7,8-Dihydroxyflavone Suppresses Oxidative Stress-Induced Base Modification in DNA via Induction of the Repair Enzyme 8-Oxoguanine DNA Glycosylase-1

The modified guanine base 8-oxoguanine (8-oxoG) is abundantly produced by oxidative stress, can contribute to carcinogenesis, and can be removed from DNA by 8-oxoguanine DNA glycosylase-1 (OGG1), which acts as an 8-oxoG glycosylase and endonuclease. This study investigated the mechanism by which 7,8-dihydroxyflavone (DHF) inhibits oxidative stress-induced 8-oxoG formation in hamster lung fibroblasts (V79-4). DHF significantly reduced the amount of 8-oxoG induced by hydrogen peroxide (H2O2) and elevated the levels of OGG1 mRNA and protein. DHF increased the binding of nuclear factor erythroid 2-related factor 2 (Nrf2) to antioxidant response element sequences in the upstream promoter region of OGG1. Moreover, DHF increased the nuclear levels of Nrf2, small Maf proteins, and the Nrf2/small Maf complex, all of which are decreased by H2O2treatment. Likewise, the level of phosphorylated Akt, which activates Nrf2, was decreased by H2O2treatment but restored by DHF treatment. The levels of OGG1 and nuclear translocation of Nrf2 protein were decreased upon treatment with PI3K inhibitor or Akt inhibitor, and DHF treatment did not restore OGG1 and nuclear Nrf2 levels in these inhibitor-treated cells. Furthermore, PI3K and Akt inhibitors abolished the protective effects of DHF in cells undergoing oxidative stress. These data indicate that DHF induces OGG1 expression via the PI3K-Akt pathway and protects cells against oxidative DNA base damage by activating DNA repair systems.

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Protective Effects of GYY4137 on Renal Ischaemia/Reperfusion Injury through Nrf2-Mediated Antioxidant Defence

Kidney & Blood Pressure Research ◽

10.1159/000509933 ◽

2021 ◽

pp. 1-9

Author(s):

Hongmei Zhao ◽

Yun Qiu ◽

Yichen Wu ◽

Hong Sun ◽

Sumin Gao

Keyword(s):

Oxidative Stress ◽

Reperfusion Injury ◽

Nuclear Translocation ◽

Organ Damage ◽

Related Factor ◽

Protective Effects ◽

Ischaemia Reperfusion Injury ◽

Renal Ischaemia ◽

Ischaemia Reperfusion ◽

Renal Histology

Introduction/Aims: Hydrogen sulfide (H2S) is considered to be the third most important endogenous gasotransmitter in organisms. GYY4137 is a long-acting donor for H2S, a gas transmitter that has been shown to prevent multi-organ damage in animal studies. We previously reported the effect of GYY4137 on cardiac ischaemia reperfusion injury (IRI) in diabetic mice. However, the role and mechanism of GYY4137 in renal IRI are poorly understood. The aims of this study were to determine whether GYY4137 can effectively alleviate the injury induced by renal ischaemia reperfusion and to explore its possible mechanism. Methods: Mice received right nephrectomy and clipping of the left renal pedicle for 45 min. GYY4137 was administered by intraperitoneal injection for 2 consecutive days before the operation. The model of hypoxia/reoxygenation injury was established in HK-2 cells, which were pre-treated with or without GYY4137. Renal histology, function, apoptosis, and oxidative stress were measured. Western blot was used to measure the target protein after renal IRI. Results: The results indicated that GYY4137 had a clear protective effect on renal IRI as reflected by the attenuation of renal dysfunction, renal tubule injury, and apoptosis. Moreover, GYY4137 remarkably reduced renal IRI-induced oxidative stress. GYY4137 significantly elevated the nuclear translocation of nuclear factor-erythroid-2-related factor 2 (Nrf2) and the expression of antioxidant enzymes regulated by Nrf2, including SOD, HO-1, and NQO-1. Conclusions: GYY4137 alleviates ischaemia reperfusion-induced renal injury through activating the antioxidant effect mediated by Nrf2 signalling.

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Gentiopicroside Ameliorates Oxidative Stress and Lipid Accumulation through Nuclear Factor Erythroid 2-Related Factor 2 Activation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/2940746 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Meiyu Jin ◽

Haihua Feng ◽

Yue Wang ◽

Siru Yan ◽

Bingyu Shen ◽

...

