scholarly journals 4-methylumbelliferone Prevents Liver Fibrosis by Affecting Hyaluronan Deposition, FSTL1 Expression and Cell Localization

2019 ◽  
Vol 20 (24) ◽  
pp. 6301 ◽  
Author(s):  
Irina N. Andreichenko ◽  
Alexandra A. Tsitrina ◽  
Alexander V. Fokin ◽  
Adelya I. Gabdulkhakova ◽  
Dmitry I. Maltsev ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Control Level ◽  
Immunohistochemical Analysis ◽  
Stellate Cells ◽  
Bioinformatic Analysis ◽  
Beta Catenin ◽  
Catabolic Gene ◽  
Cell Localization ◽  
Ccl4 Treatment

4-methylumbelliferone (4MU) is an inhibitor of hyaluronan deposition and an active substance of hymecromone, a choleretic and antispasmodic drug. 4MU reported to be anti-fibrotic in mouse models; however, precise mechanism of action still requires further investigation. Here we describe the cellular and molecular mechanisms of 4MU action on CCl4-induced liver fibrosis in mice using NGS transcriptome, Q-PCR and immunohistochemical analysis. Collagen and hyaluronan deposition were prevented by 4MU. The CCl4 stimulated expression of Col1a and αSMA were reduced, while the expression of the ECM catabolic gene Hyal1 was increased in the presence of 4MU. Bioinformatic analysis identified an activation of TGF-beta and Wnt/beta-catenin signaling pathways, and inhibition of the genes associated with lipid metabolism by CCL4 treatment, while 4MU restored key markers of these pathways to the control level. Immunohistochemical analysis reveals the suppression of hepatic stellate cells (HSCs) transdifferentiation to myofibroblasts by 4MU treatment. The drug affected the localization of HSCs and macrophages in the sites of fibrogenesis. CCl4 treatment induced the expression of FSTL1, which was downregulated by 4MU. Our results support the hypothesis that 4MU alleviates CCl4-induced liver fibrosis by reducing hyaluronan deposition and downregulating FSTL1 expression, accompanied by the suppression of HSC trans-differentiation and altered macrophage localization.

Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells

2006 ◽  
Vol 291 (5) ◽  
pp. G877-G884 ◽  
Author(s):  
Pau Sancho-Bru ◽  
Ramón Bataller ◽  
Jordi Colmenero ◽  
Xavier Gasull ◽  
Montserrat Moreno ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Portal Hypertension ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Stellate Cells ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Cell Contraction

Catecholamines participate in the pathogenesis of portal hypertension and liver fibrosis through α1-adrenoceptors. However, the underlying cellular and molecular mechanisms are largely unknown. Here, we investigated the effects of norepinephrine (NE) on human hepatic stellate cells (HSC), which exert vasoactive, inflammatory, and fibrogenic actions in the injured liver. Adrenoceptor expression was assessed in human HSC by RT-PCR and immunocytochemistry. Intracellular Ca2+ concentration ([Ca2+]i) was studied in fura-2-loaded cells. Cell contraction was studied by assessing wrinkle formation and myosin light chain II (MLC II) phosphorylation. Cell proliferation and collagen-α1(I) expression were assessed by [3H]thymidine incorporation and quantitative PCR, respectively. NF-κB activation was assessed by luciferase reporter gene and p65 nuclear translocation. Chemokine secretion was assessed by ELISA. Normal human livers expressed α1A-adrenoceptors, which were markedly upregulated in livers with advanced fibrosis. Activated human HSC expressed α1A-adrenoceptors. NE induced multiple rapid [Ca2+]i oscillations (Ca2+ spikes). Prazosin (α1-blocker) completely prevented NE-induced Ca2+ spikes, whereas propranolol (nonspecific β-blocker) partially attenuated this effect. NE caused phosphorylation of MLC II and cell contraction. In contrast, NE did not affect cell proliferation or collagen-α1(I) expression. Importantly, NE stimulated the secretion of inflammatory chemokines (RANTES and interleukin-8) in a dose-dependent manner. Prazosin blocked NE-induced chemokine secretion. NE stimulated NF-κB activation. BAY 11-7082, a specific NF-κB inhibitor, blocked NE-induced chemokine secretion. We conclude that NE stimulates NF-κB and induces cell contraction and proinflammatory effects in human HSC. Catecholamines may participate in the pathogenesis of portal hypertension and liver fibrosis by targeting HSC.

