Resveratrol increases the activation markers and changes the release of inflammatory cytokines of hepatic stellate cells

Activation of hepatic stellate cells during liver fibrosis is a major event facilitating an increase in extracellular matrix deposition. The up-regulation of smooth muscle α-actin and collagen type I is indicative of the activation process. The involvement of cysteine cathepsins, a class of lysosomal cysteine proteases, has not been studied in conjunction with the activation process of hepatic stellate cells. Here we report a nuclear cysteine protease activity partially attributed to cathepsin F, which co-localizes with nuclear speckles. This activity can be regulated by treatment with retinol/palmitic acid, known to reduce the hepatic stellate cell activation. The treatment for 48 h leads to a decrease in activity, which is coupled to an increase in cystatin B and C transcripts. Cystatin B knockdown experiments during the same treatment confirm the regulation of the nuclear activity by cystatin B. We demonstrate further that the inhibition of the nuclear activity by E-64d, a cysteine protease inhibitor, results in a differential regulation of smooth muscle α-actin and collagen type I transcripts. On the other hand, cathepsin F small interfering RNA transfection leads to a decrease in nuclear activity and a transcriptional down-regulation of both activation markers. These findings indicate a possible link between nuclear cathepsin F activity and the transcriptional regulation of hepatic stellate cell activation markers.

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Nicotinamide induces apoptosis and reduces collagen I and pro-inflammatory cytokines expression in rat hepatic stellate cells

Scandinavian Journal of Gastroenterology ◽

10.1080/00365520510023341 ◽

2005 ◽

Vol 40 (10) ◽

pp. 1226-1234 ◽

Cited By ~ 22

Author(s):

Alexandra Traister ◽

Igal Breitman ◽

Ella Bar-Lev ◽

Isabel Zvibel ◽

Avikam Harel ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Collagen I ◽

Pro Inflammatory Cytokines

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MicroRNA-124 inhibits hepatic stellate cells inflammatory cytokines secretion by targeting IQGAP1 through NF-κB pathway

International Immunopharmacology ◽

10.1016/j.intimp.2021.107520 ◽

2021 ◽

Vol 95 ◽

pp. 107520

Author(s):

Junfa Yang ◽

Changqing Xu ◽

Maomao Wu ◽

Ying Wu ◽

Xiaodi Jia ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Microrna 124 ◽

Cytokines Secretion

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Alpha Mangostin Inhibits the Proliferation and Activation of Acetaldehyde Induced Hepatic Stellate Cells through TGF-β and ERK 1/2 Pathways

Journal of Toxicology ◽

10.1155/2018/5360496 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Novriantika Lestari ◽

Melva Louisa ◽

Vivian Soetikno ◽

Averina Geffanie Suwana ◽

Putra Andito Ramadhan ◽

...

Keyword(s):

Liver Fibrosis ◽

Mechanism Of Action ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Trypan Blue Exclusion ◽

Ki 67 ◽

Activation Markers ◽

Trypan Blue Exclusion Method ◽

And Migration

Liver fibrosis is characterized by excessive accumulation of extracellular matrix in chronic liver injury. Alcohol-induced fibrosis may develop into cirrhosis, one of the major causes of liver disease mortality. Previous studies have shown that alpha mangostin can decrease ratio of pSmad/Smad and pAkt/Akt in TGF-β-induced liver fibrosis model in vitro. Further investigation of the mechanism of action of alpha mangostin in liver fibrosis model still needs to be done. The present study aimed to analyze the mechanism of action of alpha mangostin on acetaldehyde induced liver fibrosis model on TGF-β and ERK 1/2 pathways. Immortalized HSCs, LX-2 cells, were incubated with acetaldehyde, acetaldehyde with alpha mangostin (10 and 20 μM), or alpha mangostin only (10 μM). Sorafenib 10 μM was used as positive control. LX-2 viability was counted using trypan blue exclusion method. The effect of alpha mangostin on hepatic stellate cells proliferation and activation markers and its possible mechanism of action via TGF-β and ERK1/2 were studied. Acetaldehyde was shown to increase proliferation and expression of profibrogenic and migration markers on HSC, while alpha mangostin treatment resulted in a reduced proliferation and migration of HSC and decreased Ki-67 and pERK 1/2 expressions. These findings were followed with decreased expressions and concentrations of TGF-β; decreased expression of Col1A1, TIMP1, and TIMP3; increased expression of MnSOD and GPx; and reduction in intracellular reactive oxygen species. These effects were shown to be dose dependent. Therefore, we conclude that alpha mangostin inhibits hepatic stellate cells proliferation and activation through TGF-β and ERK 1/2 pathways.

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TMEM100 mediates inflammatory cytokines secretion in hepatic stellate cells and its mechanism research

Toxicology Letters ◽

10.1016/j.toxlet.2018.12.010 ◽

2019 ◽

Vol 317 ◽

pp. 82-91 ◽

Cited By ~ 1

Author(s):

Lin-xin Pan ◽

Liang-yun Li ◽

Hong Zhou ◽

Shu-qi Cheng ◽

Yu-min Liu ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Mechanism Research ◽

Cytokines Secretion

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Fibronectin and cytokines increase JNK, ERK, AP-1 activity, and transin gene expression in rat hepatic stellate cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1997.273.4.g804 ◽

1997 ◽

Vol 273 (4) ◽

pp. G804-G811 ◽

Cited By ~ 11

Author(s):

John E. Poulos ◽

Jason D. Weber ◽

Joseph M. Bellezzo ◽

Adrian M. Di Bisceglie ◽

Robert S. Britton ◽

...

Keyword(s):

Gene Expression ◽

Signal Transduction ◽

Matrix Metalloproteinase ◽

Inflammatory Cytokines ◽

Hepatic Stellate Cells ◽

Fold Increase ◽

Stellate Cells ◽

Signal Transduction Pathways ◽

Tnf Α ◽

Erk Activity

Cytokines, growth factors, and alterations in the extracellular matrix composition may play a role in maintaining hepatic stellate cells (HSC) in the activated state that is responsible for hepatic fibrogenesis. However, the signal transduction pathways that are stimulated by these factors in HSC remain to be fully elucidated. Recent evidence indicates that the mitogen-activated protein kinase (MAPK) family, including c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), plays an important role in the cellular response to stress. The aims of this study were to investigate whether fibronectin (FN) or the inflammatory cytokines interleukin-1α (IL-1α) and tumor necrosis factor-α (TNF-α) activate JNK, ERK, and AP-1 activity in HSC and induce the gene expression of the matrix metalloproteinase transin. Treatment of HSC with FN resulted in an up to 4.5-fold increase in ERK activity and a 2.1-fold increase in JNK activity. IL-1α and TNF-α produced up to a fourfold increase in JNK activity and a twofold increase in ERK activity. We then compared the effects of FN, IL-1α, and TNF-α on AP-1 activity and metalloproteinase mRNA induction. All three compounds increased AP-1 binding and promoter activity, and transin mRNA levels were increased 1.8-fold by FN, 2.2-fold by IL-1α, and 2.8-fold by TNF-α. Therefore, FN and inflammatory cytokines increase MAPK activity, stimulate AP-1 activity, and increase transin gene expression in HSC. Signal transduction pathways involving the MAPK family may play an important role in the regulation of matrix metalloproteinase expression by cytokines and FN in HSC.

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