Nutritional and Phytochemical Characterization of Freeze-Dried Raspberry (Rubus idaeus): A Comprehensive Analysis.

Several studies have highlighted the beneficial effects of consuming red raspberries on human health thanks to their high content of phytochemicals. However, the products used in these studies, both in the raw or freeze-dried form, were not fully characterized for nutrient and phytochemical composition. In this study, we aimed to determine the nutrient and non-nutrient compounds present in a freeze-dried red raspberry powder widely used by the food industry and consumers. The main sugars identified were fructose (12%), glucose (11%), and sucrose (11%). Twelve fatty acids were detected, with linoleic acid (46%), α-linolenic acid (20%), and oleic acid (15%) being the most abundant. Regarding micronutrients, vitamin C was the main hydro-soluble vitamin, while minerals, potassium, phosphorous, copper and magnesium were the most abundant, with concentrations ranging from 9 up to 96 mg/100 g, followed by manganese, iron and zinc, detected in the range 0.1-0.9 mg/100 g. Phytochemical analysis using UHPLC-DAD-HR-MS detection revealed the presence of Sanguiin H6 (0.4%), Lambertianin C (0.05%), and Sanguiin H-10 isomers (0.9%) as the main compounds. Among anthocyanins, the most representative compounds were cyanidin-3-sophoroside, cyanidin-3-glucoside and cyanidin-3-sambubioside. Our findings can serve as a reliable resource for the food industry, nutraceutical applications and for future investigations in the context of human health.

In Vitro and In Vivo Evaluation of Bioactive Compounds from Berries for Wound Healing.

Managing chronic wounds can be challenging and have a major impact on the quality of life, due to the significant financial and psychosocial burden on the affected individuals and their families. The need for safe, effective, and cost-efficient wound healing remedies has led to the identification of naturally occurring bioactive compounds with positive effects on tissue regeneration. Berry fruits are a promising source of such compounds and may therefore prove distinctively beneficial. Here, we present a qualitative review of the available evidence specifically investigating the effects of berry extracts on in vitro and in vivo models of wound healing. The evidence shows that a variety of berry extracts significantly promote wound healing through their antibacterial, antioxidant, and anti-inflammatory properties as well as their ability to stimulate collagen synthesis, re-epithelization, granulation, and vascularization pathways. However, data are still insufficient to pinpoint the differential effect that individual berries may have based on their nutrient and bioactive profile, the type and frequency of application, and the dosage required. Future research is needed in view of translating the available evidence into practice for clinical wound treatment.

Wild blueberry (V. angustifolium) improves TNFα-induced cell barrier permeability through claudin-1 and oxidative stress modulation in Caco-2 cells.

Increasing evidence links the impairment of intestinal permeability (IP), a feature of the intestinal barrier, to numerous dysmetabolic and dysfunctional conditions. Several host and environmental factors, including dietary factors, can negatively and/or positively affect IP. In this regard, polyphenol-rich foods including berries have been proposed as potential IP modulators. However, the exact mechanisms involved are not yet fully elucidated. The aim of the present study was to evaluate the effect of a wild blueberry (WB; V. angustifolium) powder, naturally rich in polyphenols, to affect Caco-2 cell monolayer permeability and to identify the potential mechanisms in modulating the IP process. Caco-2 cells were incubated with TNF-α (10 ng mL-1), as a pro-inflammatory stimulus, and supplemented for 24 hours with different concentrations (1 and 5 mg mL-1) of WB powder. The integrity of the intestinal cell monolayer was evaluated by measuring the transepithelial electrical resistance (TEER) and the paracellular transport of FITC-dextran. In addition, the production of the tight junction proteins, such as claudin-1 and occludin, as well as protein carbonyl and 8-hydroxy 2 deoxyguanosine, as oxidative stress markers, were quantified in the supernatant by ELISA kits. Overall, the treatment with WB powder (5 mg mL-1) mitigated the loss of Caco-2 cell barrier integrity, as documented by an increase in TEER and a reduction in FITC values. This modulation was accompanied by an upregulation of claudin-1 and a reduction of 8-OHdG. Conversely, no effect was documented for the lower concentration (1 mg mL-1) and the other IP markers, as well as oxidative stress markers analysed. In conclusion, our findings suggest a potential role of WB in the modulation of cell barrier integrity. This modulation process could be attributed to an increase in claudin-1 expression and a reduction in 8-OHdG. Further studies should be performed to corroborate the results obtained. In addition, since the effects were observed at doses of WB achievable with the diet, these findings should be substantiated also through in vivo approaches.