scholarly journals Suberoylanilide hydroxamic acid suppresses hepatic stellate cells activation by HMGB1 dependent reduction of NF-κB1

PeerJ ◽  
2015 ◽  
Vol 3 ◽  
pp. e1362 ◽  
Author(s):  
Wenwen Wang ◽  
Min Yan ◽  
Qiuhong Ji ◽  
Jinbiao Lu ◽  
Yuhua Ji ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Hydroxamic Acid ◽  
Molecular Mechanisms ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Cdna Array ◽  
Stellate Cells ◽  
Type I ◽  
Suberoylanilide Hydroxamic Acid

Hepatic stellate cells (HSCs) activation is essential to the pathogenesis of liver fibrosis. Exploring drugs targeting HSC activation is a promising anti-fibrotic strategy. In the present study, we found suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, prominently suppressed the activation phenotype of a human hepatic stellate cell line—LX2. The production of collagen type I andα-smooth muscle actin (α-SMA) as well as the proliferation and migration of LX2 cells were significantly reduced by SAHA treatment. To determine the molecular mechanisms underlying this suppression, genome wild gene regulation by SAHA was determined by Affymetrix 1.0 human cDNA array. Upon SAHA treatment, the abundance of 331 genes was up-regulated and 173 genes was down-regulated in LX2 cells. Bioinformatic analyses of these altered genes highlighted the high mobility group box 1 (HMGB1) pathway was one of the most relevant pathways that contributed to SAHA induced suppression of HSCs activation. Further studies demonstrated the increased acetylation of intracellular HMGB1 in SAHA treated HSCs, and this increasing is most likely to be responsible for SAHA induced down-regulation of nuclear factor kappa B1 (NF-κB1) and is one of the main underlying mechanisms for the therapeutic effect of SAHA for liver fibrosis.

scholarly journals microRNA-630 Regulates Underglycosylated IgA1 Production in the Tonsils by Targeting TLR4 in IgA Nephropathy

2020 ◽  
Vol 11 ◽  
Author(s):  
Chan Liu ◽  
Mu-Yao Ye ◽  
Wen-Zhe Yan ◽  
Xiao-Fei Peng ◽  
Li-Yu He ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Immunohistochemical Analysis ◽  
Bioinformatic Analysis ◽  
Cell Culture Supernatant ◽  
Mechanism Study ◽  
Complement Components ◽  
Mesangial Area ◽  
Primary Glomerular Disease

IgA nephropathy (IgAN) is the most common primary glomerular disease. The characteristic pathology involves immune complexes formed by the deposition of IgA1 and underglycosylated IgA1 aggregates in the mesangial area, which may be accompanied by the deposition of IgG and/or IgM and complement components. However, the molecular mechanisms of IgAN remain unclear. In the present study, microarray analysis showed that the expression of microRNA-630 (miR-630) was significantly reduced in palatal tonsils from IgAN patients compared with chronic tonsillitis. Additionally, bioinformatic analysis showed that Toll-like receptor 4 (TLR4) was the predicted target gene of miR-630 and was regulated by miR-630. When miR-630 was overexpressed in palatal tonsil mononuclear cells from IgAN patients, the expression of TLR4 was reduced and the content of IgA1 in the cell culture supernatant was decreased, and the level of galactosylation in the IgA1 hinge region was increased. Moreover, immunohistochemical analysis showed that the expression of TLR4 in IgAN patients was significantly increased. After knocking down the expression of TLR4, both the concentration of IgA1 and the binding force of IgA1 with broad bean lectin were significantly reduced in IgAN. Furthermore, the mechanism study demonstrated that TLR4 might regulate the expression of IL-1β and IL-8 through NF-κB signaling pathway to modulate the concentration of IgA1 and the glycosylation level of IgA1. This interesting finding may offer new insight into the molecular mechanism of IgAN.

scholarly journals Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

2017 ◽  
Vol 91 (6) ◽  
Author(s):  
Pradip B. Devhare ◽  
Reina Sasaki ◽  
Shubham Shrivastava ◽  
Adrian M. Di Bisceglie ◽  
Ranjit Ray ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Liver Disease ◽  
Hepatitis C ◽  
Liver Fibrosis ◽  
Intercellular Communication ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Stellate Cells ◽  
Hcv Infection ◽  
Marker Genes

