Sphingosine kinases (Sphks) are the rate-limiting enzymes in the conversion of sphingosine to biologically active sphingosine-1-phosphate. The present study aimed to determine the role of Sphk2 and its downstream targets in renal fibroblast activation and interstitial fibrosis. In the kidney interstitium of patients with renal fibrosis, Sphk2-expressing cells (mainly interstitial fibroblasts) were significantly elevated and highly correlated with disease progression in patients. In a murine model of renal interstitial fibrosis, Sphk2 was upregulated in the kidney of wild-type mice in response to disease progression. Importantly, Sphk2-knockout (KO) mice exhibited significantly lower levels of extracellular matrix (ECM) production and a suppressed inflammatory response in the kidney tissues, compared to those in their wild-type counterparts, whereas the expression of TGF-β1 was unaffected. TGF-β1 effectively upregulated Sphk2 expression in the renal interstitial fibroblast line, NRK-49F, independent of canonical Smad signaling activation. Furthermore, siRNA-mediated Sphk2 knockdown or suppression of Sphk2 activity by ABC294640 exposure effectively attenuated AKT and STAT3 activation and ECM production, but had no effects on Smad2 and Smad3 activation. Sphk2 phosphorylated Fyn to activate downstream STAT3 and AKT, thereby promoting ECM synthesis. Therefore, our findings indicate that targeting Sphk2-Fyn-STAT3/AKT signaling pathway may be a novel therapeutic approach for renal fibrosis.
Environmental pollutants, such as bisphenol A (BPA) have recently been implicated in the development of adverse birth outcomes. However, the underlying teratogenic mechanisms remain unclear. We investigated the effects of BPA on the migration and invasion of human primary extravillous trophoblast HTR-8/SVneo cells. Our results indicated that BPA reduced cell migration and invasion. Moreover, it altered the ratio of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) by downregulating MMP-2 and MMP-9, and upregulating TIMP-1 and TIMP-2. Furthermore, BPA suppressed integrin β1, integrin α5, and vimentin. Interestingly, BPA-induced invasion was partially restored by G15, a membrane G-protein-coupled estrogen receptor 30 antagonist. We further revealed that 42 proteins were differentially expressed by mass spectrometry analysis, which could be divided into three categories based on gene ontology including biological process, cellular component, and molecular function. These results suggest that BPA reduces HTR-8/SVneo cell migration and invasion by downregulating MMP-2 and MMP-9, up-regulating TIMP-1 and TIMP-2, and suppressing adhesion molecules.
Background: Dyslipidemia is common among the general population, and its prevention is urgently needed particularly for the health of students. The purpose of our study was to explore the relationship between serum iron level and blood lipids.Methods: A sample of 290 university students was collected in this cross-section study. The blood lipids and serum iron levels were determined. Pearson's correlation coefficient was used to determine the correlation between serum iron level and blood lipids.Results: The prevalence of dyslipidemia was 8.8% among male students and 5.4% among female students.The overall prevalence of dyslipidemia was7.2% among the total students. The results showed that serum iron level was negatively correlated with triglyceride (TG), but was positively correlated with high-density lipoprotein cholesterol (HDL)-cholesterol, low-density lipoprotein cholesterol (LDL)-cholesterol, and total cholesterol (TC) in female students. Female students with serum iron less than 15 mmol/L had higher levels of serum TG than female students with serum iron 15 mmol/L or above (P<0.05).Conclusions: These findings suggest that lower serum iron levels may be a risk factor of high serum TG in female students. Supplementation of iron may be a strategy for prevention of high serum TG in female students.
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