Oncotarget

Research Papers:

Modulation of HIF-1α and STAT3 signaling contributes to anti-angiogenic effect of YC-1 in mice with liver fibrosis

Tzung-Yan Lee _, Yann-Lii Leu and Chorng-Kai Wen

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Oncotarget. 2017; 8:86206-86216. https://doi.org/10.18632/oncotarget.21039

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Abstract

Tzung-Yan Lee1,2,*, Yann-Lii Leu3,4,* and Chorng-Kai Wen1

1Graduate Institute of Traditional Chinese Medicine, School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan

3Graduate Institute of Nature Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Tzung-Yan Lee, email: joyamen@mail.cgu.edu.tw

Keywords: YC-1, hypoxia-inducible factor-1α, angiogenesis, inflammation, fibrosis

Received: June 29, 2017     Accepted: August 16, 2017     Published: September 16, 2017

ABSTRACT

Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The aim of the study was to evaluate the mechanisms of HIF-1α inhibitor, YC-1, during bile duct ligation (BDL)-induced liver fibrosis in mice. Liver fibrosis was induced in mice, and YC-1 was then given intraperitoneally (50 mg/kg) once daily following 5 days. Liver injuries mice that were treated with YC-1 showed improved inflammatory response and diminished angiogenesis and hepatic fibrosis. YC-1 treatment inhibited liver neutrophil infiltration, while a decreased in TNF-α signaling as well as macrophage aggregation. In addition, YC-1 downregulates iNOS and COX-2 levels by inhibiting the activation of NF-κB and STAT3 phosphorylation by negative regulation the expression of SOCS1 and SOCS3 signaling. On the other hand, YC-1 decreased angiogenesis, as shown by the downregulation of hypoxia-inducible cascade genes, i.e. VEGF. YC-1 treatment resulted in a significant decrease in hepatic fibrogenesis, α-SMA abundance, and TGF-βR1 expression as well as hypoxia were assessed using VEGFR1, vWF and HIF-1α immunostaining. These results suggest that multi-targeted therapies directed against angiogenesis, hypoxia, and fibrosis. Therefore, it may be suggested that YC-1 treatment may be a novel therapeutic agent for the treatment of liver disease.


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