Imirestat

Cr(VI) is widely used in industry and has high toxicity, making it one of the most common environmental pollutants. Long-term exposure to Cr(VI) can cause metabolic disorders and tissue damage. However, the effects of Cr(VI) on liver and gut microbes in fish have rarely been reported. In this study, 240 fish were randomly divided into 3 groups: the control group, low-dose Cr(VI) group (0.5 mg/L), and high-dose Cr(VI) group (2 mg/L). The mechanism by which Cr(VI) affects the enterohepatic axis of common carp was elucidated via multiomic analysis, serology, histomorphology, and physiological and biochemical indices. The results revealed that Cr(VI) stress led to hepatocyte damage, nuclear lysis, inflammatory cell infiltration, and vacuolated degeneration. The structure of the intestinal villi was severely damaged, and the length and width of the intestinal villi were significantly reduced. We also found that the accumulation of Cr(VI) in tissues increased in a concentration-dependent manner, and the content of Cr(VI) in each tissue increased in the order of gut > gill > liver > muscle. Multiple omics studies have revealed that chronic Cr(VI) stress leads to disturbances in the intestinal flora, with a significant reduction in the abundance of the beneficial bacterium Akkermansia and a significant increase in the abundance of the harmful bacterium Escherichia/Shigella. Intestinal injury and dysbiosis lead to an increase in blood LPS levels, further inducing metabolic disorders in the liver. The metabolites in the liver, including geniposide, leucine, C17 sphingosine, and 9,10-DiHODE, were significantly increased, whereas the beneficial metabolites, such as carnitine propionate and palmitoyl ethanolamide, were significantly reduced. In conclusion, our results suggest that chronic Cr(VI) stress leads to disturbances in gut microbial homeostasis and disturbed fatty acid and amino acid metabolism in the liver. LPS released into the bloodstream reaches the liver through the portal circulation, further exacerbating Cr(VI) stress-induced hepatotoxicity. This study revealed the mechanism of Cr(VI) toxicity to the liver-microbiota-gut axis of common carp. Our study provides new insights into the effects of Cr(VI) on the liver-microbiota-gut axis.

Acute kidney injury (AKI) is associated with high morbidity and mortality, and no drugs are available clinically. Metabolic reprogramming resulting from the deletion of S-nitroso-coenzyme A reductase 2 (SCoR2; AKR1A1) protects mice against AKI, identifying SCoR2 as a potential drug target. Of the few known inhibitors of SCoR2, none are selective versus the related oxidoreductase AKR1B1, limiting therapeutic utility. To identify SCoR2 (AKR1A1) inhibitors with selectivity versus AKR1B1, analogs of the nonselective (dual 1A1/1B1) inhibitor imirestat were designed, synthesized, and evaluated. Among 57 compounds, JSD26 has 10-fold selectivity for SCoR2 versus AKR1B1 and inhibits SCoR2 potently through an uncompetitive mechanism. When dosed orally to mice, JSD26 inhibited SNO-CoA metabolic activity in multiple organs. Notably, intraperitoneal injection of JSD26 in mice protected against AKI through S-nitrosylation of pyruvate kinase M2 (PKM2), whereas imirestat was not protective. Thus, selective inhibition of SCoR2 has therapeutic potential to treat acute kidney injury.