Mechanistic targeting of advanced glycation end-products in age-related diseases.
Mechanistic targeting of advanced glycation end-products in age-related diseases.
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DOI：
10.1016/j.bbadis.2018.08.036
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Taylor A
中科院分区：
文献类型：
--
作者：
Rowan S;Bejarano E;Taylor A
糖应激是由细胞毒性和不可逆形成的糖源性晚期糖基化终产物（AGEs）的积累引起的，可导致与衰老、年龄相关疾病和代谢性疾病相关的发病率。在这篇综述中，我们总结了导致AGEs形成的途径，主要来自糖和糖酵解中间体，并讨论了AGE前体的解毒作用，包括乙醛酶系统和DJ-1/Park7脱糖酶。由于糖化蛋白的聚集和蛋白功能受损，AGE积累下游的疾病发病机制可能是细胞自主的，这发生在白内障中。细胞外AGEs也激活RAGE信号，导致氧化应激、炎症和糖尿病并发症（如糖尿病视网膜病变）中的白细胞停滞。药物制剂已在动物模型和临床试验，以减少糖负担。我们总结了现有的减少糖糖胁迫的策略，并指出了几个新的方向，包括：植物源性多酚作为AGE抑制剂和乙醛酶诱导剂；改善饮食模式，特别是地中海和低血糖饮食；增强泛素-蛋白酶体和自噬途径的蛋白水解能力，这些途径参与了AGEs的细胞清除。
Glycative stress, caused by the accumulation of cytotoxic and irreversibly-formed sugar-derived advanced glycation end-products (AGEs), contributes to morbidity associated with aging, age-related diseases, and metabolic diseases. In this review, we summarize pathways leading to formation of AGEs, largely from sugars and glycolytic intermediates, and discuss detoxification of AGE precursors, including the glyoxalase system and DJ-1/Park7 deglycase. Disease pathogenesis downstream of AGE accumulation can be cell autonomous due to aggregation of glycated proteins and impaired protein function, which occurs in ocular cataracts. Extracellular AGEs also activate RAGE signaling, leading to oxidative stress, inflammation, and leukostasis in diabetic complications such as diabetic retinopathy. Pharmaceutical agents have been tested in animal models and clinically to diminish glycative burden. We summarize existing strategies and point out several new directions to diminish glycative stress including: plant-derived polyphenols as AGE inhibitors and glyoxalase inducers; improved dietary patterns, particularly Mediterranean and low glycemic diets; and enhancing proteolytic capacities of the ubiquitin-proteasome and autophagy pathways that are involved in cellular clearing of AGEs.
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