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Lipid Accumulation ◽

Hepg2 Cells ◽

Regulatory Element ◽

Cell Counting ◽

Related Factor ◽

Nuclear Factor ◽

Protective Effects ◽

Akt Inhibitor

The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is closely related to the alleviation of nonalcoholic fatty liver disease (NAFLD) by regulating oxidative stress and lipid homeostasis. Gentiopicroside (GPS), an iridoid glycoside found in the Gentianaceae, possesses anti-inflammatory and antioxidant effects. However, the protective effects of GPS on lipid accumulation and oxidative damage have not been investigated thoroughly in free fatty acid- (FFA-) induced HepG2 cells and tyloxapol- (Ty-) induced hyperlipidemia mice. Cell counting kit-8 assays, Oil Red O staining, Western blotting analysis, extraction of nuclear and cytosolic proteins, and biochemical index assay were employed to explore the mechanisms by which GPS exerts a protective effect on FFA-induced HepG2 cells and Ty-induced hyperlipidemia mouse model. This paper demonstrates that GPS could effectively alleviate NAFLD by elevating cell viability, reducing fatty deposition, downregulating TG, and activating nucleus Nrf2 in FFA-induced HepG2 cells. Meanwhile, GPS significantly regulated the activation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, Nrf2 antioxidant pathway, peroxisome proliferator-activated receptor α (PPARα), and GPS-inhibited sterol regulatory element-binding protein-1c (SREBP-1c) expression in FFA-stimulated lipid accumulation of HepG2 cells and Ty-treated mice. Interestingly, we highlight that PI3K/AKT inhibitor (LY294002) markedly increased the expression of Nrf2 antioxidant pathway, PPARα, and downregulated SREBP-1c in FFA-stimulated HepG2 cells. For these reasons, we found that the deletion of Nrf2 could lose the protective effects of GPS on the Nrf2 antioxidant pathway and PPARα activation and SREBP-1c inactivation in FFA-stimulated HepG2 cells and Ty-treated mice. GPS treatment had no effect on abnormal lipogenesis and antioxidant enzymes in Ty-induced Nrf2-/- mice. This work gives a new explanation that GPS may be a useful therapeutic strategy for NAFLD through upregulation of the Nrf2 antioxidant pathway, which can alleviate oxidative damage and lipid accumulation.

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Thymoquinone Prevents Dopaminergic Neurodegeneration by Attenuating Oxidative Stress Via the Nrf2/ARE Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2020.615598 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jianjian Dong ◽

Xiaoming Zhang ◽

Shijing Wang ◽

Chenchen Xu ◽

Manli Gao ◽

...

Keyword(s):

Oxidative Stress ◽

Nuclear Translocation ◽

Nigella Sativa ◽

Drug Candidate ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Protective Effects ◽

Quinone Oxidoreductase ◽

Neuroprotective Effects ◽

Antioxidant Genes

Studies have indicated that oxidative stress plays a crucial role in the development of Parkinson’s disease (PD) and other neurodegenerative conditions. Research has also revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) triggers the expression of antioxidant genes via a series of antioxidant response elements (AREs), thus preventing oxidative stress. Thymoquinone (TQ) is the bioactive component of Nigella sativa, a medicinal plant that exhibits antioxidant and neuroprotective effects. In the present study we examined whether TQ alleviates in vivo and in vitro neurodegeneration induced by 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by acting as an activator of the Nrf2/ARE cascade. We showed that TQ significantly reduced MPP+-mediated cell death and apoptosis. Moreover, TQ significantly elevated the nuclear translocation of Nrf2 and significantly increased the subsequent expression of antioxidative genes such as Heme oxygenase 1 (HO-1), quinone oxidoreductase (NQO1) and Glutathione-S-Transferase (GST). The application of siRNA to silence Nrf2 led to an abolishment in the protective effects of TQ. We also found that the intraperitoneal injection of TQ into a rodent model of PD ameliorated oxidative stress and effectively mitigated nigrostriatal dopaminergic degeneration by activating the Nrf2-ARE pathway. However, these effects were inhibited by the injection of a lentivirus wrapped Nrf2 siRNA (siNrf2). Collectively, these findings suggest that TQ alleviates progressive dopaminergic neuropathology by activating the Nrf2/ARE signaling cascade and by attenuating oxidative stress, thus demonstrating that TQ is a potential novel drug candidate for the treatment of PD.

