N6-methyladenosine (m⁶A) plays a role in various diseases, but it has rarely been reported in acute lung injury (ALI). The fat mass and obesity-associated (FTO) protein can regulate mRNA metabolism by removing m⁶A residues. This study aimed to examine the role and mechanism of the m⁶A demethylase FTO in lipopolysaccharide (LPS)-induced ALI. Lung epithelial FTO knockout mice and FTO knockdown/overexpression A549 cell lines were constructed to evaluate the effects of FTO on ALI. Bioinformatics analysis and a series of in vivo and in vitro assays were used to examine the mechanism of FTO regulation. Rescue assays were conducted to examine whether the impact of FTO on ALI depended on the TXNIP/NLRP3 pathway. In LPS-induced ALI, RNA m⁶A modification levels were upregulated, and FTO expression was downregulated. In vivo, lung epithelial FTO knockout alleviated alveolar structure disorder, tissue oedema, and pulmonary inflammation and improved the survival of ALI mice. In vitro, FTO knockdown reduced A549 cell damage and death induced by LPS, while FTO overexpression exacerbated cell damage and death. Mechanistically, bioinformatics analysis revealed that TXNIP was a downstream target of FTO. FTO deficiency mitigated pyroptosis in LPS-induced ALI via the TXNIP/NLRP3 pathway. Rescue assays confirmed that the impact of FTO on the TXNIP/NLRP3 pathway was significantly reversed by the TXNIP inhibitor SRI-37330. Deficiency of FTO alleviates LPS-induced ALI via TXNIP/NLRP3 pathway-mediated alveolar epithelial cell pyroptosis, which might be a novel therapeutic strategy for combating ALI.

2020-09-01·Cell Metabolism1区 · 生物学

Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action

1区 · 生物学

Article

作者: Grayson, Truman B ; Chen, Junqin ; Lu, Brian ; Jo, SeongHo ; Shalev, Anath ; Jing, Gu ; Sethupathy, Praveen ; Augelli-Szafran, Corinne E ; Li, Peng ; Moukha-Chafiq, Omar ; Kanke, Matt ; Thielen, Lance A ; Xu, Guanlan ; Suto, Mark J ; Kim, Jason K

Diabetes is characterized by hyperglycemia, loss of functional islet beta cell mass, deficiency of glucose-lowering insulin, and persistent alpha cell secretion of gluconeogenic glucagon. Still, no therapies that target these underlying processes are available. We therefore performed high-throughput screening of 300,000 compounds and extensive medicinal chemistry optimization and here report the discovery of SRI-37330, an orally bioavailable, non-toxic small molecule, which effectively rescued mice from streptozotocin- and obesity-induced (db/db) diabetes. Interestingly, in rat cells and in mouse and human islets, SRI-37330 inhibited expression and signaling of thioredoxin-interacting protein, which we have previously found to be elevated in diabetes and to have detrimental effects on islet function. In addition, SRI-37330 treatment inhibited glucagon secretion and function, reduced hepatic glucose production, and reversed hepatic steatosis. Thus, these studies describe a newly designed chemical compound that, compared to currently available therapies, may provide a distinct and effective approach to treating diabetes.

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适应症	最高研发状态	国家/地区	公司	日期
1型糖尿病	临床前	美国	Southern Research Institute	-
1型糖尿病	临床前	美国	The University of Alabama at Birmingham	-
2型糖尿病	临床前	美国	The University of Alabama at Birmingham	-