Protective effect of Sulforaphane against Arsenic-induced hepatotoxicity in rats: Role of PI3K/Akt-mediated Nrf2 signaling pathway

A redox imbalance disrupts the cellcycle and the proliferation process, and contributes to the initiation of programmed cell death. One of the pathways that are important for redox homeostasis is the Nrf2-ARE signaling pathway. Fluoride as well as static magnetic fields (SMF) are associated with the concepts of oxidative stress, and thus programmed cell death. Therefore, this study aimed to assess the connection between oxidative stress and apoptosis in human cells co-exposed to fluoride and a SMF with a different magnetic induction and to determine whether the Nrf2-signaling pathway is involved in these effects. The research was realized using normal human dermal fibroblasts that had been co-exposed to fluoride (0.3 mmol/L) and a SMF with a different magnetic induction (0.45 T, 0.55 T, 0.65 T) for 12 h. The mRNA levels of the cellular antioxidant system-related genes and apoptosis-related genes were assessed using the quantitative reverse transcription polymerase chain reaction (RT-qPCR) method. Our results indicated that the increased activity of antioxidant enzymes (SOD1 (superoxide dismutase 1), SOD2 and GSR (glutathione reductase)) suggests the restoration of the cell redox homeostasis that had been disturbed by fluoride, and also that the genes whose expression is associated with the induction of apoptosis are down regulated as a result of exposure to a SMF. The SMF with a 0.65 T flux density had the strongest effect on the fibroblasts. Moreover, our findings demonstrated that the Nrf2 transcription factor plays a crucial role in the protective effect of a SMF against fluoride toxicity in human cells. The results of these studies can form the basis for developing therapeutic strategies for apoptosis and oxidative stress-related diseases.

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l-carnitine protects human hepatocytes from oxidative stress-induced toxicity through Akt-mediated activation of Nrf2 signaling pathway

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2015-0305 ◽

2016 ◽

Vol 94 (5) ◽

pp. 517-525 ◽

Cited By ~ 9

Author(s):

Jinlian Li ◽

Yanli Zhang ◽

Haiyun Luan ◽

Xuehong Chen ◽

Yantao Han ◽

...

Keyword(s):

Protective Effect ◽

Signaling Pathway ◽

Nuclear Translocation ◽

Cell Damage ◽

Binding Activity ◽

Akt Pathway ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Akt Inhibitor ◽

Nrf2 Signaling Pathway

In our previous study, l-carnitine was shown to have cytoprotective effect against hydrogen peroxide (H2O2)-induced injury in human normal HL7702 hepatocytes. The aim of this study was to investigate whether the protective effect of l-carnitine was associated with the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) pathway. Our results showed that pretreatment with l-carnitine augmented Nrf2 nuclear translocation, DNA binding activity and heme oxygenase-1 (HO-1) expression in H2O2-treated HL7702 cells, although l-carnitine treatment alone had no effect on them. Analysis using Nrf2 siRNA demonstrated that Nrf2 activation was involved in l-carnitine-induced HO-1 expression. In addition, l-carnitine-mediated protection against H2O2 toxicity was abrogated by Nrf2 siRNA, indicating the important role of Nrf2 in l-carnitine-induced cytoprotection. Further experiments revealed that l-carnitine pretreatment enhanced the phosphorylation of Akt in H2O2-treated cells. Blocking Akt pathway with inhibitor partly abrogated the protective effect of l-carnitine. Moreover, our finding demonstrated that the induction of Nrf2 translocation and HO-1 expression by l-carnitine directly correlated with the Akt pathway because Akt inhibitor showed inhibitory effects on the Nrf2 translocation and HO-1 expression. Altogether, these results demonstrate that l-carnitine protects HL7702 cells against H2O2-induced cell damage through Akt-mediated activation of Nrf2 signaling pathway.

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Protective effect of N-acetylcysteine (NAC) on renal ischemia/reperfusion injury through Nrf2 signaling pathway

Journal of Receptors and Signal Transduction ◽

10.3109/10799893.2014.908916 ◽

2014 ◽

Vol 34 (5) ◽

pp. 396-400 ◽

Cited By ~ 35

Author(s):

Liyuan Zhang ◽

Zhenhong Zhu ◽

Jianhua Liu ◽

Zhengqiu Zhu ◽

Zhao Hu

Keyword(s):

Protective Effect ◽

Reperfusion Injury ◽

Signaling Pathway ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Nrf2 Signaling Pathway ◽

Renal Ischemia Reperfusion Injury

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GSTZ1 deficiency promotes hepatocellular carcinoma proliferation via activation of the KEAP1/NRF2 pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1459-6 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 3

Author(s):

Jingjing Li ◽

Qiujie Wang ◽

Yi Yang ◽

Chong Lei ◽

Fan Yang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Aerobic Glycolysis ◽

