br Results br Discussion br STAR

Results
Discussion
STAR★Methods
Author Contributions
Acknowledgments We thank Angela Walker for assistance with the manuscript; Junlin Liu, Xiangxiang Gu, Na Chen, Lu Xue, and the BV Core Facility of iHuman Institute for their support; scientists and colleagues at Amgen Inc., Zhulun Wang, Yaxiong Sun, Jerry Ryan Holder, John G. Allen, Paul J. Dransfield, Jonathan B. Houze, and Philip Tagari, for helpful discussions and support; Jerry Ryan Holder and John G. Allen for originally identifying the potent APJR peptide agonist AMG3054; Mingming Li for ligand supplies; and former colleagues at Amgen Inc., Steve R. Jordan and Samer Chmait, for their contributions to early construct design. We thank the beamline staff at BL41XU of SPring-8 (Hyogo, Japan) for technical help during data collection. We thank Shanghai Supercomputer Center for computational resources. The part of the work conducted at iHuman was supported by the National Natural Science Foundation of China grant 31670736 (F.X.), the National “1000 Talents” young scientist grant (F.X.), Shanghai PuJiang Talent Program grant 16PJ1407300 (S.Z.), and Natural Science Foundation of Shanghai grant 16ZR1448500 (S.Z.).
Introduction The APJ/AGTRL1/APLNR/Apelin cc-5013 is a class A (rhodopsin-like) G-protein coupled receptor (GPCR) first identified in 1993 based on its sequence similarity to Angiotensin II type 1 receptor (AT1R) and called APJ [1]. Since APJ/Apelin receptor was not activated by Angiotensin II but absent of an identified cognate ligand, the receptor was deemed an orphan GPCR. In 1998, Tatemoto et al. discovered the endogenous peptide capable of binding to APJ/Apelin receptor by purification from bovine stomach extracts [1], [2]. The discovered ligand was named, Apelin, which is abbreviated from APj Endogenous LIgaNd. Apelin is widely expressed in various organs, such as heart, lung, kidney, liver, adipose tissue, gastrointestinal tract, and neuronal system [3], [4], [5], [6]. Activation of the APJ/Apelin receptor by Apelin peptide induces a wide range of physiological effects, including vasodilation, increased myocardial contractility, angiogenesis, and fluid homeostasis and energy metabolism regulation [7], [8], [9], [10], [2]. The beneficial effects of the Apellin-APJ/Apelin receptor system are well established by treating with Apelin in disease animal models as diverse as hypertension, atherosclerosis, myocardial infarction, heart failure (HF) and pulmonary arterial hypertension (PAH) [11], [12]. While physiological roles of Apelin-APJ/Apelin receptor system had been elucidated with analyses of gene knockout mice, there had been a discrepancy between the phenotypes of Apelin knockout and Apelin receptor knockout mice. Recently, Apelin receptor has been shown to be activated by a novel endogenous peptide ligand Elabela/Toddler, with an important role in cardiovascular development and function [13], [14]. The discovery contributed to solving the discrepancy in knockout phenotypes and further enriched the understanding of the physiological mechanisms of the Apelin-APJ/Apelin receptor system. This review overviews the latest advancement in understanding of the physiology of Apelin-APJ/Apelin receptor system in the heart with a view of the double ligand system of Apelin and Elabela for APJ/Apelin receptor.
Concluding remarks
Conflict of interest
Introduction Cholangiocarcinoma (CCA) is a malignancy that arises from the intrahepatic or extrahepatic biliary epithelium. It is the second most common primary liver cancer and accounts for approximately 15% of liver cancers worldwide [1]. In the United States, the incidence of CCA is approximately 1.6 cases per 100,000 people; however, the incidence in some Asian countries is much higher [2]. Risk factors strongly associated with cholangiocarcinoma development include Primary Sclerosing Cholangitis (PSC), choledochal cysts, hepatolithiasis, liver cirrhosis, thorotrast, and Opisthorcosis viverrini infection [3]. Despite multidisciplinary treatment strategies, overall 5-year survival rates for resectable intrahepatic CCA tumors remains between 30 and 35% [4]. Developing novel, tumor specific therapies for cholangiocarcinoma could broaden the scope of current treatment strategies and provide the necessary adjuncts to improve long-term survival.