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References__________________________________________________________________

(1) Sobolev AP, Ciampa A, Ingallina C, Mannina L, Capitani D, Ernesti I, Maggi E, Businaro R, Del Ben M, Engel P, Giusti AM, Donini LM, Pinto A. Blueberry-Based Meals for Obese Patients with Metabolic Syndrome: A Multidisciplinary Metabolomic Pilot Study. Metabolites. 2019 Jul 10;9(7):138. doi: 10.3390/metabo9070138.

Abstract. A pilot study was carried out on five obese/overweight patients suffering from metabolic syndrome, with the aim to evaluate postprandial effects of high fat/high glycemic load meals enriched by blueberries. Postprandial urine samples were analyzed by 1H-NMR spectroscopy after 2 and 4 h from ingestion to identify potential markers of blueberry intake. Significant decrease of methylamines, acetoacetate, acetone and succinate, known indicators of type 2 diabetes mellitus, were observed after the intake of meals enriched with blueberries. On the other hand, an accumulation of p-hydroxyphenyl-acetic acid and 3-(3'-hydroxyphenyl)-3-hydropropionic acid originating from gut microbial dehydrogenation of proanthocyanidins and procyanidins was detected. Real-time PCR-analysis of mRNAs obtained from mononuclear blood cells showed significant changes in cytokine gene expression levels after meals integrated with blueberries. In particular, the mRNAs expression of interleukin-6 (IL-6) and Transforming Growth Factor-β (TGF-β), pro and anti-inflammation cytokines, respectively, significantly decreased and increased after blueberry supplementation, indicating a positive impact of blueberry ingestion in the reduction of risk of inflammation. The combined analysis of the urine metabolome and clinical markers represents a promising approach in monitoring the metabolic impact of blueberries in persons with metabolic syndrome.

(2) Sezer ED, Oktay LM, Karadadaş E, Memmedov H, Selvi Gunel N, Sözmen E. Assessing Anticancer Potential of Blueberry Flavonoids, Quercetin, Kaempferol, and Gentisic Acid, Through Oxidative Stress and Apoptosis Parameters on HCT-116 Cells. J Med Food. 2019 Nov;22(11):1118-1126. doi: 10.1089/jmf.2019.0098. 

Abstract. In recent years, natural products gained popularity with their anti-inflammatory and antioxidant effects mediated by chemical compounds within their composition. Study results offering them as palliative therapy options in cancer or as anticancer agents with high levels of cytotoxicity brought a new approach to combine cancer treatment protocols with these products. From a different perspective, edible types of these products are suggested in daily diets due to their potential cancer preventive effects. Our preliminary work was on blueberry extracts (Vaccinium myrtillus) as a main representative of these natural products, and the contents of the extracts were analyzed with liquid chromatography tandem mass spectrometry (LC MS/MS) to reveal the composition and distribution of polyphenolic compounds within. The most abundant polyphenols detected in V. myrtillus extracts were quercetin, kaempferol, and a phenolic acid, gentisic acid (GA). The compounds were further evaluated on treated HCT-116 cells for their potential anticancer effects by measuring total antioxidant status, total oxidant status, and 8-hydroxydeoxyguanosine levels for evaluation of oxidative stress and through protein array analysis and flow cytometric analysis for evaluation of apoptosis. In analysis of oxidative stress parameters, reduced total oxidant levels and reduced oxidative stress index levels were found in cells treated with the compounds in comparison with untreated cells. In apoptosis-related protein profiles, at least twofold reduction in various apoptotic proteins was observed after quercetin and kaempferol treatment, whereas a different profile was observed for GA. Overall, results of this study showed that quercetin and kaempferol have strong cytotoxic, antioxidant, and apoptotic effects, although GA is mostly effective as an antioxidant polyphenol on HCT-116 cells.

(3) Travica N, D'Cunha NM, Naumovski N, Kent K, Mellor DD, Firth J, Georgousopoulou EN, Dean OM, Loughman A, Jacka F, Marx W. The effect of blueberry interventions on cognitive performance and mood: A systematic review of randomized controlled trials. Brain Behav Immun. 2020 Mar;85:96-105. doi: 10.1016/j.bbi.2019.04.001. 

