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

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.

scholarly journals Sulforaphane induces colorectal cancer cell proliferation through Nrf2 activation in a p53-dependent manner

2020 ◽  
Vol 63 (1) ◽  
Author(s):  
Yunjeong Gwon ◽  
Jisun Oh ◽  
Jong-Sang Kim
Keyword(s):  
Colon Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cancer Cell ◽  
Related Factor ◽  
Mild Stress ◽  
Dependent Manner ◽  
Cancer Cell Proliferation ◽  
Nrf2 Signaling Pathway ◽  
Dose Dependent

AbstractSulforaphane is a well-known phytochemical that stimulates nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant cellular response. In this study, we found that sulforaphane promoted cell proliferation in HCT116 human colon cancer cells expressing a normal p53 gene in a dose-dependent but biphasic manner. Since p53 has been reported to contribute to cell survival by regulating various metabolic pathways to adapt to mild stress, we further examined cellular responses in both p53-wild-type (WT) and p53-knockout (KO) HCT116 cells exposed to sulforaphane in vitro and in vivo. Results demonstrated that sulforaphane treatment activated Nrf2-mediated antioxidant enzymes in both p53-WT and p53-KO cells, decreased apoptotic protein expression in WT cells but increased in KO cells in a dose-dependent manner, and increased the expression of a mitochondrial biogenesis marker PGC1α in WT cells but decreased in KO cells. Moreover, a low dose of sulforaphane promoted tumor growth, upregulated the Nrf2 signaling pathway, and decreased apoptotic cell death in p53-WT HCT116 xenografts compared to that in p53-KO HCT116 xenografts in BALB/c nude mice. These findings suggest that sulforaphane can influence colon cancer cell proliferation and mitochondrial function through a crosstalk between the Nrf2 signaling pathway and p53 axis.

scholarly journals Ganoderic Acid D Protects Human Amniotic Mesenchymal Stem Cells against Oxidative Stress-Induced Senescence through the PERK/NRF2 Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-18
Author(s):  
Yan Xu ◽  
Huan Yuan ◽  
Yi Luo ◽  
Yu-Jie Zhao ◽  
Jian-Hui Xiao
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Signaling Pathway ◽  
Adult Stem Cells ◽  
Telomerase Activity ◽  
Related Factor ◽  
Dependent Manner ◽  
Ganoderic Acid ◽  
Nrf2 Signaling Pathway

Aging is an important risk factor in the occurrence of many chronic diseases. Senescence and exhaustion of adult stem cells are considered as a hallmark of aging in organisms. In this study, a senescent human amniotic mesenchymal stem cell (hAMSC) model subjected to oxidative stress was established in vitro using hydrogen peroxide. We investigated the effects of ganoderic acid D (GA-D), a natural triterpenoid compound produced from Ganoderma lucidum, on hAMSC senescence. GA-D significantly inhibited β-galactosidase (a senescence-associated marker) formation, in a dose-dependent manner, with doses ranging from 0.1 μM to 10 μM, without inducing cytotoxic side-effects. Furthermore, GA-D markedly inhibited the generation of reactive oxygen species (ROS) and the expression of p21 and p16 proteins, relieved the cell cycle arrest, and enhanced telomerase activity in senescent hAMSCs. Furthermore, GA-D upregulated the expression of phosphorylated protein kinase R- (PKR-) like endoplasmic reticulum kinase (PERK), peroxidase III (PRDX3), and nuclear factor-erythroid 2-related factor (NRF2) and promoted intranuclear transfer of NRF2 in senescent cells. The PERK inhibitor GSK2656157 and/or the NRF2 inhibitor ML385 suppressed the PERK/NRF2 signaling, which was activated by GA-D. They induced a rebound for the generation of ROS and β-galactosidase-positive cells and attenuated the differentiation capacity. These findings suggest that GA-D retards hAMSC senescence through activation of the PERK/NRF2 signaling pathway and may be a promising candidate for the discovery of antiaging agents.

