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Hepatic fibrosis is the wound healing response upon the liver tissue damage caused by multiple stimuli. Targeting activated hepatic stellate cells (HSCs), the major extracellular matrix (ECM)-producing cells within the damaged liver, has been regarded as one of the main treatments for hepatic fibrosis. In the present study, we performed preliminary bioinformatics analysis attempting to identify possible factors related to hepatic fibrosis and found that lncRNA G protein-coupled receptor 137B (Gpr137b-ps) and C-X-C motif chemokine ligand 14 (CXCL14) showed to be markedly upregulated within carbon tetrachloride (CCl4)-caused hepatic fibrotic mice tissue samples and activated HSCs. CXCL14 The silencing of lncRNA Gpr137b-ps or CXCL14 alone could significantly improve CCl4-induced fibrotic changes in mice liver in vivo and collagen I and III release by HSCs and HSC proliferation in vitro. miR-200a-3p directly targeted lncRNA Gpr137b-ps and CXCL14, respectively. LncRNA Gpr137b-ps relieved miR-200a-3p-induced inhibition on CXCL14 expression via acting as a ceRNA. In HSCs, the effects of lncRNA Gpr137b-ps silencing on collagen I and III release by HSCs and HSC proliferation were significantly reversed by miR-200a-3p inhibition, and the effects of miR-200a-3p inhibition were reversed by CXCL14 silencing. In conclusion, we demonstrated a lncRNA Gpr137b-ps/miR-200a-3p/CXCL14 axis that modulates HSC activation and might exert an effect on the pathogenesis of liver fibrosis.

Acute or chronic liver disease-caused liver failure is the cause of hepatic encephalopathy (HE), characterized by neuropsychiatric manifestations. Liver diseases potentially lead to peripheral iron metabolism dysfunction and surges of iron concentration in the brain, contributing to the pathophysiological process of degenerative disorders of the central nervous system. In this study, the mechanism of rifaximin treating HE was investigated. Ferric ammonium citrate (FAC)-induced iron overload significantly reduced the proliferation and boosted the apoptosis in SH-SY5Y cells through increasing reactive oxygen species (ROS) levels and inducing iron metabolism disorder. Rifaximin treatment could rectify the FAC-induced iron overload and lipopolysaccharide (LPS)-induced iron deposition, therefore, effectively protecting SH-SY5Y cells from ROS-induced cell injury and apoptosis. Signal transducer and activator of transcription 3 (STAT3)/nuclear factor-kappa B (NF-κB) signaling is involved in the protective function of rifaximin against LPS-induced iron deposition. The therapeutic effect of rifaximin on HE associated with acute hepatic failure in mouse model was ascertained. In conclusion, Rifaximin could effectively protect SH-SY5Y cells against injury caused by iron overload through the rectification of the iron metabolism disorder via the STAT3/NF-κB signaling pathway.

The study’s purpose was to investigate the biological function of long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) in hepatoma carcinoma (HCC). HCC tissues and cells exhibited increased levels of NEAT1 and decreased levels of miR-125a-5p. Reduction in the expression of NEAT suppressed HepG2 cell proliferation and increased apoptosis. This was accompanied by suppression of the AKT/mTOR and ERK pathways, while the opposite was observed for miR-125a-5p. Angiogenesis assay results indicated that NEAT was proangiogenic. A dual-luciferase reporter assay indicated that NEAT1 was bound to miR-125a-5p and miR-125a-5p was bound to vascular endothelial growth factor (VEGF). The proangiogenic effects of NEAT and its stimulation of AKT/mTOR and ERK were reversed by miR-125a-5p. The anti-angiogenic effects of miR-125a-5p and its inhibitory effect on AKT/mTOR and ERK pathways were reversed by co-incubation with VEGF. The conclusion was that NEAT1 enhances angiogenesis in HCC by VEGF via a competing endogenous RNA (ceRNA) of miR-125a-5p that regulates AKT/mTOR and ERK pathways.

The transformation of hepatic stellate cells (HSCs) to activated myofibroblasts plays a critical role in the progression of hepatic fibrosis, while iron-catalyzed production of free radical, including reaction and active oxygen (ROS), and activation and transformation of HSC into a myofibroblasts has been regarded as a major mechanism. In the present study, we attempted to investigate the mechanism of iron overload in hepatic fibrosis from the perspective of regulating HSC activation via oxidative stress and miR-374a/Myc axis. FAC stimulation significantly increased ROS production and TGF-β1 and IL-6 release dose-dependently in hepatocytes. miR-374a could target Myc, a co-transcription factor of both TGF-β1 and IL-6, to negatively regulate Myc expression; FAC stimulation significantly suppressed miR-374a expression, whereas the suppressive effect of FAC stimulation on miR-374a expression could be reversed by ROS inhibitor NAC, indicating that miR-374a could be modulated by iron overload-induced ROS. Via targeting Myc, miR-374a overexpression significantly reduced FAC-induced increases in TGF-β1 and IL-6 levels within L02 cells, whereas the effects of miR-374a overexpression were significantly attenuated via Myc overexpression. Finally, miR-374a overexpression attenuated FAC-induced activity of HSCs by decreasing α-SMA and Collagen I levels whereas Myc overexpression enhanced FAC-induced activity of HSCs by increasing α-SMA and Collagen I levels; the effects of miR-374a overexpression could also be significantly reversed by Myc overexpression, indicating that miR-374a suppresses the activation of HSCs by inhibiting Myc to reduce FAC-induced increases in TGF-β1 and IL-6 release. In conclusion, we demonstrate a novel mechanism of miR-374a/Myc axis modulating iron overload-induced production of ROS and the activation of HSCs via TGF-β1 and IL-6.

