scholarly journals Exemestane Attenuates Hepatic Fibrosis in Rats by Inhibiting Activation of Hepatic Stellate Cells and Promoting the Secretion of Interleukin 10

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Ya-Hui Wang ◽  
Rong-Kun Li ◽  
Ying Fu ◽  
Jun Li ◽  
Xiao-Mei Yang ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Antioxidant Activities ◽  
Culture Media ◽  
Stellate Cells ◽  
Aromatase Activity ◽  
Duct Ligation ◽  
Anti Inflammatory

Exemestane (EXE) is an irreversible steroidal aromatase inhibitor mainly used as an adjuvant endocrine therapy for postmenopausal women suffering from breast cancer. Besides inhibiting aromatase activity, EXE has multiple biological functions, such as antiproliferation, anti-inflammatory, and antioxidant activities which are all involved in hepatic fibrosis. Therefore, we investigated the role of EXE during the progress of hepatic fibrosis. The effect of EXE on liver injury and fibrosis were assessed in two hepatic fibrosis rat models, which were induced by either carbon tetrachloride (CCl4) or bile duct ligation (BDL). The influence of EXE treatment on activation and proliferation of primary rat hepatic stellate cells (HSCs) was observedin vitro. The results showed that EXE attenuated the liver fibrosis by decreasing the collagen deposition andα-SMA expressionin vivoand inhibited the activation and proliferation of primary rat HSCsin vitro. Additionally, EXE promoted the secretion of antifibrotic and anti-inflammatory cytokine IL-10in vivoand in HSC-T6 culture media. In conclusion, our findings reveal a new function of EXE on hepatic fibrosis and prompted its latent application in liver fibrotic-related disease.

M1567 CpG Motifs Induce Proinflammatory Events in Hepatic Stellate Cells and Are Involved in Bile Duct Ligation-Induced Hepatic Fibrosis In Vivo

2008 ◽  
Vol 134 (4) ◽  
pp. A-795
Author(s):  
Erwin Gäbele ◽  
Matthias Froh ◽  
Reiner Wiest ◽  
Florian Obermeier ◽  
Jürgen Schölmerich ◽  
...  
Keyword(s):  
Bile Duct ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Bile Duct Ligation ◽  
Stellate Cells ◽  
Cpg Motifs ◽  
Duct Ligation

scholarly journals Honokiol Acts as a Potent Anti-Fibrotic Agent in the Liver through Inhibition of TGF-β1/SMAD Signaling and Autophagy in Hepatic Stellate Cells

2021 ◽  
Vol 22 (24) ◽  
pp. 13354
Author(s):  
Seita Kataoka ◽  
Atsushi Umemura ◽  
Keiichiro Okuda ◽  
Hiroyoshi Taketani ◽  
Yuya Seko ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Signaling Pathway ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Smad Signaling ◽  
Smad Signaling Pathway ◽  
Tgf Β1

Chronic liver injury may result in hepatic fibrosis, which can progress to cirrhosis and eventually liver failure. There are no drugs that are specifically approved for treating hepatic fibrosis. The natural product honokiol (HNK), a bioactive compound extracted from Magnolia grandiflora, represents a potential tool in the management of hepatic fibrosis. Though HNK has been reported to exhibit suppressive effects in a rat fibrosis model, the mechanisms accounting for this suppression remain unclear. In the present study, the anti-fibrotic effects of HNK on the liver were evaluated in vivo and in vitro. In vivo studies utilized a murine liver fibrosis model, in which fibrosis is induced by treatment with carbon tetrachloride (CCl4). For in vitro studies, LX-2 human hepatic stellate cells (HSCs) were treated with HNK, and expression of markers of fibrosis, cell viability, the transforming growth factor-β (TGF-β1)/SMAD signaling pathway, and autophagy were analyzed. HNK was well tolerated and significantly attenuated CCl4-induced liver fibrosis in vivo. Moreover, HNK decreased HSC activation and collagen expression by downregulating the TGF-β1/SMAD signaling pathway and autophagy. These results suggest that HNK is a new potential candidate for the treatment of hepatic fibrosis through suppressing both TGF-β1/SMAD signaling and autophagy in HSCs.

