Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats

Paik, Yong–Han; Kim, Jung Keun; Lee, J. I.; Kang, Seong Hee; Kim, D. Y.; An, So-Young; Lee, S. J.; Lee, D. K.; Han, Kwang Hyub; Chon, Chae Yoon; Lee, K. S.; Brenner, David A.

doi:10.1136/gut.2008.157420

Cited by 102 publications

(72 citation statements)

References 42 publications

(54 reference statements)

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“…Nonetheless, data regarding the role of COX-2 on liver fibrotic process are controversial, with reports describing both exacerbation of fibrogenesis 31 and amelioration of fibrogenesis, through the induction of celecoxib-mediated apoptosis of hepatic stellate cells. 32 Our results, however, and those of others 33 using COX-2 Tg mice clearly demonstrate that COX-2 expression did not influence liver fibrogenesis even after feeding with the MCD diet.…”

Section: Discussioncontrasting

confidence: 55%

Transgenic Mice Expressing Cyclooxygenase-2 in Hepatocytes Reveal a Minor Contribution of This Enzyme to Chemical Hepatocarcinogenesis

Llorente

Mayoral

Flores

et al. 2011

The American Journal of Pathology

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Section: Discussioncontrasting

confidence: 55%

Transgenic Mice Expressing Cyclooxygenase-2 in Hepatocytes Reveal a Minor Contribution of This Enzyme to Chemical Hepatocarcinogenesis

Llorente

Mayoral

Flores

et al. 2011

The American Journal of Pathology

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“…Still, in contrast to the results here, Paik et al (2009) concluded that celecoxib was a good anti-fibrotic agent in that it exerted a pro-apoptotic effect on HSC in TAA-treated rats. Similarly, Wen et al (2014) reported celecoxib could ameliorate hepatic fibrosis and cirrhosis through a down-regulation of PGE 2 in hepatic tissues.…”

Section: Discussioncontrasting

confidence: 55%

Rebamipide retards CCl₄-induced hepatic fibrosis in rats: Possible role for PGE₂

Zakaria

El‐Sisi

2016

Journal of Immunotoxicology

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Prostaglandin E 2 (PGE 2 ) is a potent physiological suppressor of liver fibrosis. Because the anti-ulcer drug rebamipide can induce the formation of endogenous PGE 2 , this study investigated the potential effects of rebamipide on development of a hepatic fibrosis that was inducible by carbon tetrachloride (CCl 4 ). Groups of Wistar rats received intraperitoneal (IP) injections of CCl 4 (0.45 ml/kg [0.72 g CCl 4 /kg]) over the course of for 4 weeks. Sub-sets of CCl 4 -treated rats were also treated concurrently with rebamipide at 60 or 100 mg/kg. At 24 h after the final treatments, liver function and oxidative stress were indirectly assessed. The extent of hepatic fibrosis was evaluated using two fibrotic markers, hyaluronic acid (HA) and pro-collagen-III (Procol-III); isolated liver tissues underwent histology and were evaluated for interleukin (IL)-10 and PGE 2 content. The results indicated that treatment with rebamipide significantly inhibited CCl 4 -induced increases in serum ALT and AST and also reduced oxidative stress induced by CCl 4 . Fibrotic marker assays revealed that either dose of rebamipide decreased the host levels of Procol-III and HA that had become elevated due to the CCl 4 . At the higher dose tested, rebamipide appeared to be able to permit the hosts to have a normal liver histology and to minimize any CCl 4 -induced collagen precipitation in the liver. Lastly, the use of rebamipide was seen to be associated with significant increases in liver levels of both PGE 2 and the anti-inflammatory cytokine IL-10. Based on these findings, it is concluded that rebamipide can retard hepatic fibrosis induced by CCl 4 and that this effect may, in part, be mediated by an induction of PGE 2 and IL-10 in the liver itself. ARTICLE HISTORY

