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蓝莓及其花青素的健康益处研究进展

已有 7 次阅读2025-11-19 08:44 |个人分类:medicine

本文主笔 Wilhelmina Kalt 发表的其它文章

https://www.researchgate.net/scientific-contributions/Wilhelmina-Kalt-2121852269

鱼油、蓝莓及联合补充剂对主观认知障碍老年人的认知反应

2017 年 12 月

《衰老神经生物学》，Robert K Mcnamara、Wilhelmina Kalt、Marcelle D. Shidler、Robert Krikorian

鉴于有证据表明二十碳五烯酸 (EPA)、二十二碳六烯酸 (DHA) 和富含花青素的蓝莓具有神经认知益处，我们研究了长期补充这些物质对有认知障碍的老年人的影响。在一项为期 24 周的随机、双盲、安慰剂对照试验中，老年男性和女性每日服用鱼油 (FO)、蓝莓 (BB) 或两者兼有。饮食记录证实，参与者按照处方减少了 EPA、DHA 和花青素的摄入量。FO 组的红细胞 EPA + DHA 含量增加 (p = 0.0001)。补充后各组尿液中总花青素水平无显著差异，但糖苷和天然（食物来源）形式的花青素仅在补充BB的组中升高。FO组（p = 0.03）和BB组（p = 0.05）的认知症状均有所减轻，且BB组的记忆辨别能力有所提高（p = 0.04），表明补充BB可改善认知功能。BB组的认知获益与尿液中反映近期BB摄入的花青素水平相关，但与花青素代谢物无关。然而，FO+BB联合治疗并未如预期那样增强认知功能。

人体花青素生物利用度：摄入时间和剂量的影响

2017年11月

Wilhelmina Kalt、Jane E. Mcdonald、Melinda Vinqvist-Tymchuk、Sherry A E Fillmore

体外和动物实验证据支持花青素在人类健康中发挥作用，但浆果健康益处的未来发展将取决于临床干预试验的证据。由于人们对花青素在人体长期摄入过程中的行为知之甚少，因此本研究考察了几个临床设计因素。我们采用液相色谱-串联质谱法（LC-MS/MS）分析了17名每日饮用蓝莓汁的志愿者的尿液，检测了预测的花青素类黄酮衍生物，并比较了5天无花青素导入期、28天蓝莓汁摄入期、7天洗脱期以及两种不同剂量方案的影响。结果显示，17名受试者尿液中的总花青素含量和母体花青素含量差异高达10倍。 24 小时至 0 小时总花青素排泄量较高与花青素滞留量较高（即蓝莓汁摄入前 0 小时）相关。长达 7 天的洗脱期前后，总花青素排泄量无显著差异，表明花青素释放缓慢。在为期 36 天的研究中，尿花青素排泄量呈下降趋势。与每日三次、每次三分之一剂量服用相比，一次性服用每日蓝莓汁可提高 24 小时至 0 小时总花青素排泄量，但对花青素原体化合物的排泄量无显著影响。然而，一次性服用蓝莓汁可更好地保留花青素原体化合物（0 小时浓度更高）。这些发现有助于设计花青素与健康相关的临床研究。

蓝莓花青素摄入期间人体尿液中类黄酮代谢物的变化

2017年2月《农业与食品化学杂志》

作者：Wilhelmina Kalt、Jane E. McDonald、Yan Liu、Sherry A E Fillmore

花青素（Anc）和其他类黄酮对人体健康的益处已得到广泛认可。然而，摄入花青素后体内产生的类黄酮类尿代谢物尚未得到充分描述。本研究收集了17名受试者在连续28天每日饮用蓝莓汁（BJ）期间的尿液样本，并在7天洗脱期后再次收集尿液样本。对664份尿液样本进行MS/MS扫描，检测18种母体花青素（PAnc）和42种预测的花青素代谢物（AncM），共鉴定出371种产物（即MS/MS × 保留时间（RT））。类黄酮类代谢物AncM的丰度可能被低估，其丰度几乎是PAnc的20倍。 PAnc 和 AncM 合计约占每日 Anc 摄入量的 1%。苷元形式占总量的 94% 以上。对 371 种 Anc 进行聚类分析，鉴定出约 55 种主要 Anc，它们贡献了约 80% 的总 Anc。胃肠道中丰富的类黄酮 Anc 衍生物可能有助于富含 Anc 的浆果的健康益处。

Wilhelmina Kalt’s research while affiliated with Agriculture and Agri-Food Canada and other places

https://www.researchgate.net/scientific-contributions/Wilhelmina-Kalt-2121852269

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Publications (3)

Cognitive response to fish oil, blueberry, and combined supplementation in older adults with subjective cognitive impairment

Full-text available December 2017

Neurobiology of Aging, Robert K Mcnamara, Wilhelmina Kalt , Marcelle D. Shidler, Robert Krikorian

Given evidence that eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and anthocyanin-rich blueberries provide neurocognitive benefit, we investigated long-term supplementation in older adults with cognitive complaints. In a 24-week randomized, double-blind, placebo-controlled trial, elderly men and women received daily fish oil (FO) or blueberry (BB) or both. Diet records confirmed that participants reduced background consumption of EPA, DHA, and anthocyanins as prescribed. Erythrocyte EPA + DHA composition increased in the FO groups (p = 0.0001). Total urinary anthocyanins did not differ between the groups after supplementation but glycoside and native (food) forms increased only in the BB-supplemented groups. The FO (p = 0.03) and BB (p = 0.05) groups reported fewer cognitive symptoms, and the BB group showed improved memory discrimination (p = 0.04), indicating that supplementation improved cognition. Cognitive benefit in the BB group was associated with the presence of urinary anthocyanins reflecting recent BB intake but not with anthocyanin metabolites. However, combined FO + BB treatment was not associated with cognitive enhancement as expected.

Human anthocyanin bioavailability: effect of intake duration and dosing

Article November 2017

Wilhelmina Kalt, Jane E. Mcdonald, Melinda Vinqvist-Tymchuk, Sherry A E Fillmore

While in vitro and animal evidence supports a role for anthocyanins in human health, future opportunities in berry health benefits will rest upon evidence from clinical intervention trials. Because little is known about the behaviour of anthocyanins during long term intake in humans, several clinical design factors were examined. Urine from volunteers (n = 17) who consumed blueberry juice daily was analysed using LC-MS/MS for predicted flavonoid-based products of anthocyanins in relation to a 5-day anthocyanin-free run-in, 28 days of blueberry juice intake, a 7-day washout and two dosing regimens. Total and parent anthocyanin content in urine varied 10-fold among the 17 participants. A high 24–0 h total anthocyanin excretion was associated with high anthocyanin retention (i.e. 0 h, before blueberry juice intake). Total anthocyanin excretion was not different before and after up to 7 days of washout indicative of a slow release of anthocyanins. Urinary excretion of anthocyanins declined during the 36-day study. The 24–0 h excretion was greater for total anthocyanins but not for parent anthocyanins when daily blueberry juice was taken all at once rather than as ⅓ doses taken thrice daily. However parent anthocyanins were retained better (higher 0 h) with 1× dosing. These findings could aid in the design of clinical research on anthocyanins and health.

Flavonoid Metabolites in Human Urine during Blueberry Anthocyanin Intake

Article February 2017 Journal of Agricultural and Food Chemistry

Wilhelmina Kalt, Jane E. Mcdonald, Yan Liu, Sherry A E Fillmore

The human health benefits of anthocyanins (Anc) and other flavonoids are widely recognized. However the flavonoid-based urinary metabolites arising in vivo after Anc intake are not well described. Human (n=17) urine was collected while blueberry juice (BJ) was consumed daily for 28 d and once after a 7 d washout. MS/MS scanning of 664 urine samples for 18 parent Anc (PAnc) and 42 predicted Anc metabolites (AncM) yielded 371 products (i.e. MS/MS x retention time (RT)). Flavonoid-based AncM, which were likely underestimated, were almost 20-times more abundant than PAnc. Together PAnc and AncM accounted for about 1% of the daily Anc dose. Aglycone forms were > 94% of the total. Cluster analysis of the 371 Anc identified about 55 major Anc that contributed about 80% to the total Anc. The abundance of flavonoid-based Anc-derived products in the gastrointestinal tract could contribute to the health benefits of Anc-rich berries.

蓝莓及其花青素的健康益处研究进展

https://pmc.ncbi.nlm.nih.gov/articles/PMC7442370/

Wilhelmina Kalt 1,✉, Aedin Cassidy 2, Luke R Howard 3, Robert Krikorian 4, April J Stull 5, Francois Tremblay 6, Raul Zamora-Ros 7

2019年7月22日

1 加拿大农业及农业食品部，肯特维尔研究与发展中心，新斯科舍省肯特维尔，加拿大（已退休）

2 东安格利亚大学诺里奇医学院营养系，英国诺里奇

3 阿肯色大学食品科学系，美国阿肯色州费耶特维尔

4 辛辛那提大学学术健康中心精神病学与行为神经科学系，美国俄亥俄州辛辛那提

5 人类学系美国马里兰大学东海岸分校生态学系，马里兰州公主安妮

6 加拿大达尔豪斯大学眼科与视觉科学系和生理学与生物物理学系，新斯科舍省哈利法克斯

7 西班牙加泰罗尼亚肿瘤研究所贝尔维特格生物医学研究所（IDIBELL）营养与癌症研究室，癌症流行病学研究项目

✉通讯作者：WK（邮箱：Wilhelmina.kalt@icloud.com）

PMCID：PMC7442370 PMID：31329250

摘要

越来越多的积极科学证据，包括来自人体观察和临床研究以及利用动物和体外模型进行的机制研究，都证实了蓝莓对人类健康的益处。蓝莓含有大量植物化学物质，包括丰富的花青素色素。在各种植物化学物质中，花青素可能对蓝莓的健康功效影响最大。流行病学研究表明，经常适量摄入蓝莓和/或花青素与降低心血管疾病、死亡和2型糖尿病的风险，以及改善体重维持和神经保护作用相关。这些发现得到了基于生物标志物的人体临床研究证据的支持。蓝莓最重要的健康益处包括其抗炎和抗氧化作用，以及对血管和血糖调节功能的有益影响。蓝莓中的植物化学物质可能影响胃肠道菌群，并有助于宿主健康。这些方面与退行性疾病和衰老过程密切相关。我们需要更多证据，特别是人体临床证据，以更好地了解富含花青素的蓝莓对公众健康的益处。然而，人们普遍认为，经常食用美味成熟的蓝莓是值得推荐的。