Effect of fluoride on PERK-Nrf2 signaling pathway in mouse ameloblasts

2019 ◽  
Vol 38 (7) ◽  
pp. 833-845
Author(s):  
X Zhou ◽  
Z Chen ◽  
W Zhong ◽  
R Yu ◽  
L He
Keyword(s):  
Oxidative Stress ◽  
Er Stress ◽  
Signaling Pathway ◽  
Nuclear Import ◽  
Target Genes ◽  
Dental Fluorosis ◽  
Related Factor ◽  
Dependent Manner ◽  
Nrf2 Signaling Pathway ◽  
Glutamylcysteine Synthetase

In the development of dental fluorosis, oxidative stress is considered as the key mechanism. Endoplasmic reticulum (ER) stress can induce oxidative stress and activate the important antioxidative factor nuclear factor erythroid 2-related factor 2 (Nrf2) in a PKR-like ER kinase (PERK)-dependent manner, but combining ER stress and oxidative stress, the role of PERK-Nrf2 signaling pathway involved in fluoride-regulated ameloblasts is not fully defined. Here, we studied the effect of fluoride on PERK-Nrf2 signaling pathway in mouse ameloblasts. We found that low-dose and continuous fluoride exposure increased binding immunoglobulin protein expression and activated PERK–activating transcription factor 4 signaling pathway. Meanwhile, the expression of Nrf2 and its target genes (glutamylcysteine synthetase and glutathione S-transferase-P1) enhanced following ER stress. Tunicamycin increased the expression of PERK, leading to Nrf2 nuclear import, and tauroursodeoxycholate suppressed Nrf2 activation through PERK during ER stress, indicating that PERK activation is required for Nrf2 nuclear entry. Furthermore, tert-butylhydroquinone triggered the overexpression of Nrf2 to reduce ER stress, but luteolin inhibited Nrf2 nuclear localization to elevate ER stress. In summary, this study proved that fluoride under certain dose can induce ER stress and promote Nrf2 nuclear import via PERK activation and suggested that antioxidation mechanism mediated by PERK-Nrf2 can alleviate fluoride-induced ER stress effectively.

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

2016 ◽  
Vol 94 (5) ◽  
pp. 517-525 ◽  
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.

scholarly journals The Protective Effect of Hispidin against Hydrogen Peroxide-Induced Oxidative Stress in ARPE-19 Cells via Nrf2 Signaling Pathway

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 380 ◽  
Author(s):  
Huang ◽  
Chang ◽  
Chau ◽  
Chiu
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Protective Effect ◽  
Retinal Pigment ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Dependent Manner ◽  
Glutamate Cysteine Ligase ◽  
Jnk Pathway ◽  
Nrf2 Signaling Pathway

Hispidin, a polyphenol compound isolated from Phellinus linteus, has been reported to possess antioxidant activities. In this study, we aimed to investigate the mechanisms underlying the protective effect of hispidin against hydrogen peroxide (H2O2)-induced oxidative stress on Adult Retinal Pigment Epithelial cell line-19 (ARPE-19) cells. Hispidin was not cytotoxic to ARPE-19 cells at concentrations of less than 50 μM. The levels of intracellular reactive oxygen species (ROS) were analyzed by dichlorofluorescin diacetate (DCFDA) staining. Hispidin significantly restored H2O2-induced cell death and reduced the levels of intracellular ROS. The expression levels of antioxidant enzymes, such as NAD(P)H:Quinine oxidoreductase-1 (NQO-1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and glutamate-cysteine ligase modifier subunit (GCLM) were examined using real-time PCR and Western blotting. Our results showed that hispidin markedly enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), HO-1, NQO-1, GCLM, and GCLC in a dose-dependent manner. Furthermore, knockdown experiments revealed that transfection with Nrf2 siRNA successfully suppresses the hispidin activated Nrf2 signaling in ARPE-19 cells. Moreover, activation of the c-Jun N-terminal kinase (JNK) pathway is involved in mediating the protective effects of hispidin on the ARPE-19 cells. Thus, the present study demonstrated that hispidin provides protection against H2O2-induced damage in ARPE-19 cells via activation of Nrf2 signaling and up-regulation of its downstream targets, including Phase II enzymes, which might be associated with the activation of the JNK pathway.

scholarly journals Betulinic Acid Alleviates Spleen Oxidative Damage Induced by Acute Intraperitoneal Exposure to T-2 Toxin by Activating Nrf2 and Inhibiting MAPK Signaling Pathways

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 158
Author(s):  
Li Kong ◽  
Lijuan Zhu ◽  
Xianglian Yi ◽  
You Huang ◽  
Haoqiang Zhao ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Betulinic Acid ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Erythroid Cell ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nrf2 Signaling Pathway