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“…COX-2 is expressed only at low levels in normal hepatocytes, whereas it is markedly increased in chronic hepatitis and liver cirrhosis (3,4). It has been reported that the selective inhibitor of COX-2, celecoxib (20 mg/kg/day), reduced hepatic fibrosis in both CCl4-, BDL-and TAA-treated rats (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Celecoxib attenuates liver steatosis and inflammation in non-alcoholic steatohepatitis induced by high-fat diet in rats

et al. 2011

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Abstract. Cyclooxygenase-2 (COX-2) is involved in the process of non-alcoholic steatohepatitis (NASH). However, the role of the COX-2 inhibitor in NASH has not yet been elucidated. Therefore, in the present sudy, we investigated the role of celecoxib in a rat model of NASH induced by a high-fat diet (HFD). Wistar rats were administered HFD by gavage, and rats administered normal saline by gavage served as the controls. After 4 weeks of HFD feeding, the rats were treated with celecoxib (20 mg/kg/day) or placebo for 4 weeks. At the end of 4 and 8 weeks, histological changes in the livers of the rats were analyzed using hematoxylin and eosin; blood was collected to detect biochemical indicators (serum aminotransferase and triglyceride). Liver triglyceride content was measured using the triglyceride E-test kit. The liver expression of COX-2, nuclear factor-κ enhancer binding protein (NF-κB) subunits p50 and p65 was measured by real-time reverse transcription-polymerase chain reaction and/or Western blotting. Infiltration of steatosis and inflammation in cells was observed in the livers after 4 weeks of HFD administration, and marked steatosis and inflammation was induced after 8 weeks. These histological changes were significantly attenuated after celecoxib treatment. Reduced serum alanine aminotransferase and triglyceride (TG) levels and TG content in the liver were observed in the HFD rats that received celecoxib. Moreover, celecoxib suppressed hepatic COX-2 messenger RNA and protein expression. The NF-κB subunit p50 and p65 protein levels in the HFD rats were also attenuated after celecoxib treatment. The results indicate that the induction of COX-2 occurs in association with NF-κB activation in HFD-induced NASH rats. Celecoxib may protect against the development of steatohepatitis induced by HFD.

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Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats

Abstract: Celecoxib shows a proapoptotic effect on HSCs through Akt inactivation and shows antifibrogenic effects in BDL- and TAA-treated rats, suggesting celecoxib as a novel antifibrotic agent of hepatic fibrosis.

Cited by 102 publications

References 42 publications

Transgenic Mice Expressing Cyclooxygenase-2 in Hepatocytes Reveal a Minor Contribution of This Enzyme to Chemical Hepatocarcinogenesis

Transgenic Mice Expressing Cyclooxygenase-2 in Hepatocytes Reveal a Minor Contribution of This Enzyme to Chemical Hepatocarcinogenesis

Rebamipide retards CCl₄-induced hepatic fibrosis in rats: Possible role for PGE₂

Celecoxib attenuates liver steatosis and inflammation in non-alcoholic steatohepatitis induced by high-fat diet in rats

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Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats

Abstract: Celecoxib shows a proapoptotic effect on HSCs through Akt inactivation and shows antifibrogenic effects in BDL- and TAA-treated rats, suggesting celecoxib as a novel antifibrotic agent of hepatic fibrosis.

Cited by 102 publications

References 42 publications

Transgenic Mice Expressing Cyclooxygenase-2 in Hepatocytes Reveal a Minor Contribution of This Enzyme to Chemical Hepatocarcinogenesis

Transgenic Mice Expressing Cyclooxygenase-2 in Hepatocytes Reveal a Minor Contribution of This Enzyme to Chemical Hepatocarcinogenesis

Rebamipide retards CCl4-induced hepatic fibrosis in rats: Possible role for PGE2

Celecoxib attenuates liver steatosis and inflammation in non-alcoholic steatohepatitis induced by high-fat diet in rats

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Rebamipide retards CCl₄-induced hepatic fibrosis in rats: Possible role for PGE₂