Fibrosis Accelerates the Development of Enzyme–Altered Lesions in the Rat Liver

Sakaida, Isao; Hironaka, Koji; Uchida, Koichi; Suzuki, Chieko; Kayano, Kozo; Okita, Kiwamu

doi:10.1002/hep.510280512

Cited by 52 publications

(34 citation statements)

References 22 publications

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“…HCC develops in close association with fibrotic liver, [8][9][10] but the mechanisms by which development of HCC is enhanced via fibrosis have not been clarified. β1-Integrin was increased in fibrotic liver, along with α-integrin subunits.…”

Section: Huh7 Mockmentioning

confidence: 99%

“…[4][5][6] TGF-β1 is also known to participate in hepatic fibrogenesis by stimulating extracellular matrix (ECM) production in the liver, 7) and although hepatic fibrosis is associated with development of HCC, little is known about how ECM might increase the incidence of HCC. 1,[8][9][10] A balance between cell proliferation and apoptosis is critical for tissue homeostasis, and the failure of cells to undergo apoptosis could be involved in the pathogenesis of a variety of human diseases, including cancer. 11,12) Both growth factors and ECM cooperatively regulate cellular function.…”

mentioning

confidence: 99%

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Transforming growth factor‐β1‐induced apoptosis is blocked by β1‐integrin‐mediated mitogen‐activated protein kinase activation in human hepatoma cells

Zhang¹,

Ozaki²,

Mizuta³

et al. 2004

Cancer Science

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Growth factors and extracellular matrices cooperatively regulate cellular behavior. However, the interactions between transforming growth factor‐β1 (TGF‐β1) and integrins in hepatic cells are not fully understood. We investigated the effects of β1‐integrin on TGF‐β1‐regulated growth of hepatoma cells. Human hepatoma cell lines HepG2, Huh7, and Hep3B were stably transfected with β1‐integrin, and the parental, and mock‐ and β1‐integrin‐transfected hepatoma cells were treated with TGF‐β1. Modulation of apoptosis and pathways involved in the process were investigated. TGF‐β1 suppressed the growth of hepatoma cells, and apoptosis was observed in Hep3B and Huh7. Hepatoma cells transfected with β1‐integrin were protected from TGF‐β1‐induced apoptosis. Mitogen‐activated protein (MAP) kinase inhibitors, PD98059, SB203580, and SP600125, abolished this protective effect of β1‐integrin, but herbimycin A and wortmannin were ineffective. Hepatoma cells overexpressing β1‐integrin showed increased activities of MAP kinases, and TGF‐β1 induced sustained activation of MAP kinases in these cells, but only transient activation in mock‐transfected cells. These data suggest that MAP kinases activated by β1‐integrin provide a strong anti‐apoptotic signal during TGF‐β1‐induced apoptosis in human hepatoma cells. Therefore β1‐integrin‐mediated signals may contribute to the development and progression of hepatocellular carcinoma.

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Section: Huh7 Mockmentioning

confidence: 99%

mentioning

confidence: 99%

Transforming growth factor‐β1‐induced apoptosis is blocked by β1‐integrin‐mediated mitogen‐activated protein kinase activation in human hepatoma cells

Zhang¹,

Ozaki²,

Mizuta³

et al. 2004

Cancer Science

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show abstract

“…It has been reported that the risk of hepatocellular carcinoma (HCC) increases with the progression of hepatic fibrosis (14). Furthermore, the existence of fibrosis itself accelerates experimental hepatocarcinogenesis (15). Taken together, an effective therapeutic strategy for suppressing liver fibrosis should improve the overall prognosis of patients with chronic liver diseases.…”

Section: Introductionmentioning

confidence: 99%

Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-β with a combination of imatinib mesylate and ACE inhibitor in rats

Yoshiji¹,

Kuriyama²,

Noguchi³

et al. 2006

Int J Mol Med

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Abstract. Both platelet-derived growth factor (PDGF) and transforming growth factor-ß (TGF-ß) are known to be pivotal cytokines in liver fibrosis development. The aim of our current study was to elucidate the effects of dual inhibition of PDGF and TGF-ß by combination of the clinically used imatinib mesylate (STI-571) and perindopril (an ACEinhibitor; ACE-I), respectively, on ongoing liver fibrosis development in rats. The effects of STI-571 and ACE-I at clinically comparable low doses were examined in a rat model of CCl4-induced liver fibrogenesis. Treatment with both STI-571 and ACE-I inhibited liver fibrogenesis and suppressed activation of hepatic stellate cells (HSCs). Administration of both agents exerted a more potent inhibitory effect than administration of either single agent. Our in vitro study demonstrated that STI-571 and ACE-I suppressed PDGF receptor (PDGFR) phosphorylation and TGF-ß expression in activated HSCs, respectively. Dual suppression of PDGF and TGF-ß with a combination of clinically comparable low doses of STI-571 and ACE-I exerted a significant inhibitory effect on ongoing liver fibrosis development. Since both agents are widely used in clinical practice, this combination therapy may provide a new strategy against liver fibrosis in the future.

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“…The risk of HCC reportedly increases in parallel with the progression of hepatic fibrosis (31). Furthermore, the existence of fibrosis itself accelerates experimental hepatocarcinogenesis (32). Taken together, an effective therapeutic strategy for suppressing liver fibrosis should improve the overall prognosis of patients with chronic liver diseases.…”

Section: Discussionmentioning

confidence: 99%

Combination of branched-chain amino acid and angiotensin‑converting enzyme inhibitor improves liver fibrosis progression in patients with cirrhosis

et al. 2011

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Abstract. An effective therapeutic strategy for suppressing liver fibrosis should improve the overall prognosis of patients with chronic liver diseases. Although enormous efforts are ongoing to develop anti-fibrotic agents, no drugs have yet been approved as anti-fibrotic agents for humans. Insulin resistance (IR) is reportedly involved in the progression of liver fibrosis. The aim of the present study was to evaluate the effect of combination treatment with a clinically used branched-chain amino acid (BCAA) and an angiotensin-converting enzyme inhibitor (ACE-I) on several fibrotic indices in patients with liver cirrhosis under the condition of IR. BCAA granules (Livact; 12 g/day) and/or ACE-I (perindopril; 4 mg/day) were administered, and several indices were analyzed. A 48-month follow-up revealed that the combination treatment with BCAA and ACE-I markedly improved the progression of serum fibrosis markers, whereas single treatment with either BCAA or ACE-I did not exert these inhibitory effects. The plasma level of transforming growth factor-β was significantly attenuated almost in parallel with the suppression of serum fibrosis markers. Furthermore, the combined treatment with BCAA and ACE-I improved the serum albumin level and IR, which was evaluated using the homeostasis model assessment method for IR. Taken together, since both BCAA and ACE-I are widely used with safety in clinical practice, these results indicate that this combination therapy may represent a potential new future strategy against liver fibrosis development in patients with liver cirrhosis under the condition of IR.

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Fibrosis Accelerates the Development of Enzyme–Altered Lesions in the Rat Liver

Cited by 52 publications

References 22 publications

Transforming growth factor‐β1‐induced apoptosis is blocked by β1‐integrin‐mediated mitogen‐activated protein kinase activation in human hepatoma cells

Transforming growth factor‐β1‐induced apoptosis is blocked by β1‐integrin‐mediated mitogen‐activated protein kinase activation in human hepatoma cells

Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-β with a combination of imatinib mesylate and ACE inhibitor in rats

Combination of branched-chain amino acid and angiotensin‑converting enzyme inhibitor improves liver fibrosis progression in patients with cirrhosis

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