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Salidroside Alleviates Oxidative Stress and Apoptosis via AMPK/Nrf2 Pathway in DHT-induced Human Granulosa Cell Line KGN

10.21203/rs.3.rs-842159/v1 ◽

2021 ◽

Author(s):

Rui Ji ◽

Fang-yuan Jia ◽

Xin Chen ◽

Ze-hao Wang ◽

Wen-yi Jin ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Line ◽

Nuclear Translocation ◽

Tumor Cell Line ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Protective Effects ◽

Nrf2 Activation ◽

Nrf2 Signaling Pathway ◽

Antioxidant Proteins

Abstract Background: In the past few years, emerging evidence established persistent oxidative stress to be a key player in the pathogenesis of polycystic ovary syndrome (PCOS). Particularly, it damages the function of granulosa cells, and thus hinders the development of follicles. The present study aimed to explore and establish the protective effects of salidroside on dihydrotestosterone (DHT)‐induced Granulosa‐like tumor cell line (KGN), mediated via antioxidant mechanisms.Methods: KGN cells were treated with DHT as a PCOS cell model, and then incubated with salidroside in different concentrations. Apoptosis and reactive oxygen species (ROS) accumulation were assessed by flow cytometry, mitochondrial membrane potential depolarization and the nuclear translocation of Nrf2 were detected by immunofluorescence staining, and the level of apoptosis-related proteins and antioxidant proteins was assessed by western blotting.Results: Salidroside partly reversed DHT mediated effects, via stimulation of nuclear factor erythroid 2‐related factor 2 (Nrf2) signaling pathway and the downstream antioxidant proteins heme oxygenase‐1(HO‐1) and quinine oxidoreductase 1(NQO1). Additionally, knockdown of Nrf2 resulted in a deterioration in DHT‐induced oxidative stress and apoptosis. It partly moderated the protective effects of salidroside as well. Mechanistically, AMPK was identified to be the upstream signaling involved in salidroside‐induced Nrf2 activation, as silencing of AMPK partly prevented the upregulation of Nrf2 and the downstream proteins HO‐1 and NQO1. Conclusion: The present study is the first to effectively demonstrate the inhibitory effect of salidroside on DHT‐stimulated oxidative stress and apoptosis in KGN cells, which was dependent on Nrf2 activation that involved AMPK.

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An Update on the Role of Nrf2 in Respiratory Disease: Molecular Mechanisms and Therapeutic Approaches

International Journal of Molecular Sciences ◽

10.3390/ijms22168406 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8406

Author(s):

Jooyeon Lee ◽

Jimin Jang ◽

Sung-Min Park ◽

Se-Ran Yang

Keyword(s):

Oxidative Stress ◽

Respiratory Diseases ◽

Molecular Mechanisms ◽

Antioxidant Response ◽

Atmospheric Environment ◽

Chronic Obstructive ◽

Related Factor ◽

Protective Effects ◽

Cell Protection ◽

Obstructive Pulmonary Disease

Nuclear factor erythroid 2-related factor (Nrf2) is a transcriptional activator of the cell protection gene that binds to the antioxidant response element (ARE). Therefore, Nrf2 protects cells and tissues from oxidative stress. Normally, Kelch-like ECH-associated protein 1 (Keap1) inhibits the activation of Nrf2 by binding to Nrf2 and contributes to Nrf2 break down by ubiquitin proteasomes. In moderate oxidative stress, Keap1 is inhibited, allowing Nrf2 to be translocated to the nucleus, which acts as an antioxidant. However, under unusually severe oxidative stress, the Keap1-Nrf2 mechanism becomes disrupted and results in cell and tissue damage. Oxide-containing atmospheric environment generally contributes to the development of respiratory diseases, possibly leading to the failure of the Keap1-Nrf2 pathway. Until now, several studies have identified changes in Keap1-Nrf2 signaling in models of respiratory diseases, such as acute respiratory distress syndrome (ARDS)/acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and asthma. These studies have confirmed that several Nrf2 activators can alleviate symptoms of respiratory diseases. Thus, this review describes how the expression of Keap1-Nrf2 functions in different respiratory diseases and explains the protective effects of reversing this expression.

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Protective effects of curcumin against mercury-induced hepatic injuries in rats, involvement of oxidative stress antagonism, and Nrf2-ARE pathway activation

Human & Experimental Toxicology ◽

10.1177/0960327116677355 ◽

2016 ◽

Vol 36 (9) ◽

pp. 949-966 ◽

Cited By ~ 21

Author(s):

W Liu ◽

Z Xu ◽

H Li ◽

M Guo ◽

T Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Radical Scavenging ◽

Antioxidant Response ◽

Serum Lactate ◽

Serum Lactate Dehydrogenase ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Protective Effects ◽

