Quercetin Alleviates Oxidative Damage by Activating Nuclear Factor Erythroid 2-Related Factor 2 Signaling in Porcine Enterocytes

Oxidative stress has been implicated in the etiology of multiple gastrointestinal disorders, such as irritable bowel syndrome and inflammatory bowel disease. This study was conducted to evaluate effects of natural product quercetin on diquat-induced oxidative stress in porcine enterocytes and underlying mechanisms. Intestinal porcine epithelial cell line 1 (IPEC-1) cells pretreated with or without quercetin (5 μM, 24 h) were incubated with vehicle or diquat (100 μM) for 6 h. The results showed that diquat treatment induced apoptosis in a caspase-3-dependent manner, as accompanied by elevated reactive oxygen species (ROS) production, increased mitochondrial depolarization, and reduced the abundance of tight junction proteins. These adverse effects of diquat were remarkably abrogated by quercetin administration. Further study indicated that the protective effect of quercetin was associated with elevated protein abundance of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased intracellular glutathione (GSH) content. Interestingly, the beneficial effects of quercetin on diquat-induced oxidative damage were abolished by all-trans-retinoic acid (Atra), a specific inhibitor of Nrf2, indicating a Nrf2-dependent regulation manner. The results show that quercetin attenuates diquat-induced cell injury by promoting protein abundance of Nrf2 and regulating GSH-related redox homeostasis in enterocytes. These findings provide new insights into a function role of quercetin in maintaining intestinal homeostasis.

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S-Allyl Cysteine Alleviates Hydrogen Peroxide Induced Oxidative Injury and Apoptosis through Upregulation of Akt/Nrf-2/HO-1 Signaling Pathway in HepG2 Cells

BioMed Research International ◽

10.1155/2018/3169431 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 6

Author(s):

Chitra Basu ◽

Runa Sur

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Oxidative Damage ◽

Hepg2 Cells ◽

Liver Diseases ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Dependent Manner ◽

Cell Viability Assay

Hydrogen peroxide (H2O2) mediated oxidative stress leading to hepatocyte apoptosis plays a pivotal role in the pathophysiology of several chronic liver diseases. This study demonstrates that S-allyl cysteine (SAC) renders cytoprotective effects on H2O2 induced oxidative damage and apoptosis in HepG2 cells. Cell viability assay showed that SAC protected HepG2 cells from H2O2 induced cytotoxicity. Further, SAC treatment dose dependently inhibited H2O2 induced apoptosis via decreasing the Bax/Bcl-2 ratio, restoring mitochondrial membrane potential (∆Ψm), inhibiting mitochondrial cytochrome c release, and inhibiting proteolytic cleavage of caspase-3. SAC protected cells from H2O2 induced oxidative damage by inhibiting reactive oxygen species accumulation and lipid peroxidation. The mechanism underlying the antiapoptotic and antioxidative role of SAC is the induction of the heme oxygenase-1 (HO-1) gene in an NF-E2-related factor-2 (Nrf-2) and Akt dependent manner. Specifically SAC was found to induce the phosphorylation of Akt and enhance the nuclear localization of Nrf-2 in cells. Our results were further confirmed by specific HO-1 gene knockdown studies which clearly demonstrated that HO-1 induction indeed played a key role in SAC mediated inhibition of apoptosis and ROS production in HepG2 cells, thus suggesting a hepatoprotective role of SAC in combating oxidative stress mediated liver diseases.

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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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Sulforaphane Protects Pancreatic Acinar Cell Injury by Modulating Nrf2-Mediated Oxidative Stress and NLRP3 Inflammatory Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/7864150 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 34

Author(s):

Zhaojun Dong ◽

Haixiao Shang ◽

Yong Q. Chen ◽

Li-Long Pan ◽

Madhav Bhatia ◽

...