结论

本文介绍了部分研究，这些研究证实了蓝莓作为一种健康食品的益处。本文概述了蓝莓和花青素在人类健康中的作用，首先基于人体观察和临床证据，然后介绍了利用动物和体外模型进行的机制研究。蓝莓疗法通常在涉及压力或疾病风险的实验模型中产生更显著的效果。

支持蓝莓对心血管、血糖调节、神经保护和视力有益的证据相对较少。例如，虽然有大量流行病学证据表明蓝莓和花青素具有心脏保护作用，但缺乏蓝莓或花青素对人类视力有益的流行病学证据。此外，虽然有大量临床证据表明蓝莓可以改善认知和脑功能，但花青素在这方面的流行病学证据相对较少。

蓝莓成分的抗炎、抗氧化和血管保护作用共同促进了胰岛素敏感组织葡萄糖的良好输送和代谢功能的正常发挥。这些作用均与健康老龄化的多个方面密切相关。值得注意的是，心血管代谢功能障碍的生物标志物与晚年血管性痴呆和阿尔茨海默病型痴呆的风险相关（92, 93），这可能与神经炎症的减轻有关。

蓝莓摄入与抗炎生物标志物改善相关，这一结论得到了观察性研究（8）、临床研究（48）、动物实验（87）和体外实验（114）的支持。蓝莓的抗炎和免疫益处可能与粘蛋白相关及其他结肠微生物群有关（67），这构成了浆果健康研究的一个新领域。

在短期（例如，参见参考文献18、78和100）和长期（例如，参见参考文献76和94）的人体干预中均观察到了蓝莓的益处，这表明其作用机制多种多样。

在蓝莓健康研究中，一些重要领域仍知之甚少。例如，临床疗效的剂量依赖性大多尚不明确（18, 101, 142）。花青素代谢物在体内的生物活性，无论是整体还是单个活性，以及组织中花青素对健康的重要性，仍然大多未知。另一个重要问题是，蓝莓花青素酚类分解产物在结肠中的相对生物活性与其他植物性食物中的类似酚类化合物相比如何。值得注意的是，这些知识空白并不妨碍我们通过增加公众消费来利用蓝莓的健康益处。

希望这篇研究综述能够帮助消费者、医疗保健提供者以及食品和健康产业了解目前关于蓝莓与健康的认知现状。可以肯定的是，每日适量摄入蓝莓（50毫克花青素，约三分之一杯蓝莓）可以降低西方世界一些具有重大社会经济意义的疾病和健康问题的风险。

引言

蓝莓最初因其丰富的多酚类化合物具有很高的体外抗氧化能力而被誉为“超级水果”。然而，由于多酚类化合物的生物利用度较低（1），它们在体内直接发挥抗氧化作用的可能性似乎不大。尽管如此，过去二十年来关于健康食品的研究揭示了蓝莓具有多种生物活性并有益于健康的途径。越来越多的证据表明，蓝莓和花青素能够降低多种疾病的生物标志物水平，并减轻包括心血管疾病（CVD）、2型糖尿病（T2DM）和神经功能衰退在内的重大社会经济负担。在这些观察性分析中，花青素的益处通常优于其他植物性食物化学物质，包括其他类黄酮（2-6）。即使每日摄入适量的蓝莓（约三分之一杯）和花青素（<50毫克），也与降低疾病风险相关（2-4, 6-9）。

本文综述了蓝莓在心血管代谢健康、神经保护、视力和食品加工方面的作用。文中呈现了观察性证据以及来自人体临床研究、动物和体外研究的结果。本综述引用的近200篇论文中，超过一半发表于过去十年。蓝莓研究是本综述的主要关注点。然而，本文也会在相关部分讨论花青素的相关文献。人们对蓝莓潜在的健康益处越来越感兴趣。

当前知识状况

蓝莓品种及成分

具有商业价值的蓝莓品种包括高丛蓝莓（Vaccinium corymbosum L.）、兔眼蓝莓（V. virgatum Aiton）、矮丛蓝莓（V. angustifolium Aiton）和欧洲越橘（V. myrtillus L.）。蓝莓是常见水果中花青素含量最丰富的来源之一（10-12）（表1）。花青素是赋予成熟浆果红色、蓝色和紫色的色素。在浆果成熟过程中，花青素含量会显著增加，从而为区分早熟果实和完全成熟果实提供视觉线索（13）。

表 1.

美国常见水果的总花青素浓度

水果名称描述样本数量总花青素含量（mg/100 g 鲜果）

苹果1 红皮 6 12

苹果1 黄皮 2 0

香蕉2 — 0

黑莓2 — 4 245

蓝莓2 高丛蓝莓 7 387

蓝莓2 矮丛蓝莓 1 487

哈密瓜2 — 0

甜樱桃2 — 4 122

葡萄2 红皮和果肉 5 27

葡萄2 紫皮和果肉 1 120

猕猴桃2 — 0

油桃3 黄皮 5 15

橙子2 橙肉 — 0

李子3 黄皮 1 0

李子3 红皮 2 20

李子3 黑皮 2 116

覆盆子（红）2 — 5 92

草莓2 8 21

西瓜2 — 0

1参考文献11. 2参考文献10. 3参考文献12.

在80个高丛蓝莓和135个矮丛蓝莓表型中，90%的表型花青素浓度范围在1.6倍以内（14）。在总共215个蓝莓表型中，每克鲜重中花青素-3-葡萄糖苷当量（第10和第90百分位数）的范围为0.925至2.1毫克（14）。

蓝莓多酚化合物

花青素类黄酮占成熟蓝莓中总多酚含量的60%（13）。因此，花青素可能是蓝莓健康益处的主要贡献者。蓝莓多酚化合物包括黄酮类和非黄酮类化合物。蓝莓中发现的其他黄酮类化合物包括原花青素（15, 16）和黄酮醇（17, 18）。蓝莓中含量丰富的非黄酮类多酚化合物是羟基肉桂酸酯（尤其是绿原酸）（16, 17, 19, 20）。

花青素的生物利用度

将花青素的体内代谢产物与健康结果联系起来一直很困难。摄入后，花青素会通过化学反应以及人体和微生物代谢转化为多种产物。花青素代谢产物的清除时间差异很大（21, 22）。例如，人类摄入13C标记的花青素后6小时内，呼出气体中检测到大量13C标记的CO2，这表明花青素被快速且完全地分解代谢。然而，超过50%的48 小时后，13C 仍残留在体内 (21)。花青素及其 II 期代谢物在摄入花青素后仍会在尿液中长期存在 (23)，这可能是由于它们通过胆汁运输所致 (24, 25)。此外，花青素及其代谢物会在身体组织中定位 (24, 26–29)。由于胃肠道菌群对花青素和其他食物多酚的分解代谢作用，酚酸类产物在大肠中含量非常丰富 (30)。

心血管健康

人群心血管健康研究、浆果和花青素

一项包含 6 项研究的荟萃分析显示，较高的花青素摄入量与全因死亡风险降低之间的关联主要归因于心血管死亡风险的降低 (31)。一项针对所有心血管疾病的荟萃分析也报告了类似的结果（RR：0.89；95% CI：0.83–0.96）(32)。在3项队列研究中，较高的花青素摄入量与冠状动脉疾病风险降低约25%相关，包括致命性和非致命性心肌梗死(33, 34)。较高的蓝莓、草莓和总花青素摄入量均与心肌梗死发生率降低32%相关，且这种关联独立于已知的危险因素(2)。然而，在2项前瞻性队列研究中，未发现花青素摄入量与卒中风险之间存在关联(34, 35)。

在5项队列研究中，较高的花青素摄入量与高血压风险降低约8%–10%相关(3, 36, 37)。在一项对超过 87,000 名参与者进行长达 14 年的队列研究中，较高的花青素摄入量与高血压发病风险降低 10% 相关 (3)。风险降低最显著的是 ≤60 岁的女性 (3)。一项对 1898 例经过仔细表型分析的双胞胎进行的横断面研究测量了一种生物标志物——血管僵硬度。该研究发现，使用脉搏波速度测量的血管调节功能的临床相关改善与较高的花青素摄入量相关 (6)。

心血管疾病、肥胖、浆果和体重维持方面的人群研究

肥胖和超重是心血管疾病风险的主要因素 (38)。即使是轻微的体重增加也会增加高血压 (39) 和心血管疾病 (40, 41) 的风险。BMI 降低 1-3 kg/m² 与心血管疾病事件 (41) 和死亡 (42) 风险降低 2-13% 相关。在一项对16种常见水果摄入量进行比较的前瞻性研究中，超过133,000名男性和女性接受了≤24年的随访，结果显示蓝莓摄入量最高与体重增加最少相关（4年内减少0.64公斤）(43)。在另一项针对124,000名受试者的研究中，6类黄酮中花青素摄入量较高与体重增加较少的相关性最强（每增加10毫克花青素，体重减少0.1公斤）(44)。

在一项基于双能X射线吸收法（DXA）体成分评估的研究中，健康女性双胞胎（n = 2734）的研究表明，较高的花青素摄入量与脂肪量减少3-9%以及中心性肥胖减少相关(45, 46)。该研究发现，蓝莓摄入量较高的双胞胎的脂肪量比值低于其同卵双胞胎(45)。双胞胎研究的结果之所以引人注目，是因为它们不受遗传和共同环境因素的影响。

