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Apoptotic effects of rhein through the mitochondrial pathways, two death receptor pathways, and reducing autophagy in human liver L02 cells.
- Source :
-
Environmental toxicology [Environ Toxicol] 2019 Dec; Vol. 34 (12), pp. 1292-1302. Date of Electronic Publication: 2019 Aug 21. - Publication Year :
- 2019
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Abstract
- Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid) is a major component of many medicinal herbs such as Rheum palmatum L. and Polygonum multiflorum. Despite being widely used, intoxication cases associated with rhein-containing herbs are often reported. Currently, there are no available reports addressing the effects of rhein on apoptosis in human liver L02 cells. Thus, the aim of this study is to determine the cytotoxic effects and the underlying mechanism of rhein on human normal liver L02 cells. In the present study, the methyl thiazolyl tetrazolium assay demonstrated that rhein decreased the viability of L02 cells in dose-dependent and time-dependent ways. Rhein was found to trigger apoptosis in L02 cells as shown by Annexin V-fluoresceine isothiocyanate (FITC) apoptosis detection kit and cell mitochondrial membrane potential (MMP) assay, with nuclear morphological changes demonstrated by Hoechst 33258 staining. Detection of intracellular superoxide dismutase activity, lipid oxidation (malondialdehyde) content, and reactive oxygen species (ROS) levels showed that apoptosis was associated with oxidative stress. Moreover, it was observed that the mechanism implicated in rhein-induced apoptosis was presumably via the death receptor pathway and the mitochondrial pathway, as illustrated by upregulation of TNF-α, TNFR1, TRADD, and cleaved caspase-3, and downregulation of procaspase-8, and it is suggested that rhein may increase hepatocyte apoptosis by activating the increase of TNF-α level. Meanwhile, rhein upregulates the expression of Bax and downregulates the expression of procaspase-9 and -3, and it is suggested that the mitochondrial pathway is activated and rhein-induced apoptosis may be involved. In addition, we also want to explore whether rhein-induced apoptosis is related to the autophagic changes induced by rhein. The results showed that rhein treatment increased P62 and decreased LC3-II and beclin-1, which means that autophagy was weakened. The results of our studies indicated that rhein induced caspase-dependent apoptosis via both the Fas death pathway and the mitochondrial pathway by generating ROS, and meanwhile the autophagy tended to weaken.<br /> (© 2019 Wiley Periodicals, Inc.)
- Subjects :
- Caspase 3 metabolism
Cells, Cultured
Gene Expression Regulation drug effects
Hepatocytes cytology
Hepatocytes metabolism
Humans
Membrane Potential, Mitochondrial drug effects
Mitochondria metabolism
Oxidative Stress drug effects
Reactive Oxygen Species metabolism
Rheum chemistry
Rheum metabolism
Superoxide Dismutase metabolism
Anthraquinones toxicity
Apoptosis drug effects
Autophagy drug effects
Death Domain Receptor Signaling Adaptor Proteins metabolism
Mitochondria drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1522-7278
- Volume :
- 34
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Environmental toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 31436023
- Full Text :
- https://doi.org/10.1002/tox.22830