作者: Zhu, Shiyi ; Li, Jiani ; Luo, Xu ; Tao, Yihao ; Zhou, You ; Tang, Jiping ; Chen, Xionghui ; Wu, Lei ; Dong, Siyuan ; Flores, Jerry J ; Zhang, John H ; Yu, Qian ; Yuan, Ye ; Han, Mingyang ; Sherchan, Prativa ; Huang, Lei ; He, Qiuguang ; Kanamaru, Hideki ; Xie, Zongyi

BACKGROUND AND PURPOSESubarachnoid hemorrhage (SAH) is a devastating stroke, in which acidosis is one of detrimental complications. The extracellular pH reduction can activate G protein-coupled receptor 4 (GPR4) in the brain. Yet, the extent to which proton-activated GPR4 contributes to the early brain injury (EBI) post-SAH remains largely unexplored. Ferroptosis, iron-dependent programmed cell death, has recently been shown to contribute to EBI. We aimed to investigate the effects of GPR4 inhibition on neurological deficits and neuronal ferroptosis after SAH in rats.METHODSA total 253 Sprague Dawley (SD) male rats (weighing 275-330g) were utilized in this study. SAH was induced by endovascular perforation. NE-52-QQ57 (NE), a selective antagonist of GPR4 was administered intraperitoneally 1-hour post-SAH. To explore the mechanisms, RhoA activator U-46619 and YAP activator PY-60 were delivered intracerebroventricularly. Short- and long-term neurobehavior, SAH grading, western blot assay, ELISA assay, immunofluorescence staining, and transmission electron microscopy was performed post-SAH.RESULTSFollowing SAH, there was an upregulation of GPR4 expression in neurons. GPR4 inhibition by NE improved both short-term and long-term neurological outcomes post-SAH. NE also reduced neuronal ferroptosis, as evidenced by decreased lipid peroxidation products 4HNE and MDA levels in brain tissues, and reduced mitochondrial shrinkage, increased mitochondria crista and decreased membrane density. The application of either U-46619 or PY-60 partially offset the neuroprotective effects of NE on neuronal ferroptosis in SAH rats.CONCLUSIONSThis study demonstrated that acid-sensing receptor GPR4 contributed to neuronal ferroptosis after SAH via RhoA/YAP pathway, and NE may be a potential therapeutic strategy to attenuate GPR4 mediated neuronal ferroptosis and EBI after SAH.

2024-04-28·Journal of Clinical and Translational Hepatology

RAMP1 Protects Hepatocytes against Ischemia-reperfusion Injury by Inhibiting the ERK/YAP Pathway

Article

作者: Tang, Yongsheng ; Jia, Changchang ; Qiu, Chunhui ; Zhang, Qi ; Yuan, Zenan ; Lu, Xu ; Fu, Binsheng ; Zhu, Shuguang ; Song, Yingqiu ; Li, Hua

Background and AimsHepatic ischemia-reperfusion injury (HIRI) is a prevalent complication of liver transplantation, partial hepatectomy, and severe infection, necessitating the development of more effective clinical strategies. Receptor activity-modifying protein 1 (RAMP1), a member of the G protein-coupled receptor adapter family, has been implicated in numerous physiological and pathological processes. The study aimed to investigate the pathogenesis of RAMP1 in HIRI.MethodsWe established a 70% liver ischemia-reperfusion model in RAMP1 knockout (KO) and wild-type mice. Liver and blood samples were collected after 0, 6, and 24 h of hypoxia/reperfusion. Liver histological and serological analyses were performed to evaluate liver damage. We also conducted in-vitro and in-vivo experiments to explore the molecular mechanism underlying RAMP1 function.ResultsLiver injury was exacerbated in RAMP1-KO mice compared with the sham group, as evidenced by increased cell death and elevated serum transaminase and inflammation levels. HIRI was promoted in RAMP1-KO mice via the induction of hepatocyte apoptosis and inhibition of proliferation. The absence of RAMP1 led to increased activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and yes-associated protein (YAP) phosphorylation, ultimately promoting apoptosis. SCH772984, an ERK/MAPK phosphorylation inhibitor, and PY-60, a YAP phosphorylation inhibitor, reduced apoptosis in in-vitro and in-vivo experiments.ConclusionsOur findings suggest that RAMP1 protects against HIRI by inhibiting ERK and YAP phosphorylation signal transduction, highlighting its potential as a therapeutic target for HIRI and providing a new avenue for intervention.

100 项与 PY-60 相关的药物交易

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