心血管健康临床研究

在蓝莓的临床研究中，受试者通常具有一定的心血管疾病风险（例如，代谢综合征标志物、2型糖尿病）。在一项针对58名糖尿病患者的安慰剂对照研究中，蓝莓的摄入导致低密度脂蛋白胆固醇、甘油三酯和脂联素水平下降，而高密度脂蛋白胆固醇水平升高（47）。150名高胆固醇血症患者连续12周摄入纯化花青素后，高密度脂蛋白胆固醇水平升高，低密度脂蛋白胆固醇水平降低，内皮功能（肱动脉血流介导的血管舒张）得到改善（48）。随后，这150名高胆固醇血症患者连续24周摄入花青素后，炎症标志物水平降低，包括血清高敏C反应蛋白、可溶性血管黏附分子-1和血浆白细胞介素-1β（IL-1β）（49）。

在患有高血压前期和1期高血压的女性中，食用蓝莓8周后，动脉僵硬度降低，收缩压和舒张压均下降5-6%（50, 51）。在具有心血管疾病风险因素的中年未服药男性中也观察到了类似的益处（51）。在代谢综合征患者中，食用蓝莓6周后，血管内皮功能得到改善，但血压未受影响（52）。在一项针对代谢综合征患者（n = 115）的蓝莓研究中，受试者分别服用0克、75克或150克蓝莓6个月后，每日服用75克蓝莓组的心血管代谢功能生物标志物未发生变化。然而，每日服用150克蓝莓组的血管功能和血脂状况持续改善。两种剂量的蓝莓均未影响胰岛素抵抗（53）。一些临床研究报告称，食用蓝莓对血压的影响甚微或无影响（54, 55）。与这些长期研究相反，在一项为期 6 小时的急性研究设计中，蓝莓摄入量与……相关一项针对 21 名健康男性的研究表明，蓝莓可以短期改善血管功能，具体表现为血流介导的血管舒张功能 (56)。

心血管获益机制

蓝莓和花青素通过抗氧化和抗炎作用 (49, 57)、对血浆脂质水平的积极影响以及对葡萄糖代谢和内皮功能的调节（参见综述，58, 59）来促进心血管健康。蓝莓以多种方式保护血管，这些保护作用可以通过血管反应性、血压和动脉硬度来检测 (18, 50–52, 60)。这些益处可能涉及 NO 代谢 (53, 61) 以及对内皮成分 (62) 和血浆脂质 (47, 48, 63) 的影响。大多数情况下，心血管研究模型会采用相关的应激处理（例如饮食或疾病）或研究具有既有风险因素的人群。

浆果花青素的非黄酮类代谢产物主要存在于大肠中 (1)，它们可能与肠道菌群相互作用，引发抗炎或其他有助于心脏保护作用的反应 (64)。蓝莓补充剂改变了大鼠的结肠菌群 (65, 66)。通过基因测序，研究人员发现 3 个新的门和 22 个新的属的微生物与蓝莓喂养密切相关 (66)。这些基因变化约占整个基因组的 9%，与肠道黏蛋白层中的菌种、更好的细菌入侵防护以及更强的异生物质代谢能力相关 (66)。在一项高脂饮食喂养大鼠的研究中，蓝莓摄入减轻了高脂饮食对炎症和胰岛素信号传导的负面影响，并导致了肠道菌群的改变 (67)。

糖尿病前期和2型糖尿病

2型糖尿病、蓝莓和花青素的人群研究

糖尿病前期和2型糖尿病影响着美国约1亿成年人（68）。糖尿病前期和2型糖尿病的特征都是对胰岛素刺激反应不良（即胰岛素抵抗），导致胰岛素敏感组织对葡萄糖的摄取和代谢效率低下（69）。在3项前瞻性研究中分析的所有水果中，蓝莓与2型糖尿病风险降低的关联性最强，风险降低了26%（RR：0.74；95% CI：0.66–0.83）（70）。在同一队列中，当考察日常摄入的类黄酮（黄酮醇、黄酮、黄烷酮、黄烷-3-醇和花青素）的摄入量时，发现摄入花青素，尤其是蓝莓，每周摄入≥2份或每月≤1份，可使2型糖尿病风险降低23%。未发现总类黄酮或其他类黄酮组的摄入量与2型糖尿病风险降低之间存在关联(4)。

一项来自美国3个队列的荟萃分析表明，较高的花青素摄入量（RR：0.85，95% CI：0.80–0.91）和浆果类水果摄入量（RR：0.82，95% CI：0.76–0.89）与2型糖尿病风险降低相关(71)。一项波兰队列研究发现，花青素摄入量增加与2型糖尿病风险降低之间存在类似的关联（RR：0.68，95% CI：0.48–0.98）(72)。一项针对女性的横断面研究发现，花青素和黄酮类化合物的日常摄入量较高与胰岛素抵抗的改善相关，而只有花青素与炎症和高敏C反应蛋白的降低相关(8)。肥胖与2型糖尿病风险呈正相关(73)。蓝莓和花青素摄入量增加与老年人体重增加较少相关(43–45)，因此可能有助于降低2型糖尿病风险。值得注意的是，并非所有观察性研究都发现花青素或浆果摄入量与降低2型糖尿病风险相关(74, 75)。

2型糖尿病的临床研究

在一项针对肥胖、胰岛素抵抗成年人的安慰剂对照研究中，蓝莓摄入6周后胰岛素敏感性提高（76）。胰岛素敏感性采用高胰岛素-正常血糖钳夹技术进行评估，该技术可直接测量全身葡萄糖处置率（77）。

与安慰剂相比，每日服用80毫克越橘和黑加仑花青素提取物可改善58名2型糖尿病患者的胰岛素敏感性（HOMA-IR）、血脂谱，并降低血浆氧化应激标志物水平（47）。在另一项研究中，研究人员在2型糖尿病人群中单次口服安慰剂或0.47克含36%（w/w）花青素的标准化越橘提取物后，考察了其对葡萄糖调节的影响。结果显示，越橘摄入可降低口服葡萄糖耐量试验中的血浆葡萄糖和胰岛素曲线下面积（AUC）（78）。一项针对 54 名超重青年的为期 12 周的试验表明，每日用 50 克蓝莓替代 50 克碳水化合物可有效降低体重、胰岛素、胆固醇和其他代谢指标 (63)。

2 型糖尿病的动物和机制研究

具有糖尿病前期和 2 型糖尿病表型及代谢特征，并伴有饮食诱导肥胖的啮齿动物常被用于研究药物的作用机制。喂食高脂 (60%) 饮食 8 周的 C57BL/6 小鼠，在高脂饮食中添加蓝莓后，胰岛素敏感性有所提高 (79)。此外，喂食高脂饮食加蓝莓的小鼠的葡萄糖曲线下面积 (AUC) 也显著降低。蓝莓组与喂食低脂饮食的小鼠组相似 (79)。

在一项研究中，Zucker肥胖大鼠分别喂食高脂（45%）或低脂（10%）饮食，12周后，喂食高脂饮食加2%蓝莓组和喂食低脂饮食组的大鼠代谢指标均优于喂食高脂饮食但不喂蓝莓的大鼠。此时，喂食高脂饮食加蓝莓组的大鼠空腹胰岛素水平、胰岛素抵抗（HOMA-IR）和葡萄糖曲线下面积（AUC）均优于高脂饮食对照组 (80)。蓝莓摄入降低了高脂饮食喂养的易肥胖大鼠的代谢综合征和脂肪堆积指标 (80)。

在肥胖小鼠中，补充蓝莓饮食12-15周后，胰岛素抵抗（HOMA-IR）和葡萄糖耐量得到改善 (81-83)。与对照组相比，食用吸附浓缩于脱脂豆粉上的蓝莓粉的肥胖高血糖小鼠的口服葡萄糖耐量和空腹血糖浓度均有所改善 (83)。

在肥胖的Zucker大鼠中，蓝莓摄入可使部分（但并非全部）葡萄糖代谢生物标志物恢复正常 (84)。在其他肥胖啮齿动物研究中，蓝莓摄入可改善葡萄糖耐量 (85)，但也有研究未发现改善 (86)，一些研究还发现胰岛素反应并未改善 (65, 84, 85, 87)。然而，在高脂饮食喂养的小鼠中，与肥胖相关的炎症标志物和高血压均有所减轻 (87)。

浆果摄入可促进有益的黏蛋白产生菌的生长，这些细菌能够保护胃肠道内壁，从而减轻下肠道和全身炎症，并改善代谢结果 (88, 89)。

神经保护、认知与蓝莓

神经科学、蓝莓和花青素的人群研究

一项对近15万名受试者进行的两项美国队列研究的汇总分析显示，花青素（RR：0.76）和浆果（RR：0.77）摄入量最高五分之一的人群患帕金森病的风险较低（P = 0.02）(90)。在护士健康研究中，一项对1.6万名女性进行的前瞻性分析显示，蓝莓和草莓摄入量较高与老年人认知能力下降速度减缓相关，估计可延缓认知能力下降约2.5年(5)。

阿尔茨海默病和其他痴呆症的风险与心血管和代谢健康风险生物标志物相关，包括中年时期的肥胖和胰岛素抵抗(91-93)。由于花青素对心血管疾病和2型糖尿病具有保护作用，因此摄入更多花青素可能与降低晚年患阿尔茨海默病样痴呆的风险有关。

神经科学与蓝莓的临床研究

老年人每日饮用蓝莓汁（94）或康科德葡萄汁（95）12周后，认知能力有所改善。健康老年人补充蓝莓90天后，任务切换能力增强，记忆干扰减少（96）。39名有认知障碍的老年人服用蓝莓粉后，记忆力略有改善，日常生活功能也得到主观提升（97）。这些改善反映了执行能力的提高（97）。有趣的是，与轻度认知障碍患者相比，认知功能正常的老年人获益相对较小（96, 97）。

健康老年人在认知挑战中，连续12周食用蓝莓后，磁共振成像检测到其大脑活动增强。该检测结果与认知功能相关脑区的灌注增强有关 (98)。同样，在记忆测试中，MRI 检测到的局部血氧水平依赖性活动 (99) 在服用蓝莓的受试者中增强，而在服用安慰剂的受试者中未见增强。本研究中的所有受试者均患有轻度认知障碍 (99)。

