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Wild blueberry (poly)phenols can improve vascular function and cognitive performance in healthy older individuals: a double-blind randomized controlled trial.
Wood, E, Hein, S, Mesnage, R, Fernandes, F, Abhayaratne, N, Xu, Y, Zhang, Z, Bell, L, Williams, C, Rodriguez-Mateos, A
The American journal of clinical nutrition. 2023;117(6):1306-1319
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The risk of developing both cardiovascular and neurodegenerative diseases increases with aging. Growing evidence from epidemiological and human intervention trials indicates that (poly)phenols may have cardioprotective properties as well as the ability to improve cognitive function. The aim of this study was to investigate the effects of daily wild blueberry (WBB) (poly)phenol consumption on vascular function and cognitive performance in healthy older individuals. This study was a randomised, double-blinded, placebo-controlled parallel design study. A total of 61 healthy older individuals were recruited and randomly assigned to one of the two arms; placebo intervention or blueberry intervention group. Results showed that long-term consumption of a dietary achievable amount of WBB enhanced vascular and cognitive function in older adults. Authors conclude that gut microbiota and vascular blood flow may play important roles in mediating the cognitive benefits shown by the consumption of (poly)phenol-rich foods.
Abstract
BACKGROUND Evidence suggests that the intake of blueberry (poly)phenols is associated with improvements in vascular function and cognitive performance. Whether these cognitive effects are linked to increases in cerebral and vascular blood flow or changes in the gut microbiota is currently unknown. METHODS A double-blind, parallel randomized controlled trial was conducted in 61 healthy older individuals aged 65-80 y. Participants received either 26 g of freeze-dried wild blueberry (WBB) powder (302 mg anthocyanins) or a matched placebo (0 mg anthocyanins). Endothelial function measured by flow-mediated dilation (FMD), cognitive function, arterial stiffness, blood pressure (BP), cerebral blood flow (CBF), gut microbiome, and blood parameters were measured at baseline and 12 wk following daily consumption. Plasma and urinary (poly)phenol metabolites were analyzed using microelution solid-phase extraction coupled with liquid chromatography-mass spectrometry. RESULTS A significant increase in FMD and reduction in 24 h ambulatory systolic BP were found in the WBB group compared with the placebo group (0.86%; 95% CI: 0.56, 1.17, P < 0.001; -3.59 mmHg; 95% CI: -6.95, -0.23, P = 0.037; respectively). Enhanced immediate recall on the auditory verbal learning task, alongside better accuracy on a task-switch task was also found following WBB treatment compared with placebo (P < 0.05). Total 24 h urinary (poly)phenol excretion increased significantly in the WBB group compared with placebo. No changes in the CBF or gut microbiota composition were found. CONCLUSIONS Daily intake of WBB powder, equivalent to 178 g fresh weight, improves vascular and cognitive function and decreases 24 h ambulatory systolic BP in healthy older individuals. This suggests that WBB (poly)phenols may reduce future CVD risk in an older population and may improve episodic memory processes and executive functioning in older adults at risk for cognitive decline. Clinical Trial Registration number in clinicaltrials.gov: NCT04084457.
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The effect of high-polyphenol Mediterranean diet on visceral adiposity: the DIRECT PLUS randomized controlled trial.
Zelicha, H, Kloting, N, Kaplan, A, Yaskolka Meir, A, Rinott, E, Tsaban, G, Chassidim, Y, Bluher, M, Ceglarek, U, Isermann, B, et al
BMC medicine. 2022;20(1):327
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Visceral adipose tissue (VAT) accumulation is one of the main key factors that differentiate between metabolic healthy and unhealthy obese individuals. VAT is closely related to the development of multiple cardiovascular risk factors. The Mediterranean (MED) diet, high in polyphenol content and rich in plant food sources, was shown to have an enhanced effect on VAT reduction in combination with physical activity (PA), regardless of weight loss The aim of this study was to assess the effect of the MED diet, further enriched with polyphenols, and lower in red and processed meat (“green-MED diet”) on visceral adiposity in the 18-month Dietary Intervention Randomized Controlled Trial-Polyphenols, Unprocessed trial. This study is a randomised controlled trial. Participants were randomly assigned to one of three intervention groups (1:1:1 ratio): healthy dietary guidelines, MED diet, or green-MED diet, all included PA recommendations, with a free gym membership and educational sessions promoting moderate-intensity PA. Results show that participants following the green-MED diet achieved more than twice the degree of VAT reduction compared to those following the MED diet, despite similar weight loss. In fact, VAT loss was specifically related to lower red meat intake and increased walnuts, green tea, Wolfa globosa, and dietary fibre (this was reflected by higher plasma polyphenol and serum folate levels). Authors conclude that a green-MED diet enriched with polyphenols and decreased red meat consumption might serve as an improved version of the MED diet for targeted VAT reduction.
