Involvement of the activation of Nrf2/HO-1, p38 MAPK signaling pathways and endoplasmic reticulum stress in furazolidone induced cytotoxicity and S phase arrest in human hepatocyte L02 cells: modulation of curcumin

IF 2.8 4区医学 Q2 TOXICOLOGY

Toxicology Mechanisms and Methods Pub Date : 2017-01-08 DOI:10.1080/15376516.2016.1273424

Chongshan Dai, L. Lei, Bin Li, Yang Lin, Xilong Xiao, Shusheng Tang

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引用次数: 18

Abstract

Abstract Furazolidone (FZD) is extensively used as the antiprotozoal and antibacterial drug in clinic. The previous study has shown that curcumin pretreatment could improve FZD induced cytotoxicity by inhibiting oxidative stress and mitochondrial apoptotic pathway. The current study aimed to investigate the potential roles of endoplasmic reticulum (ER) stress, p38 mitogen-activated protein kinases (p38 MAPK) signaling pathway in curcumin against FZD cytotoxicity by using human hepatocyte L02 cells. The results showed that curcumin could markedly attenuate FZD induced cytotoxicity. Compared with FZD alone group, curcumin pretreatment significantly reduced the expression of phospho (p)-p38, cyclin D1, p-checkpoint kinase 1 (ChK1) and breast cancer associated gene 1 (BRCA1) protein, followed to attenuate S phase arrest. Meanwhile, curcumin pretreatment prevented FZD induced ER stress, evidenced by the inhibition of glucose-regulated protein 78 and DNA damage inducible gene 153/C/EBP-homologous protein (GADD153/CHOP) protein expression. Moreover, compared with the control, FZD exposure activated the protein and mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), which were further activated by curcumin treatment. These results reveal that curcumin could prevent FZD induced cytotoxicity and S phase arrest, which may involve the activation of Nrf2/HO-1 pathway and the inhibition of p38 MAPK pathway and ER stress.

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Nrf2/HO-1、p38 MAPK信号通路的激活和内质网应激参与呋喃唑酮诱导的人肝细胞L02细胞的细胞毒性和S期阻滞:姜黄素的调节

摘要呋喃唑酮（FZD）是临床上广泛应用的抗原生动物和抗菌药物。先前的研究表明，姜黄素预处理可以通过抑制氧化应激和线粒体凋亡途径来改善FZD诱导的细胞毒性。本研究旨在利用人肝细胞L02细胞研究内质网（ER）应激、p38丝裂原活化蛋白激酶（p38 MAPK）信号通路在姜黄素抗FZD细胞毒性中的潜在作用。结果表明，姜黄素能明显减弱FZD诱导的细胞毒性。与单独的FZD组相比，姜黄素预处理显著降低了磷酸（p）-p38、细胞周期蛋白D1、p检查点激酶1（ChK1）和乳腺癌症相关基因1（BRCA1）蛋白的表达，随后减轻了S期阻滞。同时，姜黄素预处理通过抑制葡萄糖调节蛋白78和DNA损伤诱导基因153/C/EBP同源蛋白（GADD153/CHOP）蛋白表达来阻止FZD诱导的ER应激。此外，与对照组相比，FZD暴露激活了核因子红系2相关因子2（Nrf2）和血红素加氧酶1（HO-1）的蛋白质和mRNA表达水平，姜黄素处理进一步激活了这些表达水平。这些结果表明，姜黄素可以阻止FZD诱导的细胞毒性和S期阻滞，这可能涉及激活Nrf2/HO-1通路、抑制p38 MAPK通路和ER应激。

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来源期刊

Toxicology Mechanisms and Methods TOXICOLOGY-

自引率

3.10%

发文量

期刊介绍： Toxicology Mechanisms and Methods is a peer-reviewed journal whose aim is twofold. Firstly, the journal contains original research on subjects dealing with the mechanisms by which foreign chemicals cause toxic tissue injury. Chemical substances of interest include industrial compounds, environmental pollutants, hazardous wastes, drugs, pesticides, and chemical warfare agents. The scope of the journal spans from molecular and cellular mechanisms of action to the consideration of mechanistic evidence in establishing regulatory policy. Secondly, the journal addresses aspects of the development, validation, and application of new and existing laboratory methods, techniques, and equipment. A variety of research methods are discussed, including: In vivo studies with standard and alternative species In vitro studies and alternative methodologies Molecular, biochemical, and cellular techniques Pharmacokinetics and pharmacodynamics Mathematical modeling and computer programs Forensic analyses Risk assessment Data collection and analysis.