在一项急性研究中，学龄儿童服用蓝莓粉后 2 小时，列表学习任务的表现有所改善，而服用安慰剂的儿童则未见改善，结果显示认知获益 (100)。儿童执行功能和长期记忆的改善与其蓝莓粉的摄入量相关，并存在剂量反应关系（15 克蓝莓粉与 30 克蓝莓粉相比） (101)。在一项针对 7 至 10 岁儿童的交叉试验中，单次服用 30 克蓝莓粉可提高儿童在限时分级执行功能任务中的执行功能表现 (102)。

通过增加认知负荷的任务，可以更有效地检测蓝莓对健康儿童的认知益处 (102)。事实上，认知评估工具的进步将有助于研究特定人群。尤其需要开发能够测量蓝莓对非病理性衰老相关认知领域（而非受阿尔茨海默病等神经病理影响的领域）影响的方法。诸如协变量控制和差异分数等统计技术有助于在认知等因素的个体间差异不受控制的情况下，识别花青素等植物化学物质的影响。能力、II期代谢和肠道菌群。

蓝莓与大脑的动物和机制研究

蓝莓改善了老年大鼠的认知和运动能力，使其与年轻动物相当（103, 104）。在老年小鼠中也观察到了类似的与年龄相关的改善（105）。蓝莓对啮齿动物长期空间记忆的改善作用已被广泛报道（29, 105–108）。蓝莓在涉及工作记忆和学习的任务中的认知益处也已被证实（105, 108, 109）。

补充蓝莓可以保护中年小鼠免受高脂饮食引起的认知能力下降（110）。鉴于肥胖相关代谢紊乱的发病率不断上升（111）以及中年人心血管代谢标志物与晚年阿尔茨海默病风险之间的关联（91–93），这一发现尤为引人关注。

在由高能粒子暴露引起的加速衰老的大鼠模型中，补充蓝莓可保护脆弱的大脑区域，减少空间记忆缺陷，并减轻炎症和氧化应激标志物（112, 113）。在红藻氨酸诱导炎症的细胞培养模型中，用蓝莓多酚组分治疗可改善钙缓冲能力并减少海马神经元丢失（114）。补充蓝莓与海马 cAMP 反应元件结合蛋白磷酸化水平和脑源性神经营养因子浓度的增加相关，并改善老年动物的空间工作记忆任务表现（115）。

据报道，蓝莓喂养可上调老年（106）和年轻（107）啮齿动物的神经发生、神经可塑性、脑源性神经营养因子和胰岛素样生长因子 1。蓝莓花青素苷及其二期代谢产物能够穿过血脑屏障，并在多种脑组织中被检测到（24, 27–29, 116, 117）。

蓝莓与花青素在视觉和眼部健康中的作用

视觉功能、视网膜应激与花青素

视觉过程中，到达眼睛的光线经角膜、晶状体和玻璃体进行波长过滤，并聚焦于视网膜上。随后，视网膜感光细胞将光能转化为电信号，并通过视网膜神经节细胞（RGC）的轴突传递至大脑的视觉中枢。

视网膜是所有哺乳动物组织中呼吸频率最高的（118, 119），也是氧化应激的重要来源。视网膜感光细胞的外节富含感光色素（视蛋白和11-顺式视黄醇），这些感光色素嵌入富含多不饱和脂肪酸的细胞膜中，且细胞膜不断更新（120），从而为氧化应激创造了非常有利的条件（121）。视网膜辐射（122）、新生血管形成（123）和炎症（124, 125）等病理反应会加剧氧化应激和细胞增殖。氧化应激和炎症标志物会随着正常衰老而增加，并可触发组织适应性反应（副炎症）以恢复视网膜的稳态（126）。

尽管视网膜受到视网膜色素上皮（RPE）处活性血脑屏障的保护，但仍可在眼组织中检测到花青素。在大鼠和兔中，口服、静脉注射或腹腔注射花青素后，花青素选择性地分布于眼部组织（26）。在饲喂含0%、1%、2%或4%（w/w）蓝莓日粮的猪中，花青素在全眼中的含量呈剂量依赖性（127）。

关于花青素与视力的人群研究

目前，关于花青素摄入量与眼部疾病风险之间关系的观察性研究非常少。一项针对10054名芬兰受试者的研究表明，较高的总类黄酮摄入量与白内障风险降低相关（128）。在一项纳入超过35,000名年龄≥45岁女性的前瞻性队列研究中，蓝莓摄入量与新发总体黄斑变性和视力显著性年龄相关性黄斑变性的风险降低显著相关，但与新发白内障无关（H Sesso，布里格姆妇女医院，个人交流，2019）。尽管黄斑变性是发达国家老年人视力障碍的主要原因，但目前尚无研究探讨花青素摄入量与黄斑变性之间的关系。

浆果花青素与视力的临床研究

与动物和体外研究相比，探讨花青素对人类视力影响的临床研究相对较少，尤其是那些充分满足设计标准（包括随机化、盲法、安慰剂对照和交叉设计）的研究，如前所述（129, 130）。在30例眼压正常的青光眼患者中，每日服用黑加仑花青素（50毫克）6个月后，视野缺损稳定，眼部血流改善，血浆内皮素水平恢复正常（131）。一项试验也观察到了类似的益处。接受药物治疗的开角型青光眼患者每日服用 25 mg 花青素，持续 2 年 (132)。一项交叉研究 (n = 21) 也观察到，每日服用 50 mg 花青素仅 4 周后，眼压也得到改善 (133)。

Mirtogenol（越橘和松树皮提取物），相当于每日服用约 30 mg 花青素，持续 6 个月，可为正在服用常用青光眼治疗药物——前列腺素 F2α 类似物（拉坦前列素）的眼压升高患者带来额外益处 (134) (135)。Mirtogenol 的额外作用可能是由于毛细血管滤过正常化所致，这是一种与血管通透性相关的降压作用。一项使用 Tegens（一种与 Mirtogenol 类似的药物）治疗糖尿病视网膜病变患者的研究也提示了这种作用 (136)。在一项蓝莓研究中，研究人员在脂毒性诱导的血管内皮功能障碍体外模型中证实了蓝莓的保护作用，该模型中较高的NO生物利用度与蓝莓的作用相关(137)。

在一项针对非增殖性糖尿病视网膜病变患者的研究中，每日服用510毫克越橘花青素（溶于Tagen-F中）12个月后，受试者的对比敏感度有所提高(138)。在一项为期1个月的交叉试验中，分别纳入了30名(139)和60名(140)正常受试者，结果表明，花青素的摄入与近视患者视觉调节能力的提高和眼疲劳的减轻相关，这可能是通过提高对比敏感度实现的。

研究还发现，单次服用12.5、20或50毫克/剂量的黑加仑浓缩汁后，受试者的暗适应阈值较安慰剂组有所改善，且视觉调节偏移也得到改善(141)。在另外两项近期针对视力正常成年人（n = 60 和 72）的交叉研究中，蓝莓汁的摄入对暗适应、暗适应视力或对比敏感度均无影响，但发现视网膜光漂白后的恢复时间有轻微改善（142）。有趣的是，每日服用 7 毫克或 346 毫克蓝莓花青素，并在服用 3 周和 12 周后均观察到了光漂白恢复效应。在健康人短期服用低剂量花青素的研究中，暗适应阈值、视力或对比敏感度均未得到改善（143-146），这与早期报道此类益处的研究结果相矛盾（详见参考文献 129 和 130）。

蓝莓和花青素在动物视觉模型中的作用

在利用光诱导视网膜感光细胞变性（一种广泛用于模拟人类视网膜营养不良的模型 (147)）的研究中，蓝莓属植物的神经保护作用得到了令人信服的证实。长期（5-35 天）(148, 149) 和短期（2-72 小时）(149-153) 的预防性治疗，每日给予 10 至 500 毫克花青素，均能有效保护视网膜。视网膜炎症是许多眼部疾病的标志性特征，在腹腔注射脂多糖 (LPS) 诱导炎症后，小鼠连续 4 天喂食越橘提取物（500 毫克/公斤体重）可减轻视网膜炎症 (154)。与对照组相比，越橘组小鼠的视网膜电生理功能得到改善，视紫红质得到保护，感光细胞损伤也更少 (154)。在类似的视网膜炎症模型中，小鼠连续5天每日摄入50-200毫克越橘，结果显示神经毒性NO和丙二醛水平呈剂量依赖性下降，同时由于谷胱甘肽、维生素C、超氧化物歧化酶和谷胱甘肽过氧化物酶的增加，神经保护性抗氧化能力增强（155）。

其他主要针对视网膜神经节细胞（RGC）的眼部疾病也已被研究。在视神经损伤小鼠模型中，摄入越橘提取物[100毫克/(公斤·天)]可减轻体内RGC的退化。在体外，1%的越橘提取物可减轻3-(4-吗啉基)西多尼明盐酸盐诱导的氧化条件下RGC的损伤（156）。此外，在玻璃体内注射N-甲基-D-天冬氨酸（20-100微克/眼）诱导的氧化条件下，越橘也能保护小鼠体内的RGC（156）。

浆果的摄入可以对眼部发育产生实验性影响。当通过在雏鸡眼前放置强负透镜诱导近视时，在处理前3天喂食黑加仑提取物（400 mg/kg 体重）的雏鸡受到的影响较小（157）。在表现出衰老加速表达和寿命缩短的高血压OXYS大鼠中，越橘提取物（20 mg/kg 体重）可以减缓视网膜变性和白内障的发展（158）。在新生大鼠中，通过皮下注射亚硒酸钠诱导白内障后，每日给予富含多酚的越橘提取物40 mg足以预防白内障的形成（159）。这种作用可能通过调节晶状体中的核因子E2相关因子2和血红素加氧酶-1来实现（159）。

