Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats

Wright, Matthew C.; Issa, Razao; Smart, David E.; Trim, Nathan; Murray, Graeme I.; Primrose, John; Arthur, Michael J. P.; Iredale, John P.; Mann, Derek A.

doi:10.1053/gast.2001.27188

Cited by 337 publications

(316 citation statements)

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“…Although both TNF-a and TGF-b1 are well-known activators of HSCs [1][2][3][4], and the mRNA expressions of TNF-a and TGF-b1 genes were upregulated in hepatic fibrotic rats in the present study, our current in vitro results did not suggest that HSC activation by TNF-a would result in, or was mediated through, TGF-b1 signaling pathways. Several studies showed that HSC activation is associated with elevated NFjB activity [12,13,47]. In the present study, using double staining technique, we demonstrated the co-localization of NFjB with activated HSCs (a-SMA-positive cells) in the DMN-induced fibrotic rats.…”

Section: Discussionsupporting

confidence: 68%

Anti-Fibrotic Effects of Thalidomide on Hepatic Stellate Cells and Dimethylnitrosamine-Intoxicated Rats

Chong¹,

Hsu²,

Chiu

et al. 2006

J Biomed Sci

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SummaryTumor necrosis factor-alpha (TNF-a) plays a central role in cellular necrosis, apoptosis, organ failure, tissue damage, inflammation and fibrosis. These processes, occurring in liver injury, may lead to cirrhosis. Thalidomide, a-N-phthalidoglutarimide, (C 13 H 10 N 2 ) 4 , has been shown to have immunomodulatory and anti-inflammatory properties, possibly mediated through its anti-TNF-a effect. In this study, we investigated the in vitro and in vivo effects of thalidomide on hepatic fibrosis. A cell line of rat hepatic stellate cells (HSC-T6) was stimulated with transforming growth factor-b1 (TGF-b1) or TNF-a. The inhibitory effects of thalidomide on the NFjB signaling cascade and fibrosis markers including a-smooth muscle actin (a-SMA) and collagen, were assessed. An in vivo therapeutic study was conducted in dimethylnitrosamine (DMN)-treated rats, which were randomly assigned to 1 of 4 groups: vehicle (0.7% carboxyl methyl cellulose, CMC), thalidomide (40 mg/kg), thalidomide (200 mg/kg), or silymarin (50 mg/kg), each given by gavage twice daily for 3 weeks starting after 1 week of DMN administration. Thalidomide (100-800 nM) concentration-dependently inhibited NFjB transcriptional activity induced by TNF-a, including IKKa expression and IjBa phosphorylation in HSC-T6 cells. In addition, thalidomide also suppressed TGF-b1-induced a-SMA expression and collagen deposition in HSC-T6 cells. Fibrosis scores of livers from DMNtreated rats receiving high dose of thalidomide (0.89±0.20) were significantly reduced in comparison with those of DMN-treated rats receiving vehicle (1.56±0.18). Hepatic collagen contents of DMN rats were also significantly reduced by either thalidomide or silymarin treatment. Immunohistochemical double staining results showed that a-SMA-and NFjB-positive cells were decreased in the livers from DMN rats receiving either thalidomide or silymarin treatment. In addition, real-time PCR analysis indicated that hepatic mRNA expressions of TGF-b1, a-SMA, collagen 1a2, TNF-a and iNOS genes were attenuated by thalidomide treatment. In conclusion, our results showed that thalidomide inhibited activation of HSC-T6 cells by TNF-a and ameliorated liver fibrosis in DMN-intoxicated rats.

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Section: Discussionsupporting

confidence: 68%

Anti-Fibrotic Effects of Thalidomide on Hepatic Stellate Cells and Dimethylnitrosamine-Intoxicated Rats

Chong¹,

Hsu²,

Chiu

et al. 2006

J Biomed Sci

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“…46 In vivo studies have demonstrated the ability of NF-B inhibitors such as gliotoxin, sulfasalazine, and thalidomide to promote HM apoptosis and stimulate resolution of fibrosis and regeneration of normal liver tissue. 13,46,47 Angiotensin blockade, an antifibrotic strategy currently in clinical trials, may also act by inhibiting NF-B activity. 48 It would now be of interest to determine the effects of selective and/or inducible knockout of IKK/NF-B in HMs in the context of models of inflammation-driven HCC to establish if targeting the NF-B activity of HMs will be of therapeutic benefit.…”

Section: Nf-b As a Tumor Suppressor In Hepatocytesmentioning

confidence: 99%

Nuclear factor‐κB and the hepatic inflammation‐fibrosis‐cancer axis†

2007

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Nuclear factor-B (NF-B) is a transcriptional regulator of genes involved in immunity, inflammatory response, cell fate, and function. Recent attention has focused on the pathophysiological role of NF-B in the diseased liver. In vivo studies using rodent models of liver disease and cell-targeted perturbation of NF-B activity have revealed complex and multicellular functions in hepatic inflammation, fibrosis, and the development of hepatocellular carcinoma-a process we have termed the "inflammation-fibrosis-cancer axis". This review summarizes the current state of knowledge and provides insight into the vast complexity of the hepatic NF-B signaling system, which should provide a rich source of new therapeutic targets. (HEPATOLOGY 2007;46:590-597.)

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“…For example, gliotoxin induces apoptosis of activated HSC which resulted in the resolution of liver fibrosis induced by carbon tetrachloride in experimental animals. 44 In addition, sulfasalazine has been shown to induce apoptosis of activated rat and human stellate cells in vitro, and promote accelerated recovery from carbon tetrachlorideinduced fibrosis in rats. 45 This effect was mediated through the inhibition of the inhibitor of kappaB kinases, blocking the NF B pathway.…”

Section: B1 Apoptosis Of Activated Hscsmentioning

confidence: 99%