Amygdalin inhibits TGFβ1-induced activation of hepatic stellate cells (HSCs) in vitro and CCl4-induced hepatic fibrosis in rats in vivo

2021 ◽  
Vol 90 ◽  
pp. 107151
Author(s):  
Ruoyu Wang ◽  
Dong Zhang ◽  
Dan Tang ◽  
Kewei Sun ◽  
Jianping Peng ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells

scholarly journals COX-2 Regulates the Proliferation and Apoptosis of Activated Hepatic Stellate Cells through CDC27

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Yang Hu ◽  
Nian Fu ◽  
Li Xian Chen ◽  
Jian Hua Xiao ◽  
Xue Feng Yang
Keyword(s):  
Cell Proliferation ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Cycle Arrest ◽  
Proliferation And Apoptosis ◽  
Cox 2 ◽  
Activated Hepatic Stellate Cells

Cyclooxygenase-2 (COX-2) is an important rate-limiting enzyme in the synthesis of prostaglandins (PGs), which can be upregulated by various stimuli. COX-2 has been shown to be involved in the occurrence and development of hepatic fibrosis by regulating the proliferation and apoptosis of hepatic stellate cells (HSCs) in previous studies. The aims of the study are to study the mechanism of how COX-2 regulates the proliferation and apoptosis of HSCs and to provide new targets for the prevention and treatment of hepatic fibrosis. A short hairpin RNA targeting COX-2 was constructed, and the changes in proliferation and apoptosis of liver tissue cells and HSCs were observed, respectively. COX-2-shRNA-1 significantly suppressed the proliferation of HSCs in vivo. Moreover, knockdown of COX-2 significantly suppressed cell proliferation and accelerated cell cycle arrest and apoptosis in vitro. Among those differential genes related to cell proliferation and apoptosis, CDC27 and Sh3kbp1 were upregulated, but Plcd4 was suppressed. Mechanistically, the influence of COX-2 on HSCs partly depends on upregulating CDC27. Our results demonstrated that COX-2 regulates the proliferation and apoptosis of activated hepatic stellate cells through the CDC27 pathway. This study contributes to our understanding of the effect of COX-2 for the treatment of hepatic fibrosis.

Increased contractility of hepatic stellate cells in cirrhosis is mediated by enhanced Ca2+-dependent and Ca2+-sensitization pathways

2011 ◽  
Vol 300 (6) ◽  
pp. G1010-G1021 ◽  
Author(s):  
Masateru Iizuka ◽  
Takahisa Murata ◽  
Masatoshi Hori ◽  
Hiroshi Ozaki
Keyword(s):  
Smooth Muscle ◽  
Hepatic Stellate Cells ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Regulatory Proteins ◽  
Muscle Actin ◽  
Rock Inhibitor ◽  
Duct Ligation

