Electrophilic thymol isobutyrate from Inula nervosa Wall. (Xiaoheiyao) ameliorates steatosis in HepG2 cells via Nrf2 activation

Oxidative stress induced by reactive oxygen species is the main cause of various liver diseases. This study investigated the hepatoprotective effect of Epimedium koreanum Nakai water extract (EKE) against arachidonic acid (AA)[Formula: see text][Formula: see text][Formula: see text]iron-mediated cytotoxicity in HepG2 cells and carbon tetrachloride (CCl4-)-mediated acute liver injury in mice. Pretreatment with EKE (30 and 100[Formula: see text][Formula: see text]g/mL) significantly inhibited AA[Formula: see text][Formula: see text][Formula: see text]iron-mediated cytotoxicity in HepG2 cells by preventing changes in the expression of cleaved caspase-3 and poly(ADP-ribose) polymerase. EKE attenuated hydrogen peroxide production, glutathione depletion, and mitochondrial membrane dysfunction. EKE also increased the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), transactivated anti-oxidant response element harboring luciferase activity, and induced the expression of anti-oxidant genes. Furthermore, the cytoprotective effect of EKE against AA[Formula: see text][Formula: see text][Formula: see text]iron was blocked in Nrf2 knockout cells. Ultra-performance liquid chromatography analysis showed that EKE contained icariin, icaritin, and quercetin; icaritin and quercetin were both found to protect HepG2 cells from AA[Formula: see text][Formula: see text][Formula: see text]iron via Nrf2 activation. In a CCl4-induced mouse model of liver injury, pretreatment with EKE (300[Formula: see text]mg/kg) for four consecutive days ameliorated CCl4-mediated increases in serum aspartate aminotransferase activity, histological activity index, hepatic parenchyma degeneration, and inflammatory cell infiltration. EKE also decreased the number of nitrotyrosine-, 4-hydroxynonenal-, cleaved caspase-3-, and cleaved poly(ADP-ribose) polymerase-positive cells in hepatic tissues. These results suggest EKE is a promising candidate for the prevention or treatment of oxidative stress-related liver diseases via Nrf2 activation.

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Lipoic acid regulates glutathione, heme oxygenase gene expression and nuclear Nrf2 activation as a mechanism of protection against arsenic exposure in HepG2 cells

Toxicology Letters ◽

10.1016/j.toxlet.2008.06.657 ◽

2008 ◽

Vol 180 ◽

pp. S35

Author(s):

Selene G Huerta-Olvera ◽

José Macías-Barragán ◽

Miriam R Bueno-Topete ◽

Fernando Díaz Barriga-Martínez ◽

Agustín Luz-Madrigal ◽

...

Keyword(s):

Gene Expression ◽

Heme Oxygenase ◽

Lipoic Acid ◽

Hepg2 Cells ◽

Arsenic Exposure ◽

Nrf2 Activation

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Polymeric procyanidin fraction from defatted grape seeds protects HepG2 cells against oxidative stress by inducing phase II enzymes via Nrf2 activation

Food Science and Biotechnology ◽

10.1007/s10068-013-0105-x ◽

2013 ◽

Vol 22 (2) ◽

pp. 485-491 ◽

Cited By ~ 4

Author(s):

Younghwa Kim ◽

Youngmin Choi ◽

Hyeonmi Ham ◽

Heon-Sang Jeong ◽

Junsoo Lee

Keyword(s):

Oxidative Stress ◽

Phase Ii ◽

Hepg2 Cells ◽

Grape Seeds ◽

Phase Ii Enzymes ◽

Nrf2 Activation

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Alpha-lipoic acid regulates heme oxygenase gene expression and nuclear Nrf2 activation as a mechanism of protection against arsenic exposure in HepG2 cells

Environmental Toxicology and Pharmacology ◽

10.1016/j.etap.2009.12.004 ◽

2010 ◽

Vol 29 (2) ◽

pp. 144-149 ◽

Cited By ~ 23

Author(s):

Selene G. Huerta-Olvera ◽

José Macías-Barragán ◽

Martha E. Ramos-Márquez ◽

Juan Armendáriz-Borunda ◽

Fernando Díaz-Barriga ◽

...

Keyword(s):

Gene Expression ◽

Heme Oxygenase ◽

Lipoic Acid ◽

Hepg2 Cells ◽

Arsenic Exposure ◽

Alpha Lipoic Acid ◽

Nrf2 Activation

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The Protective Effects of Isoliquiritigenin and Glycyrrhetinic Acid against Triptolide-Induced Oxidative Stress in HepG2 Cells Involve Nrf2 Activation

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/8912184 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 16

Author(s):

Ling-Juan Cao ◽

Huan-De Li ◽

Miao Yan ◽

Zhi-Hua Li ◽

Hui Gong ◽

...

