Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2 Plays a Key Role in Stellate Cell Activation and Liver Fibrogenesis In Vivo

Jiang, Joy X.; Venugopal, Senthil K.; Serizawa, Nobuko; Chen, Xiangling; Scott, Fiona L.; Li, Yong; Adamson, Roger H.; Devaraj, Sridevi; Shah, Vijay H.; Gershwin, M. Eric; Friedman, Scott L.; Török, Natalie J.

doi:10.1053/j.gastro.2010.05.074

Cited by 108 publications

(128 citation statements)

References 34 publications

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“…Ongoing hepatocyte apoptosis or necroptosis, as occurs predominantly in liver diseases characterized by enhanced oxidative and endoplasmic reticulum stress, lysosomal activation, and mitochondrial damage (ASH, NASH), is a strong trigger of fibrogenesis (16,50). Phagocytosis of apoptotic hepatocytes by myofibroblasts triggers their fibrogenic activation via NADPH oxidase 2 (NOX2) (51) and the JAK/STAT and PI3K/ Akt pathways (52). Notably, inhibition of hepatocyte apoptosis by a pan-caspase inhibitor or an antagonist of cathepsin B (a lysosomal trigger of apoptosis) ameliorated (biliary) fibrosis in mice…”

Section: Figurementioning

confidence: 99%

Evolving therapies for liver fibrosis

Schuppan

Kim²

2013

J. Clin. Invest.

542

529

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Fibrosis is an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. With protracted damage, fibrosis can progress toward excessive scarring and organ failure, as in liver cirrhosis. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development, with enormous potential but also high risks. Preclinical research has yielded numerous targets for antifibrotic agents, some of which have entered early-phase clinical studies, but progress has been hampered due to the relative lack of sensitive and specific biomarkers to measure fibrosis progression or reversal. Here we focus on antifibrotic approaches for liver that address specific cell types and functional units that orchestrate fibrotic wound healing responses and have a sound preclinical database or antifibrotic activity in early clinical trials. We also touch upon relevant clinical study endpoints, optimal study design, and developments in fibrosis imaging and biomarkers.

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Section: Figurementioning

confidence: 99%

Evolving therapies for liver fibrosis

Schuppan

Kim²

2013

J. Clin. Invest.

542

529

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“…A role for the NADPH oxidases in chronic liver diseases, such as fibrosis and viral hepatitis, related to chronic inflammation, has been proposed (9,10). In the pathogenesis of alcoholic liver steatosis, there is an increase in NADPH oxidase activity and predominance of pro-oxidant agents, exceeding the capacity of the organic antioxidant defense (8).…”

Section: Introductionmentioning

confidence: 99%

Hypercholesterolemic diet induces hepatic steatosis and alterations in mRNA expression of NADPH oxidase in rat livers