Expert Review
Conflicts of interest:
None
Take Home Message:
- The positive health effects of the traditional MED diet, moderately high in PUFAs and MUFAs and low in red meat, are well-established
- Higher levels of total plasma polyphenol and serum folate may reflect higher consumption of “green” dietary components, which were significantly associated with greater VAT loss
- The green-MED diet, richer in dietary polyphenols and green plant-based proteins and lower in red meat, might be a more effective strategy for VAT loss than the traditional healthy MED diet, achieving more than twice the degree of VAT reduction, despite similar weight loss.
- VAT loss was specifically related to lower red meat intake and increased walnuts, green tea, Wolffia globosa, and dietary fibre and was reflected by higher plasma polyphenol and serum folate levels.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
A mediterranean (MED) diet is a rich source of polyphenols, which benefit adiposity by several mechanisms. Visceral adipose tissue (VAT) accumulation is one of the main factors that differentiate between metabolic healthy and unhealthy obese individuals.
In this Dietary Intervention Randomised Controlled Trial PoLyphenols UnproceSsed (DIRECT‐ PLUS) weight‐loss trial, 294 participants were randomised to: (A) healthy dietary guidelines (HDG), (B) MED, or (C) green‐MED diets, all combined with physical activity. The study duration was 18‐months.
This study explored the effect of the green‐MED diet, twice fortified in dietary polyphenols and lower in red/processed meat, on visceral adipose tissue (VAT) and used magnetic resonance imaging (MRI) to quantify the abdominal adipose tissues.
Both isocaloric (with the same calorific value) MED groups consumed 28 g/day of walnuts (+ 440 mg/day polyphenols). The green‐MED group further consumed green tea (3–4 cups/day) and Wolffia globosa (duckweed strain) plant green shake (100 g frozen cubes/day) (+ 800mg/day polyphenols) and reduced red meat intake.
The mean weight loss (HDG: −0.4% (5.0), MED: −2.7% (5.6), green-MED: −3.9% (6.5)) and WC loss (HDG: −3.6% (5.1), MED: −4.7% (5.0), green-MED: −5.7%(5.7)) after 18 months were similar between the two MED diets (p > 0.05 for all) and higher as compared to the HDG (weight: HDG vs. MED: p = 0.02; HDG vs. green+MED: p < 0.001; WC: HDG vs. MED: p = 0.33, HDG vs. green+MED: p = 0.02).
All three abdominal fat depots decreased over 18 months of intervention (p < 0.05 vs. baseline for all). The green-MED group achieved a greater reduction in VAT than the other intervention groups (HDG: −4.2% (22.5), MED: −6.0%(31.3), green-MED: −14.1%(27.7); p < 0.05 green-MED vs. MED or vs. HDG groups). These differences in VAT loss across the groups remained significant after adjusting for age, sex, and 18-month WC change (green-MED vs. MED p = 0.023; green-MED vs. HDG p = 0.002) (Fig. 1)
Limitations of the study included a low proportion of women, and different VAT proportions at baseline across groups limit the generalisability of findings to women.
The authors of the study did not identify the exact components responsible for the dietary effects when they compared dietary regimens and not specific nutrients.
Adherence was by a validated, self-reported dietary intake assessment tool, which the authors acknowledge is subject to error
Strengths of the study included the relatively large sample size, high retention rate, and use of 3-T MRI measurements (considered one of the gold standards tools for the quantification of specific fat depots
Clinical practice applications:
- This trial shows that, when combined with a Mediterranean diet, higher dietary consumption of green tea, walnuts, and dietary fibre and reduced red meat consumption were significantly associated with greater %VAT loss
- The authors observed a significant synergistic interaction effect between decreased red meat consumption and increased serum folate on VAT loss
- A reduction in VAT accumulation, known as a key risk factor in CVD development, may reduce metabolic complications, improve the lipid profile, and decrease cardiometabolic risk.
