EP3 受体/G 信号轴作为糖尿病和心血管疾病的治疗靶点。
The EP3 Receptor/G Signaling Axis as a Therapeutic Target for Diabetes and Cardiovascular Disease.
机构信息
Interdisciplinary Graduate Program in Nutritional Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, 4148 UW Medical Foundation Centennial Building, 1685 Highland Ave, Madison, Wisconsin, 53705, USA.
Research Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA.
出版信息
AAPS J. 2017 Sep;19(5):1276-1283. doi: 10.1208/s12248-017-0097-1. Epub 2017 Jun 5.
Abstract
Cardiovascular disease is a common co-morbidity found with obesity-linked type 2 diabetes. Current pharmaceuticals for these two diseases treat each of them separately. Yet, diabetes and cardiovascular disease share molecular signaling pathways that are increasingly being understood to contribute to disease pathophysiology, particularly in pre-clinical models. This review will focus on one such signaling pathway: that mediated by the G protein-coupled receptor, Prostaglandin E Receptor 3 (EP3), and its associated G protein in the insulin-secreting beta-cell and potentially the platelet, G. The EP3/G signaling axis may hold promise as a dual target for type 2 diabetes and cardiovascular disease.
摘要
心血管疾病是肥胖相关 2 型糖尿病常见的合并症。目前针对这两种疾病的药物分别对其进行治疗。然而，糖尿病和心血管疾病共享分子信号通路，这些信号通路越来越多地被认为有助于疾病的病理生理学，特别是在临床前模型中。本综述将重点介绍其中一种信号通路：由 G 蛋白偶联受体前列腺素 E 受体 3 (EP3)及其在胰岛素分泌β细胞中相关 G 蛋白介导的信号通路，以及在血小板中的作用。EP3/G 信号轴可能有希望成为 2 型糖尿病和心血管疾病的双重靶点。
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2
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3
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4
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Adipocyte. 2016 Oct 10;5(4):384-388. doi: 10.1080/21623945.2016.1245818. eCollection 2016 Oct-Dec.
5
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J Cancer. 2016 Nov 26;7(15):2346-2359. doi: 10.7150/jca.16884. eCollection 2016.
6
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