Kaempferol

People who eat or drink more foods with antioxidant flavonols, which are found in several fruits and vegetables as well as tea and wine, may have a slower rate of memory decline, according to a new study. People who eat or drink more foods with antioxidant flavonols, which are found in several fruits and vegetables as well as tea and wine, may have a slower rate of memory decline, according to a study published in the November 22, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology. "It's exciting that our study shows making specific diet choices may lead to a slower rate of cognitive decline," said study author Thomas M. Holland, MD, MS of Rush University Medical Center in Chicago. "Something as simple as eating more fruits and vegetables and drinking more tea is an easy way for people to take an active role in maintaining their brain health." Flavonols are a type of flavonoid, a group of phytochemicals found in plant pigments known for its beneficial effects on health. The study involved 961 people with an average age of 81 without dementia. They filled out a questionnaire each year on how often they ate certain foods. They also completed annual cognitive and memory tests including recalling lists of words, remembering numbers and putting them in the correct order. They were also asked about other factors, such as their level of education, how much time they spent doing physical activities and how much time they spent doing mentally engaging activities such as reading and playing games. They were followed for an average of seven years. The people were divided into five equal groups based on the amount of flavonols they had in their diet. While the average amount of flavonol intake in US adults is about 16 to 20 milligrams (mg) per day, the study population had an average dietary intake of total flavonols of approximately 10 mg per day. The lowest group had an intake of about 5 mg per day and the highest group consumed an average of 15 mg per day; which is equivalent to about one cup of dark leafy greens. To determine rates of cognitive decline, researchers used an overall global cognition score summarizing 19 cognitive tests. The average score ranged from 0.5 for people with no thinking problems to 0.2 for people with mild cognitive impairment to -0.5 for people with Alzheimer's disease. After adjusting for other factors that could affect the rate of memory decline, such as age, sex and smoking, researchers found that the cognitive score of people who had the highest intake of flavonols declined at a rate of 0.4 units per decade more slowly than people whose had the lowest intake. Holland noted this is probably due to the inherent antioxidant and anti-inflammatory properties of flavonols. The study also broke the flavonol class down into the four constituents: kaempferol, quercetin, myricetin and isorhamnetin. The top food contributors for each category were: kale, beans, tea, spinach and broccoli for kaempferol; tomatoes, kale, apples and tea for quercetin; tea, wine, kale, oranges and tomatoes for myricetin; and pears, olive oil, wine and tomato sauce for isorhamnetin. People who had the highest intake of kaempferol had a 0.4 units per decade slower rate of cognitive decline compared to those in the lowest group. Those with the highest intake of quercetin had a 0.2 units per decade slower rate of cognitive decline compared to those in the lowest group. And people with the highest intake of myricetin had a 0.3 units per decade slower rate of cognitive decline compared to those in the lowest group. Dietary isorhamnetin was not tied to global cognition. Holland noted that the study shows an association between higher amounts of dietary flavonols and slower cognitive decline but does not prove that flavonols directly cause a slower rate of cognitive decline. Other limitations of the study are that the food frequency questionnaire, although valid, was self-reported, so people may not accurately remember what they eat. The study was supported by the National Institutes of Health, National Institute on Aging, and USDA Agricultural Research Service.