Keyword(s):

Oxidative Stress ◽

Hepg2 Cells ◽

Target Genes ◽

Biological Activities ◽

Antioxidant Response ◽

Current Data ◽

Glycyrrhetinic Acid ◽

Protective Effects ◽

Nrf2 Activation ◽

Wide Range

Triptolide (TP), an active ingredient ofTripterygium wilfordiiHook f., possesses a wide range of biological activities. Oxidative stress likely plays a role in TP-induced hepatotoxicity. Isoliquiritigenin (ISL) and glycyrrhetinic acid (GA) are potent hepatoprotection agents. The aim of the present study was to investigate whether Nrf2 pathway is associated with the protective effects of ISL and GA against TP-induced oxidative stress or not. HepG2 cells were treated with TP (50 nM) for 24 h after pretreatment with ISL and GA (5, 10, and 20 μM) for 12 h and 24 h, respectively. The results demonstrated that TP treatment significantly increased ROS levels and decreased GSH levels. Both ISL and GA pretreatment decreased ROS and meanwhile enhanced intracellular GSH content. Additionally, TP treatment obviously decreased the protein expression of Nrf2 and its target genes including HO-1 and MRP2 except NQO1. Moreover, both ISL and GA displayed activities as inducers of Nrf2 and increased the expression of HO-1, NQO1, and MRP2. Taken together the current data confirmed that ISL and GA could activate the Nrf2 antioxidant response in HepG2 cells, increasing the expression of its target genes which may be partly associated with their protective effects in TP-induced oxidative stress.

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Pachypodol, a Methoxyflavonoid Isolated from Pogostemon cablin Bentham Exerts Antioxidant and Cytoprotective Effects in HepG2 Cells: Possible Role of ERK-Dependent Nrf2 Activation

International Journal of Molecular Sciences ◽

10.3390/ijms20174082 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4082 ◽

Cited By ~ 3

Author(s):

Eun Kyung Kim ◽

Ji Hoon Kim ◽

Soyeon Jeong ◽

Yong Won Choi ◽

Hyun Jung Choi ◽

...

Keyword(s):

Oxidative Stress ◽

Hepg2 Cells ◽

Antioxidant Defense ◽

Molecular Mechanisms ◽

Luciferase Activity ◽

Nuclear Fraction ◽

Mrna Levels ◽

Nrf2 Activation ◽

Pogostemon Cablin ◽

Antioxidant Defense Systems

Oxidative stress has been implicated in the pathogenesis of many diseases including chronic liver diseases. Nrf2 is a master transcriptional factor regulating the induction of cellular antioxidant defense systems. Here, the Nrf2-activating effect of the crude methanol extract of dried leaves of Pogostemon cablin Bentham was demonstrated by measuring the antioxidant response element (ARE)-driven luciferase activity and pachypodol, 4′,5-dihydroxy-3,3′,7-trimethoxyflavone, was isolated by bioactivity-guided fractionation and further separation using chromatographic techniques. To our knowledge, this is the first study to evaluate the antioxidant and cytoprotective effects of pachypodol in HepG2 cells as well as the underlying molecular mechanisms. Indeed, pachypodol protected HepG2 cells from cell death caused by tert-butylhydroperoxide-induced oxidative stress and also attenuated ROS production. The ability of pachypodol to activate Nrf2/ARE pathway was further confirmed by observing Nrf2 expression in nuclear fraction, mRNA levels of Nrf2 target antioxidants, and cellular glutathione content in HepG2 cells. Extracellular signal-regulated kinase (ERK) is one of the important kinases involved in Nrf2 activation. Pachypodol increased ERK phosphorylation and ERK inhibition by PD98059 totally abrogated the increase in ARE luciferase activity, nuclear Nrf2 accumulation and mRNA levels of antioxidant enzymes by pachypodol. In conclusion, pachypodol isolated from P. cablin can protect hepatocytes from oxidative injury, possibly mediated by enhancing endogenous antioxidant defense system through ERK-dependent Nrf2 activation.

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Prodigiosin Promotes Nrf2 Activation to Inhibit Oxidative Stress Induced by Microcystin-LR in HepG2 Cells

Toxins ◽

10.3390/toxins11070403 ◽

2019 ◽

Vol 11 (7) ◽

pp. 403 ◽

Cited By ~ 11

Author(s):

Jihua Chen ◽

Yuji Li ◽

Fuqiang Liu ◽

De-Xing Hou ◽

Jingjing Xu ◽

...

Keyword(s):

Oxidative Stress ◽

Hepg2 Cells ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Nuclear Factor ◽

Oxygen Species ◽

Anticancer Properties ◽

Nrf2 Activation ◽

Nrf2 Protein ◽

Related Phase

Microcystin-LR (MC-LR), a cyanotoxin produced by cyanobacteria, induces oxidative stress in various types of cells. Prodigiosin, a red linear tripyrrole pigment, has been recently reported to have antimicrobial, antioxidative, and anticancer properties. How prodigiosin reacts to reactive oxygen species (ROS) induced by MC-LR is still undetermined. This study aimed to examine the effect of prodigiosin against oxidative stress induced by MC-LR in HepG2 cells. Ros was generated after cells were treated with MC-LR and was significantly inhibited with treatment of prodigiosin. In prodigiosin-treated cells, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-related phase II enzyme heme oxygenase-1 (HO-1) were increased. Besides, prodigiosin contributed to enhance nuclear Nrf2 level and repressed ubiquitination. Furthermore, prodigiosin promoted Nrf2 protein level and inhibited ROS in Nrf2 knocked down HepG2 cells. Results indicated that prodigiosin reduced ROS induced by MC-LR by enhancing Nrf2 translocation into the nucleus in HepG2 cells. The finding presents new clues for the potential clinical applications of prodigiosin for inhibiting MC-LR-induced oxidative injury in the future.

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