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).

Berry Dietary Interventions in Metabolic Syndrome: New Insights.

Metabolic Syndrome (MetS) is characterized by a group of dysmetabolic conditions, including abdominal obesity, dyslipidemia, glucose intolerance and/or insulin resistance, and hypertension. Generally, MetS is accompanied by an exacerbation of oxidative stress, inflammation, and vascular dysfunction. Increasing evidence suggests that berries and berry bioactives could play a potential role in the prevention and mitigation of the risk factors associated with MetS. The present systematic review summarizes the more recently available evidence deriving from human intervention studies investigating the effect of berries in subjects with at least three out of five MetS parameters. The PubMed, Scopus, and Embase databases were systematically searched from January 2010 until December 2022. A total of 17 human intervention trials met the inclusion criteria. Most of them were focused on blueberry (n = 6), cranberry (n = 3), and chokeberry (n = 3), while very few or none were available for the other berries. If considering MetS features, the main positive effects were related to lipid profile (low and high-density lipoproteins, cholesterol, and triglycerides) following blueberries and chokeberries, while conflicting results were documented for anthropometric parameters, blood pressure, and fasting blood glucose levels. Other markers analyzed within the studies included vascular function, oxidative stress, and inflammation. Here, the main positive effects were related to inflammation with a reduction in interleukin 6 and tumor necrosis factor-alpha following the intake of different berries. In conclusion, although limited, the evidence seems to support a potential role for berries in the modulation of lipid profile and inflammation in subjects with MetS. Furthermore, high-quality intervention trials are mandatory to demonstrate the role of berries in reducing risk factors for MetS and related conditions. In the future, such a demonstration could bring the adoption of berries as a potential dietary strategy to prevent/counteract MetS and related risk factors.

Blueberries and their bioactives in the modulation of oxidative stress, inflammation and cardio/vascular function markers: a systematic review of human intervention studies.

Blueberries represent a rich source of (poly)phenols and other bioactive compounds. Numerous in vitro and animal model studies documented the potential health-promoting properties of blueberries and blueberry-bioactives, while little is still known about their effects in humans. The objective of the present systematic review is to provide main evidence and the potential mechanisms of action of blueberry and its (poly)phenols in the regulation of markers related to oxidative stress, inflammation, vascular and cardiometabolic function in health and disease states. A total of 45 human intervention studies were included in this review. Overall, the evidence suggests that blueberries may play a role in the improvement of markers of vascular function. Their effects were observed following both post-prandial and long-term consumption, particularly in subjects with risk factors and/or disease conditions. Conversely, the conflicting results on inflammation, oxidative stress and cardiometabolic risk markers were most likely due to differences among studies in terms of study design, subject characteristics, duration of intervention, dosage, and type of biomarkers analyzed. For these reasons, high-quality, well-designed, human intervention studies are warranted to strengthen the current findings on vascular function and provide more evidence about the impact of blueberries on the different markers considered. In addition, studies focusing on the relationship between the structure and the function of (poly)phenols will be fundamental for a better comprehension of the mechanisms behind the health effects observed.

The Role of Berry Consumption on Blood Pressure Regulation and Hypertension: An Overview of the Clinical Evidence.

The existence of a relationship between the consumption of dietary berries and blood pressure reduction in humans has been repeatedly hypothesized and documented by an increasing body of epidemiological and clinical evidence that has accumulated in recent years. However, results are mixed and complicated by a number of potentially confounding factors. The objective of this article is to review and summarize the available clinical evidence examining the effects of berry consumption on blood pressure regulation as well as the prevention or treatment of hypertension in humans, providing an overview of the potential contribution of distinctive berry polyphenols (anthocyanins, condensed tannins and ellagic acid), and results of dietary interventions with blueberries, bilberries, cranberries, raspberries, strawberries, chokeberries, cherries, blackcurrants and açai berries. We conclude that, while there is insufficient evidence supporting the existence of a direct blood pressure lowering effect, there is stronger evidence for specific types of berries acting indirectly to normalize blood pressure in subjects that are already hypertensive.