Keyword(s):

Oxidative Stress ◽

Acinar Cell ◽

Cell Injury ◽

Acinar Cells ◽

Pancreatic Injury ◽

Pancreatic Acinar Cell ◽

Related Factor ◽

Nuclear Factor ◽

Pyrin Domain ◽

Cellular Oxidation

Acute pancreatitis (AP) is characterized by early activation of intra-acinar proteases followed by acinar cell death and inflammation. Cellular oxidative stress is a key mechanism underlying these pathological events. Sulforaphane (SFN) is a natural organosulfur antioxidant with undescribed effects on AP. Here we investigated modulatory effects of SFN on cellular oxidation and inflammation in AP. AP was induced by cerulean hyperstimulation in BALB/c mice. Treatment group received a single dose of 5 mg/kg SFN for 3 consecutive days before AP. We found that SFN administration attenuated pancreatic injury as evidenced by serum amylase, pancreatic edema, and myeloperoxidase, as well as by histological examination. SFN administration reverted AP-associated dysregulation of oxidative stress markers including pancreatic malondialdehyde and redox enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx). In acinar cells, SFN treatment upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes including quinoneoxidoreductase-1, heme oxidase-1, SOD1, and GPx1. In addition, SFN selectively suppressed cerulein-induced activation of the nucleotide-binding domain leucine-rich repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome, in parallel with reduced nuclear factor- (NF-) κB activation and modulated NF-κB-responsive cytokine expression. Together, our data suggested that SFN modulates Nrf2-mediated oxidative stress and NLRP3/NF-κB inflammatory pathways in acinar cells, thereby protecting against AP.

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Nuclear Factor Erythroid-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.785057 ◽

2021 ◽

Vol 15 ◽

Author(s):

Bianca Seminotti ◽

Mateus Grings ◽

Paolo Tucci ◽

Guilhian Leipnitz ◽

Luciano Saso

Keyword(s):

Oxidative Stress ◽

Transcription Factor ◽

Metabolic Disorders ◽

Current Knowledge ◽

Redox Homeostasis ◽

Neurological Dysfunction ◽

Related Factor ◽

Type I ◽

Nuclear Factor ◽

Inherited Metabolic Disorders

Inherited metabolic disorders (IMDs) are rare genetic conditions that affect multiple organs, predominantly the central nervous system. Since treatment for a large number of IMDs is limited, there is an urgent need to find novel therapeutical targets. Nuclear factor erythroid-related factor 2 (Nrf2) is a transcription factor that has a key role in controlling the intracellular redox environment by regulating the expression of antioxidant enzymes and several important genes related to redox homeostasis. Considering that oxidative stress along with antioxidant system alterations is a mechanism involved in the neuropathophysiology of many IMDs, this review focuses on the current knowledge about Nrf2 signaling dysregulation observed in this group of disorders characterized by neurological dysfunction. We review here Nrf2 signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Additionally, beneficial effects of different Nrf2 activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf2 pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection.

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Oxidative Damage and Nrf2 Translocation Induced by Toxicities of Deoxynivalenol on the Placental and Embryo on Gestation Day 12.5 d and 18.5 d

Toxins ◽

10.3390/toxins10090370 ◽

2018 ◽

Vol 10 (9) ◽

pp. 370 ◽

Cited By ~ 4

Author(s):

Miao Yu ◽

Zhi-Yuan Wei ◽

Zhou-Heng Xu ◽

Jia-Qi Pan ◽

Jian-Huan Chen

Keyword(s):

Oxidative Stress ◽

Superoxide Dismutase ◽

Oxidative Damage ◽

Elevated Level ◽

Molecular Mechanisms ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Nuclear Factor ◽