新生小鼠暴露于高氧环境中会发生类似于早产儿视网膜病变的血管并发症。人类。新生儿暴露于氧气后，眼内注射越橘提取物（300 ng/眼）可抑制新生血管簇的形成，其机制可能是通过抑制血管内皮生长因子A及其下游调控的激酶（160）。

蓝莓、花青素与视觉生理的体外研究

体外研究表明，蓝莓及其花青素具有抗氧化能力，可用于预防或治疗，其作用机制已在与氧气供体（161, 162）、单线态氧猝灭（163）、谷胱甘肽合成（149, 164）以及谷氨酸损伤（165）相关的视觉模型中得到证实，这些模型适用于视网膜色素上皮细胞（RPE）和视网膜神经节细胞（RGC）原代培养细胞系。

花青素作为分子变构效应剂的作用已在视紫红质受体蛋白（166）和贝斯特卵黄状视网膜营养不良相关蛋白（167）中得到研究。已有报道指出，花青素和类黄酮的变构作用可抑制体外白内障的发生（168-171）。

越橘花青素可提高培养的人角膜上皮细胞的活力和分化能力（172），野生中国蓝莓（V. uliginosum L.）对RPE细胞系D407也具有类似的益处（173）。蓝莓处理可提高光诱导衰老和体外多次复制后人RPE细胞的活力和分化能力（174）。

多项研究表明，类黄酮可能通过影响视紫红质再生速率（166, 175–177）、调节参与光转导级联反应的下游G蛋白的抑制（178, 179）或下调类视黄醇结合蛋白（163）来提高体外视网膜感光细胞的敏感性。在体外牛睫状肌制备中，花青素与内皮素-1通路相互作用，降低肌肉收缩力，这与近视眼远视的调节过程有关（180）。

蓝莓、花青素与食品加工

新鲜蓝莓娇嫩，通常在采摘后尽快加工保存。速冻是蓝莓保存的常用方法，可以保留维生素C、总酚、花青素和抗氧化能力（181）。在-18°C下储存10个月后，蓝莓花青素的损失率为12% (181)。

干蓝莓可在室温下储存。传统的热脱水方法会导致花青素的大量损失 (182)，而冻干是一种在去除水分的同时保留蓝莓植物化学成分的有效方法 (183)。冻干蓝莓粉的花青素损失与温度相关，在25°C、42°C和60°C下储存的半衰期分别为139天、39天和12天 (184)。

蓝莓提取物的辐射区干燥不会影响花青素或总酚含量 (185)。非热技术，例如高压和脉冲电场，与冷藏相结合，有助于在加工后立即保留蓝莓中的维生素C、总酚和花青素 (186)。蓝莓可以加工成保质期长的产品（例如罐头水果、果汁和果酱）；然而，加工过程会导致其植物化学成分发生变化。在果汁和果泥加工过程中，热、氧气和酶会降解蓝莓中的植物化学成分，其中维生素C和花青素的损失最为显著。蓝莓的抗坏血酸含量低，花青素含量高（187），值得注意的是，花青素很容易被抗坏血酸降解（188, 189）。

整粒蓝莓的均质化会导致花青素、原花青素和黄酮醇的氧化损失，这是由于多酚氧化酶的作用（190）。在研磨和脱果胶之前进行漂烫可以减轻酶催化的氧化损伤（191）。巴氏杀菌法灭活微生物和酶通常会导致蓝莓多酚化合物的少量损失（<10%），但可能会对产品风味产生不利影响 (192)。当压榨饼中富含多酚的果皮和种子被物理去除时，多酚化合物也会损失 (193–195)。

常温保存的蓝莓产品，如果酱 (196)、果汁 (197) 和提取物 (198)，在室温下储存时会损失多酚化合物，而冷藏可以减少损失。蓝莓加工会显著改变果实成分；因此，优化有益健康化合物的提取和货架稳定性的加工方法是值得追求的目标。

致谢

RZ-R 感谢西班牙卡洛斯三世健康研究所“米格尔·塞尔维特”项目 (CP15/00100) 和欧洲社会基金的资助。作者的职责如下——WK：编辑稿件，并参与撰写关于蓝莓与视力的内容；WK、AC、LRH、RK、AJS、FT、RZ-R：各自撰写了关于其主题的草稿；所有作者：审阅并可修改编辑（WK）提交的后续版本，并阅读和批准最终稿件。

Recent Research on the Health Benefits of Blueberries and Their Anthocyanins

https://pmc.ncbi.nlm.nih.gov/articles/PMC7442370/

Wilhelmina Kalt ^1,^✉, Aedin Cassidy ², Luke R Howard ³, Robert Krikorian ⁴, April J Stull ⁵, Francois Tremblay ⁶, Raul Zamora-Ros ⁷

2019 Jul 22

¹ Agriculture and Agri-Food Canada, Kentville Research and Development Centre, Kentville, Nova Scotia, Canada (retired)

² Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, United Kingdom

³ Department of Food Science, University of Arkansas, Fayetteville, AR, USA

⁴ Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati Academic Health Center, Cincinnati, OH, USA

⁵ Department of Human Ecology, University of Maryland Eastern Shore, Princess Anne, MD, USA

⁶ Department of Ophthalmology and Visual Sciences and Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada

⁷ Unit of Nutrition and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain

^✉

Address correspondence to WK (e-mail: Wilhelmina.kalt@icloud.com)

PMCID: PMC7442370 PMID: 31329250

ABSTRACT

Awareness of the human health benefits of blueberries is underpinned by a growing body of positive scientific evidence from human observational and clinical research, plus mechanistic research using animal and in vitro models. Blueberries contain a large number of phytochemicals, including abundant anthocyanin pigments. Of their various phytochemicals, anthocyanins probably make the greatest impact on blueberry health functionality. Epidemiological studies associate regular, moderate intake of blueberries and/or anthocyanins with reduced risk of cardiovascular disease, death, and type 2 diabetes, and with improved weight maintenance and neuroprotection. These findings are supported by biomarker-based evidence from human clinical studies. Among the more important healthful aspects of blueberries are their anti-inflammatory and antioxidant actions and their beneficial effects on vascular and glucoregulatory function. Blueberry phytochemicals may affect gastrointestinal microflora and contribute to host health. These aspects have implications in degenerative diseases and conditions as well as the aging process. More evidence, and particularly human clinical evidence, is needed to better understand the potential for anthocyanin-rich blueberries to benefit public health. However, it is widely agreed that the regular consumption of tasty, ripe blueberries can be unconditionally recommended.

Conclusions

Selected research documenting blueberries as a health-promoting food has been presented. Evidence supporting a role for blueberries and anthocyanins in human health is outlined according to human observational and clinical evidence, followed by mechanistic research using animal and in vitro models. Blueberry treatments generally produce larger effects in experimental models involving stress or disease risk.

The relative amount of evidence presented supporting cardiovascular, glucoregulation, neuroprotection, and vision benefits differs. For example, whereas there is abundant epidemiological evidence for the cardioprotective effects of blueberries and anthocyanins, epidemiological evidence for blueberry or anthocyanin benefits in human vision is lacking. And where there is substantial clinical evidence showing blueberry-related improvements in cognition and brain function, there is relatively little epidemiological evidence on anthocyanins in this area.

The anti-inflammatory, antioxidant, and vasoprotective effects of blueberry components together contribute to well-regulated glucose delivery to insulin-sensitive tissues and good metabolic function. Each of these aspects has implications in multiple areas of healthy aging. Notably, biomarkers of cardiometabolic dysfunction are associated with risk for vascular and Alzheimer-type dementia in late life (92, 93), which may be related to the mitigation of neuroinflammation.

Improvement in anti-inflammatory biomarkers associated with blueberry intake is supported by observational (8), clinical (48), animal (87), and in vitro (114) evidence. Anti-inflammatory and immune benefits of blueberries may involve mucin-associated and other colonic microbiota (67), which constitutes a new domain for berry health research.

Blueberry benefits have been observed in both short-term (see, for example, references 18, 78, and 100) and long-term human interventions (see, for example, references 76 and 94), which suggests multiple modes of action.

In blueberry health research, several important areas remain poorly understood. For example, the dose dependency of clinical effects is mostly unclear (18, 101, 142). The bioactivity of anthocyanin metabolites in vivo, both collectively and individually, is still mostly unknown, as is the importance to health of anthocyanins localized in tissues. Another important question is the relative bioactivity in the colon of phenolic breakdown products of blueberry anthocyanins compared with similar phenolic compounds from other plant foods in the diet. Notably, these gaps in knowledge do not detract from our ability to tap into blueberry health benefits by increasing public consumption.

This review of research findings will hopefully aid consumers, healthcare providers, and the food and health industry to understand the current state of knowledge on blueberries and health. It can be safely stated that daily moderate intake (50 mg anthocyanins, one-third cup of blueberries) can mitigate the risk of diseases and conditions of major socioeconomic importance in the Western world.

Introduction

Blueberries were first popularized as a “super fruit” due mainly to the high in vitro antioxidant capacity of their abundant polyphenolic compounds. However, direct antioxidant action of polyphenolic compounds in situ appears unlikely due to their poor bioavailability (1). Nonetheless, research regarding foods for health performed during the past 2 decades has revealed a multitude of ways in which blueberries are bioactive and beneficial to health.

An increasing body of evidence suggests that blueberries and anthocyanins reduce biomarkers and risk of diseases that constitute major socioeconomic burdens, including cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and neurological decline. In these observational analyses, anthocyanins often provide benefits over and above other plant food phytochemicals, including other flavonoids (2–6). The intake of even moderate amounts of blueberries (approximately one-third cup) and anthocyanins (<50 mg) daily is associated with disease risk reduction (2–4, 6–9).

In this narrative, research on the role of blueberries in cardiometabolic health, neuroprotection, vision, and food processing is reviewed. Observational evidence is presented along with results from human clinical studies, and from animal and in vitro research. Over half of the nearly 200 papers cited in this review were published in the last decade. Blueberry research is the primary focus of this review; however, anthocyanin literature is also discussed where relevant. Interest continues to grow in the potential human health benefits of blueberries.

