Abstract
Pelargonidin chloride (PC) is one of the major anthocyanin found in berries, radish and other natural foods. Many natural chemopreventive compounds have been shown to be potent inducers of phase II detoxification genes and its up-regulation is important for oxidative stress related disorders. In the present study, we investigated the effect of PC in ameliorating citrinin (CTN) induced cytotoxicity and oxidative stress. The cytotoxicity of CTN was evaluated by treating HepG2 (Human hepatocellular carcinoma) cells with CTN (0–150 μM) in a dose dependent manner for 24 h, and the IC50 was determined to be 96.16 μM. CTN increased lactate dehydrogenase leakage (59%), elevated reactive oxygen species (2.5-fold), depolarized mitochondrial membrane potential as confirmed by JC-1 monomers and arrested cell cycle at G2/M phase. Further, apoptotic and necrotic analysis revealed significant changes followed by DNA damage. To overcome these toxicological effects, PC was pretreated for 2 h followed by CTN exposure for 24 h. Pretreatment with PC resulted in significant increase in cell viability (84.5%), restored membrane integrity, reactive oxygen species level were maintained and cell cycle phases were normal. PC significantly up-regulated the activity of detoxification enzymes: heme oxygenase 1 (HO-1), glutathione transferase, glutathione peroxidase, superoxide dismutase and quinone reductase. Nrf2 translocation into the nucleus was also observed by immunocytochemistry analysis. These data demonstrate the protective effect of PC against CTN-induced oxidative stress in HepG2 cells and up-regulated the activity of detoxification enzyme levels through Keap1/Nrf2 signaling pathway.
Highlights
Citrinin (CTN) is a fungal secondary metabolite first isolated from Penicillium citrinum Thom (Hetherington and Raistrick, 1931) and produced by many strains of Penicillium, Aspergillus, and Monascus (El-Banna et al, 1987; Blanc et al, 1995)
Pelargonidin chloride, 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyl-tetrazolium bromide (MTT), 2,7 -Dichlorofluorescin diacetate (DCFH2-DA), dimethyl sulfoxide (DMSO), minimum modified Eagle’s medium (MEM), hoechst 33342, propidium iodide (PI), ethidium bromide, dichlorophenol indophenol, flavin adenine dinucleotide, dicumarol, protease inhibitor cocktail, fluoroshield, RIPA buffer were purchased from Sigma–Aldrich, St
To test the cytoprotective efficacy of pelargonidin chloride, HepG2 cells were pretreated with PC for 2 h at concentrations 50 and 100 μM followed by CTN treatment for 24 h
Summary
Citrinin (CTN) is a fungal secondary metabolite first isolated from Penicillium citrinum Thom (Hetherington and Raistrick, 1931) and produced by many strains of Penicillium, Aspergillus, and Monascus (El-Banna et al, 1987; Blanc et al, 1995). CTN is a naturally occurring contaminant in food and feeds, and is classified as a group III carcinogen by The International Agency for Research on Cancer (International Agency for Research on Cancer [IARC], 1986). It has been implicated in human diseases such as “yellow rice” disease in Japan and Balkan Endemic Nephropathy (BEN) in some parts of southeastern Europe (Vrabcheva et al, 2000). CTN cytotoxicity is observed in a number of cell lines where its role in apoptosis and in activation of caspases, signaling pathways have been well established (Yu et al, 2006; Chan, 2007; Chang et al, 2009; Chen and Chan, 2009)
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