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Interleukin 33 (IL33) has been found to be cardioprotective on various cardiovascular pathologies. However, it is not clear whether IL33 may inhibit myocardial infarction-related ventricular remodeling through inducing macrophage polarization. The objective of present study is to assess whether IL33 can improve ventricular remodeling after myocardial infarction by inducing macrophage polarization. In this study, the direct influence of IL33 on the polarization of macrophages and its mechanism in vitro were investigated. The potential protective effects of IL33 on acute and chronic myocardial infarction (MI) in vivo as well as its underlying mechanism through macrophage polarization were also determined. We found that IL33 significantly enhanced M2 macrophage and decreased the proportion of M1 macrophage. Importantly, IL33 induced M2 macrophage polarization by activating the JAK/STAT signaling pathway. In vivo , IL33 weaken the inflammatory level and myocardial apoptosis after MI and improved the systolic and diastolic function of the heart. Furthermore, IL33 significantly reduced infarct area and prevented the progression of fibrosis by inducing M2 macrophage polarization. The protective effects of IL33 were suppressed by JAK/STAT signaling pathway inhibitor. Our findings highlighted that IL33 not only reduced the early inflammatory response and inhibited myocardial apoptosis, but also increased the number of M2 macrophage in the infarcted area, significantly reduced infarct area and prevented the progression of fibrosis by activating JAK/STAT pathway. Therefore, IL33 may be a novel cardiac protective cytokine for myocardial infarction. [ABSTRACT FROM AUTHOR]

Osteoporosis is an osteolytic disease with a disrupted balance between the resorption and formation of bone as well as bone microstructure degeneration, leading to bone loss and increased fracture risk, which greatly affects patients' quality of life. Currently, inhibition of osteoclast bone resorption remains the mainstream treatment for osteoporosis. Onc201, a new compound, induces the gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and has an efficient anticancer effect in clinical trials. However, its effects on osteolytic disease and the mechanism of action are unclear. We examined the effect of Onc201 on nuclear factor κB ligand-receptor activator (RANKL)-induced osteoclasts via Cell Counting Kit-8, bone resorption assay, luciferase reporter assay, immunofluorescence staining, calcium ion intensity assay and employed an ovariectomy model to investigate the effect of Onc201 on osteoporosis in the mice. Results showed that Onc201 inhibited the function and formation of osteoclasts induced by RANKL in a manner that was dependent on time and concentration, and did not cause cytotoxicity. Mechanistically, Onc201 inhibited osteoclast-relevant genes and NFATc1 expression, the main transcriptional regulatory factor of the formation of osteoclasts induced by RANKL; meanwhile, downregulating the expressions of the osteoclast cytoskeleton key signal molecules integrin αvβ3, focal adhesion kinase (FAK), c-Src, and spleen-associated tyrosine kinase (SYK). In addition, Onc201 had a protective effect on the mouse model of bone loss caused by ovariectomy-induced estrogen deficiency, which is consistent with the in vitro results. Our findings suggest that the new small-molecular compound Onc201 has the potential to prevent osteoclast-related osteolytic diseases. • Onc201, a new compound, can inhibit the function and formation of osteoclasts induced by RANKL. • Onc201 downregulates the expressions of the osteoclast cytoskeleton key signal molecules integrin αvβ3. • Onc201 has a protective effect on the mouse model of bone loss caused by ovariectomy-induced estrogen deficiency. [ABSTRACT FROM AUTHOR]

Liver fibrosis is characterized by the abnormal deposition of the extracellular matrix with a severe inflammatory response and/or metabolic disorder. Asiatic acid (AA), a natural compound derived from Centella asiatica , exhibited potent anti-fibrosis effects. This investigation first confirmed the anti-fibrosis effects of AA in TGF- β -LX-2 cells and CCl 4 -induced liver fibrosis mice, and then sought to elucidate a novel mechanism of action by integrating network pharmacology and lipidomics. Network pharmacology was used to find potential targets of AA, while lipidomics was used to identify differential metabolites between fibrosis and recovered cohorts. AA could suppress hepatic stellate cell activation in vitro and improve liver fibrosis in vivo. Network pharmacology unveiled the genes involved in pathways in cancer, peroxisome proliferators-activated receptors signaling pathway, and arachidonic acid metabolism pathway. Furthermore, five key genes were found in the both human and mouse databases, indicating that arachidonic acid metabolism was important. Changes in lyso-phosphocholine (22:5), prostaglandin F2α, and other related lipid metabolites also suggested the involvement of arachidonic acid metabolism the anti-fibrotic effect. In summary, our integrated strategies demonstrated that AA targeted multiple targets and impeded the progression of liver fibrosis by ameliorating arachidonic acid metabolism. [ABSTRACT FROM AUTHOR]

Tumor chemoresistance is often a major cause for the failure of chemotherapy. The resistance of hepatocellular carcinoma (HCC) cells to sorafenib significantly limits its therapeutic effect in HCC patients. For the first time, we found that FXYD domain-containing ion transport regulator 5 (FXYD5) is highly expressed in sorafenib-resistant HCC cells. In addition, the protein expression level of FXYD5 was markedly higher in HCC tissues than in paracancerous tissues. Remarkably, downregulation of FXYD5 expression in Huh7/sora cells reversed their resistance to sorafenib. Moreover, overexpression of FXYD5 reduced the sensitivity of HCC cells to sorafenib, while the downregulation of its expression in HCC cells had the opposite effect. We also found abnormal activation of the Akt/mTOR signaling pathway in Huh7/sora cells. Furthermore, MK2206, an Akt inhibitor, was found to significantly increase the sensitivity of HCC cells to sorafenib. More importantly, the expression level of p-Akt was positively correlated with the expression of FXYD5 in HCC tissues. Therefore, mechanistically, FXYD5 enhances the resistance of HCC cells to sorafenib by activating the Akt/mTOR signaling pathway. In conclusion, this study showed that the activation of the FXYD5/Akt/mTOR signaling axis plays key role in the resistance of HCC cells to sorafenib, and FXYD5 may represent a new potential target for HCC therapy. [ABSTRACT FROM AUTHOR]