Glutamylcysteine Synthetase ◽

Subunit Expression

Mercury (Hg) represents a ubiquitous environmental heavy metal that could lead to severe toxic effects in a variety of organs usually at a low level. The present study focused on the liver oxidative stress, one of the most important roles playing in Hg hepatotoxicity, by evaluation of different concentrations of mercuric chloride (HgCl2) administration. Moreover, the protective potential of curcumin against Hg hepatotoxic effects was also investigated. Eighty-four rats were randomly divided into six groups for a three-days experiment: control, dimethyl sulfoxide control, HgCl2 treatment (0.6, 1.2, and 2.4 mg kg−1 day−1), and curcumin pretreatment (100 mg kg−1 day−1) groups. Exposure of HgCl2 resulted in acute dose-dependent hepatotoxic effects. Administration of 2.4 mg kg−1 HgCl2 significantly elevated total Hg, nonprotein sulfhydryl, reactive oxygen species formation, malondialdehyde, apoptosis levels, serum lactate dehydrogenase, and alanine transaminase activities, with an impairment of superoxide dismutase and glutathione peroxidase in the liver. Moreover, HgCl2 treatment activated nuclear factor-E2-related factor 2-antioxidant response element (Nrf2-ARE) signaling pathway in further investigation, with a significant upregulation of Nrf2, heme oxygenase-1, and γ-glutamylcysteine synthetase heavy subunit expression, relative to control. Pretreatment with curcumin obviously prevented HgCl2-induced liver oxidative stress, which may be due to its free radical scavenging or Nrf2-ARE pathway-inducing properties. Taking together these data suggest that curcumin counteracts HgCl2 hepatotoxicity through antagonizing liver oxidative stress.

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Protective effects of isothiocyanates on blood-CSF barrier disruption induced by oxidative stress

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00518.2011 ◽

2012 ◽

Vol 303 (1) ◽

pp. R1-R7 ◽

Cited By ~ 20

Author(s):

Jianming Xiang ◽

Gina N. Alesi ◽

Ningna Zhou ◽

Richard F Keep

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Neurological Disorders ◽

Nuclear Translocation ◽

Normal Function ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Protective Effects ◽

Brain Response

The choroid plexuses (CPs) form the blood-cerebrospinal fluid (CSF) barrier (BCSFB) and play an important role in maintaining brain normal function and the brain response to injury. Many neurological disorders are associated with oxidative stress that can impact CP function. This study examined the effects of isothiocyanates, an abundant component in cruciferous vegetables, on H2O2-induced BCSFB disruption and CP cell death in vitro. It further examined the potential role of a transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), in isothiocyanate-induced protection. Sulforaphane (SF) significantly reduced H2O2-induced BCSFB disruption as assessed by transepithelial electrical resistance (29 ± 7% reduction vs. 92 ± 2% decrease in controls) and [3H]mannitol permeability. Allyl-isothiocyanate (AITC) had a similar protective effect. H2O2-induced epithelial cell death was also reduced by these isothiocyanates. In primary CP cells, SF and AITC reduced cell death by 42 ± 3% and 53 ± 10%, respectively. Similar protection was found in a CP cell line Z310. Protection was only found with pretreatment for 12–48 h and not with acute exposure (1 h). The protective effects of SF and AITC were associated with Nrf2 nuclear translocation and upregulated expression of antioxidative systems regulated by Nrf2, including heme oxygenase-1, NAD(P)H quinine oxidoreductase, and cysteine/glutamate exchange transporter. Thus isothiocyanates, as diet or medicine, may be a method for protecting BCSFB in neurological disorders.

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(−)-Loliolide Isolated from Sargassum horneri Protects against Fine Dust-Induced Oxidative Stress in Human Keratinocytes

Antioxidants ◽

10.3390/antiox9060474 ◽

2020 ◽

Vol 9 (6) ◽

pp. 474

Author(s):

Mawalle Kankanamge Hasitha Madhawa Dias ◽

Dissanayaka Mudiyanselage Dinesh Madusanka ◽

Eui Jeong Han ◽

Min Ju Kim ◽

You-Jin Jeon ◽

...

Keyword(s):

Oxidative Stress ◽

Nuclear Translocation ◽

Human Keratinocytes ◽

Sargassum Horneri ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Protective Effects ◽

