OBJECTIVESTo investigate the role of protein tyrosine phosphatase non-receptor type 1 (PTPN1) in mitophagy during sepsis and its underlying mechanisms and determine the therapeutic potential of PTPN1 inhibitors in endotoxemia-induced cardiac dysfunction.METHODSA mouse model of endotoxemia was established by administering an intraperitoneal injection of lipopolysaccharide (LPS). The therapeutic effect of targeting PTPN1 was evaluated using its inhibitor Claramine (CLA). Mitochondrial structure and function as well as the expression of mitophagy-related proteins were evaluated. Rat H9c2 cardiomyocytes were exposed to mouse RAW264.7 macrophage-derived conditioned medium. Cryptotanshinone, a specific p-STAT3 (Y705) inhibitor, was used to confirm the role of STAT3 in PTPN1-mediated mitophagy following LPS exposure. Electrophoretic mobility shift and dual luciferase reporter assays were performed to discern the mechanisms by which STAT3 regulated the expression of PINK1 and PRKN.RESULTSCLA alleviated LPS-induced myocardial damage, cardiac dysfunction, and mitochondrial injury and dysfunction in the mouse heart. PTPN1 upregulation exacerbated LPS-induced mitochondrial injury and dysfunction in H9c2 cardiomyocytes, but inhibited LPS-induced mitophagy. LPS promoted the interaction between PTPN1 and STAT3 and reduced STAT3 phosphorylation at Tyr705 (Y705), which was required to inhibit mitophagy by PTPN1. Upon LPS stimulation, PTPN1 negatively regulated the transcription of PINK1 and PRKN through dephosphorylation of STAT3 at Y705. STAT3 regulated the transcription of PINK1 and PRKN by binding to STAT3-responsive elements in their promoters.CONCLUSIONPTPN1 upregulation aggravates endotoxemia-induced cardiac dysfunction by impeding mitophagy through dephosphorylation of STAT3 at Y705 and negative regulation of PINK1 and PRKN transcription.

2023-05-01·European Journal of Pharmacology

A comprehensive overview of PPM1B: From biological functions to diseases

Review

作者: Zeng, Kewu ; Zhou, Qian ; Chen, Ruoyu ; Li, Zhongyao ; Lu, Zhiyuan ; Zhao, Baobing ; Li, Yanxia ; Zhao, Huanxin

Reversible phosphorylation of proteins is an important mechanism that regulates cellular processes, which are precisely regulated by protein kinases and phosphatases. PPM1B is a metal ion-dependent serine/threonine protein phosphatase, which regulates multiple biological functions by targeting substrate dephosphorylation, such as cell cycle, energy metabolism, inflammatory responses. In this review, we summarized the occurrent understandings of PPM1B focused on its regulation of signaling pathways, related diseases, and small-molecular inhibitors, which may provide new insights for the identification of PPM1B inhibitors and the treatment of PPM1B-related diseases.

2021-10-01·Central Nervous System Agents in Medicinal Chemistry

Pharmacophore Modelling and Virtual Screening Studies for the Discovery of Potential Natural Products Based PDE1B Inhibitor Lead Compounds

Article

作者: Shy, Teng Woei ; Gaurav, Anand

Aim:The aim of the present study was to apply pharmacophore based virtual screening to a natural product database to identify potential PDE1B inhibitor lead compounds for neurodegenerative and neuropsychiatric disorders.Background:Neurodegenerative and neuropsychiatric disorders are a major health burden globally. The existing therapies do not provide optimal relief and are associated with substantial adverse effects. This has resulted in a huge unmet medical need for newer and more effective therapies for these disorders. Phosphodiesterase (PDEs) enzymes have been identified as potential targets of drugs for neurodegenerative and neuropsychiatric disorders, and one of the subtypes, i.e., PDE1B, accounts for more than 90 % of total brain PDE activity associated with learning and memory process, making it an interesting drug target for the treatment of neurodegenerative disorders.Objectives:The present study has been conducted to identify potential PDE1B inhibitor lead compounds from the natural product database.Methods:Ligand-based pharmacophore models were generated and validated; they were then employed for virtual screening of Universal Natural Products Database (UNPD) followed by docking with PDE1B to identify the best hit compound.Results:Virtual screening led to the identification of 85 compounds which were then docked into the active site of PDE1B. Out of the 85 compounds, six showed a higher affinity for PDE1B than the standard PDE1B inhibitors. The top scoring compound was identified as Cedreprenone.Conclusion:Virtual screening of UNPD using Ligand based pharmacophore led to the identification of Cedreprenone, a potential new natural PDE1B inhibitor lead compound.

100 项与 PTP1B inhibitors(Dalian University Of Technology/Second Military Medical University PLA/North China Pharmaceutical Group Corp ) 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
炎症	临床前	中国	华北制药集团爱诺有限公司	2012-01-01
2型糖尿病	临床前	中国	中国人民解放军第二军医大学	-
2型糖尿病	临床前	中国	华北制药集团有限责任公司	-
2型糖尿病	临床前	中国	大连理工大学产业投资有限公司	-