Activation of hepatic stellate cells (HSCs) results in cirrhosis and portal hypertension due to intrahepatic resistance. Activated HSCs increase their contraction after receptor agonist stimulation; however, the signaling pathways for the regulation of contraction are not fully understood. The aim of this study was to elucidate the change in contractile mechanisms of HSCs after cirrhotic activation. The expression pattern of contractile regulatory proteins was analyzed with quantitative RT-PCR and Western blotting. The phosphorylation levels of myosin light chain (MLC), 17-kDa PKC-potentiated protein phosphatase 1 inhibitor protein (CPI-17), and MLC phosphatase targeting subunit 1 (MYPT1) after endothelin-1 (ET-1) stimulation in culture-activated HSCs were measured using phosphorylation-specific antibodies. In vivo-activated HSCs were isolated from rats subjected to bile duct ligation and repeated dimethylnitrosoamine injections. HSCs showed increased expression of not only α-smooth muscle actin, but also the contractile regulatory proteins MLC kinase (MLCK), Rho kinase 2 (ROCK2), and CPI-17 during HSC activation in vitro. In culture-activated HSCs, ET-1 increased phosphorylation of CPI-17 at Thr18, which was markedly inhibited by the PKC inhibitor Ro-31–8425. ET-1 induced phosphorylation of MYPT1 at Thr853, which was suppressed by the ROCK inhibitor Y-27632. ET-1 induced sustained phosphorylation of MLC at Thr18/Ser19, which was inhibited by both Ro-31–8425 and Y-27632. Consistent with the data obtained from the in vitro study, HSCs isolated from cirrhotic rats showed increased expression of α-smooth muscle actin, MLCK, CPI-17, and ROCK2 compared with HSCs from nontreated rats. Furthermore, MLC phosphorylation in in vivo-activated HSCs was increased, according to enhanced phosphorylation of CPI-17 and MYPT1 in the presence of ET-1. These results suggest that activated HSCs may participate in constriction of hepatic sinusoids in the cirrhotic liver through both Ca2+-dependent (MLCK pathway) and Ca2+-sensitization mechanism (CPI-17 and MYPT1 pathways).

iRhom2 inhibits bile duct obstruction–induced liver fibrosis

2019 ◽  
Vol 12 (605) ◽  
pp. eaax1194 ◽  
Author(s):  
Balamurugan Sundaram ◽  
Kristina Behnke ◽  
Andrea Belancic ◽  
Mazin A. Al-Salihi ◽  
Yasser Thabet ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Duct Ligation ◽  
Tnf Α ◽  
Primary Mouse ◽  
Factor Α

Chronic liver disease can induce prolonged activation of hepatic stellate cells, which may result in liver fibrosis. Inactive rhomboid protein 2 (iRhom2) is required for the maturation of A disintegrin and metalloprotease 17 (ADAM17, also called TACE), which is responsible for the cleavage of membrane-bound tumor necrosis factor–α (TNF-α) and its receptors (TNFRs). Here, using the murine bile duct ligation (BDL) model, we showed that the abundance of iRhom2 and activation of ADAM17 increased during liver fibrosis. Consistent with this, concentrations of ADAM17 substrates were increased in plasma samples from mice after BDL and in patients suffering from liver cirrhosis. We observed increased liver fibrosis, accelerated disease progression, and an increase in activated stellate cells after BDL in mice lacking iRhom2 (Rhbdf2−/−) compared to that in controls. In vitro primary mouse hepatic stellate cells exhibited iRhom2-dependent shedding of the ADAM17 substrates TNFR1 and TNFR2. In vivo TNFR shedding after BDL also depended on iRhom2. Treatment of Rhbdf2−/− mice with the TNF-α inhibitor etanercept reduced the presence of activated stellate cells and alleviated liver fibrosis after BDL. Together, these data suggest that iRhom2-mediated inhibition of TNFR signaling protects against liver fibrosis.

scholarly journals Hepatic stellate cells retain retinoid-laden lipid droplets after cellular transdifferentiation into activated myofibroblasts

2018 ◽  
Vol 315 (5) ◽  
pp. G713-G721 ◽  
Author(s):  
Loretta L. Jophlin ◽  
Yiannis Koutalos ◽  
Chunhe Chen ◽  
Vijay Shah ◽  
Don C. Rockey
Keyword(s):  
Hepatic Stellate Cells ◽  
Lipid Droplets ◽  
Bile Duct Ligation ◽  
Ex Vivo ◽  
Stellate Cells ◽  
Duct Ligation ◽  
Oil Red O