Current Status of Knowledge

Blueberry species and composition

Blueberry species of commercial importance include highbush blueberry (Vaccinium corymbosum L.), rabbiteye blueberry (V. virgatum Aiton), lowbush blueberry (V. angustifolium Aiton), and European bilberry (V. myrtillus L.). Blueberries are one of the richest sources of anthocyanins among common fruits (10–12) (Table 1). Anthocyanins are the pigments that confer the red, blue, and purple coloration to ripe berries. During berry ripening, anthocyanin content rises dramatically to provide a visual cue to distinguish between early to fully ripe fruit (13).

TABLE 1.

Total anthocyanin concentration of popular fruit consumed in the United States

Fruit	Description	Number of samples	Total anthocyanins (mg/100 g fresh)
Apple¹	Red peel	6	12
Apple¹	Yellow peel	2	0
Banana²		—	0
Blackberry²		4	245
Blueberry²	Highbush	7	387
Blueberry²	Lowbush	1	487
Cantaloupe²		—	0
Cherry (sweet)²		4	122
Grape²	Red peel and flesh	5	27
Grape²	Purple peel and flesh	1	120
Kiwifruit²		—	0
Nectarine³	Yellow peel	5	15
Orange²	Orange flesh	—	0
Plum³	Yellow peel	1	0
Plum³	Red peel	2	20
Plum³	Black peel	2	116
Raspberry (red)²		5	92
Strawberry²		8	21
Watermelon²		—	0

Reference 11.

Reference 10.

Reference 12.

Among a selection of 80 highbush and 135 lowbush blueberry phenotypes, 90% of the phenotypes spanned a 1.6-fold range in anthocyanin concentration (14). Among the total 215 blueberry phenotypes, the range between the 10th and 90th percentiles of cyanidin-3-glucoside equivalents/g fresh weight was 0.925 to 2.1 mg (14).

Blueberry polyphenolic compounds

Anthocyanin flavonoids account for up to 60% of the total polyphenolics in ripe blueberries (13). Therefore, anthocyanins probably make the greatest contribution to blueberry health benefits. Blueberry polyphenolic compounds include both flavonoid and nonflavonoid types. Other classes of flavonoids found in blueberries include proanthocyanidins (15, 16) and flavonols (17, 18). Abundant nonflavonoid polyphenolic compounds in blueberries are the hydroxycinnamic acid esters (especially chlorogenic acid) (16, 17, 19, 20).

Anthocyanin bioavailability

Associating the in vivo metabolites of anthocyanins with health outcomes has been difficult. After ingestion, anthocyanins are converted to a large number of products via chemical events and human and microbial metabolism. Clearance time for anthocyanin metabolites varies widely (21, 22). To illustrate, within 6 h after humans ingested ¹³C-labeled anthocyanin, substantial ¹³C-labeled CO₂ was detected in exhaled breath, which demonstrated rapid and complete anthocyanin catabolism. However, >50% of the ¹³C still remained in the body after 48 h (21). Anthocyanins and their phase 2 metabolites persist in urine long after anthocyanin intake (23), probably due to their transport in bile (24, 25). Also, anthocyanins and their metabolites become localized in body tissues (24, 26–29). Due to the catabolic action of gastrointestinal microflora on anthocyanins and other food polyphenolics, phenolic acid products are very abundant in the large intestine (30).

Cardiovascular Health

Population studies in cardiovascular health, berries, and anthocyanins

The association between a higher anthocyanin intake and reduction in all-cause mortality risk in a meta-analysis of 6 studies was principally due to a decreased cardiovascular mortality risk (31). Similar findings were reported in a meta-analysis of total CVD (RR: 0.89; 95% CI: 0.83–0.96) (32). In 3 cohort studies, a higher anthocyanin intake was associated with an ~25% reduced risk of coronary artery disease, including fatal and nonfatal myocardial infarction (33, 34). Higher intakes of blueberries, strawberries, and total anthocyanins were all associated with a 32% lower rate of myocardial infarction, and this association was independent of established risk factors (2). However, in 2 prospective cohort studies no association was found between anthocyanin intake and stroke risk (34, 35).

Higher anthocyanin intake was associated with an ~8–10% reduction in hypertension risk in 5 cohort studies (3, 36, 37). A higher anthocyanin intake was associated with a 10% lower risk of incident hypertension in a cohort of over 87,000 participants examined over a period of 14 y (3). The greatest risk reduction was observed in women aged ≤60 y (3). One biomarker, vascular stiffness, was measured in a cross-sectional study of 1898 carefully phenotyped twins. In this study, a clinically relevant improvement in vascular modulation, measured using pulse wave velocity, was associated with greater anthocyanin intake (6).

Population studies in CVD, obesity, berries, and weight maintenance

Obesity and overweight are major contributors to CVD risk (38). Even minor weight gain can increase the risk of hypertension (39) and CVD (40, 41). Reducing BMI by 1–3 kg/m² was associated with a 2–13% lower risk of CVD events (41) and mortality (42). In a comparison of intakes of 16 common fruits, the highest blueberry intake was associated with the least weight gain (−0.64 kg over 4 y) in a prospective study of over 133,000 men and women followed for ≤24 y (43). Among 6 classes of flavonoids, a higher anthocyanin intake had the strongest association with less weight gain (−0.1 kg per 10 mg anthocyanins) in a study of 124,000 individuals (44).

Greater anthocyanin intake was associated with 3–9% lower fat mass and less central adiposity in healthy female twins (n = 2734) (45) based on body composition assessment using DXA (46). In this study, the twin with the higher blueberry intake had a lower fat mass ratio than the co-twin (45). Results of the twin studies are most interesting because they are independent of genetic and common environmental factors.

Clinical studies in cardiovascular health

In clinical research on blueberries, subjects most often have some CVD risk (e.g., metabolic syndrome markers, T2DM). In a placebo-controlled study of 58 diabetic patients, blueberry intake led to a decline in LDL cholesterol, triglycerides, and adiponectin and an increase in HDL cholesterol (47). Intake of purified anthocyanin for 12 wk by 150 hyper-cholesterolemic subjects was associated with an increase in HDL cholesterol and a decrease in LDL cholesterol as well as improved endothelial function (brachial flow-mediated dilation) (48). Then, after 24 wk of anthocyanin intake by the same 150 hypercholesterolemic patients, a reduction was documented in inflammatory markers, including serum high-sensitivity C-reactive protein, soluble vascular adhesion molecule-1, and plasma IL-1β (49).

Arterial stiffness was reduced and both systolic and diastolic blood pressure were decreased by 5–6% after 8 wk of blueberry intake in women with pre- and stage 1 hypertension (50, 51). Similar benefits were observed in middle-aged unmedicated men with CVD risk factors (51). In subjects with metabolic syndrome, vascular endothelial function was improved although blood pressure was unaffected by blueberry intake for 6 wk (52). In a blueberry study examining participants with metabolic syndrome (n = 115), after 6 mo of taking either 0, 75, or 150 g, biomarkers of cardiometabolic function were unchanged in the group taking 75 g blueberries daily. However, the group taking 150 g blueberries daily had sustained improvements in vascular function and lipid status. Insulin resistence was not affected by either dose of blueberries (53). Some clinical studies have reported little to no effect of blueberry intake on blood pressure (54, 55). In contrast to these long-term studies, in a 6-h acute study design, blueberry intake was associated with short-term improvements in vascular function measured by flow-mediated dilation in 21 healthy men (56).

Mechanisms of cardiovascular benefit

Blueberries and anthocyanins benefit cardiovascular health via antioxidant and anti-inflammatory effects (49, 57) positive effects on plasma lipid levels, and modulation of glucose metabolism and endothelial function (see reviews, 58, 59). Blueberries protect vasculature in various ways that can be detected by vascular responsiveness, blood pressure, and arterial stiffness (18, 50–52, 60). These benefits may involve NO metabolism (53, 61) and effects on endothelium composition (62) and plasma lipids (47, 48, 63). Most often, cardiovascular research models employ a relevant stress treatment (e.g., diet or disease) or examine a population with existing risk condition(s).

Nonflavonoid catabolites of berry anthocyanins predominate in the large intestine (1) and could interact with the microbiota to elicit anti-inflammatory or other responses that contribute to cardioprotective benefits (64). Blueberry supplementation modified the colonic microflora of rats (65, 66). By use of gene sequencing, 3 new phyla and 22 new genera of micro-organisms were found to be specifically associated with blueberry feeding (66). These gene changes accounted for ~9% of the entire genome and were associated with species in the intestinal mucin layer, as well as better protection from bacterial invasion and greater capacity for xenobiotic metabolism (66). In a study with high-fat–fed rats, blueberry intake moderated the negative effects of the high-fat diet on inflammation and insulin signaling and also led to modification of the gut microbiota (67).

Prediabetes and T2DM

Population studies in T2DM, blueberries, and anthocyanins

Prediabetes and T2DM affect ~100 million adults in the United States (68). Both prediabetes and T2DM are characterized by poor response to insulin stimulation (i.e., insulin resistance) leading to inefficient glucose uptake and metabolism in insulin-sensitive tissues (69). Of all the fruits analyzed in 3 prospective studies, blueberries provided the strongest association, with T2DM risk reduction of 26% (RR: 0.74; 95% CI: 0.66–0.83) (70). In the same cohorts, when the intake of habitually consumed flavonoids (flavonols, flavones, flavanones, flavan-3-ols, and anthocyanins) was examined, intake of anthocyanins and particularly blueberries provided a similar degree of risk reduction of 23% with consumption of ≥2 servings weekly or ≤1 serving monthly. There was no association found between the intake of total flavonoid or other flavonoid groups and reduced T2DM risk (4).

