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Protective Effect of Caffeic Acid Derivatives on tert-Butyl Hydroperoxide-Induced Oxidative Hepato-Toxicity and Mitochondrial Dysfunction in HepG2 Cells

1
Department of Dentistry, Keelung Chang-Gung Memorial Hospital, Keelung 204, Taiwan
2
Department of Pediatrics, Taipei Tzu-Chi Hospital, Buddhist Tzu-Chi Medical Foundation, New Taipei City 231, Taiwan
3
Department of Pediatrics, College of Medicine, Buddhist Tzu-Chi University, Hualien 970, Taiwan
4
Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan
5
Institute of Microbiology and Biochemistry, and Department of Biochemical Science and Technology, National Taiwan University, Taipei 106, Taiwan
6
Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 404, Taiwan
7
Department of Biotechnology, Asia University, Taichung 413, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Diego Muñoz-Torrero
Molecules 2017, 22(5), 702; https://doi.org/10.3390/molecules22050702
Received: 20 February 2017 / Revised: 19 April 2017 / Accepted: 25 April 2017 / Published: 28 April 2017
(This article belongs to the Section Medicinal Chemistry)
Oxidative stress results in structural and functional abnormalities in the liver and is thought to be a crucial factor in liver diseases. The aim of this study was to investigate the cytoprotective and antioxidant effects of caffeic acid (CA) derivatives on tert-butyl hydroperoxide (t-BHP)-induced oxidative stress in HepG2 cells. Nine CA derivatives were synthesized, including N-phenylethyl caffeamide (PECA), N-(3-florophen)methyl caffeamide (FMCA), N-(4-methoxy-phen)methyl caffeamide (MPMCA), N-heptyl caffeamide (HCA), N-octyl caffeamide (OCA), octyl caffeate (CAOE), phenpropyl caffeate (CAPPE), phenethyl caffeate (CAPE), and phenmethyl caffeate (CAPME). The results showed that CA and its derivatives significantly inhibited t-BHP-induced cell death of HepG2 cells. The rank order of potency of the CA derivatives for cytoprotection was CAOE > HCA > OCA > FMCA > CAPPE > CAPME > CAPE > PECA > MPMCA > CA. Their cytoprotective activity was associated with lipophilicity. The antioxidant effect of these compounds was supported by the reduction in the levels of thiobarbituric acid reactive substrates, a biomarker of lipid peroxidation, in HepG2 cells. Pre-treatment of CA derivatives significantly prevented the depletion of glutathione, the most important water-soluble antioxidant in hepatocytes. Pre-treatment of CA derivatives before t-BHP exposure maintained mitochondrial oxygen consumption rate and ATP content in the injured HepG2 cells. CA derivatives except OCA and HCA significantly suppressed t-BHP-induced hypoxia-inducible factor-1α (HIF-1α) protein level. In addition, all of these CA derivatives markedly increased the nuclear factor erythroid 2-related factor 2 (Nrf2) accumulation in the nucleus, indicating that their cytoprotection may be mediated by the activation of Nrf2. Our results suggest that CA derivatives might be a hepatoprotective agent against oxidative stress. View Full-Text
Keywords: caffeic acid derivatives; tert-butyl hydroperoxide; antioxidant; liver protection caffeic acid derivatives; tert-butyl hydroperoxide; antioxidant; liver protection
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MDPI and ACS Style

Tsai, T.-H.; Yu, C.-H.; Chang, Y.-P.; Lin, Y.-T.; Huang, C.-J.; Kuo, Y.-H.; Tsai, P.-J. Protective Effect of Caffeic Acid Derivatives on tert-Butyl Hydroperoxide-Induced Oxidative Hepato-Toxicity and Mitochondrial Dysfunction in HepG2 Cells. Molecules 2017, 22, 702.

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