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Acetaminophen Responsive miR-19b Modulates SIRT1/Nrf2 Signaling Pathway in Drug-Induced Hepatotoxicity

32 Pages Posted: 3 Oct 2018

See all articles by Xing Liu

Xing Liu

China Three Gorges University (CTGU) - College of Medical Science; China Three Gorges University (CTGU) - The Institute of Infection and Inflammation

Hongqian Zhao

China Three Gorges University (CTGU) - College of Medical Science; China Three Gorges University (CTGU) - The Institute of Infection and Inflammation

Chunyan Luo

China Three Gorges University (CTGU) - College of Medical Science; China Three Gorges University (CTGU) - The Institute of Infection and Inflammation

Debin Du

China Three Gorges University (CTGU) - Third Teaching Hospital of Clinical Medicine (Gezhouba Central Hospital); China Three Gorges University (CTGU) - The Institute of Infection and Inflammation

Jinlong Huang

China Three Gorges University (CTGU) - College of Medical Science; China Three Gorges University (CTGU) - The Institute of Infection and Inflammation

Quan Ming

China Three Gorges University (CTGU) - The Institute of Infection and Inflammation; China Three Gorges University (CTGU) - Third Teaching Hospital of Clinical Medicine (Gezhouba Central Hospital)

Fen Jin

China Three Gorges University (CTGU) - College of Medical Science; China Three Gorges University (CTGU) - The Institute of Infection and Inflammation

Decheng Wang

China Three Gorges University (CTGU) - College of Medical Science; China Three Gorges University (CTGU) - The Institute of Infection and Inflammation; China Three Gorges University (CTGU) - Third Teaching Hospital of Clinical Medicine (Gezhouba Central Hospital)

Weifeng Huang

China Three Gorges University (CTGU) - College of Medical Science; China Three Gorges University (CTGU) - The Institute of Infection and Inflammation; China Three Gorges University (CTGU) - Third Teaching Hospital of Clinical Medicine (Gezhouba Central Hospital)

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Abstract

Previous studies suggest that activation of SIRT1 protects against acetaminophen (APAP)-induced liver injury, however, the underlying mechanism of SIRT1 modulation is still incompletely. This study was to investigate the pathophysiological role of SIRT1 in APAP-mediated hepatotoxicity. We found that SIRT1 expression were markedly  upregulated in hepatocytes after APAP treatment. Knockdown SIRT1 expression exacerbated APAP-induced oxidative stress and liver injury, which was accompanied by the reduced expression of Nrf2 and subsequent downregulation of several  antioxidant genes. Intriguingly, SRT1720, the specific SIRT1 activator, reversed APAP induced hepatic liver injury. Furthermore, the APAP-responsive decrease of miR-19b is  an obligatory step for the induction of SIRT1. Moreover, hepatic miR-19b overexpression worsened the APAP-hepatotoxicity in mice livers. Together, our results  supports the notion that the elevation of SIRT1 by APAP responsive miR-19b may represent a compensatory mechanism to protect against the drug-induced hepatotoxicity, at least in part by enhancing Nrf2-mediated antioxidant capacity in the  liver.

Funding: This work was supported by National Natural Science Foundation of China (Grant No. 81100281 to W.H; Grant Nos 31772709 and 31572485 to D.W), Medical and Health Research Project from Yichang Science and Technology Bureau (No. A15301-35 to W. H), the new faculty startup research fund of China Three Gorges University (Grant No.KJ2014B023 to D.W).

Declaration of Interest: The authors declare no conflict of interest.

Ethical Approval: Animal experiment was approved by the Animal Care and Use Committee of China Three Gorges University (2016090A).

Keywords: SIRT1; APAP; Hepatotoxicity; Oxidative stress; miR-19b; Nrf2

Suggested Citation

Liu, Xing and Zhao, Hongqian and Luo, Chunyan and Du, Debin and Huang, Jinlong and Ming, Quan and Jin, Fen and Wang, Decheng and Huang, Weifeng, Acetaminophen Responsive miR-19b Modulates SIRT1/Nrf2 Signaling Pathway in Drug-Induced Hepatotoxicity (August 31, 2018). Available at SSRN: https://ssrn.com/abstract=3244825

Xing Liu (Contact Author)

China Three Gorges University (CTGU) - College of Medical Science

Yichang
China

China Three Gorges University (CTGU) - The Institute of Infection and Inflammation

China

Hongqian Zhao

China Three Gorges University (CTGU) - College of Medical Science

Yichang
China

China Three Gorges University (CTGU) - The Institute of Infection and Inflammation

China

Chunyan Luo

China Three Gorges University (CTGU) - College of Medical Science

Yichang
China

China Three Gorges University (CTGU) - The Institute of Infection and Inflammation

China

Debin Du

China Three Gorges University (CTGU) - Third Teaching Hospital of Clinical Medicine (Gezhouba Central Hospital)

China

China Three Gorges University (CTGU) - The Institute of Infection and Inflammation

China

Jinlong Huang

China Three Gorges University (CTGU) - College of Medical Science

Yichang
China

China Three Gorges University (CTGU) - The Institute of Infection and Inflammation

China

Quan Ming

China Three Gorges University (CTGU) - The Institute of Infection and Inflammation

China

China Three Gorges University (CTGU) - Third Teaching Hospital of Clinical Medicine (Gezhouba Central Hospital)

China

Fen Jin

China Three Gorges University (CTGU) - College of Medical Science

Yichang
China

China Three Gorges University (CTGU) - The Institute of Infection and Inflammation

China

Decheng Wang

China Three Gorges University (CTGU) - College of Medical Science ( email )

Yichang
China

China Three Gorges University (CTGU) - The Institute of Infection and Inflammation ( email )

China

China Three Gorges University (CTGU) - Third Teaching Hospital of Clinical Medicine (Gezhouba Central Hospital) ( email )

China

Weifeng Huang

China Three Gorges University (CTGU) - College of Medical Science ( email )

Yichang
China

China Three Gorges University (CTGU) - The Institute of Infection and Inflammation ( email )

China

China Three Gorges University (CTGU) - Third Teaching Hospital of Clinical Medicine (Gezhouba Central Hospital) ( email )

China

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