Oxidative stress, KLF6 and transforming growth factor-β up-regulation differentiate non-alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats

ABSTRACT Viral hepatitis-induced oxidative stress accompanied by increased levels of transforming growth factor β (TGF-β) and hepatic fibrosis are hallmarks of hepatitis C virus (HCV) infection. The mechanisms of redox regulation in the pathogenesis of HCV-induced liver disease are not clearly understood. The results of our current studies suggest that reactive oxygen species (ROS) derived from Nox4, a member of the NADPH oxidase (Nox) family, could play a role in HCV-induced liver disease. We found that the expression of HCV (genotype 1a) cDNA constructs (full-length and subgenomic), core protein alone, viral RNA, or replicating HCV (JFH-AM2) induced Nox4 mRNA expression and ROS generation in human hepatocyte cell lines (Huh-7, Huh-7.5, HepG2, and CHL). Conversely, hepatocytes expressing Nox4 short hairpin RNA (shRNA) or an inactive dominant negative form of Nox4 showed decreased ROS production when cells were transfected with HCV. The promoters of both human and murine Nox4 were used to demonstrate transcriptional regulation of Nox4 mRNA by HCV, and a luciferase reporter tied to an ∼2-kb promoter region of Nox4 identified HCV-responsive regulatory regions modulating the expression of Nox4. Furthermore, the human Nox4 promoter was responsive to TGF-β1, and the HCV core-dependent induction of Nox4 was blocked by antibody against TGF-β or the expression of dominant negative TGF-β receptor type II. These findings identified HCV as a regulator of Nox4 gene expression and subsequent ROS production through an autocrine TGF-β-dependent mechanism. Collectively, these data provide evidence that HCV-induced Nox4 contributes to ROS production and may be related to HCV-induced liver disease.

Download Full-text

Transforming Growth Factor-β and Oxidative Stress in Cancer: A Crosstalk in Driving Tumor Transformation

Cancers ◽

10.3390/cancers13123093 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3093

Author(s):

Valeria Ramundo ◽

Giuliana Giribaldi ◽

Elisabetta Aldieri

Keyword(s):

Oxidative Stress ◽

Growth Factor ◽

Cancer Cell ◽

Transforming Growth Factor ◽

Cell Metabolism ◽

Transforming Growth Factor Β ◽

Ros Production ◽

Redox Imbalance ◽

Cancer Cell Metabolism ◽

And Oxidative Stress

Cancer metabolism involves different changes at a cellular level, and altered metabolic pathways have been demonstrated to be heavily involved in tumorigenesis and invasiveness. A crucial role for oxidative stress in cancer initiation and progression has been demonstrated; redox imbalance, due to aberrant reactive oxygen species (ROS) production or deregulated efficacy of antioxidant systems (superoxide dismutase, catalase, GSH), contributes to tumor initiation and progression of several types of cancer. ROS may modulate cancer cell metabolism by acting as secondary messengers in the signaling pathways (NF-kB, HIF-1α) involved in cellular proliferation and metastasis. It is known that ROS mediate many of the effects of transforming growth factor β (TGF-β), a key cytokine central in tumorigenesis and cancer progression, which in turn can modulate ROS production and the related antioxidant system activity. Thus, ROS synergize with TGF-β in cancer cell metabolism by increasing the redox imbalance in cancer cells and by inducing the epithelial mesenchymal transition (EMT), a crucial event associated with tumor invasiveness and metastases. Taken as a whole, this review is addressed to better understanding this crosstalk between TGF-β and oxidative stress in cancer cell metabolism, in the attempt to improve the pharmacological and therapeutic approach against cancer.

Download Full-text

Melamine Induces Human Renal Proximal Tubular Cell Injury via Transforming Growth Factor-β and Oxidative Stress

Toxicological Sciences ◽

10.1093/toxsci/kfs231 ◽

2012 ◽

Vol 130 (1) ◽

pp. 17-32 ◽

Cited By ~ 35

Author(s):

Tusty-Jiuan Hsieh ◽

Pei-Chen Hsieh ◽

Yi-Hong Tsai ◽

Chia-Fang Wu ◽

Chia-Chu Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Growth Factor ◽

Cell Injury ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Proximal Tubular Cell ◽

Renal Proximal Tubular Cell ◽

Proximal Tubular ◽

Renal Proximal Tubular ◽

And Oxidative Stress

Download Full-text

Glutathione Levels Discriminate between Oxidative Stress and Transforming Growth Factor-β Signaling in Activated Rat Hepatic Stellate Cells

Journal of Biological Chemistry ◽

10.1074/jbc.274.48.33881 ◽

1999 ◽

Vol 274 (48) ◽

pp. 33881-33887 ◽

Cited By ~ 111

Author(s):

Pieter J. De Bleser ◽

Guoxiong Xu ◽

Krista Rombouts ◽

Vera Rogiers ◽

Albert Geerts

Keyword(s):

Oxidative Stress ◽

Growth Factor ◽

Hepatic Stellate Cells ◽

Transforming Growth Factor ◽

Stellate Cells ◽

Transforming Growth Factor Β

Download Full-text

Chymase as a Possible Therapeutic Target for Amelioration of Non-Alcoholic Steatohepatitis

International Journal of Molecular Sciences ◽

10.3390/ijms21207543 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7543

Author(s):

Shinji Takai ◽

Denan Jin

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

Growth Factor ◽

Mast Cells ◽

Matrix Metalloproteinase ◽

Therapeutic Target ◽

Transforming Growth Factor ◽

Inflammatory Cells ◽

Alcoholic Steatohepatitis ◽

Chymase Inhibitor

The development and progression of non-alcoholic steatohepatitis (NASH) are linked to oxidative stress, inflammation, and fibrosis of the liver. Chymase, a chymotrypsin-like enzyme produced in mast cells, has various enzymatic actions. These actions include activation of angiotensin II, matrix metalloproteinase (MMP)-9, and transforming growth factor (TGF)-β, which are associated with oxidative stress, inflammation, and fibrosis, respectively. Augmentation of chymase activity in the liver has been reported in various NASH models. Generation of hepatic angiotensin II and related oxidative stress is upregulated in NASH but attenuated by treatment with a chymase inhibitor. Additionally, increases in MMP-9 and accumulation of inflammatory cells are observed in NASH but are decreased by chymase inhibitor administration. TGF-β and collagen I upregulation in NASH is also attenuated by chymase inhibition. These results in experimental NASH models demonstrate that a chymase inhibitor can effectively ameliorate NASH via the reduction of oxidative stress, inflammation, and fibrosis. Thus, chymase may be a therapeutic target for amelioration of NASH.

Download Full-text