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Protective effects of cilostazol on ethanol-induced damage in primary cultured hepatocytes

Cell Stress and Chaperones volume 23, pages 203–211 (2018)Cite this article

Abstract

Alcoholic liver disease (ALD) caused by excessive alcohol consumption is associated with oxidative stress, mitochondrial dysfunction, and hepatocellular apoptosis. Cilostazol, a licensed clinical drug used to treat intermittent claudication, has been reported to act as a protective agent in a spectrum of diseases. However, little information regarding its role in ethanol-induced hepatocellular toxicity has been reported. In the current study, we investigated the protective effects and mechanisms of cilostazol on ethanol-induced hepatocytic injury. Rat primary hepatocytes were pretreated with cilostazol prior to ethanol treatment. MTT and LDH assay indicated that ethanol-induced cell death was ameliorated by cilostazol in a dose-dependent manner. Our results display that overproduction of intracellular reactive oxygen species (ROS) and 4-hydroxy-2-nonenal (4-HNE) induced by ethanol was attenuated by pretreatment with cilostazol. Furthermore, cilostazol significantly inhibited ethanol-induced generation of ROS in mitochondria. Importantly, it was shown that cilostazol could improve mitochondrial function in primary hepatocytes by restoring the levels of ATP and mitochondrial membrane potential (MMP). Additionally, cilostazol was found to reduce apoptosis induced by ethanol using a terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Mechanistically, we found that cilostazol prevented mitochondrial pathway-mediated apoptotic signals by reversing the expression of Bax and Bcl2, the level of cleaved caspase-3, and attenuating cytochrome C release. These findings suggest the possibility of novel ALD therapies using cilostazol.

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Affiliations

  1. Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, Zhengzhou, Henan, 450052, China

    Xuhua Xie, Changyu Sun & Zujiang Yu

  2. Department of Physical Examination, The Third People’s Hospital of Henan Province, Zhengzhou, Henan, 450006, China

    Xiaopei Xu

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  1. Xuhua Xie
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  2. Xiaopei Xu
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  3. Changyu Sun
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  4. Zujiang Yu
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Correspondence to Zujiang Yu.

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Xie, X., Xu, X., Sun, C. et al. Protective effects of cilostazol on ethanol-induced damage in primary cultured hepatocytes. Cell Stress and Chaperones 23, 203–211 (2018). https://doi.org/10.1007/s12192-017-0828-3

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  • DOI: https://doi.org/10.1007/s12192-017-0828-3

Keywords

  • Alcoholic liver disease
  • Ethanol
  • Cilostazol
  • Oxidative stress
  • Mitochondria
  • Apoptosis