Pathway Activation ◽

Different Doses

Deoxynivalenol (DON) is a kind of natural pollutant belonging to the trichothecenes family. The aim of this study is to use diverse assays to evaluate oxidative damage as well as translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), and to investigate their mechanisms in DON-induced toxicities on a placenta and embryo. Pregnant C57BL/6 mice were randomly assigned to three groups with different doses of DON: 0, 1.0, 2.5 mg/(kg·day). In gestation day (GD) 12.5 d and 18.5 d, DON induced an elevated resorption rate of the embryos as well as structural and functional damage of the placenta. In the placenta, altered levels of the antioxidant enzymes malondialdehyde, superoxide dismutase and glutathione indicated remarkable oxidative stress. Furthermore, an elevated level of heme oxygenase-1 (HO-1) and the translocation of Nrf2 from nucleus to cytoplasm indicated Nrf2/HO-1 pathway activation in DON-L group (1.0 mg/(kg·day)). It is noteworthy that the results in this experiment in GD 12.5 d were similar to those in GD 18.5 d. In conclusion, DON-induced placental oxidative damage and Nrf2 translocation were similar in GD 12.5 d and GD 18.5 d. Oxidative stress is one of the most important molecular mechanisms for embryotoxicity induced by DON, and Nrf2 translocation may play a substantial role against it.

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The Role of Nrf2 in Skeletal Muscle on Exercise Capacity

Antioxidants ◽

10.3390/antiox10111712 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1712

Author(s):

Yu Kitaoka

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Exercise Physiology ◽

Redox Homeostasis ◽

Muscle Metabolism ◽

Related Factor ◽

Nuclear Factor ◽

Nitrogen Species ◽

Special Issue

Nuclear factor erythroid 2-related factor 2 Nfe2l2 (Nrf2) is believed to play a crucial role in protecting cells against oxidative stress. In addition to its primary function of maintaining redox homeostasis, there is emerging evidence that Nrf2 is also involved in energy metabolism. In this review, we briefly discuss the role of Nrf2 in skeletal muscle metabolism from the perspective of exercise physiology. This article is part of a special issue “Mitochondrial Function, Reactive Oxygen/Nitrogen Species and Skeletal Muscle” edited by Håkan Westerblad and Takashi Yamada.

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Activation of nuclear factor erythroid 2-related factor 2 and PPARγ plays a role in the genistein-mediated attenuation of oxidative stress-induced endothelial cell injury

British Journal Of Nutrition ◽

10.1017/s0007114512001110 ◽

2012 ◽

Vol 109 (2) ◽

pp. 223-235 ◽

Cited By ~ 34

Author(s):

Ting Zhang ◽

Fan Wang ◽

Hong-Xia Xu ◽

Long Yi ◽

Yu Qin ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Endothelial Cell ◽

Cell Viability ◽

Cell Injury ◽

B Cell Lymphoma ◽

Related Factor ◽

Nuclear Factor ◽

Antioxidant Genes ◽

Endothelial Cell Injury

We investigate the cytoprotective effects and the molecular mechanism of genistein in oxidative stress-induced injury using an endothelial cell line (EA.hy926). An oxidative stress model was established by incubating endothelial cells with H2O2. According to the present results, genistein pretreatment protected endothelial cells against H2O2-induced decreases in cell viability and increases in apoptosis. Genistein also prevented the inhibition of B-cell lymphoma 2 and the activation of caspase-3 induced by H2O2. Genistein increased superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels and attenuated the decrease in these antioxidants during oxidative stress. We also found that genistein induced the promoter activity of both nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ. Additionally, genistein induced the nuclear translocation of Nrf2 and PPARγ. While genistein caused the up-regulation of both Nrf2 and PPARγ, it also activated and up-regulated the protein expression and transcription of a downstream protein, haem oxygenase-1 (HO-1). Moreover, the use of Nrf2 small interfering RNA transfection and HO-1- or PPARγ-specific antagonists (Znpp and GW9662, respectively) blocked the protective effects of genistein on endothelial cell viability during oxidative stress. Therefore, we conclude that oxidative stress-induced endothelial cell injury can be attenuated by treatment with genistein, which functions via the regulation of the Nrf2 and PPARγ signalling pathway. Additionally, the endogenous antioxidants SOD, CAT and GSH appear to play a role in the antioxidant activity of genistein. The present findings suggest that the beneficial effects of genistein involving the activation of cytoprotective antioxidant genes may represent a novel strategy in the prevention and treatment of cardiovascular endothelial damage.