A meta-analysis of data from 3 US cohorts associated T2DM risk reduction with higher intake of anthocyanins (RR: 0.85, 95% CI: 0.80–0.91) and berry fruits (RR: 0.82, 95% CI: 0.76–0.89) (71). A similar association between T2DM risk reduction with greater anthocyanin intake was determined in a Polish cohort (RR: 0.68, 95% CI: 0.48–0.98) (72). In a cross-sectional study in women, higher habitual intake of anthocyanins and flavones was associated with improvements in insulin resistance, whereas only anthocyanin was associated with a decrease in inflammation and high-sensitivity C-reactive protein (8). Obesity is positively associated with T2DM risk (73). Greater blueberry and anthocyanin intake is associated with less weight gain during aging (43–45) and therefore would support reduced T2DM risk. Notably, not all observational studies identified an association of anthocyanin or berry intake with reduced T2DM risk (74, 75).

Clinical studies in T2DM

In a placebo-controlled study of obese, insulin-resistant adults, insulin sensitivity was greater after 6 wk of blueberry intake (76). Insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp, which directly measures whole-body glucose disposal (77).

Anthocyanin extract from bilberry and black currant (80 mg daily) improved insulin sensitivity (HOMA-IR), plasma lipid profiles, and reduced plasma markers of oxidative stress among 58 T2DM patients compared to placebo (47). When glucose-modulation effects were examined in a T2DM population after a single oral dose of either placebo or 0.47 g standardized bilberry extract containing 36% (w/w) anthocyanins, bilberry intake lowered plasma glucose and insulin AUC in the oral glucose tolerance test (78). In a 12-wk trial of 54 overweight young adults, replacing 50 g carbohydrate with 50 g blueberries daily produced favorable reductions in body weight (BW), insulin, cholesterol, and other metabolic factors (63).

Animal and mechanistic studies in T2DM

Rodents with a phenotype and metabolic features of prediabetes and T2DM, plus diet-induced obesity, are often used to investigate mechanisms of action. C57BL/6 mice fed a high-fat (60%) diet for 8 wk had better insulin sensitivity when blueberries were added to the high-fat diet (79). Also, the glucose AUC of the mice fed a high-fat diet plus blueberries was similar to that of mice fed the low-fat diet (79).

In a study where Zucker fatty rats were fed a high-fat (45%) or low-fat (10%) diet, after 12 wk rats receiving a high-fat diet plus 2% blueberries and those fed a low-fat diet had better metabolic markers than mice fed a high-fat diet without blueberries. At that time rats fed a high-fat diet plus blueberries had better measures of fasting insulin levels, insulin resistance (HOMA-IR), and glucose AUC than high-fat–fed controls (80). Blueberry intake reduced markers of metabolic syndrome and adiposity in high-fat–fed, obesity-prone rats (80).

Insulin resistance (HOMA-IR) and glucose tolerance in obese mice were improved after 12–15 wk of diet supplementation with blueberries (81–83). Obese hyperglycemic mice that consumed blueberry powder that was sorbed and concentrated on defatted soybean flour had improved oral glucose tolerance and fasting glucose concentration, compared to controls (83).

Several but not all biomarkers of glucose metabolism were normalized by blueberry intake in obese Zucker rats (84). In other obese rodent studies, blueberry intake improved glucose tolerance (85) or not (86), and in some studies insulin responses were not improved (65, 84, 85, 87). However, in high-fat–fed mice, inflammatory markers and hypertension that are associated with obesity were mitigated (87).

Berry intake supports the growth of favorable mucin-producing bacteria that can protect of the lining of the gastrointestinal tract, which may mitigate lower intestinal and systemic inflammation and improve metabolic outcomes (88, 89).

Neuroprotection, Cognition, and Blueberries

Population studies in neuroscience, blueberries, and anthocyanins

In a pooled analysis of 2 US cohort studies which examined almost 150,000 people, lower Parkinson disease risk was associated with the highest quintile of anthocyanin (RR: 0.76) and berry (RR: 0.77) intake (P = 0.02) (90). In a prospective analysis of 16,000 women in the Nurse's Health Study, greater intake of blueberries and strawberries was associated with slower rates of cognitive decline in older adults, with an estimated delay in decline of about 2.5 y (5).

The risk for Alzheimer disease and other dementias is associated with cardiovascular and metabolic health risk biomarkers, including obesity and insulin resistance in midlife (91–93). Inasmuch as anthocyanins are protective against CVD and T2DM risks, greater anthocyanin intake may be associated with reduced risk of Alzheimer-type dementia in late life.

Clinical studies in neuroscience and blueberries

Cognitive performance in elderly adults improved after 12 wk of daily intake of blueberry (94) or Concord grape (95) juice. Better task switching and reduced interference in memory was found in healthy older adults after 90 d of blueberry supplementation (96). Blueberry powder intake led to modest benefits in memory performance and subjective improvements in everyday function among 39 older adults with cognitive complaints (97). These kinds of improvements reflected better executive ability (97). Interestingly, relatively modest benefits were found in cognitively unimpaired older adults (96, 97) compared with benefits measured in participants with mild cognitive impairment.

After 12 wk of blueberry consumption, greater brain activity was detected using magnetic resonance imaging in healthy older adults during a cognitive challenge. The detection was associated with enhanced perfusion in regions mediating cognitive function (98). Similarly, during a memory test, regional blood oxygen level-dependent activity detected by MRI (99) was enhanced in the subjects taking blueberry, but not in those taking placebo. All subjects in this study had mild cognitive impairment (99).

Cognitive benefits were detected in school-aged children in an acute study design where performance on a list-learning task was improved 2 h after consuming a single dose of blueberry powder but not placebo (100). Improvement in executive and long-term memory in children was associated with their intake of blueberry powder, with evidence of a dose-response (15 compared with 30 g powder) (101). In a crossover trial with children 7- to 10-y old, a single 30-g dose of blueberry powder produced enhanced executive performance on a timed and graded executive task (102).

Detecting cognitive benefits of blueberries in healthy children could be facilitated by tasks that involve a greater cognitive demand (102). Indeed, advancements in cognitive assessment tools will aid in examining specific populations. In particular, methods are needed to measure blueberry effects in cognitive domains involved in nonpathological aging, as opposed to domains affected by neuropathologies like Alzheimer disease. Statistical techniques such as covariate control and difference scores can help to identify the effects of phytochemicals like anthocyanins amid uncontrolled interindividual variation in factors such as cognitive capability, phase 2 metabolism, and intestinal microflora.

Animal and mechanistic studies on blueberries and the brain

Blueberries improved cognitive and motor performance of aged rats, making them comparable to young animals (103, 104). Similar age-related improvements were observed in old mice (105). Blueberry-related improvements in long-term spatial memory of rodents is widely reported (29, 105–108). Cognitive benefits of blueberries in tasks that engaged working memory and learning are also documented (105, 108, 109).

Blueberry supplementation protected middle-aged mice from deficits in cognitive performance related to a high-fat diet (110). This is interesting in light of the rising incidence of obesity-related metabolic disorders (111) and the association between cardiometabolic markers in middle-aged humans and Alzheimer dementia risk later in life (91–93).

Blueberry supplementation protected vulnerable brain regions, reduced deficits in spatial memory, and mitigated markers of inflammation and oxidative stress in a rat model of accelerated aging due to high-energy particle exposure (112, 113). In a cell culture model of kainic acid–induced inflammation, treatment with blueberry polyphenolic fractions led to improved calcium buffering and reduced hippocampal neuron loss (114). Blueberry supplementation correlated with increases in hippocampal cAMP response element–binding protein phosphorylation and concentrations of brain-derived neurotrophic factor and improved performance in spatial working memory tasks of old animals (115).

Blueberry feeding is reported to upregulate neurogenesis, neuroplasticity, brain-derived neurotrophic factor, and insulin-like growth factor 1 in aged (106) and in young (107) rodents. Blueberry anthocyanidin glycosides and their phase 2 metabolites can cross the blood–brain barrier and are detectable in various brain tissues (24, 27–29, 116, 117).

Blueberries and Anthocyanins in Vision and Eye Health

Visual function, retinal stress, and anthocyanins

During vision, light reaching the eye is wavelength-filtered through the cornea, lens, and vitreous humor and focused onto the neural retina. Then retinal photoreceptors convert light energy into an electrical signal that is transmitted to the brain's visual centers via the axons of the retinal ganglion cells (RGCs).

The retina has the highest respiratory rate of any other mammalian tissue (118, 119) and is a significant source of oxidative stress. The outer segment of the retinal photo-receptor cell is rich in photopigments (opsin and 11-cis retinol) imbedded in membranes rich in polyunsaturated fatty acids which are constantly being renewed (120), thereby creating very favorable conditions for oxidative stress (121). Oxidative stress and cell proliferation are exacerbated by pathological responses to irradiation of the retina (122), neovascularization (123), and inflammation (124, 125). Markers of oxidative stress and inflammation increase with normal aging and can trigger a tissue-adaptive response (parainflammation) to restore homeostasis in the retina (126).

Although the retina is protected by an active blood–brain barrier at the retinal pigmentary epithelium (RPE), anthocyanins can be detected in ocular tissues. Anthocyanins were selectively distributed to ocular tissues after oral, intravenous, or intraperitoneal administration in rats and rabbits (26). In pigs fed diets containing 0%, 1%, 2%, or 4% (w/w) blueberries, anthocyanins were detected in the whole eye in a dose-dependent manner (127).

Population studies on anthocyanins and vision

There are currently very few observational studies examining anthocyanin intake in relation to ocular disease risk. A higher total flavonoid intake was associated with a reduced risk of cataracts in a Finnish population of 10,054 subjects (128). In a prospective cohort study of >35,000 women aged ≥45 y, there was a significant association between blueberry intake and a reduced risk of incident total and visually significant age-related macular degeneration, but there was no association with incident cataract (H Sesso, Brigham and Women's Hospital, personal communication, 2019). Although macular degeneration is the leading cause of visual impairment during aging in the developed world, there are no studies that examine anthocyanin intake in relation to macular degeneration.