Background Human umbilical cord blood mesenchymal stem cells (HUCB-MSCs) can exert a protective effect in rat models of acute liver failure (ALF). Vascular endothelial growth factor 165 (VEGF165 ) is the predominant VEGF isoform and possesses a strong pro-angiogenic function. In the present study, HUCB-MSC served as the gene delivery vehicle for the VEGF165 gene, and we explored the therapeutic effects of this system on ALF. Methods HUCB-MSCs were infected with an adenovirus expressing green fluorescent protein (GFP)-VEFG fusion protein (Ad-VEGF165 ) to overexpress VEGF165 or an adenovirus expressing GFP (Ad-GFP) as control. The control and modified HUCB-MSCs were then transplanted into ALF model rats. Liver function and liver pathological changes were assessed by biochemical tests and liver histology. Immunohistochemistry was carried out to determine the expression of, CD34, Ki67 and VEGF. Results VEGF165 overexpression enhanced the multipotency of HUCB-MSCs and promoted the homing and colonization of HUCB-MSC in the liver tissues of ALF rats. Furthermore, although HUCB-MSC transplantation ameliorated liver damage and promoted liver regeneration to some extent in ALF rats, Ad-VEGF165 -HUCB-MSC transplantation showed stronger therapeutic effects on ALF. Conclusions In summary, transplantation of VEGF165 -modified HUCB-MSCs exert stronger therapeutic effects on ALF than HUCB-MSCs. The present study provides a novel therapeutic approach for ALF.

Human umbilical cord blood mesenchymal stem cells (HUCB-MSCs) can exert a protective effect in rat models of acute liver failure (ALF). Vascular endothelial growth factor 165 (VEGFHUCB-MSCs were infected with an adenovirus expressing green fluorescent protein (GFP)-VEFG fusion protein (Ad-VEGFVEGFIn summary, transplantation of VEGF

Human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) have been used to facilitate healing in animal models of liver injury, while granulocyte colony-stimulating factor (G-CSF) has been shown to stimulate stem cell mobilization and these cells may contribute to liver repair. hUCB-MSCs were characterized by flow cytometry, and transplanted into rats with d-galactosamine (D-GalN)/lipopolysaccharides (LPS)-induced acute liver failure (ALF) together with granulocyte colony-stimulating factor (G-CSF). Liver function, oxidative stress and pro-inflammatory cytokines expressions were examined using enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was used to observe the morphological changes. Apoptosis was investigated by terminal dUTP nick end labeling (TUNEL) staining. Bromodeoxyuridine (BrdU) cell proliferation assay was analyzed by immunofluorescence and immunohistochemistry. In the results, cultured hUCB-MSCs displayed proliferation and adipogenic and osteogenic differentiation potentials. hUCB-MSCs in combination with G-CSF significantly attenuated ALF-induced liver function injury. Furthermore, hUCB-MSCs and G-CSF treatment remarkably suppressed the secretions of pro-inflammatory cytokines and MDA activation induced by ALF. In addition, inflammation, lesions and cell apoptosis in liver tissues were obviously ameliorated by application of hUCB-MSCs and G-CSF. In conclusion, hUCB-MSCs, alone or co-treatment with G-CSF could ameliorate ALF in rats by inhibiting liver function injury, production of pro-inflammatory cytokines, oxidative stress, and liver cell apoptosis.

This paper focused on evaluating the effect of TLR4-MyD88-NF-κB signaling pathway in the progression of secondary hepatic injury and fibrosis in hepatolithiasis. The levels of inflammatory factors (IL-1β, IL-6, TNF-α) and serum biochemical values (ALT, AST, Tbil, Dbil, ALP, GGT) were detected by ELISA. IHC was used to detected the expression level of TLR4 in liver tissues of hepatolithiasis patients and mice. The pathological changes of liver tissue were observed by HE staining. The levels of MyD88, NF-κB, IκB, Laminin (LN), and chitosan enzyme 3-like protein 1 (CHI3L1) were detected by western blotting. In hepatolithiasis patients, the levels of TNF-α, IL-1β, and IL-6 were distinctly raised and proteins associated with TLR4-MyD88-NF-κB signaling pathway (such as TLR4, MyD88, NF-κB, and IκB) in liver tissues were significantly up-regulated. In Bile duct ligation (BDL) model of mice, the results showed that in addition to the significant increase of inflammatory factors, liver function indexes, and fibrosis indexes in BDL mice were also significantly up-regulated. Additionally, TLR4-MyD88-NF-κB signaling pathway was activated in BDL mice. After TLR4 knockdown in BDL mice, inflammatory factors, liver function indexes, and fibrosis indexes were significantly down-regulated. TLR4-MyD88-NF-κB signaling pathway proteins were restrained. TLR4-MyD88-NF-κB signaling pathway took part in the progression of secondary hepatic injury and fibrosis in hepatolithiasis. Inhibition of TLR4-MyD88-NF-κB signaling pathway can reduce the progression of secondary hepatic injury and fibrosis in hepatolithiasis.