T-2 toxin, which is mainly produced by specific strains of Fusarium in nature, can induce immunotoxicity and oxidative stress, resulting in immune organ dysfunction and apoptosis. Betulinic acid (BA), a pentacyclic triterpenoids from nature plants, has been demonstrated to possess immunomodulating and antioxidative bioactivities. The purpose of the study was to explore the effect of BA on T-2 toxin-challenged spleen oxidative damage and further elucidate the underlying mechanism. We found that BA not only ameliorated the contents of serum total cholesterol (TC) and triglyceride (TG) but also restored the number of lymphocytes in T-2 toxin-induced mice. BA dose-dependently reduced the accumulation of reactive oxygen species (ROS), enhanced superoxide dismutase (SOD) activity, and decreased malondialdehyde (MDA) content, as well as increased the total antioxidant capacity (T-AOC) in the spleen of T-2-toxin-exposed mice. Moreover, BA reduced inflammatory cell infiltration in the spleen, improved the morphology of mitochondria and enriched the number of organelles in splenocytes, and dramatically attenuated T-2 toxin-triggered splenocyte apoptosis. Furthermore, administration of BA alleviated the protein phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERK); decreased the protein expression of kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein1 (Keap1); and increased the protein expression of nuclear factor erythroid 2 [NF-E2]-related factor (Nrf2) and heme oxygenase-1 (HO-1) in the spleen. These findings demonstrate that BA defends against spleen oxidative damage associated with T-2 toxin injection by decreasing ROS accumulation and activating the Nrf2 signaling pathway, as well as inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway.

scholarly journals Nitro-linoleic acid inhibits vascular smooth muscle cell proliferation via the Keap1/Nrf2 signaling pathway

2007 ◽  
Vol 293 (1) ◽  
pp. H770-H776 ◽  
Author(s):  
Luis Villacorta ◽  
Jifeng Zhang ◽  
Minerva T. Garcia-Barrio ◽  
Xi-lin Chen ◽  
Bruce A. Freeman ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Linoleic Acid ◽  
Vascular Smooth Muscle ◽  
Signaling Pathway ◽  
Related Factor ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Vsmc Proliferation ◽  
Nrf2 Signaling Pathway

Nitroalkenes, the nitration products of unsaturated fatty acids formed via NO-dependent oxidative reactions, have been demonstrated to exert strong biological actions in endothelial cells and monocytes/macrophages; however, little is known about their effects on vascular smooth muscle cells (VSMCs). The present study examined the role of nitro-linoleic acid (LNO2) in the regulation of VSMC proliferation. We observed that LNO2 inhibited VSMC proliferation in a dose-dependent manner. In addition, LNO2 induced growth arrest of VSMCs in the G1/S phase of the cell cycle with an upregulation of the cyclin-dependent kinase inhibitor p27kip1. Furthermore, LNO2 triggered nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and activation of the antioxidant-responsive element-driven transcriptional activity via impairing Kelch-like ECH-associating protein 1 (Keap1)-mediated negative control of Nrf2 activity in VSMCs. LNO2 upregulated the expression of Nrf2 protein levels, but not mRNA levels, in VSMCs. A forced activation of Nrf2 led to an upregulation of p27kip1 and growth inhibition of VSMCs. In contrast, knock down of Nrf2 using an Nrf2 siRNA approach reversed the LNO2-induced upregulation of p27kip1 and inhibition of cellular proliferation in VSMCs. These studies provide the first evidence that nitroalkene LNO2 inhibits VSMC proliferation through activation of the Keap1/Nrf2 signaling pathway, suggesting an important role of nitroalkenes in vascular biology.

scholarly journals Protective Effect of Chrysanthemum morifolium cv. Fubaiju Hot-Water Extracts Against ARPE-19 Cell Oxidative Damage by Activating PI3K/Akt-Mediated Nrf2/HO-1 Signaling Pathway

2021 ◽  
Vol 8 ◽  
Author(s):  
Yiming Hao ◽  
Yanfang Li ◽  
Jie Liu ◽  
Ziyuan Wang ◽  
Boyan Gao ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Protective Effect ◽  
Signaling Pathway ◽  
Chrysanthemum Morifolium ◽  
Hot Water ◽  
Expression Level ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Dependent Manner ◽  
Water Extracts

Chrysanthemum morifolium cv. Fubaiju is a kind of widely consumed herb tea with multiple health benefits. The present study was aimed to evaluate the protective capacity of C. morifolium cv. Fubaiju hot-water extracts (CMs) against ARPE-19 cell oxidative damage. The results showed that pretreatment with 100 μg/mL CM could significantly reduce cell oxidative damage and apoptosis. Proapoptotic protein expression such as Bax, cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase (PARP) was significantly decreased after CM addition, while the expression level of antioxidant enzymes including catalase, glutamate-cysteine ligase catalytic subunit (GCLc), superoxide dismutase 2 (SOD2), and NAD(P)H:quinone oxidoreductase 1 (NQO-1) was significantly promoted. Meanwhile, CM treatment upregulated Akt phosphorylation, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, and the expression level of antioxidant gene heme oxygenase-1 (HO-1) in a dose-dependent manner under oxidative stress. Knockdown of Nrf2 by targeted small interfering RNA (siRNA) alleviated CM-mediated HO-1 transcription and almost abolished CM-mediated protection against hydrogen peroxide (H2O2)-induced cell damage. Correspondingly, the protective effect of CM was dramatically blocked after interference with phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor LY294002, indicating that the protective effect of CM on cell oxidative damage was attributed to PI3K/Akt-mediated Nrf2/HO-1 signaling pathway.

