A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease (NAFLD), coupled with hepatitis and insulin resistance. Yet the details of the underlying mechanisms are not fully understood. Here, we unraveled that the expression of the transcription factor Zbtb18 is markedly decreased in the livers of both patients and murine models of NAFLD. Hepatic Zbtb18 knockout promoted NAFLD features like impaired energy expenditure and fatty acid oxidation (FAO), and induced insulin resistance. Conversely, hepatic Zbtb18 overexpression alleviated hepato-steatosis, insulin resistance, and hyperglycemia in mice fed on a high-fat diet (HFD) or in diabetic mice. Notably, in vitro and in vivo mechanistic studies revealed that Zbtb18 transcriptional activation of Farnesoid X receptor (FXR) mediated FAO and Clathrin Heavy Chain (CLTC) protein hinders NLRP3 inflammasome activity. This key mechanism by which hepatocyte’s Zbtb18 expression alleviates NAFLD and consequent liver fibrosis was further verified by FXR’s deletion and forced expression in mice and cultured mouse primary hepatocytes (MPHs). Moreover, CLTC deletion significantly abrogated the hepatic Zbtb18 overexpression-driven inhibition of NLRP3 inflammasome activity in macrophages. Altogether, Zbtb18 transcriptionally activates the FXR-mediated FAO and CLTC expression, which inhibits NLRP3 inflammasome’s activity alleviating inflammatory stress and insulin resistance, representing an attractive remedy for hepatic steatosis and fibrosis.

Objectives: Farnesoid X receptor (FXR) activation is involved in ameliorating inflammatory bowel disease (IBD), such as ulcerative colitis (UC), and inflammatory regulation may be involved in its mechanism. Ginsenoside Rc (Rc) is a major component of Panax ginseng, and it plays an excellent role in the anti-inflammatory processes. Our aim is to explore the alleviative effect of Rc on dextran sulfate sodium (DSS)-induced inflammation and deficiencies in barrier function based on FXR signaling.Materials and Methods:In vitro, we treated human intestinal epithelial cell lines (LS174T) with LPS to explore the anti-inflammatory effect of Rc supplementation. In vivo, a DSS-induced IBD mice model was established, and the changes in inflammatory and barrier function in colons after Rc treatment were measured using the disease activity index (DAI), hematoxylin and eosin (H&E) staining, immunofluorescence, ELISA, and qPCR. Molecular docking analysis, luciferase reporter gene assay, and qPCR were then used to analyze the binding targets of Rc. DSS-induced FXR-knockout (FXR^−/-) mice were used for further validation.Results: Rc significantly recovered the abnormal levels of inflammation indexes (TNF-α, IL-6, IL-1β, and NF-KB) induced by LPS in LS174T. DSS-induced C57BL/6 mice exhibited a significantly decreased body weight and elevated DAI, as well as a decrease in colon weight and length. Increased inflammatory markers (TNF-α, IL-6, IL-1β, ICAM1, NF-KB, F4/80, and CD11b displayed an increased expression) and damaged barrier function (Claudin-1, occludin, and ZO-1 displayed a decreased expression) were observed in DSS-induced C57BL/6 mice. Nevertheless, supplementation with Rc mitigated the increased inflammatory and damaged barrier function associated with DSS. Further evaluation revealed an activation of FXR signaling in Rc-treated LS174T, with FXR, BSEP, and SHP found to be upregulated. Furthermore, molecular docking indicated that there is a clear interaction between Rc and FXR, while Rc activated transcriptional expression of FXR in luciferase reporter gene assay. However, these reversal abilities of Rc were not observed in DSS-induced FXR^−/- mice.Conclusion: Our findings suggest that Rc may ameliorate inflammation and barrier function in the intestine, which in turn leads to the attenuation of DSS-induced UC, in which Rc may potentially activate FXR signaling to protect the intestines from DSS-induced injury.

Our aims were to evaluate the depression model of early maternal separation (MS) combined with adolescent chronic unpredictable mild stress (CUMS) in female adult SD rats to observe the behavior and the expressions of synaptic proteins in rats and to provide a reference for the screening of antidepressant drug activity. In our study, MS and CUMS were conducted to establish a dual stress model on female rats. Behavioral tests, including the sucrose preference test, open field test, and zero maze test, were used to detect depression-like and anxiety-like behavior of animals. Nissl staining was used to detect the number of neuronal cells in the hippocampus CA1 and DG regions of rats from each group. Synaptophysin (SYN), postsynaptic density-95 (PSD-95), and growth-associated protein-43 (GAP-43) expressions in the hippocampus were detected by western blot. Expression of the hippocampus SYN protein was further detected by immunohistochemistry. Rats in the MS+CUMS group presented more serious depression-like and anxiety-like behavior than in the MS group. Also, few Nissl bodies in the hippocampus CA1 and DG regions, less percentage of SYN-positive cells, and downregulated expressions of SYN, PSD-95, and GAP43 were found in the hippocampus of rats in MS+CUMS group. In conclusion, adult female rats that underwent MS and CUMS performed more critical depression-like and anxiety-like behaviors, and this process may be resulted from synaptic plasticity impairment.

Sinensetin (SIN), a polymethoxylated flavonoid, exists widely in citrus fruits with abundant biological activities, such as antioxidant and anti-inflammatory properties, delaying the progression of lung fibers and ameliorating inflammatory lung injury. Herein, an in vivo model of LPS-induced acute lung injury (ALI) in mice and an in vitro model of LPS + IFN-γ-induced M1 polarization in RAW264.7 cells were established to assess the effects and molecular mechanisms of SIN in ameliorating ALI. In the present study, the results showed that SIN significantly reduced BALF IL1β, IL6, and TNF-α levels and neutrophil infiltration, inhibited lung tissue COX2 and iNOS expression, reduced serum and lung tissue inflammatory factor levels, and attenuated lung tissue inflammatory infiltration and ROS levels in animal experiments. RNA sequencing analysis showed that SIN markedly inhibited the expression of inflammation-related pathway genes such as NOD-like receptor signaling. Further mechanistic studies confirmed that SIN significantly inhibited the dissociation of Txnip and Trx-1 and decreased the expression of NLRP3, ASC, pro-Caspase-1, cleavage Caspase-1 p10, NEK7, Caspase-8, IL1β, IL18, and GSDMD. Meanwhile, SIN docked to NLRP3 with strong affinity and bound stably in the hydrophobic docking pocket. Similarly, the same results were observed in in vitro macrophage M1 polarization experiments. In conclusion, the results revealed that SIN ameliorated the onset and progression of ALI by inhibiting Txnip/NLRP3/Caspase-1/GSDMD signaling-mediated inflammatory responses and pyroptosis. These findings emphasize the significant role of SIN in ameliorating ALI and provide insights into the strategy for exploring the functional effects of foods.