Loss of retinyl ester (RE)-rich lipid droplets (LDs) from hepatic stellate cells (HSCs) is cited as a key event in their cellular transdifferentiation to activated, pro-fibrotic myofibroblasts; however, it remains unclear if changes in LD morphology or RE content are causal for transdifferentiation. To better understand LD dynamics in vitro within a common model of HSC activation, we used novel approaches preserving LD morphology and allowing for quantitation of RE. The size and quantity of LDs within in vitro and in vivo bile duct ligation (BDL)-activated HSCs were quantitated using adipocyte differentiation-related protein (ADRP) labeling and oil red o (ORO) staining (gold standard), and RE content was determined using fluorescence microscopy. We found during HSC activation in vitro that LD number differed significantly when measured by ADRP and ORO, respectively ( day 1: 56 vs. 5, P = 0.03; day 4: 101 vs. 39, P = 0.03; day 14: 241 vs. 12, P = 0.02). Ex vivo HSCs activated in vivo contained the same number of LDs as day 4 in vitro activated HSCs (118 vs. 101, P = 0.54). Decline in LD RE occurred beyond day 4 in vitro and day 1 ex vivo , after HSC transdifferentiation was underway. Lastly, in situ HSCs examined using electron microscopy show LDs tend to be smaller but are ultimately retained in BDL injured livers. Therefore, we conclude that during HSC transdifferentiation, LDs are not lost but are retained, decreasing in size. Additionally, RE content declines after transdifferentiation is underway. These data suggest that these LD changes are not causal for HSC transdifferentiation. NEW & NOTEWORTHY Loss of retinoid-laden lipid droplets from hepatic stellate cells has long been held as a hallmark of their transdifferentiation into activated myofibroblasts, the dominant cells that drive hepatic fibrosis. This study demonstrates that stellate cells activated in culture and after liver injury in vivo retain their lipid droplets and that these droplets become smaller and more numerous, with decreases in droplet retinoid concentration occurring only after cellular transdifferentiation is underway.

scholarly journals Inhibitory effect of oestradiol on activation of rat hepatic stellate cells in vivo and in vitro

Gut ◽  
1999 ◽  
Vol 44 (1) ◽  
pp. 127-136 ◽  
Author(s):  
I Shimizu ◽  
Y Mizobuchi ◽  
M Yasuda ◽  
M Shiba ◽  
Y-R Ma ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Inhibitory Effect ◽  
Type I ◽  
Mrna Levels ◽  
Pig Serum

BackgroundHepatic stellate cells play a key role in the pathogenesis of hepatic fibrosis.AimsTo examine the inhibitory effect of oestradiol on stellate cell activation.MethodsIn vivo, hepatic fibrosis was induced in rats by dimethylnitrosamine or pig serum. In vitro, rat stellate cells were activated by contact with plastic dishes resulting in their transformation into myofibroblast-like cells.ResultsIn the dimethylnitrosamine and pig serum models, treatment with oestradiol at gestation related doses resulted in a dose dependent suppression of hepatic fibrosis with restored content of hepatic retinyl palmitate, reduced collagen content, lower areas of stellate cells which express α smooth muscle actin (α-SMA) and desmin, and lower procollagen type I and III mRNA levels in the liver. In cultured stellate cells, oestradiol inhibited type I collagen production, α-SMA expression, and cell proliferation. These findings suggest that oestradiol is a potent inhibitor of stellate cell transformation.ConclusionThe antifibrogenic role of oestradiol in the liver may contribute to the sex associated differences in the progression from hepatic fibrosis to cirrhosis.

Erratum: Study on the in vitro and in vivo activation of rat hepatic stellate cells by Raman spectroscopy

2007 ◽  
Vol 12 (5) ◽  
pp. 059801
Author(s):  
Aiguo Shen ◽  
Zhangxiu Liao ◽  
Hui Wang ◽  
Iiho Goan ◽  
Yong Wu ◽  
...  
Keyword(s):  
Raman Spectroscopy ◽  
Hepatic Stellate Cells ◽  
Stellate Cells
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