Exposure memory and susceptibility to ambient PM2.5: A perspective from hepatic cholesterol and bile acid metabolism.

Both epidemiological and experimental studies increasingly show that exposure to ambient fine particulate matter (PM2.5) is related to the occurrence and development of chronic diseases, such as metabolic diseases. However, whether PM2.5 has "exposure memory" and how these memories affect chronic disease development like hepatic metabolic homeostasis are unknown. Therefore, we aimed to explore the effects of exposure transition on liver cholesterol and bile acids (BAs) metabolism in mice. In this study, C57BL/6 mice were exposed to concentrated ambient PM2.5 or filtered air (FA) in a whole-body exposure facility for an initial period of 10 weeks, followed by another 8 weeks of exposure switch (PM2.5 to FA and FA to PM2.5) comparing to non-switch groups (FA to FA and PM2.5 to PM2.5), which were finally divided into four groups (FF of FA to FA, PP of PM2.5 to PM2.5, PF of PM2.5 to FA, and FP of FA to PM2.5). Our results showed no significant difference in food intake, body composition, glucose homeostasis, and lipid metabolism between FA and PM2.5 groups after the initial exposure before the exposure switch. At the end of the exposure switch, the mice switched from FA to PM2.5 exposure exhibited a high sensitivity to late-onset PM2.5 exposure, as indicated by significantly elevated hepatic cholesterol levels and disturbed BAs metabolism. However, the mice switched from PM2.5 to FA exposure retained a certain memorial effects of previous PM2.5 exposure in hepatic cholesterol levels, cholesterol metabolism, and BAs metabolism. Furthermore, 18-week PM2.5 exposure significantly increased hepatic free BAs levels, which were completely reversed by the FA exposure switch. Finally, the changes in small heterodimeric partner (SHP) and nuclear receptor subfamily 5 group A member 2 (LRH1) in response to exposure switch mechanistically explained the above alterations. Therefore, mice switching from PM2.5 exposure to FA showed only a weak memory of prior PM2.5 exposure. In contrast, the early FA caused mice to be more susceptible to subsequent PM2.5 exposure.

Discovery of Novel Cinnamic Acid Derivatives as Fungicide Candidates.

Structural diversity derivatization from natural products is an important and effective method of discovering novel green pesticides. Cinnamic acids are abundant in plants, and their unparalleled structures endow them with various excellent biological activities. A series of novel cinnamic oxime esters were designed and synthesized to develop high antifungal agrochemicals. The antifungal activity, structure-activity relationship, and action mechanism were systematically studied. Compounds 7i, 7u, 7v, and 7x exhibited satisfactory activity against Gaeumannomyces graminis var. tritici, with inhibition rates of ≥90% at 50 µg/mL. Compounds 7z and 7n demonstrated excellent activities against Valsa mali and Botrytis cinerea, with median effective concentration (EC50) values of 0.71 and 1.41 µg/mL, respectively. Compound 7z exhibited 100% protective and curative activities against apple Valsa canker at 200 µg/mL. The control effects of 7n against gray mold on tomato fruits and leaves were all >96%, exhibiting superior or similar effects to those of the commercial fungicide boscalid. Furthermore, the quantitative structure-activity relationship was established to guide the further design of higher-activity compounds. The preliminary results on the action mechanism revealed that 7n treatment could disrupt the function of the nucleus and mitochondria, leading to reactive oxygen species accumulation and cell membrane damage. Its primary biochemical mechanism may be inhibiting fungal ergosterol biosynthesis. The novel structure, simple synthesis, and excellent activity of cinnamic oxime esters render them promising potential fungicides.

The hepatic integrated stress response suppresses the somatotroph axis to control liver damage in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) can be ameliorated by calorie restriction, which leads to the suppressed somatotroph axis. Paradoxically, the suppressed somatotroph axis is associated with patients with NAFLD and is correlated with the severity of fibrosis. How the somatotroph axis becomes dysregulated and whether the repressed somatotroph axis impacts liver damage during the progression of NAFLD are unclear. Here, we identify a regulatory branch of the hepatic integrated stress response (ISR), which represses the somatotroph axis in hepatocytes through ATF3, resulting in enhanced cell survival and reduced cell proliferation. In mouse models of NAFLD, the ISR represses the somatotroph axis, leading to reduced apoptosis and inflammation but decreased hepatocyte proliferation and exacerbated fibrosis in the liver. NAD+ repletion reduces the ISR, rescues the dysregulated somatotroph axis, and alleviates NAFLD. These results establish that the hepatic ISR suppresses the somatotroph axis to control cell fate decisions and liver damage in NAFLD.