Abreu

Guerra

Pereira

et al. 2014

Arq Bras Endocrinol Metab

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Objective: This study aimed to determine whether a hypercholesterolemic diet induces hepatic steatosis, alterations in mRNA expression of NADPH oxidase subunits, and antioxidant defenses. Materials and methods: Fischer rats were divided into two groups of eight animals according to the treatment, control (C) and hypercholesterolemic diet (H). Those in group C were fed a standard diet (AIN-93M), and those of the group H were fed a hypercholesterolemic diet (25% soybean oil and 1% cholesterol). Results: The hypercholesterolemic diet did not affect body weight, but resulted in the accumulation of lipids in the liver, increased serum activities of aminotransferases and cholesterol levels. Biomarker of lipid peroxidation (TBARS) and mRNA expression of NADPH oxidase subunits p22 phox and p47 phox were increased in the liver of animals in group H. Besides, the activity and expression of antioxidant enzymes were altered. Conclusion:The results show increased mRNA expression of NADPH oxidase subunits and changes in antioxidant enzyme activities in diet-induced hepatic steatosis. Arq Bras Endocrinol Metab. 2014;58(3):251-9 Keywords Antioxidant enzymes; hepatic steatosis; hypercholesterolemic diet; NADPH oxidase; non-alcoholic fatty liver disease; oxidative stress RESUMO Objetivo: Determinar se uma dieta hipercolesterolemiante induz esteatose hepática, alterações na expressão de mRNA da NADPH oxidase e nas defesas antioxidantes. Materiais e métodos: Ratas Fischer foram divididas em dois grupos de oito animais de acordo com o tratamento recebido, controle (C) e hipercolesterolêmico (H). Aquelas do grupo C foram alimentadas com dieta padrão (AIN-93M) e as do grupo H foram alimentadas com dieta hipercolesterolemiante (25% de óleo de soja e 1% de colesterol). As dietas foram oferecidas por oito semanas. Resultados: O grupo H apresentou acúmulo de lipídios no fígado, aumento das atividades de ALT e AST e da concentração de colesterol no soro comparado ao grupo C. O marcador da peroxidação lipídica (TBARS) e os níveis de mRNA das subunidades p47 phox da NADPH-oxidase e p22 phox foram aumentados no fígado de animais do grupo H, além de alteração da atividade e expressão de enzimas antioxidantes. Conclusão: Os resultados mostram um aumento na expressão de subunidades da NADPH oxidase e alterações na atividade das enzimas antioxidantes na esteatose hepática induzida por dieta hipercolesterolemiante. Arq Bras Endocrinol Metab. 2014;58(3):251-9 Descritores Enzimas antioxidantes; esteatose hepática; dieta hipercolesterolemiante; NADPH oxidase; doença hepática gordurosa não alcoólica; estresse oxidativo

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“…The results are consistent with previous studies reporting that TGF-b increased ROS production in numerous types of nonphagocytic cells, including aortic smooth muscle cells; prostatic stromal cells; hepatic stellate cells; and cardiac, lung, and skin fibroblasts (Hecker et al, 2009;Bocchino et al, 2010;Bondi et al, 2010;Michaeloudes et al, 2011;Sampson et al, 2011;Baek et al, 2012). It has been shown that TGF-b increases the activity of NAD(P)H oxidase and the expression of Nox2 and Nox4, and that both of these two homologs of the Nox family are the ones that mainly mediate the TGFb-induced ROS accumulation (Hecker et al, 2009;Jiang et al, 2010;Crestani et al, 2011;Sampson et al, 2011). Here we also found that the mRNA and protein expression levels of Nox4 were up-regulated in corneal fibroblasts treated with TGF-b, suggesting that TGF-b may be involved in the myofibroblast differentiation of corneal fibroblasts via a pathway involving Nox4-mediated ROS generation.…”

Section: Discussionmentioning

confidence: 99%

Trichostatin A Inhibits Transforming Growth Factor-β–Induced Reactive Oxygen Species Accumulation and Myofibroblast Differentiation via Enhanced NF-E2-Related Factor 2-Antioxidant Response Element Signaling

Yang

Wang

et al. 2013

Molecular Pharmacology

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Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-b (TGF-b)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-b in the presence of TSA, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by a-smooth muscle actin (a-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H 2 O 2 , intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-b-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, TSA also decreased cellular ROS and H 2 O 2 accumulation induced by TGF-b, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-b-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling.

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Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2 Plays a Key Role in Stellate Cell Activation and Liver Fibrogenesis In Vivo

Cited by 108 publications

References 34 publications

Evolving therapies for liver fibrosis

Evolving therapies for liver fibrosis

Hypercholesterolemic diet induces hepatic steatosis and alterations in mRNA expression of NADPH oxidase in rat livers

Trichostatin A Inhibits Transforming Growth Factor-β–Induced Reactive Oxygen Species Accumulation and Myofibroblast Differentiation via Enhanced NF-E2-Related Factor 2-Antioxidant Response Element Signaling

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