Flavokawain B inhibits NF-κB inflammatory signaling pathway activation in inflammatory bowel disease by targeting TLR2.

Inflammatory bowel disease (IBD) is characterized by recurrent inflammatory reactions in the intestinal mucosa, including ulcerative colitis (UC) and Crohn's disease (CD). The expression of Toll-like receptor 2 (TLR2) has been observed to increase during the progression of IBD. Flavokawain B (FKB), a natural chalcone with potent anti-inflammatory activity, exerts its effects through inhibition of the NF-κB pathway. In this study, we aimed to investigate the effects and mechanisms of FKB targeting TLR2 in IBD. C57BL/6 J mice were treated with 2.5% dextran sulfate sodium (DSS) for 7 days, with administration of FKB or TLR2 inhibitor C29 starting on day 2 to establish the model of IBD. In vitro, bone marrow-derived macrophages (BMDMs) were stimulated with the TLR2 agonist Pam3CSK4 to explore the therapeutic effect of FKB and its pharmacological mechanism. Compared with the model group, the FKB-treated group showed significant reductions in colitis-related injuries in the IBD mouse model, including weight gain, increased colon length and reduced inflammation. FKB decreased the formation of TLR2-MyD88 complex by targeting TLR2, leading to suppression of downstream NF-κB signaling pathway. Similar therapeutic effects were observed in the C29-treated group. Additionally, in vitro data suggested that FKB exerted its anti-inflammatory effect by targeting TLR2 and inhibiting Pam3CSK4-induced activation of the NF-κB pathway. The anti-inflammatory effects of FKB were demonstrated through drug affinity responsive target stability assay and cellular thermal shift assay, revealing its binding affinity to TLR2. By inhibiting the activation of the TLR2/NF-κB signaling pathway, FKB effectively prevented DSS-induced IBD and exhibited promising potential as a therapeutic candidate for IBD treatment.

Macrophage-specific FGFR1 deletion alleviates high-fat-diet-induced liver inflammation by inhibiting the MAPKs/TNF pathways.

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disease that is substantially associated with obesity-induced chronic inflammation. Macrophage activation and macrophage-medicated inflammation play crucial roles in the development and progression of NAFLD. Furthermore, fibroblast growth factor receptor 1 (FGFR1) has been shown to be essentially involved in macrophage activation. This study investigated the role of FGFR1 in the NAFLD pathogenesis and indicated that a high-fat diet (HFD) increased p-FGFR1 levels in the mouse liver, which is associated with increased macrophage infiltration. In addition, macrophage-specific FGFR1 knockout or administration of FGFR1 inhibitor markedly protected the liver from HFD-induced lipid accumulation, fibrosis, and inflammatory responses. The mechanistic study showed that macrophage-specific FGFR1 knockout alleviated HFD-induced liver inflammation by suppressing the activation of MAPKs and TNF signaling pathways and reduced fat deposition in hepatocytes, thereby inhibiting the activation of hepatic stellate cells. In conclusion, the results of this research revealed that FGFR1 could protect the liver of HFD-fed mice by inhibiting MAPKs/TNF-mediated inflammatory responses in macrophages. Therefore, FGFR1 can be employed as a target to prevent the development and progression of NAFLD.

ß-elemene alleviates hyperglycemia-induced cardiac inflammation and remodeling by inhibiting the JAK/STAT3-NF-κB pathway.

BACKGROUND: Hyperglycemic induced cardiac hypertrophy and cardiac inflammation are important pathological processes in diabetic cardiomyopathy. ß-elemene (Ele) is a natural compound extracted from Curcuma Rhizoma and has anti-tumor effects. It also has therapeutic effects in some inflammatory diseases. However, the therapeutic effect of Ele on diabetic cardiomyopathy is not clear. The purpose of this study was to evaluate the effect of Ele on hyperglycemia-caused cardiac remodeling and heart failure. METHODS: C57BL/6 mice were intraperitoneally injected with streptozotocin to induce DCM, and Ele was administered intragastric after 8 weeks to investigate the effect of Ele. RNA sequencing of cardiac tissue was performed to investigate the mechanism. RESULTS: Ele markedly inhibited cardiac inflammation, fibrosis and hypertrophy in diabetic mice, as well as in high glucose-induced cardiomyocytes. RNA sequencing showed that cardioprotective effect of Ele involved the JAK/STAT3-NF-κB signaling pathway. Ele alleviated heart and cardiomyocyte inflammation in mice by blocking diabetes-induced JAK2 and STAT3 phosphorylation and NF-κB activation. CONCLUSIONS: The study found that Ele preserved the hearts of diabetic mice by inhibiting JAK/STAT3 and NF-κB mediated inflammatory responses, suggesting that Ele is an effective therapy for DCM.