Angiogenesis is Differentially Modulated by Anthocyanin and Phenolic Acid Extracts from Wild Blueberry (V. angustifolium) Through PI3K Pathway.

Wild blueberries rank very high in anthocyanins (ACNs) and phenolic acids (PA) among other berries. Previous work from our group has documented their beneficial effects. In this study, human umbilical vein endothelial cells were used, and ACNs, PAs, and their combination (ACNs:PAs) at concentrations of 0.002, 8, 15, 60, and 120 µg/mL were tested for endothelial tube formation. Treatment with ACNs decreased, while treatment with PAs and ACNs:PAs increased overall endothelial cell tube formation compared to control. Endothelial cells exposed to ACNs downregulated gene expression of AKT1 and endothelial nitric oxide synthase (eNOS), while PAs upregulated AKT1 and vascular endothelial growth factor (VEGF) gene expression. Combination of ACNs:PAs decreased gene expression of AKT1 and eNOS, while protein levels of AKT1 increased. In summary, based on the type of wild blueberry extract, angiogenesis is differentially modulated and is concentration dependent. Further experiments will delineate the mechanism(s) of the differential action of the aforementioned extracts on angiogenesis.

Whole Red Raspberry (Rubus idaeus)-Enriched Diet Is Hepatoprotective in the Obese Zucker Rat, a Model of the Metabolic Syndrome.

Non-alcoholic fatty liver disease is a major risk factor of the metabolic syndrome (MetS). The effect of whole red raspberry (WRR) consumption on lipid metabolism was investigated in the obese Zucker rat (OZR), a model for the MetS. Male OZRs (n = 16) and their lean littermates (lean Zucker rat) (n = 16) at 8 weeks of age were placed on a control or an 8% WRR-enriched diet for 8 weeks. Plasma triglycerides (TGs), total cholesterol, high-density lipoprotein cholesterol (HDL-C), and non-HDL-C levels, and hepatic concentration of TG were measured. The expression of nine genes related to lipid metabolism was evaluated, both in liver and adipose tissue. A WRR-enriched diet reduced plasma cholesterol and HDL-C and increased plasma TG, while it decreased hepatic TG accumulation in the OZR. The OZR assigned to a WRR exhibited upregulation of microsomal triglyceride transfer protein (Mttp) and downregulation of fatty acid synthase (Fas) expression in the liver. Results showed a decrease in accumulation of liver TG and gene expression modulation of enzymes and transcription factors associated with lipid metabolism, suggesting a possible hepatoprotective role of a WRR-enriched diet.

Modulation of Adhesion Process, E-Selectin and VEGF Production by Anthocyanins and Their Metabolites in an in vitro Model of Atherosclerosis.

The present study aims to evaluate the ability of peonidin and petunidin-3-glucoside (Peo-3-glc and Pet-3-glc) and their metabolites (vanillic acid; VA and methyl-gallic acid; MetGA), to prevent monocyte (THP-1) adhesion to endothelial cells (HUVECs), and to reduce the production of vascular cell adhesion molecule (VCAM)-1, E-selectin and vascular endothelial growth factor (VEGF) in a stimulated pro-inflammatory environment, a pivotal step of atherogenesis. Tumor necrosis factor-α (TNF-α; 100 ng mL-1) was used to stimulate the adhesion of labelled monocytes (THP-1) to endothelial cells (HUVECs). Successively, different concentrations of Peo-3-glc and Pet-3-glc (0.02 µM, 0.2 µM, 2 µM and 20 µM), VA and MetGA (0.05 µM, 0.5 µM, 5 µM and 50 µM) were tested. After 24 h, VCAM-1, E-selectin and VEGF were quantified by ELISA, while the adhesion process was measured spectrophotometrically. Peo-3-glc and Pet-3-glc (from 0.02 µM to 20 µM) significantly (p < 0.0001) decreased THP-1 adhesion to HUVECs at all concentrations (-37%, -24%, -30% and -47% for Peo-3-glc; -37%, -33%, -33% and -45% for Pet-3-glc). VA, but not MetGA, reduced the adhesion process at 50 µM (-21%; p < 0.001). At the same concentrations, a significant (p < 0.0001) reduction of E-selectin, but not VCAM-1, was documented. In addition, anthocyanins and their metabolites significantly decreased (p < 0.001) VEGF production. The present findings suggest that while Peo-3-glc and Pet-3-glc (but not their metabolites) reduced monocyte adhesion to endothelial cells through suppression of E-selectin production, VEGF production was reduced by both anthocyanins and their metabolites, suggesting a role in the regulation of angiogenesis.

