommendations (Table 5). Future investigations should address the concerns mentioned related to quality of study design and incorporate long-term follow-up to assess sustained effects of berry intake.
factors (e.g., dyslipidemia compared to obesity). The studies also had heterogeneity in berries used, dosage, and time of exposure. The difference in dosage and time of exposure challenges the ability to make meaningful dietary recommendations based on these findings. Despite these limitations, the present review followed the structured and focused search and selection processes as defined by the PRISMA 2020 statement, which strengthens the evaluation of the findings [23].

Conclusions
In conclusion, the effect of berry intake on oxidative stress and antioxidant status in individuals with cardiometabolic risk factors is promising, but inconsistent across berry type and exposure time. Based on the included studies, berries yield greater effects on oxidative stress biomarkers in individuals with features of MetS compared to those with only overweight or obesity (Figure 2). Berries did positively affect antioxidant capacity in both sets of participants. Due to the quality of study design, the evidence from the parallel trials is stronger than that of crossover trials, thus some results should be analyzed with caution. That said, clinical practice and public health nutrition approaches can still incorporate the findings of this review as the promotion of berry intake aligns with standard nutrition recommendations (Table 5). Future investigations should address the concerns mentioned related to quality of study design and incorporate long-term follow-up to assess sustained effects of berry intake.  Increased enzymatic activity [58] Reduced blood pressure [58] Increased high-density lipoprotein cholesterol [58] 22 g blueberries (freeze-dried) Reduced cellular oxidative stress [42] Reduced lipid peroxidation byproducts [48,56] Increased enzymatic activity [48] Reduced blood pressure [48,56]   Increased enzymatic activity [58] Reduced blood pressure [58] Increased high-density lipoprotein cholesterol [58] 22 g blueberries (freeze-dried) Reduced cellular oxidative stress [42] Reduced lipid peroxidation byproducts [48,56] Increased enzymatic activity [48] Reduced blood pressure [48,56] 250 mL chokeberry juice None reported Increased antioxidant concentration [62] Reduced triglycerides [58] Reduced serum glucose [62] 240 mL cranberry juice Reduced lipid peroxidation byproducts [55] Increased antioxidant capacity [55] Reduced waist circumference [63] Increased high-density lipoprotein cholesterol [63] 14 g goji berry Reduced lipid peroxidation byproducts [39] Increased enzymatic activity [39] Increased antioxidant concentration [39] Increased antioxidant capacity [39] Reduced waist circumference [39]  Increased enzymatic activity [64] Reduced triglycerides [64] 500 mg raspberry ketones None reported Increased antioxidant concentration [73] Reduced waist circumference [73] 10-25 g strawberries (freeze-dried) Reduced lipid peroxidation byproducts [50] Increased enzymatic activity [27,46]