Abstract. Blueberries are rich in polyphenols that may be beneficial to cognitive performance and mood. The aim of this systematic review was to evaluate randomized controlled trials investigating the effects of blueberries and blueberry products on measures of cognition and mood. In total, eleven articles (that included 12 studies) were identified using freeze-dried blueberries (n = 9 studies), whole blueberries (n = 2) and blueberry concentrate (n = 1). These studies were conducted in children (n = 5), young adults (n = 1), and older people with either no known cognitive impairment (n = 4) or indicated cognitive impairment (n = 2). Eight studies reported blueberry consumption or supplementation at various doses and time lengths to improve measures of cognitive performance, particularly short- and long-term memory and spatial memory. For mood, one study reported significant between-group improvements in positive affect from blueberry products, whereas four studies reported no improvement. Low risk of bias were observed across all studies. Based on the current evidence, blueberries may improve some measures of cognitive performance. However, considerable differences in study design, dosages, and anthocyanin content hinder between-study comparison. The use of standardized blueberry interventions, consideration of placebo formulations, and consistently reported cognitive performance tools are recommended in future trials. PROSPERO registration no. CRD42018100888.

(4) Liu Y, Liu M, Chen Q, Liu GM, Cao MJ, Sun L, Lu Z, Guo C. Blueberry Polyphenols Ameliorate Visible Light and Lipid-Induced Injury of Retinal Pigment Epithelial Cells. J Agric Food Chem. 2018 Dec 5;66(48):12730-12740. doi: 10.1021/acs.jafc.8b05272. 

Abstract. Although dietary polyphenols are known to be beneficial to vision, the protective distinctions among different types of polyphenols are unclear. In this work, the visual benefits of various blueberry polyphenols were evaluated using an in vitro model of visible light-lipid-induced injury of retinal pigment epithelial cells. Results showed that, at 10.0 μg/mL, the phenolic acid-rich fraction was superior in inhibiting cell death (93.6% ± 2.8% of cell viability). Anthocyanin- and flavonoid-rich fractions shared similar advantages in preventing the expression of senescence-associated β-galactosidase (34.8% ± 11.1% and 32.2% ± 9.7% of aged cells, respectively) and overexpression of vascular endothelial growth factor (51.8 ± 3.5 and 54.1 ± 6.5 pg/mL, respectively). The flavonoid-rich fraction also showed high activity in ameliorating phagocytosis (70.3% ± 12.6%) and cellular oxidative stress. These results were further confirmed by using the corresponding polyphenol standards. Improved inhibitory effects of polyphenol mixture on cell death and senescence-associated β-galactosidase expression were also observed. Therefore, various polyphenols play diverse roles and exert synergistic effects in nourishing the retina.

(5) Barfoot KL, May G, Lamport DJ, Ricketts J, Riddell PM, Williams CM. The effects of acute wild blueberry supplementation on the cognition of 7-10-year-old schoolchildren. Eur J Nutr. 2019 Oct;58(7):2911-2920. doi: 10.1007/s00394-018-1843-6. 

Abstract. Purpose: Previous evidence suggests consumption of flavonoids, a sub-class of polyphenols, is associated with improved cognitive function across the lifespan. In particular, acute intervention of a flavonoid-rich wild blueberry (WBB) drink has been shown to boost executive function (EF), short-term memory and mood 2-6 h post-consumption in 7-10-year-old children. However, confirmation of the aspects of EF and memory susceptible to WBB ingestion is required, particularly during childhood, a critical period of neurological development. In addition, the child literature on berry flavonoid supplementation and cognition highlights the potential for such interventions to elicit positive benefits to real-world educational scenarios, such as reading, a complex ability which relies upon aspects of cognition already known to improve following WBB.....Conclusion: Consumption of WBB was found to significantly improve memory and attentional aspects of EF. This indicates that a flavonoid-rich blueberry product, equivalent to 240 g or 1½ cups of fresh blueberries can provide acute cognitive benefits in children. These findings support accumulating evidence that flavonoid-rich products are beneficial for healthy brain function, particularly during critical developmental periods. However, the lack of findings relating to reading ability suggested acute WBB may not be sufficient to elicit benefits to reading. Chronic supplementation and other more sensitive reading measures should be considered for examining the effects of WBB on such a complex skill in the future.