{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T20:42:05Z","timestamp":1772656925112,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T00:00:00Z","timestamp":1493337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 &gt; HCA &gt; OCA &gt; FMCA &gt; CAPPE &gt; CAPME &gt; CAPE &gt; PECA &gt; MPMCA &gt; 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-1\u03b1 (HIF-1\u03b1) 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.<\/jats:p>","DOI":"10.3390\/molecules22050702","type":"journal-article","created":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T11:57:04Z","timestamp":1493380624000},"page":"702","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Protective Effect of Caffeic Acid Derivatives on tert-Butyl Hydroperoxide-Induced Oxidative Hepato-Toxicity and Mitochondrial Dysfunction in HepG2 Cells"],"prefix":"10.3390","volume":"22","author":[{"given":"Tzung-Hsun","family":"Tsai","sequence":"first","affiliation":[{"name":"Department of Dentistry, Keelung Chang-Gung Memorial Hospital, Keelung 204, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8993-6371","authenticated-orcid":false,"given":"Chun-Hsien","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Taipei Tzu-Chi Hospital, Buddhist Tzu-Chi Medical Foundation, New Taipei City 231, Taiwan"},{"name":"Department of Pediatrics, College of Medicine, Buddhist Tzu-Chi University, Hualien 970, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Ping","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Ting","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching-Jang","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Biochemistry, and Department of Biochemical Science and Technology, National Taiwan University, Taipei 106, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5935-6755","authenticated-orcid":false,"given":"Yueh-Hsiung","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 404, Taiwan"},{"name":"Department of Biotechnology, Asia University, Taichung 413, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4681-0685","authenticated-orcid":false,"given":"Po-Jung","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1007\/s12072-009-9158-6","article-title":"Role of free radicals in liver diseases","volume":"3","author":"Muriel","year":"2009","journal-title":"Hepatol. 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