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Open AccessArticle

Triggering Apoptotic Death of Human Epidermal Keratinocytes by Malic Acid: Involvement of Endoplasmic Reticulum Stress- and Mitochondria-Dependent Signaling Pathways

1
Institute of Medicine, Chung Shan Medical University, 402 Taichung, Taiwan
2
Department of Dermatology, Chung Shan Medical University Hospital, 402 Taichung, Taiwan
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Department of Biochemistry and Molecular Biology, National Yang-Ming University, 112 Taipei, Taiwan
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Department of Pathology, Chung Shan Medical University Hospital, 402 Taichung, Taiwan
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Department of Dermatology, Buddhist Tzu Chi General Hospital, 907 Hualien, Taiwan
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School of Medicine, Tzu Chi University, 907 Hualien, Taiwan
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School of Biological Science and Biotechnology, China Medical University, 404 Taichung, Taiwan
*
Author to whom correspondence should be addressed.
Academic Editor: Florian Lang
Toxins 2015, 7(1), 81-96; https://doi.org/10.3390/toxins7010081
Received: 9 September 2014 / Accepted: 26 December 2014 / Published: 9 January 2015
(This article belongs to the Special Issue Plant Toxins)
Malic acid (MA) has been commonly used in cosmetic products, but the safety reports in skin are sparse. To investigate the biological effects of MA in human skin keratinocytes, we investigated the potential cytotoxicity and apoptotic effects of MA in human keratinocyte cell lines (HaCaT). The data showed that MA induced apoptosis based on the observations of DAPI staining, DNA fragmentation, and sub-G1 phase in HaCaT cells and normal human epidermal keratinocytes (NHEKs). Flow cytometric assays also showed that MA increased the production of mitochondrial superoxide (mito-SOX) but decreased the mitochondrial membrane potential. Analysis of bioenergetics function with the XF 24 analyzer Seahorse extracellular flux analyzer demonstrated that oxygen consumption rate (OCR) was significantly decreased whereas extracellular acidification rate (ECAR) was increased in MA-treated keratinocytes. The occurrence of apoptosis was proved by the increased expressions of FasL, Fas, Bax, Bid, caspases-3, -8, -9, cytochrome c, and the declined expressions of Bcl-2, PARP. MA also induced endoplasmic reticulum stress associated protein expression such as GRP78, GADD153, and ATF6α. We demonstrated that MA had anti-proliferative effect in HaCaT cell through the inhibition of cell cycle progression at G0/G1, and the induction of programmed cell death through endoplasmic reticulum stress- and mitochondria-dependent pathways. View Full-Text
Keywords: malic acid (MA); HaCaT cells; seahorse XF 24 analyzer; apoptosis malic acid (MA); HaCaT cells; seahorse XF 24 analyzer; apoptosis
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MDPI and ACS Style

Hsiao, Y.-P.; Lai, W.-W.; Wu, S.-B.; Tsai, C.-H.; Tang, S.-C.; Chung, J.-G.; Yang, J.-H. Triggering Apoptotic Death of Human Epidermal Keratinocytes by Malic Acid: Involvement of Endoplasmic Reticulum Stress- and Mitochondria-Dependent Signaling Pathways. Toxins 2015, 7, 81-96.

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