Potential Factors Influencing the Effects of Anthocyanins on Blood Pressure Regulation in Humans: A Review.

Dietary intake of anthocyanins (ACNs) is associated with a reduced risk of cardiovascular and coronary heart disease. While the anti-inflammatory, antioxidant, and lipid-lowering effects of ACN consumption have been consistently reported, their effect(s) on blood pressure regulation is less consistent and results from human studies are mixed. The objective of this review is attempting to identify potential patterns which may explain the variability in results related to blood pressure. To do so, we review 66 human intervention trials testing the effects on blood pressure of purified ACN or ACN-rich extracts, or whole berries, berry juices, powders, purees and whole phenolic extracts, from berries that are rich in ACN and have ACNs as predominant bioactives. Several factors appear to be involved on the mixed results reported. In particular, the baseline characteristics of the population in terms of blood pressure and total flavonoid intake, the dose and duration of the intervention, the differential effects of individual ACN and their synergistic effects with other phytochemicals, the ACN content and bioavailability from the food matrix, and individual differences in ACN absorption and metabolism related to genotype and microbiota enterotypes.

Impact of anthocyanin-rich whole fruit consumption on exercise-induced oxidative stress and inflammation: a systematic review and meta-analysis.

CONTEXT: Supplementing with fruits high in anthocyanins to reduce exercise-induced oxidative stress and inflammation has produced mixed results. OBJECTIVE: This systematic review and meta-analysis aims to discuss the impact of whole fruits high in anthocyanins, including processing methods and the type and amount of fruit, on inflammation and oxidative stress. DATA SOURCES: PICOS reporting guidelines and a customized coding scheme were used to search 5 databases (SPORTDiscus, Science Direct, Web of Science [BIOSIS], Medline [Pubmed], and the Cochrane Collaboration) with additional cross-referencing selection. DATA EXTRACTION: A random-effects meta-analysis was used to measure effects of the fruit supplements with 3 statistics; the QTotal value based on a χ2 distribution, τ2 value, and I2 value were used to determine homogeneity of variances on 22 studies (out of 807). Outliers were identified using a relative residual value. RESULTS: A small significant negative summary effect across the sum of all inflammatory marker outcomes (P < 0.001) and a moderate negative effect for the sum of all oxidative stress marker outcomes (P = 0.036) were found. Moderator analyses did not reveal significant (P > 0.05) differences between subgrouping variables. CONCLUSIONS: Results indicate that consumption of whole fruit high in anthocyanins can be beneficial for reducing inflammation and oxidative stress.

Role of Berry Anthocyanins and Phenolic Acids on Cell Migration and Angiogenesis: An Updated Overview.

Cell migration is a critical process that is highly involved with normal and pathological conditions such as angiogenesis and wound healing. Important members of the RHO GTPase family are capable of controlling cytoskeleton conformation and altering motility characteristics of cells. There is a well-known relationship between small GTPases and the PI3K/AKT pathway. Endothelial cell migration can lead to angiogenesis, which is highly linked to wound healing processes. Phenolics, flavonoids, and anthocyanins are major groups of phytochemicals and are abundant in many natural products. Their antioxidant, antimicrobial, anti-inflammatory, antidiabetic, angiogenenic, neuroprotective, hepatoprotective, and cardioprotective properties have been extensively documented. This comprehensive review focuses on the in vitro and in vivo role of berry extracts and single anthocyanin and phenolic acid compounds on cell migration and angiogenesis. We aim to summarize the most recent published studies focusing on the experimental model, type of berry extract, source, dose/concentration and overall effect(s) of berry extracts, anthocyanins, and phenolic acids on the above processes.

Phenolic and anthocyanin fractions from wild blueberries (V. angustifolium) differentially modulate endothelial cell migration partially through RHOA and RAC1.