Considerations for future research:
- Future studies are needed to explore the exact mechanisms of specific polyphenol-rich foods on visceral adiposity.
- Future studies could explore whether the results are replicable in both male and female participants, as this sample was largely male.
Abstract
BACKGROUND Mediterranean (MED) diet is a rich source of polyphenols, which benefit adiposity by several mechanisms. We explored the effect of the green-MED diet, twice fortified in dietary polyphenols and lower in red/processed meat, on visceral adipose tissue (VAT). METHODS In the 18-month Dietary Intervention Randomized Controlled Trial PoLyphenols UnproceSsed (DIRECT-PLUS) weight-loss trial, 294 participants were randomized to (A) healthy dietary guidelines (HDG), (B) MED, or (C) green-MED diets, all combined with physical activity. Both isocaloric MED groups consumed 28 g/day of walnuts (+ 440 mg/day polyphenols). The green-MED group further consumed green tea (3-4 cups/day) and Wolffia globosa (duckweed strain) plant green shake (100 g frozen cubes/day) (+ 800mg/day polyphenols) and reduced red meat intake. We used magnetic resonance imaging (MRI) to quantify the abdominal adipose tissues. RESULTS Participants (age = 51 years; 88% men; body mass index = 31.2 kg/m2; 29% VAT) had an 89.8% retention rate and 79.3% completed eligible MRIs. While both MED diets reached similar moderate weight (MED: - 2.7%, green-MED: - 3.9%) and waist circumference (MED: - 4.7%, green-MED: - 5.7%) loss, the green-MED dieters doubled the VAT loss (HDG: - 4.2%, MED: - 6.0%, green-MED: - 14.1%; p < 0.05, independent of age, sex, waist circumference, or weight loss). Higher dietary consumption of green tea, walnuts, and Wolffia globosa; lower red meat intake; higher total plasma polyphenols (mainly hippuric acid), and elevated urine urolithin A polyphenol were significantly related to greater VAT loss (p < 0.05, multivariate models). CONCLUSIONS A green-MED diet, enriched with plant-based polyphenols and lower in red/processed meat, may be a potent intervention to promote visceral adiposity regression. TRIAL REGISTRATION ClinicalTrials.gov , NCT03020186.
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A randomized, phase 1, placebo-controlled trial of APG-157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor-associated microbes.
Basak, SK, Bera, A, Yoon, AJ, Morselli, M, Jeong, C, Tosevska, A, Dong, TS, Eklund, M, Russ, E, Nasser, H, et al
Cancer. 2020;126(8):1668-1682
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APG-157 is a botanical drug containing multiple polyphenols that delivers the active components to oromucosal tissues near the tumour target. APG-157 slowly disintegrates in the oral cavity over 15 to 20 minutes to release the drug substance. The drug substance is a precise, rational combination of multiple molecules derived from Curcuma longa wherein curcumin is the principal component. The main aim of this study was to determine the pharmacokinetics and safety of the orally delivered pastille (APG-157) when used by normal subjects and patients with cancer. This study is a randomised, double-blind, placebo-controlled trial. A total of 32 subjects were enrolled, and 25 completed the study (13 normal individuals and 12 patients with oral cancer). Results demonstrated that transoral APG-157 treatment leads to systemic absorption of curcumin and its analogs. There was a statistically significant concentration reduction in inflammatory cytokines and Bacteroides species noted in the salivary cells. Pre-treatment and post-treatment tumour samples from patients with cancer demonstrated T-cell recruitment to the tumour microenvironment. Authors conclude that APG-157 is absorbed well, reduces inflammation, and attracts T-cells to the tumour thus, it can be potentially used in combination with immunotherapy drugs. Furthermore, a long-term evaluation of immune checkpoint blockade with and without APG-157 could provide a clear understanding of the usefulness of APG-157 as either an adjuvant or neoadjuvant therapeutic agent for patients with advanced or recurrent head and neck cancer.
Abstract
BACKGROUND Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target. METHODS A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity. RESULTS Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1β, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment. CONCLUSIONS The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy. LAY SUMMARY Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.