MicroRNA-146a-5p attenuates irradiation-induced and LPS-induced hepatic stellate cell activation and hepatocyte apoptosis through inhibition of TLR4 pathway

Yuan

Journal Cellular Physiology

et al. 2020

Self Cite

The role of circular RNA (circRNA) in radiation‐induced liver disease (RILD) remains largely unknown. In this study, Ras‐related C3 botulinum toxin substrate 1 (RAC1) was elevated in irradiated human hepatic stellate cell (HSC) line LX2, the important effector cell mediating RILD. Overexpression of RAC1 promotes cell proliferation, proinflammatory cytokines production, and α‐smooth muscle actin expression, which were blocked by microRNA (miR)‐146a‐5p mimics. CircRNA RSF1 (circRSF1) was upregulated in irradiated LX2 cells and predicted to harbor binding site for miR‐146a‐5p. Biotinylated‐RNA pull down and dual‐luciferase reporter detection confirmed the direct interaction of circRSF1 and miR‐146a‐5p. Enforced expression of circRSF1 increased RAC1 expression by acting as miR‐146a‐5p sponge to inhibit miR‐146a‐5p activity, and thus enhanced the cell viability, and promoted inflammatory and fibrotic phenotype of irradiated LX2 cells. These findings indicate a functional regulatory axis composing of circRSF1, miR‐146a‐5p, and RAC1 in irradiated HSC, which may provide attractive therapeutic targets for RILD.

Section: Discussionsupporting

confidence: 74%

Circular RNA RSF1 promotes inflammatory and fibrotic phenotypes of irradiated hepatic stellate cell by modulating miR‐146a‐5p

Yuan

Journal Cellular Physiology

et al. 2020

Self Cite

“…Li et al showed that inhibiting the expression of TLR4 in cartilage lessened the severity of OA in the rat model (34). miRNAs have been found to affect the activation of TLR4 (35-38). For example, Chen et al found that miR-20a negatively regulated TLR4 signaling under atherosclerotic risk (39).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‑93 inhibits chondrocyte apoptosis and inflammation in osteoarthritis by targeting the TLR4/NF‑κB signaling pathway

et al. 2018

Osteoarthritis (OA) is a serious disease of the articular cartilage, and inflammation has been implicated in its pathogenesis. Previously, microRNAs (miRNAs) have been proposed as novel regulators of inflammation, however, the functional role of microRNAs in regulating inflammation in OA remains to be fully elucidated. The aim of the present study was to investigate the roles of miRNAs in OA inflammation and the underlying molecular mechanism. Firstly, the miRNA expression patterns were analyzed in the articular cartilage tissues from experimental OA mice using an miRNA microarray. miRNA (miR)-93 was identified with particular interest due to its reported effects on apoptosis and inflammation suppression. Subsequently, the expression of miR-93 was further validated in the articular cartilage tissues of OA mice and lipopolysaccharide (LPS)-stimulated primary chondrocytes. Using this LPS-induced chondrocyte injury model, the overexpression of miR-93 enhanced cell viability, improved cell apoptosis and attenuated the inflammatory response, as reflected by reductions in pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. In addition, Toll-like receptor 4 (TLR4), an important regulator of the nuclear factor-κB (NF-κB) signaling pathway, was identified as a direct target of miR-93 in chondrocytes. Furthermore, the restoration of TLR4 markedly abrogated the inhibitory effects of miR-93 on the chondrocyte apoptosis and inflammation induced by LPS. In addition, the overexpression of miR-93 by agomir-miR-93 significantly inhibited the levels of pro-inflammatory cytokines and cell apoptosis, whereas antagomir-93 exacerbated apoptosis and inflammation in vivo. Taken together, the results of the study suggested that miR-93 may be a promising therapeutic target for the treatment of human OA.

“…Inflammatory inducer LPS has been shown to induce autophagy in the liver hepatocytes and HSCs [32][33][34] . We firstly established in vitro trials on HSC-T6 cells by LPS stimulus.…”

Section: G-rg3 Exerted Anti-fibrotic Effect Through Inhibiting Lpsindmentioning

confidence: 99%

Ginsenoside Rg3 promotes regression from hepatic fibrosis through reducing inflammation-mediated autophagy signaling pathway

Liu

Wang

et al. 2020

Cell Death Dis

Inflammation and autophagy occur during hepatic fibrosis development caused by various pathogens, and effectively curbing of autophage may delay the occurrence of hepatic fibrosis. The current study aimed to unravel the inhibitory effects of Ginsenoside Rg3 (G-Rg3) on inflammation-mediated hepatic autophagy to curb hepatic fibrosis caused by thioacetamide (TAA)-induced subacute and chronic hepatic injury. TAA is mainly metabolized in the liver to cause liver dysfunction. After intraperitoneal injection of TAA for 4 or 10 weeks (TAA-chronic mouse models), severe inflammatory infiltration and fibrosis occurred in the liver. Treatment with G-Rg3 alleviated hepatic pathological changes and reversed hepatic fibrosis in the TAA-chronic models with decreased deposition of collagen fibers, reduced expression of HSCs activation marker (α-SMA), and reduced secretion of profibrogenic factors (TGF-β1). G-Rg3 decreased expressions of autophagy-related proteins in mice of TAA-chronic models. Notably, G-Rg3 inhibited the survival of activated rat hepatic stellate cells (HSC-T6), but had no cytotoxicity on human hepatocytes (L02 cell lines). G-Rg3 dosedependently inhibited autophagy in vitro with less expression of p62 and fewer LC3a transformation into LC3b in inflammatory inducer lipopolysaccharide (LPS)-induced rat HSC-T6 cells. Furthermore, G-Rg3 enhanced the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) in vivo and in vitro. Besides, mTOR inhibitor Rapamycin and PI3K inhibitors LY294002 were employed in LPS-treated HSC-T6 cell cultures to verify that Rg3 partially reversed the increase in autophagy in hepatic fibrosis in vitro. Taken together, G-Rg3 exerted anti-fibrosis effect through the inhibition of autophagy in TAA-treated mice and LPS-stimulated HSC-T6 cells. These data collectively unravel that G-Rg3 may serve a promising anti-hepatic fibrosis drug.