The present study investigates the effect of anthocyanin (ACN), phenolic acid (PA) fractions, and their combination (ACNs:PAs) from wild blueberry powder (Vaccinum angustifolium) on the speed of endothelial cell migration, gene expression, and protein levels of RAC1 and RHOA associated with acute exposure to different concentrations of ACNs and PAs. Time-lapse videos were analyzed and endothelial cell speed was calculated. Treatment with ACNs at 60 µg/mL inhibited endothelial cell migration rate ( P ≤ 0.05) while treatment with PAs at 0.002 µg/mL ( P ≤ 0.0001), 60 µg/mL ( P ≤ 0.0001), and 120 µg/mL ( P ≤ 0.01) significantly increased endothelial cell migration rate compared with control. Moreover, exposure of HUVECs to ACNs:PAs at 8:8 µg/mL ( P ≤ 0.05) and 60:60 µg/mL increased ( P ≤ 0.001) endothelial cell migration. Gene expression of RAC1 and RHOA significantly increased 2 hours after exposure with all treatments. No effect of the above fractions was observed on the protein levels of RAC1 and RHOA. Findings suggest that endothelial cell migration is differentially modulated based on the type of blueberry extract (ACN or PA fraction) and is concentration-dependent. Future studies should determine the mechanism of the differential action of the above fractions on endothelial cell migration.

A serving of blueberry (V. corymbosum) acutely improves peripheral arterial dysfunction in young smokers and non-smokers: two randomized, controlled, crossover pilot studies.

Several studies have documented the important role of polyphenol-rich foods in the modulation of vascular remodelling and function. This study aimed to evaluate the capacity of a single portion of blueberry (V. corymbosum) to acutely improve peripheral arterial dysfunction in a group of young volunteers. Twenty-four healthy males (12 non-smokers and 12 smokers) were recruited for two different randomized, controlled, crossover pilot acute studies. In the first study, non-smokers were exposed to a control treatment (C; 300 mL of water with sugar) and a blueberry treatment (BB; 300 g of blueberry). In the second study, smokers underwent 3 different protocols: (1) - smoking treatment (S); (2) - control treatment (CS; 300 mL of water with sugar + smoking); (3) - blueberry treatment (BS; 300 g of blueberry + smoking). Each treatment (1 day long) was separated by a one week washout period. Blood pressure, peripheral arterial function (reactive hyperemia index, RHI, a marker of endothelial function) and arterial stiffness (digital augmentation index, dAix and dAix normalized by considering a heart rate of 75 bpm, dAix@75) were measured before and after each treatment. In the first study, the consumption of blueberry and control treatment acutely increased peripheral arterial function in the group of non-smokers. The improvement in RHI was higher and significantly different after blueberry treatment compared to the control treatment (54.8 ± 8.4% BB vs. 28.2 ± 8.3% C; p = 0.01). No effects were observed for markers of arterial stiffness, blood pressure and heart rate. Acute cigarette smoke significantly increased blood pressure and heart rate, while no significant effect was registered in peripheral arterial function and stiffness. The intake of blueberry and control treatment before a cigarette did not counteract the increase in blood pressure and heart rate, while it significantly improved peripheral arterial function. In particular, a significant increase was observed following BS (35.2 ± 7.5% RHI; p = 0.02) and CS treatments (34.6 ± 11.9% RHI; p = 0.02) when compared to only smoking treatment. No difference between BS and CS was detected. In conclusion, the intake of blueberry and control treatments acutely improved peripheral arterial dysfunction both in smoker and in non-smoker subjects. Further studies should be performed to confirm the results obtained and reveal the potential mechanisms of blueberry in the improvement of endothelial function.

Berry Fruit Consumption and Metabolic Syndrome.

Metabolic Syndrome is a cluster of risk factors which often includes central obesity, dyslipidemia, insulin resistance, glucose intolerance, hypertension, endothelial dysfunction, as well as a pro-inflammatory, pro-oxidant, and pro-thrombotic environment. This leads to a dramatically increased risk of developing type II diabetes mellitus and cardiovascular disease, which is the leading cause of death both in the United States and worldwide. Increasing evidence suggests that berry fruit consumption has a significant potential in the prevention and treatment of most risk factors associated with Metabolic Syndrome and its cardiovascular complications in the human population. This is likely due to the presence of polyphenols with known antioxidant and anti-inflammatory effects, such as anthocyanins and/or phenolic acids. The present review summarizes the findings of recent dietary interventions with berry fruits on human subjects with or at risk of Metabolic Syndrome. It also discusses the potential role of berries as part of a dietary strategy which could greatly reduce the need for pharmacotherapy, associated with potentially deleterious side effects and constituting a considerable financial burden.