近日，国家药品监督管理局批准华领医药技术（上海）有限公司申报的1类创新药多格列艾汀片（商品名：华堂宁）上市。该药品适用于改善成人2型糖尿病患者的血糖控制。图1 获批公告（图片来源：NMPA官网）值得骄傲的是，多格列艾汀是我国自主创新研发的降糖药物，也是全球第一款批准上市的GK激动剂。全球首创、中国首发！多格列艾汀赢在哪儿？多格列艾汀为何成功多格列艾汀是葡萄糖激酶（GK）激活剂，作用于胰岛、肠道内分泌细胞以及肝脏等葡萄糖储存与输出器官中的葡萄糖激酶靶点，改善2型糖尿病患者血糖稳态失调。图2 多格列艾汀结构式（图片来源：PubChem）临床研究显示2型糖尿病患者应用多格列艾汀治疗24周，餐后2小时的降幅较基线下降了2.81mmol/L，糖化血红蛋白从基线的最小平方平均变化（95%置信区间）为-1.07%[-1.19%，-0.95%]，糖化血红蛋白达标率达到了42.5%，在24周时达到了降低HbA1c水平的主要疗效终点。安全性评价中，多格列艾汀作为二甲双胍的附加疗法，在整个52周的治疗期间具有良好的耐受性和安全性，没有发生过多的药物相关的SAE或严重低血糖。图3 多格列艾汀3期临床试验(图片来源：参考文献[6])据悉，GK最早于1960s被发现，到2001年葡萄糖激酶激活剂（GKA）的药理学基础被报道后，有关GKA的研究蓬勃发展，迄今为止已经公布了100多项GKA专利，20多种GKA药物已经进入临床研究阶段，而华领医药的dorzagliatin（多格列艾汀）无疑是进展最快的一个（图4）。图4 葡萄糖激酶药理学及药物开发相关的重要事件（图片来源：华领官网）还有哪些GK激动剂？葡萄糖激酶（GK）是糖酵解中的关键酶之一，它的作用是维持葡萄糖的稳态。自2003年以来，大量关于GK激活剂的合成和传统抗糖尿病植物的研究被报道，GK激活剂与离活性位点20Å的变构位点相互作用，激活GK。该变构位点有一个宽阔的空腔，因此，可以容纳不同的化学结构(图5)。图5 GK变构结合位点（图片来源：PDB:1V4S，图片由pyMol绘制）由于GK激活剂有潜在的不良反应，如低血糖、高甘油三酯血症、脂肪肝或肝脂肪变性，因此，研究人员一直致力于获得无不良反应的GK激活剂来治疗糖尿病。2003年，罗氏公司的科学家们首先描述了小分子GK激动剂。随后，许多其他小组也披露了葡萄糖激酶。Grimsby等人通过筛选12万个结构不同的合成化合物发现葡萄糖激酶的激活剂。通过对最初苗头化合物进行优化，确定了RO-28-0450（图6），R构型的RO-28-1675具有双重作用机制。它增强了胰腺的胰岛素释放，并刺激了肝脏的葡萄糖利用。图6 RO-28-0450的结构式（图片来源：参考文献3）Array BioPharma公司的报道了GK激动剂ARRY-403，随后被授权给Amgen公司，成为AMG-151。它是一种口服的异生葡萄糖激酶（GK）激活剂，体外有效地激活人类葡萄糖激酶（GK）（EC50=79 nM），具有良好的体外类药物特性（水溶性、细胞渗透性、低低的药物相互作用潜力、低的预测肝脏清除率），以及对广泛的受体和酶的选择性。图7 AMG-151的化学结构（图片来源：PubChem）其他一些制药公司，针对GK也有所布局，这些小分子GK激动剂的可以按化学结构分类（尿素基团、取代的芳基中心酰胺和其他类型）。例如，化合物1-5（图7）是已进入II期临床试验的一些GKA，这些化合物从结构上看，都具有一些共同的结构特征（图8，蓝色）图8 代表性GK激动剂（图片来源：J.Med.Chem.2014,57,8180−8186）除了合成的小分子化合物，一些植物（如Allium hirtifolium和Sapiumellipticum）的提取物或活性成分（如ganoderan B、glucolipsins A和B、eupatilin、coagulanolide、mangiferin和kaempferol）也具有强大的GK激动活性。GK激动剂面临挑战GK激活剂面临的最大问题，是关于疗效和安全性的方面的问题。研究证明，低血糖症、脂肪肝的开始、肝细胞脂质化，以及随着时间的推移疗效下降是使用GK激活剂观察到的最重要的副作用。例如，Piragliatin和MK-0941被证明会频繁地引起低血糖发作。此外，根据与激活GK有关的病理生理过程，GK激动剂可能会导致血脂异常，使肝脏新生脂肪生成的增加，例如，化合物MK-0941被证明可引起急性高脂血症。为了应对这些副作用，研究人员设计了（1）对葡萄糖水平有较高依赖性的部分激活剂，以减少低葡萄糖浓度下过度激活的风险。例如，使用部分GK激活剂PF-04937319，可以降低了发生低血糖的几率。（2）开发肝脏选择性的剂型，来降低副作用。例如TTP399，正在被开发为T1D患者的胰岛素辅助治疗。2021年4月，FDA授予TTP399治疗T1D的突破性疗法称号。小结糖尿病是一种影响全世界人民的代谢性疾病，其发病率在发达国家和发展中国家都在逐日增加。激活GK的小分子药物为恢复/改善T2D患者的血糖调节提供了一种替代策略。GK激活剂通过增加胰岛素分泌和糖原合成来减少肝脏葡萄糖的产生。随着双作用的新型GK激活剂多格列艾汀的上市以及和肝脏选择性的新型GK激活剂TTP399的报道后，可以预见，疗效更可靠、副作用更低的新一代的GK激动剂的研究会迎来新的热潮。参考文献[1]https://www.nmpa.gov.cn/yaowen/ypjgyw/20221008173753169.html[2]https://www.huamedicine.com/dorzagliatin[3]Grimsby J,Sarabu R,Corbett W L,et al.Allosteric activators of glucokinase:potential role in diabetes therapy[J].Science,2003,301(5631):370-373.[4]Sharma P,Singh S,Sharma N,et al.Targeting human Glucokinase for the treatment of type 2 diabetes:an overview of allosteric Glucokinase activators[J].Journal of Diabetes&Metabolic Disorders,2022:1-9.[5]Gaitonde P,Garhyan P,Link C,et al.A Comprehensive Review of Novel Drug–Disease Models in Diabetes Drug Development[J].Clinical pharmacokinetics,2016,55(7):769-788.[6]Zhu D,Li X,Ma J,et al.Dorzagliatin in drug-naïve patients with type 2 diabetes:a randomized,double-blind,placebo-controlled phase 3 trial[J].Nature Medicine,2022,28(5):965-973.声明：如需转载，请务必注明文章作者和来源。如涉及作品内容、版权和其它问题，请您留言，我们将在第一时间删除。责任编辑 | 八角商务合作 | 张老师 13368443108转载开白 | 马老师 18323856316（同微信）药智网原创作品 | 尽情分享朋友圈 | 转载请联系授权— Tips —如果您有医药行业相关的线索或对医药政策、研发创新、资本市场、产业发展有深度观察欢迎投稿给我们马老师 18323856316（同微信）邮箱：maxuelian@yaozh.com发现“分享”和“赞”了吗，戳我看看吧