Clinical studies on berry anthocyanins and vision

Compared to animal and in vitro research, there are relatively few clinical studies examining anthocyanin effects on human vision, particularly studies that adequately satisfy design criteria, including randomization, blinding, placebo control, and crossover, as previously described (129, 130). In normotensive glaucoma patients (n = 30), visual field defects were stabilized, ocular blood flow was improved, and plasma endothelin was normalized after 6 mo of daily intake of black currant anthocyanin (50 mg) (131). Similar benefits were observed in a trial in patients medicated for open-angle glaucoma, who received 25 mg anthocyanin daily for 2 y (132). Beneficial effects on intraocular pressure were also observed in a crossover study (n = 21) after only 4 wk of 50 mg daily intake (133).

Mirtogenol (bilberry and pine bark extract), corresponding to ~30 mg anthocyanin taken daily for 6 mo, provided additive benefit to ocular hypertensive patients (134), who were taking a widely used glaucoma treatment, prostaglandin F2a analog (Latanoprost) (135). The additive effect of Mirtogenol could have been due to normalization of capillary filtration, an antihypertensive effect related to vascular permeability. This effect was also suggested in a study of diabetic retinopathy patients using Tegens, a product similar to Mirtogenol (136). In a study of blueberries, the same protective effect was documented in an in vitro model of lipotoxicity-induced vascular endothelial dysfunction where greater NO bioavailability was linked to the blueberry effect (137).

An improvement in contrast sensitivity was associated with the intake of 510 mg bilberry anthocyanins daily in Tagen-F for 12 mo in human subjects with nonproliferative diabetic retinopathy (n = 88) (138). In a 1-mo crossover trial of 30 (139) and 60 normal subjects (140), anthocyanin intake was associated with an improved capacity for visual accommodation and a decrease in ocular fatigue of myopic subjects, possibly by improving contrast sensitivity.

Improvements were reported in dark adaptation threshold between highest dose and placebo, and visual accommodation shifts after a single dose ingestion of black currant concentrate at 12.5, 20, or 50 mg/dose (141). In two other recent crossover studies of normal-sighted adults (n = 60 and 72) there was no effect of blueberry juice intake on dark adaptation or dark-adapted visual acuity or contrast sensitivity, although a mild improvement in recovery time after retinal photobleaching was found (142). Interestingly, photobleaching recovery effects occurred with daily doses of either 7 or 346 mg blueberry anthocyanins and after both 3 and 12 wk of intake. In studies where low doses of anthocyanins were taken by healthy humans for a short term, there was no improvement in dark adaptation threshold, visual acuity, or contrast sensitivity (143–146), which conflicts with earlier research which reported such benefits (for review, see references 129 and 130).

Blueberry and anthocyanin effects in animal models of vision

In studies using light-induced retinal photoreceptor degeneration, which is a widely used model of human retinal dystrophies (147), neuroprotection by blueberry species was convincingly documented with both long-term (5–35 d) (148, 149) and short-term (2–72 h) (149–153) prophylactic treatments with daily anthocyanin doses between 10 and 500 mg. Retinal inflammation, which is a hallmark of many ocular pathologies, was mitigated in mice fed bilberry extract (500 mg/kg BW) for 4 d after inflammation was induced by intraperitoneal injection of LPS (154). In the bilberry group, retinal electrophysiology was improved, rhodopsin was preserved, and there was less damage to photoreceptors compared to controls (154). In a similar model of retinal inflammation, mice fed for 5 d with 50–200 mg/d bilberry showed a dose-dependent decrease in neurotoxic NO and malondialdehyde, combined with an increase in neuroprotective antioxidant capacity due to glutathione, vitamin C, superoxide dismutase, and glutathione peroxidase (155).

Other ocular pathologies targeting primarily the RGC have also been investigated. The degeneration of RGC in vivo was mitigated with bilberry extract intake [100 mg/(kg ⋅ d)] in a mouse model of optic nerve injury. Bilberry extract (1%) mitigated RGC damage in vitro during oxidative conditions created with 3-(4-morpholinyl) sydnonimine hydrochloride (156). Bilberry also protected RGC of mice in vivo under oxidative conditions created by N-methyl-d-aspartic acid injected into the vitreous (20–100 µg/eye) (156).

Ocular development can be experimentally influenced by berry intake. When myopia was induced in young chicks by interposing a strong minus lens in front of the eye, the impact was less in chicks fed black currant extract (400 mg/kg BW) for 3 d prior to treatment (157). Retinal degeneration and cataract development were slowed with bilberry extract (20 mg/kg BW) in hypertensive OXYS rats that demonstrate senescence-accelerated expression of traits and a short lifespan (158). In neonatal rats where cataracts were induced by subcutaneous injection of sodium selenite, administration of a polyphenol-enriched fraction of bilberry at 40 mg/d was sufficient to prevent cataract formation (159). This effect was probably modulated through the regulation of nuclear factor erythroid 2–related factor 2 and hemoxygenase-1 in the lens (159).

Neonatal mice exposed to a high level of oxygen develop vascular complications similar to the retinopathy of prematurity in humans. Intraocular injection of bilberry extract (300 ng/eye) after neonatal oxygen exposure inhibited the formation of neovascular tufts by possible inhibition of vascular endothelial growth factor A and its downstream-regulated kinases (160).

Blueberries, anthocyanins, and vision physiology examined in vitro

The in vitro antioxidative capacity of blueberries and their anthocyanins, used either prophylactically or as a treatment, has been demonstrated in vision-relevant models related to oxygen donation (161, 162), quenching of singlet oxygen (163), glutathione synthesis (149, 164), and glutamate insults (165) in both RPE and RGC primary culture cell lines.

The action of anthocyanins as molecular allosteric effectors has been investigated with the receptor protein rhodopsin (166) and with bestrophin, a protein involved in Best vitelliform retinal dystrophy (167). The allosteric actions of anthocyanins and flavonoids to inhibit cataractogenesis in vitro has been reported (168–171).

Bilberry anthocyanins improved viability and differentiation of cultured human corneal epithelial cells (172) and wild Chinese blueberry (V. uliginosum L.) produced similar benefits in the RPE cell line D407 (173). Blueberry treatment improved the viability and differentiation of human RPE cells during light-induced aging and after multiple replications in vitro (174).

Several studies document a potential role for flavonoids to improve retinal photoreceptor sensitivity in vitro by affecting the rate of rhodopsin regeneration (166, 175–177), or by modulating the inhibition of downstream G proteins involved in the phototransduction cascade (178, 179), or by downregulating retinoid-binding proteins (163). In an in vitro bovine ciliary muscle preparation, anthocyanins interacted with the endothelin-1 pathway to reduce muscle contractility, which relates to accommodative processes for distance vision in myopic eyes (180).

Blueberries, Anthocyanins, and Food Processing

Fresh blueberries are delicate and often processed soon after harvest to preserve them. Individual quick freezing is a widely used means to preserve blueberries, to retain vitamin C, total phenolics, anthocyanins, and antioxidant capacity (181). The percentage loss of blueberry anthocyanins during −18°C storage was 12% after 10 mo of storage (181).

Dried blueberries can be stored at room temperature. Whereas conventional thermal dehydration can cause significant losses to anthocyanins (182), freeze-drying is an excellent means to remove water while preserving blueberry phytochemical quality (183). Freeze-dried blueberry powder loses anthocyanins in a temperature-dependent manner with a half-life of 139, 39, and 12 d when stored at 25, 42, and 60°C, respectively (184).

Radiant zone drying of blueberry extract did not affect anthocyanin or total phenolic content (185). Nonthermal technologies such as high pressure and pulsed electric fields used in conjunction with refrigerated storage helped to retain blueberry vitamin C, total phenolics, and anthocyanins immediately after processing (186).

Blueberries can be processed into shelf-stable products (e.g., canned fruit, juices, and preserves); however, processing can lead to changes in the phytochemical profile. During juice and purée processing, heat, oxygen, and enzymes can degrade blueberry phytochemicals, with greatest losses to vitamin C and anthocyanins. Blueberries are low in ascorbic acid and high in anthocyanins (187), and notably anthocyanins are readily degraded by ascorbic acid (188, 189).

Homogenization of whole blueberries leads to oxidative loss of anthocyanins, proanthocyanidins, and flavonols, due to polyphenol oxidase (190). Enzyme-catalyzed oxidative damage can be mitigated by blanching prior to milling and depectinization (191). Pasteurization to inactivate micro-organisms and enzymes typically results in minor (<10%) losses of blueberry polyphenolic compounds, although product flavor can be adversely affected (192). Polyphenolic compounds are lost when polyphenolic-rich skins and seeds in the press cake are physically removed (193–195).

Shelf-stable blueberry products like jam (196), juice (197), and extracts (198) can lose polyphenolic compounds when stored at ambient temperature whereas refrigeration mitigates losses. Blueberry processing can drastically change fruit composition; therefore, processing methods that optimize extraction and shelf stability of health-beneficial compounds are worthy objectives.

ACKNOWLEDGEMENTS

RZ-R thanks the “Miguel Servet” program (CP15/00100) from the Institute of Health Carlos III (Spain) and the European Social Fund. The authors' responsibilities were as follows—WK: edited the manuscript and also co-authored content on blueberries and vision; WK, AC, LRH, RK, AJS, FT, RZ-R: each prepared a draft on their topic; and all authors: reviewed and could revise subsequent versions received from the editor (WK) and read and approved the final manuscript.

Notes

The United States Highbush Blueberry Council (USHBC) offered support for this article by providing an honorarium to each author but had no role in the design and conduct of the review.

Author disclosures: AC, LRH, RZ-R, no conflicts of interest. AC acts as an advisor to the USHBC grant committee and has received research support from the USHBC. RK, WK, AJS, and FT have received research funding from the USHBC and have no conflict of interest.The USHBC is an agricultural federal research and promotion board established by the USDA. It was founded by and is funded by its members who are blueberry farmers, processors, and importers. The USHBC does not sell any product and operates with independent oversight from the USDA.

Abbreviations used: BW, body weight; CVD, cardiovascular disease; RGC, retinal ganglion cell; RPE, retinal pigmentary epithelium; T2DM, type 2 diabetes mellitus.

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