Department of Clinical and Biological Sciences, University of Turin, Torino, Italy.
Department of Life Sciences and Systems Biology, University of Turin, Torino, Italy.
Curr Med Chem. 2018;25(11):1294-1310. doi: 10.2174/0929867324666170407123522.
In the last decades, the extension of life expectancy and the increased consumption of foods rich in saturated fats and added sugars have exposed the general population to emerging health problems. The prevalence of metabolic syndrome (MS), composed of a cluster of factors as obesity, dyslipidemia, hyperglycemia, and hypertension, is rapidly increasing in industrialized and developing countries leading to precocious onset of age-related diseases. Indeed, oxidative stress, accumulation of advanced glycation endproducts, and a chronic low-grade inflammation are common features of MS and physiological ageing. In particular, the entire set of MS factors contributes to the development of an inflammatory status named metaflammation, which has been associated with activation of early innate immune response through the assembling of the multiprotein complex inflammasome. The most investigated family of inflammasome platforms is the NOD-like receptor pyridine containing (NLRP) 3, which is activated by several exogenous and endogenous stimuli, leading to the sequential cleavage of caspase-1 and IL-1β, followed by secretion of active IL-1β. We here collect the most recent findings on NLRP3 activation in MS providing evidence of its central role in disease progression and organ dysfunction in target tissues of metaflammation, in particular in cardiovascular, hepatic and renal complications, with a focus on oxidative stress and advanced glycation endproducts. A wide overview of the most promising strategies for the modulation of NLRP3 activation and related metabolic repercussions is also provided, since the finding of specific pharmacological tools is an urgent requirement to reduce the social and economic burden of MS- and elderly-associated diseases.
在过去的几十年里，预期寿命的延长和富含饱和脂肪和添加糖的食物的消费增加，使普通人群面临新的健康问题。代谢综合征（MS）的患病率在工业化和发展中国家迅速增加，其特征是肥胖、血脂异常、高血糖和高血压等因素的聚集，导致与年龄相关的疾病提前发生。事实上，氧化应激、晚期糖基化终产物的积累和慢性低度炎症是 MS 和生理衰老的共同特征。特别是，MS 的所有因素都有助于发展一种称为代谢炎症的炎症状态，这种状态与通过多蛋白复合物炎症小体的组装激活早期先天免疫反应有关。研究最多的炎症小体平台是含吡啶的 NOD 样受体（NLRP）3，它被多种外源性和内源性刺激激活，导致半胱天冬酶-1 和白细胞介素-1β的顺序切割，随后分泌活性白细胞介素-1β。在这里，我们收集了 NLRP3 在 MS 中的最新激活发现，为其在炎症小体的靶组织中的代谢并发症中的疾病进展和器官功能障碍中的中心作用提供了证据，特别是在心血管、肝脏和肾脏并发症中，重点是氧化应激和晚期糖基化终产物。我们还提供了 NLRP3 激活和相关代谢反应的最有前途的调节策略的广泛概述，因为发现特定的药理工具是减少 MS 和老年相关疾病的社会和经济负担的迫切需要。