ABSTRACT Fibrogenic pathways in the liver are principally regulated by activation of hepatic stellate cells (HSC). Fibrosis is associated with chronic hepatitis C virus (HCV) infection, although the mechanism is poorly understood. HSC comprise the major population of nonparenchymal cells in the liver. Since HCV does not replicate in HSC, we hypothesized that exosomes secreted from HCV-infected hepatocytes activate HSC. Primary or immortalized human hepatic stellate (LX2) cells were exposed to exosomes derived from HCV-infected hepatocytes (HCV-exo), and the expression of fibrosis-related genes was examined. Our results demonstrated that HCV-exo internalized to HSC and increased the expression of profibrotic markers. Further analysis suggested that HCV-exo carry miR-19a and target SOCS3 in HSC, which in turn activates the STAT3-mediated transforming growth factor β (TGF-β) signaling pathway and enhances fibrosis marker genes. The higher expression of miR-19a in exosomes was also observed from HCV-infected hepatocytes and in sera of chronic HCV patients with fibrosis compared to healthy volunteers and non-HCV-related liver disease patients with fibrosis. Together, our results demonstrated that miR-19a carried through the exosomes from HCV-infected hepatocytes activates HSC by modulating the SOCS-STAT3 axis. Our results implicated a novel mechanism of exosome-mediated intercellular communication in the activation of HSC for liver fibrosis in HCV infection. IMPORTANCE HCV-associated liver fibrosis is a critical step for end-stage liver disease progression. However, the molecular mechanisms for hepatic stellate-cell activation by HCV-infected hepatocytes are underexplored. Here, we provide a role for miR-19a carried through the exosomes in intercellular communication between HCV-infected hepatocytes and HSC in fibrogenic activation. Furthermore, we demonstrate the role of exosomal miR-19a in activation of the STAT3–TGF-β pathway in HSC. This study contributes to the understanding of intercellular communication in the pathogenesis of liver disease during HCV infection.

scholarly journals Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-β and STAT3 activation

2009 ◽  
Vol 206 (4) ◽  
pp. 819-831 ◽  
Author(s):  
Atsushi Hosui ◽  
Akiko Kimura ◽  
Daisuke Yamaji ◽  
Bing-mei Zhu ◽  
Risu Na ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Null Mouse ◽  
Protein Levels ◽  
Β Protein ◽  
Ccl4 Treatment ◽  
The Stability

The molecular mechanisms underlying the development of hepatocellular carcinoma are not fully understood. Liver-specific signal transducer and activator of transcription (STAT) 5A/B–null mice (STAT5-LKO) were treated with carbon tetrachloride (CCl4), and histological analyses revealed liver fibrosis and tumors. Transforming growth factor (TGF)–β levels and STAT3 activity were elevated in liver tissue from STAT5-LKO mice upon CCl4 treatment. To define the molecular link between STAT5 silencing and TGF-β up-regulation, as well as STAT3 activation, we examined STAT5-null mouse embryonic fibroblasts and primary hepatocytes. These cells displayed elevated TGF-β protein levels, whereas messenger RNA levels remained almost unchanged. Protease inhibitor studies revealed that STAT5 deficiency enhanced the stability of mature TGF-β. Immunoprecipitation and immunohistochemistry analyses demonstrated that STAT5, through its N-terminal sequences, could bind to TGF-β and that retroviral-mediated overexpression of STAT5 decreased TGF-β levels. To confirm the in vivo significance of the N-terminal domain of STAT5, we treated mice that expressed STAT5 lacking the N terminus (STAT5-ΔN) with CCl4. STAT5-ΔN mice developed CCl4-induced liver fibrosis but no tumors. In conclusion, loss of STAT5 results in elevated TGF-β levels and enhanced growth hormone–induced STAT3 activity. We propose that a deregulated STAT5–TGF-β–STAT3 network contributes to the development of chronic liver disease.

scholarly journals CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuzo Koda ◽  
Toshiaki Teratani ◽  
Po-Sung Chu ◽  
Yuya Hagihara ◽  
Yohei Mikami ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Stellate Cells ◽  
Dependent Manner ◽  
Resolution Model ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome ◽  
Resident Memory T Cells

AbstractNon-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8+ tissue-resident memory CD8+ T (CD8+ Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69+CD103−CD8+ Trm cell enrichment in NASH resolution livers. The reduction of liver CD8+ Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8+ Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69+CD8+ Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8+ Trm in fibrosis resolution.

scholarly journals The role of miR-29a in the regulation, function, and signaling of liver fibrosis

2018 ◽  
Author(s):  
Ying-Hsien Huang ◽  
Ya-Ling Yang ◽  
Feng-Sheng Wang
Keyword(s):  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Stellate Cells ◽  
Experimental Therapy ◽  
Complete Understanding ◽  
Chronic Liver Damage ◽  
Clinical Challenge ◽  
Non Coding Rna ◽  
Regulation Function

