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Emerging evidence suggests that atherosclerosis, one of the leading phenotypes of cardiovascular diseases, is a chronic inflammatory disease. During the atherosclerotic process, immune cells play critical roles in vascular inflammation and plaque formation. Meanwhile, gastrointestinal disorder is considered a risk factor in mediating the atherosclerotic process. The present study aimed to utilize sivelestat, a selective inhibitor of neutrophil elastase, to investigate its pharmacological benefits on atherosclerosis and disclose the gastrointestinal-vascular interaction. The activation of intestinal neutrophil was increased during atherosclerotic development in Western diet-fed ApoE -/- mice. Administration of sivelestat attenuated atherosclerotic phenotypes, including decreasing toxic lipid accumulation, vascular monocyte infiltration, and inflammatory cytokines. Sivelestat decreased intestinal permeability and endotoxemia in atherosclerotic mice. Mechanistically, sivelestat upregulated the expression of zonula occludens-1 in the atherosclerotic mice and recombinant neutrophil elastase protein-treated intestinal epithelial cells. Meanwhile, treatment of sivelestat suppressed the intestinal expression of inflammatory cytokines and NF-κB activity. In contrast, administration of lipopolysaccharides abolished the anti-atherosclerotic benefits of sivelestat in the Western diet-fed ApoE -/- mice. Further clinical correlation study showed that the circulating endotoxin level and intestinal neutrophil elastase activity were positively correlated with carotid intima-medial thickness in recruited subjects. In conclusion, sivelestat had pharmacological applications in protection against atherosclerosis, and intestinal homeostasis played one of the critical roles in atherosclerotic development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nie, Xiong, Lan, Song, Yu, Chen, Wang, Ren, Chen, Liu and Zhou.)

Background: There is a big difference in the expression of miRNAs of plasma exosomes of patients with HBV infection. This study aims to analyze four molecular markers of peripheral blood plasma exosomes to evaluate their potential diagnostic values in HBV infection., Methods: A total of 55 cases of patients with chronic hepatitis B were in Experimental Group 1; 49 cases of hepatitis B carriers were in Experimental Group 2, and 46 cases were in the healthy control group. The total RNA of the plasma exosome was used to analyze the specificity and sensitivity and draw ROC curves., Results: There was a significant difference in the expression of miRNA-1246, miRNA-150-5p, miRNA-5787, and miRNA-8069 down-regulated by plasma exosomes in Experimental Group 1 and Group 2 and Control Group, with a p value of less than 0.05., Conclusions: The molecular markers down-regulated were miRNA-1246, miRNA-150-5p, miRNA-5787, and miRNA-8069. The four miRNAs were initially identified as new markers of miRNAs of peripheral blood plasma exosomes after HBV infection. It is better to use multiple markers for combined diagnosis.

Emerging evidence suggests that microRNAs (miRNAs) are essential for metabolic haemostasis of liver tissues. Among them, miR-33a is supposed to modulate the cholesterol export and fatty acid oxidation, but whether miR-33a involves in the process of fatty liver disease is unclear. To disclose the hypothesis, we utilized miR-33a mimic and antisense to explore their effects in primary hepatocytes or high-fat diet (HFD)-fed mice. Treatment with palmitic acid (PA) or HFD significantly increased the expression of miR-33a in hepatocytes or liver tissues. In primary hepatocytes, miR-33a mimic decreased mitochondrial function, including reduction of ATP production and oxygen consumption, whereas miR-33a inhibition protected PA-induced mitochondrial dysfunction. Interestingly, miR-33a selectively suppressed mitochondrial complex I activity and protein expression, but not other complexes. Through bioinformatics prediction, we found miR-33a directly targeted on the 3'-UTR of NDUFA5. Dual-luciferase reporter analysis further confirmed the direct suppression of miR-33a on NDUFA5 expression. More importantly, administration of miR-33a antisense could effectively restore HFD-induced mitochondrial dysfunction through up-regulation of NDUFA5 levels. Mice treated with miR-33a antisense also exhibited improved liver function and structural disorders under obese status. Taken together, miR-33a was an important mediator of hepatocyte mitochondrial function, and the therapeutic benefits implied miR-33a antisense had the potential clinical application in combating the fatty liver disease., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Non-alcoholic fatty liver disease (NAFLD) affects obesity-associated metabolic syndrome, which exhibits hepatic steatosis, insulin insensitivity and glucose intolerance. Previous studies indicated that hepatic microRNAs (miRs) play critical roles in the development of NAFLD. In this study, we aim to explore the pathophysiological role of miR-194 in obesity-mediated metabolic dysfunction. Our findings show that the high fat diet or palmitic acid treatment significantly increase hepatic miR-194 levels in vivo and in vitro. Silence of miR-194 protects palmitic acid-induced inflammatory response in cultured hepatocytes, and attenuates structural disorders, lipid deposits and inflammatory response in fatty liver. MiR-194 inhibitor also improves glucose and insulin intolerance in obese mice. Through dual luciferase assay, we demonstrate that miR-194 directly binds to FXR/Nr1h4 3'-UTR, and inhibits gene expression of FXR/Nr1h4. Furthermore, overexpression of miR-194 downregulates FXR/Nr1h4 in cultured hepatocytes, but miR-194 inhibitor reversely increases FXR/Nr1h4 expression in obese mouse liver tissues. On the contrast, silence of FXR/Nr1h4 abolishes the hepatic benefits in obese mice treated with miR-194 inhibitor. Present study provides a novel finding that suppression of miR-194 attenuates dietary-induced NAFLD via upregulation of FXR/Nr1h4. The findings suggest miR-194/FXR are potential diagnostic markers and therapeutic targets for NAFLD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Hepatocyte nuclear factor-3β (HNF-3β) plays a critical role in hepatocyte differentiation and controls liver-specific gene expression during the development of hepatocellular carcinoma (HCC), but the molecular basis of this process has not been fully elucidated. microRNAs (miRNAs) are powerful, post-transcriptional regulators of gene expression. Whether miRNAs can impact the effects of HNF-3β in HCC is still unknown., Methods: HNF-3β and miR-141 expression levels were detected in HepG2 cells, using real-time quantitative RT-PCR (qRT-PCR). Luciferase reporter assays and Western blots were used to validate HNF-3β as a direct target gene of miR-141. Cell proliferation, invasion, and apoptosis were also examined to confirm whether miR-141 could impact on HNF-3β in HCC., Results: In this study, we found that HNF-3β protein levels were consistently upregulated in HCC clinical tissues compared with matched normal adjacent tissues. However, the mRNA levels of HNF-3β varied in random tissues, suggesting that a post-transcriptional mechanism was involved in its regulation. We used bioinformatic analyses to search for miRNAs that could potentially target HNF-3β, and identified specific targeting sites for miR-141 in the 3'-untranslated region (3'-UTR) of the HNF-3β gene. By overexpressing miR-141 in HepG2 cells, we experimentally validated that miR-141 directly regulated HNF-3β expression. Furthermore, the biological consequences of targeting HNF-3β by miR-141 were examined using cell proliferation, invasion and apoptosis assays in vitro. We demonstrated that the repression of HNF-3β by miR-141 suppressed the proliferation and invasion and promoted the apoptosis of HepG2 cells., Conclusions: miR-141 functions as a tumor suppressor in HCC cells through the inhibition of HNF-3β translation.