scholarly journals Panaxatriol Saponins Attenuated Oxygen-Glucose Deprivation Injury in PC12 Cells via Activation of PI3K/Akt and Nrf2 Signaling Pathway

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Yongliang Huang ◽  
Jie Yu ◽  
Fang Wan ◽  
Wenwu Zhang ◽  
Huarong Yang ◽  
...  
Keyword(s):  
Protective Effect ◽  
Signaling Pathway ◽  
Pc12 Cells ◽  
Glucose Deprivation ◽  
Pharmacological Intervention ◽  
Oxygen Glucose Deprivation ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nrf2 Signaling Pathway ◽  
Main Components

Panaxatriol saponins (PTS), the main components extracted fromPanax notoginseng, have been shown to be efficacious in the prevention and treatment of cerebrovascular diseases in China. NF-E2-related factor 2 (Nrf2), a transcription factor regulating antioxidant and cytoprotective responses to oxidative stress, has received particular attention as a molecular target for pharmacological intervention of ischemic diseases. The aim of this study was to characterize the effect of PTS on the activation of Nrf2 signaling pathway and the potential role in its protective effect. We found that PTS induced heme oxygenase-1 (HO-1) expression in PC12 cells via activating Nrf2 signaling pathway. Phosphatidylinositol 3-kinase (PI3K)/Akt kinase was involved in the upstream of this PTS activated pathway. Moreover, combination of the main components in PTS significantly enhanced the expression of Nrf2 mediated phase II enzymes. Importantly, the protective effect of PTS against oxygen-glucose deprivation-reperfusion (OGD-Rep) induced cell death was significantly attenuated by PI3K inhibitor and antioxidant response element (ARE) decoy oligonucleotides, suggesting that both PI3K/Akt and Nrf2 signaling pathway are essential during this protective process. Taken together, our results suggest that PTS may activate endogenous cytoprotective mechanism against OGD-Rep induced oxidative injury via the activation of PI3K/Akt and Nrf2 signaling pathway.

scholarly journals Nrf2 Activation Attenuates Acrylamide-Induced Neuropathy in Mice

2021 ◽  
Vol 22 (11) ◽  
pp. 5995
Author(s):  
Chand Basha Davuljigari ◽  
Frederick Adams Ekuban ◽  
Cai Zong ◽  
Alzahraa A. M. Fergany ◽  
Kota Morikawa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Messenger Rna ◽  
Hepatic Necrosis ◽  
Related Factor ◽  
Necrosis Factor Alpha ◽  
Adult Mice ◽  
Nrf2 Signaling Pathway ◽  
Antioxidant Proteins ◽  
Oxide Synthase

Acrylamide is a well characterized neurotoxicant known to cause neuropathy and encephalopathy in humans and experimental animals. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in acrylamide-induced neuropathy, male C57Bl/6JJcl adult mice were exposed to acrylamide at 0, 200 or 300 ppm in drinking water and co-administered with subcutaneous injections of sulforaphane, a known activator of the Nrf2 signaling pathway at 0 or 25 mg/kg body weight daily for 4 weeks. Assessments for neurotoxicity, hepatotoxicity, oxidative stress as well as messenger RNA-expression analysis for Nrf2-antioxidant and pro-inflammatory cytokine genes were conducted. Relative to mice exposed only to acrylamide, co-administration of sulforaphane protected against acrylamide-induced neurotoxic effects such as increase in landing foot spread or decrease in density of noradrenergic axons as well as hepatic necrosis and hemorrhage. Moreover, co-administration of sulforaphane enhanced acrylamide-induced mRNA upregulation of Nrf2 and its downstream antioxidant proteins and suppressed acrylamide-induced mRNA upregulation of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS) in the cerebral cortex. The results demonstrate that activation of the Nrf2 signaling pathway by co-treatment of sulforaphane provides protection against acrylamide-induced neurotoxicity through suppression of oxidative stress and inflammation. Nrf2 remains an important target for the strategic prevention of acrylamide-induced neurotoxicity.

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