Both fibrosis and cirrhosis of the liver are the end results of most kinds of chronic liver damage and present a common but difficult clinical challenge throughout the world. The inhibition of the fibrogenic, proliferative, and migratory effects of hepatic stellate cells (HSCs) has become an experimental therapy for preventing and even reversing hepatic fibrosis. Furthermore, a complete understanding of the function of non-coding RNA-mediated epigenetic mechanisms in HSC activation may improve our perception of liver fibrosis pathogenesis. This review focuses on an evolving view of molecular mechanisms in which HSC activation by miR-29a signaling may moderate their profibrogenic phenotype, thus supporting the use of miR-29a agonists as a potential therapy for treating liver fibrosis in the future.

scholarly journals Cellular Interplay as a Consequence of Inflammatory Signals Leading to Liver Fibrosis Development

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 461 ◽  
Author(s):  
Simona-Rebeca Ignat ◽  
Sorina Dinescu ◽  
Anca Hermenean ◽  
Marieta Costache
Keyword(s):  
Cell Death ◽  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Stellate Cells ◽  
Innate Immune ◽  
Sterile Inflammation ◽  
Innate Immune Cells ◽  
Inflammatory Signals ◽  
Molecular Patterns ◽  
Pro Inflammatory Cytokines

Inflammation has been known to be an important driver of fibrogenesis in the liver and onset of hepatic fibrosis. It starts off as a process meant to protect the liver from further damage, but it can become the main promoter of liver fibrosis. There are many inflammation-related pathways activated during liver fibrosis that lead to hepatic stellate cells (HSCs) activation and collagen-deposition in the liver. Such events are mostly modulated upstream of HSCs and involve signals from hepatocytes and innate immune cells. One particular event is represented by cell death during liver injury that generates multiple inflammatory signals that further trigger sterile inflammation and enhancement of inflammatory response. The assembly of inflammasome that responds to danger-associated molecular patterns (DAMPs) stimulates the release of pro-inflammatory cytokines and at the same time, initiates programmed cell death called pyroptosis. This review focuses on cellular and molecular mechanisms responsible for initiation and progress of inflammation in the liver.

scholarly journals Berberine alleviates liver fibrosis through inducing ferrous redox to activate ROS-mediated hepatic stellate cells ferroptosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jiazhi Yi ◽  
Shuyun Wu ◽  
Siwei Tan ◽  
Yunfei Qin ◽  
Xing Wang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Mouse Liver ◽  
Molecular Mechanisms ◽  
Stellate Cells ◽  
Iron Release ◽  
Iron Storage ◽  
Redox Active ◽  
Liver Fibrogenesis ◽  
Underlying Mechanisms

AbstractBerberine (BBR) has been explored as a potential anti-liver fibrosis agent, but the underlying mechanisms are unknown. In the current study, we aimed to investigate the molecular mechanisms underlying the effect of BBR against liver fibrogenesis in thioacetamide (TAA) and carbon tetrachloride (CCl4) induced mouse liver fibrosis. In addition to i.p. injection with TAA or CCl4, mice in the treatment group received BBR intragastrically. Concurrently, combined with TAA and BBR treatment, mice in the inhibitor group were injected i.p. with ferrostatin-1 (Fer-1). Hepatic stellate cells (HSCs) were also used in the study. Our results showed that BBR obviously alleviated mouse liver fibrosis and restored mouse liver function; however, the pharmacological effects of BBR against liver fibrosis were significantly diminished by Fer-1 treatment. Mechanically, BBR impaired the autophagy–lysosome pathway (ALP) and increased cell reactive oxygen species (ROS) production in HSCs. ROS accelerated the breakdown of the iron-storage protein ferritin and sped up iron release from ferritin, which resulted in redox-active iron accumulation in HSCs. Lipid peroxidation and glutathione (GSH) depletion triggered by the Fenton reaction promoted ferroptosis and attenuated liver fibrosis. Furthermore, impaired autophagy enhanced BBR-mediated ferritin proteolysis to increase cellular ferrous overload via the ubiquitin–proteasome pathway (UPS) in HSCs and triggered HSC ferroptosis. Collectively, BBR alleviated liver fibrosis by inducing ferrous redox to activate ROS-mediated HSC ferroptosis. Our findings may be exploited clinically to provide a potential novel therapeutic strategy for liver fibrosis.

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