Fine Dust ◽

Apoptosis Pathway ◽

Sustainable Solutions

The emergence of fine dust (FD) among air pollutants has taken a toll during the past few decades, and it has provided both controversy and a platform for open conversation amongst world powers for finding sustainable solutions and effective treatments for health issues. The present study emphasizes the protective effects of (–)-loliolide (HTT) isolated from Sargassum horneri against FD-induced oxidative stress in human HaCaT keratinocytes. The purification of (–)-loliolide was carried out by centrifugal partition chromatography. HTT did not show any cytotoxicity, and it further illustrated the potential to increase cell viability by reducing the reactive oxygen species (ROS) production in FD-stimulated keratinocytes. Furthermore, HTT suppressed FD-stimulated DNA damage and the formation of apoptotic bodies, and it reduced the population of cells in the sub-G1 apoptosis phase. FD-induced apoptosis was advancing through the mitochondria-mediated apoptosis pathway. The cytoprotective effects of the HTT against FD-stimulated oxidative damage is mediated through squaring the nuclear factor E2-related factor 2 (Nrf2)-mediated heme oxygenase-1 (HO-1) pathway, dose-dependently increasing HO-1 and NAD(P)H dehydrogenase (quinone) 1 (NQO1) levels in the cytosol while concomitantly improving the nuclear translocation of Nrf2. Future studies could implement the protective functionality of HTT in producing pharmaceuticals that utilize natural products and benefit the diseased.

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Liraglutide Ameliorates Lipotoxicity-Induced Oxidative Stress by Activating the NRF2 Pathway in HepG2 Cells

Hormone and Metabolic Research ◽

10.1055/a-1157-0166 ◽

2020 ◽

Vol 52 (07) ◽

pp. 532-539 ◽

Cited By ~ 1

Author(s):

Chong-gui Zhu ◽

Ying Luo ◽

Hao Wang ◽

Jun-Yi Li ◽

Jie Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Antioxidant Enzymes ◽

Mrna Expression ◽

Hepg2 Cells ◽

Target Genes ◽

Nuclear Translocation ◽

Thiobarbituric Acid ◽

Related Factor ◽

Protective Effects ◽

Alcoholic Fatty Liver

AbstractAlthough glucagon-like peptide-1 (GLP-1) analogue has been reported to suppress oxidative stress in non-alcoholic fatty liver disease (NAFLD), an effective therapeutic agent for NAFLD is currently unavailable. Therefore, in this study, we aimed to investigate the protective effects of the GLP-1 analogue liraglutide against lipotoxicity-induced oxidative stress in HepG2 cells and to elucidate the underlying mechanisms. HepG2 cells were cultured for 48 hours and treated with a free fatty acid (FFA) mixture: FFA mixture and liraglutide or FFA mixture, liraglutide, and exendin (9–39). Lipid accumulation was examined by oil red O staining. Oxidative stress was assessed by measuring the levels of intracellular reactive oxygen species using 2′,7′-dichlorofluorescein diacetate and thiobarbituric acid-reactive substances, whereas antioxidant capacity was assessed by measuring the activity of superoxide dismutase and catalase. Expression of the nuclear factor erythroid-2-related factor 2 (NRF2) gene and the genes encoding antioxidant enzymes was analyzed using quantitative RT-PCR. Cellular and nuclear NRF2 expression levels were assessed using immunofluorescence cell staining and western blotting. Liraglutide treatment reduced high fat-induced lipid formation and the levels of oxidative stress markers and increased antioxidant enzyme activity in HepG2 cells. Liraglutide treatment increased the mRNA expression of NRF2 target genes, induced NRF2 nuclear translocation, and increased nuclear NRF2 levels without altering NRF2 mRNA expression. Collectively, these results indicate that liraglutide exhibits a protective effect against lipotoxicity-induced oxidative stress, possibly via modulation of NRF2 and expression of antioxidant enzymes in liver cells.

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Role of Nrf2 in Synaptic Plasticity and Memory in Alzheimer’s Disease

Cells ◽

10.3390/cells10081884 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1884

Author(s):

Don A. Davies ◽

Aida Adlimoghaddam ◽

Benedict C. Albensi

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Neurodegenerative Disorders ◽

Nuclear Translocation ◽

Antioxidant Response ◽

Related Factor ◽

Amyloid Aβ ◽

Novel Therapeutic

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that reduces oxidative stress. When reactive oxygen species (ROS) or reactive nitrogen species (RNS) are detected, Nrf2 translocates from the cytoplasm into the nucleus and binds to the antioxidant response element (ARE), which regulates the expression of antioxidant and anti-inflammatory genes. Nrf2 impairments are observed in the majority of neurodegenerative disorders, including Alzheimer’s disease (AD). The classic hallmarks of AD include β-amyloid (Aβ) plaques, and neurofibrillary tangles (NFTs). Oxidative stress is observed early in AD and is a novel therapeutic target for the treatment of AD. The nuclear translocation of Nrf2 is impaired in AD compared to controls. Increased oxidative stress is associated with impaired memory and synaptic plasticity. The administration of Nrf2 activators reverses memory and synaptic plasticity impairments in rodent models of AD. Therefore, Nrf2 activators are a potential novel therapeutic for neurodegenerative disorders including AD.

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