Hepatoma Cell ◽

Related Factor ◽

Promising Therapeutic Approach ◽

Nrf2 Signaling Pathway ◽

Hcc Cells

Abstract Background Glutathione S-transferase zeta 1 (GSTZ1) is the penultimate enzyme in phenylalanine/tyrosine catabolism. GSTZ1 is dysregulated in cancers; however, its role in tumorigenesis and progression of hepatocellular carcinoma (HCC) is largely unknown. We aimed to assess the role of GSTZ1 in HCC and to reveal the underlying mechanisms, which may contribute to finding a potential therapeutic strategy against HCC. Methods We first analyzed GSTZ1 expression levels in paired human HCC and adjacent normal tissue specimens and the prognostic effect of GSTZ1 on HCC patients. Thereafter, we evaluated the role of GSTZ1 in aerobic glycolysis in HCC cells on the basis of the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Furthermore, we assessed the effect of GSTZ1 on HCC proliferation, glutathione (GSH) concentration, levels of reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (NRF2) signaling via gain- and loss- of GSTZ1 function in vitro. Moreover, we investigated the effect of GSTZ1 on diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) induced hepatocarcinogenesis in a mouse model of HCC. Results GSTZ1 was downregulated in HCC, thus indicating a poor prognosis. GSTZ1 deficiency significantly promoted hepatoma cell proliferation and aerobic glycolysis in HCC cells. Moreover, loss of GSTZ1 function depleted GSH, increased ROS levels, and enhanced lipid peroxidation, thus activating the NRF2-mediated antioxidant pathway. Furthermore, Gstz1 knockout in mice promoted DEN/CCl4-induced hepatocarcinogenesis via activation of the NRF2 signaling pathway. Furthermore, the antioxidant agent N-acetylcysteine and NRF2 inhibitor brusatol effectively suppressed the growth of Gstz1-knockout HepG2 cells and HCC progression in Gstz1−/− mice. Conclusions GSTZ1 serves as a tumor suppressor in HCC. GSH depletion caused by GSTZ1 deficiency elevates oxidative stress, thus constitutively activating the NRF2 antioxidant response pathway and accelerating HCC progression. Targeting the NRF2 signaling pathway may be a promising therapeutic approach for this subset of HCC.

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Phytochemicals protect L02 cells against hepatotoxicity induced by emodin via the Nrf2 signaling pathway

Toxicology Research ◽

10.1039/c9tx00220k ◽

2019 ◽

Vol 8 (6) ◽

pp. 1028-1034

Author(s):

Yan Yan ◽

Kang Wang ◽

Xu Tang ◽

Jun-feng Gao ◽

Bin-yu Wen

Keyword(s):

Bile Acid ◽

Protein Expression ◽

Protective Effect ◽

Cell Viability ◽

Signaling Pathway ◽

Pharmaceutical Preparations ◽

Related Factor ◽

Dependent Manner ◽

Nrf2 Signaling Pathway ◽

L02 Cells

Abstract Dihydromyricetin (DMY), hyperoside and silybin are phytochemicals that belong to a class called flavonoids, and they have been used in liver protection pharmaceutical preparations, but the specific mechanism of these chemicals is still unclarified. This study aims to investigate the hepatoprotective effects and potential mechanism of these phytochemicals. The immortalized human hepatocyte cell line L02 was treated with 200 μM emodin for 48 h, and this was used as a hepatocyte injury model. The L02 cells were treated with both 200 μM emodin and different concentrations of DMY/hyperoside/silybin for 48 h to investigate the protective effects of these phytochemicals. The CCK-8 assay was used to detect cell viability. RT-qPCR and western blotting were performed to examine the mRNA and protein expression, respectively, of the classic bile acid synthetic pathway gene CYP7A1, the bile acid efflux transporter bile salt export pump (BSEP), the nuclear factor erythroid-2-related factor 2 (Nrf2) and the drug processing gene CYP1A2. DMY, hyperoside and silybin prevented the impairment of cell viability that was caused by emodin-induced hepatotoxicity in a dose-dependent manner, and at a low concentration (10 μM), the protective effect followed the order hyperoside > DMY > silybin, while at a high concentration (160 μM), the protective effect followed the order DMY > hyperoside > silybin. These phytochemicals reduced the expression of CYP7A1 at both the mRNA and protein levels. BSEP was not influenced by the phytochemical intervention. When 200 μM emodin was used for 48 h with the addition of the phytochemicals at 200 μM, the nuclear protein expression of Nrf2 significantly increased and CYP1A2 expression decreased. DMY, hyperoside and silybin prevented the hepatotoxicity induced by emodin in the L02 cells, potentially, via the Nrf2 signaling pathway.

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