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河马/Yes相关蛋白信号通路:糖尿病及血管并发症的新治疗靶点。

Hippo/YAP signaling pathway: a new therapeutic target for diabetes mellitus and vascular complications.

作者信息

Wei Lan, Gao Jingjing, Wang Liangzhi, Tao Qianru, Tu Chao

机构信息

Department of Internal Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.

Zhonglou District Center for Disease Control and Prevention, Changzhou, Jiangsu, China.

出版信息

Ther Adv Endocrinol Metab. 2023 Dec 25;14:20420188231220134. doi: 10.1177/20420188231220134. eCollection 2023.

Abstract

Diabetic angiopathy, which includes diabetic kidney disease (DKD), cardio-cerebrovascular disease, and diabetic retinopathy (DR) among other diseases, is one of the most common complications affecting diabetic patients. Among these, DKD, which is a major cause of morbidity and mortality, affects about 40% of diabetic patients. Similarly, DR involves retinal neovascularization and neurodegeneration as a result of chronic hyperglycemia and is the main cause of visual impairment and blindness. In addition, inflammation also promotes atherosclerosis and diabetes, with atherosclerosis-related cardiovascular diseases being often a main cause of disability or death in diabetic patients. Given that vascular diseases caused by diabetes negatively impact human health, it is therefore important to identify appropriate treatments. In this context, some studies have found that the Hippo/Yes-associated protein (YAP) pathway is a highly evolutionarily conserved protein kinase signal pathway that regulates organ growth and size through its effector signaling pathway Transcriptional co-Activator with PDZ-binding motif (TAZ) and its YAP. YAP is a key factor in the Hippo pathway. The activation of YAP regulates gluconeogenesis, thereby regulating glucose tolerance levels; silencing the YAP gene thereby prevents the formation of glomerular fibrosis. YAP can combine with TEA domain family members to regulate the proliferation and migration of retinal vascular endothelial cells (ECs), so YAP plays a prominent role in the formation and pathology of retinal vessels. In addition, YAP/TAZ activation and translocation to the nucleus promote endothelial inflammation and monocyte-EC attachment, which can increase diabetes-induced cardiovascular atherosclerosis. Hippo/YAP signaling pathway provides a potential therapeutic target for diabetic angiopathy, which can prevent the progression of diabetes to DR and improve renal fibrosis and cardio-vascular atherosclerosis.

摘要

糖尿病血管病变包括糖尿病肾病(DKD)、心脑血管疾病、糖尿病视网膜病变(DR)等,是影响糖尿病患者的最常见并发症之一。其中,作为发病和死亡的主要原因,DKD影响约40%的糖尿病患者。同样,DR是慢性高血糖导致视网膜新生血管形成和神经退行性变,是视力损害和失明的主要原因。此外,炎症还会促进动脉粥样硬化和糖尿病,与动脉粥样硬化相关的心血管疾病往往是糖尿病患者致残或死亡的主要原因。鉴于糖尿病引起的血管疾病对人类健康有负面影响,因此确定合适的治疗方法很重要。在这种情况下,一些研究发现,Hippo/Yes相关蛋白(YAP)信号通路是一条高度进化保守的蛋白激酶信号通路,通过其效应信号通路——含PDZ结合基序的转录共激活因子(TAZ)及其YAP来调节器官的生长和大小。YAP是Hippo信号通路中的关键因子。YAP的激活调节糖异生,从而调节葡萄糖耐量水平;沉默YAP基因可防止肾小球纤维化的形成。YAP可与TEA结构域家族成员结合,调节视网膜血管内皮细胞(ECs)的增殖和迁移,因此YAP在视网膜血管的形成和病理过程中发挥着重要作用。此外,YAP/TAZ的激活和向细胞核的转位会促进内皮炎症和单核细胞与内皮细胞的黏附,这会增加糖尿病引起的心血管动脉粥样硬化。Hippo/YAP信号通路为糖尿病血管病变提供了一个潜在的治疗靶点,可防止糖尿病进展为DR,并改善肾纤维化和心血管动脉粥样硬化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b12/10752099/62b9a6f0a47f/10.1177_20420188231220134-fig1.jpg

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