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The Protective Effects of Flavonoids in Cataract Formation through the Activation of Nrf2 and the Inhibition of MMP-9

Nutrients ◽

10.3390/nu12123651 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3651

Author(s):

Aaron Hilliard ◽

Patricia Mendonca ◽

Tanya D. Russell ◽

Karam F. A. Soliman

Keyword(s):

Oxidative Stress ◽

Redox Homeostasis ◽

Nuclear Factor Κb ◽

Protective Role ◽

Related Factor ◽

Nuclear Factor ◽

Protective Effects ◽

Cataract Formation ◽

Contributing Factors ◽

Cataract Development

Cataracts account for over half of global blindness. Cataracts formations occur mainly due to aging and to the direct insults of oxidative stress and inflammation to the eye lens. The nuclear factor-erythroid-2-related factor 2 (Nrf2), a transcriptional factor for cell cytoprotection, is known as the master regulator of redox homeostasis. Nrf2 regulates nearly 600 genes involved in cellular protection against contributing factors of oxidative stress, including aging, disease, and inflammation. Nrf2 was reported to disrupt the oxidative stress that activates Nuclear factor-κB (NFκB) and proinflammatory cytokines. One of these cytokines is matrix metalloproteinase 9 (MMP-9), which participates in the decomposition of lens epithelial cells (LECs) extracellular matrix and has been correlated with cataract development. Thus, during inflammatory processes, MMP production may be attenuated by the Nrf2 pathway or by the Nrf2 inhibition of NFκB pathway activation. Moreover, plant-based polyphenols have garnered attention due to their presumed safety and efficacy, nutritional, and antioxidant effects. Polyphenol compounds can activate Nrf2 and inhibit MMP-9. Therefore, this review focuses on discussing Nrf2’s role in oxidative stress and cataract formation, epigenetic effect in Nrf2 activity, and the association between Nrf2 and MMP-9 in cataract development. Moreover, we describe the protective role of flavonoids in cataract formation, targeting Nrf2 activation and MMP-9 synthesis inhibition as potential molecular targets in preventing cataracts.

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Protective Role of Nuclear Factor E2-Related Factor 2 against Acute Oxidative Stress-Induced Pancreaticβ-Cell Damage

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/639191 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 21

Author(s):

Jingqi Fu ◽

Hongzhi Zheng ◽

Huihui Wang ◽

Bei Yang ◽

Rui Zhao ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Damage ◽

Dimethyl Fumarate ◽

Protective Role ◽

Related Factor ◽

Dependent Manner ◽

Nuclear Factor ◽

Min6 Cells ◽

Cell Dysfunction ◽

Glucose Stimulated Insulin Secretion

Oxidative stress is implicated in the pathogenesis of pancreaticβ-cell dysfunction that occurs in both type 1 and type 2 diabetes. Nuclear factor E2-related factor 2 (NRF2) is a master regulator in the cellular adaptive response to oxidative stress. The present study found that MIN6β-cells with stable knockdown ofNrf2(Nrf2-KD) and islets isolated fromNrf2-knockout mice expressed substantially reduced levels of antioxidant enzymes in response to a variety of stressors. In scramble MIN6 cells or wild-type islets, acute exposure to oxidative stressors, including hydrogen peroxide (H2O2) and S-nitroso-N-acetylpenicillamine, resulted in cell damage as determined by decrease in cell viability, reduced ATP content, morphology changes of islets, and/or alterations of apoptotic biomarkers in a concentration- and/or time-dependent manner. In contrast, silencing ofNrf2sensitized MIN6 cells or islets to the damage. In addition, pretreatment of MIN6β-cells with NRF2 activators, including CDDO-Im, dimethyl fumarate (DMF), andtert-butylhydroquinone (tBHQ), protected the cells from high levels of H2O2-induced cell damage. Given that reactive oxygen species (ROS) are involved in regulating glucose-stimulated insulin secretion (GSIS) and persistent activation of NRF2 blunts glucose-triggered ROS signaling and GSIS, the present study highlights the distinct roles that NRF2 may play in pancreaticβ-cell dysfunction that occurs in different stages of diabetes.

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Anti-Inflammatory and Antioxidant Effects of Carpesium cernuum L. Methanolic Extract in LPS-Stimulated RAW 264.7 Macrophages

Mediators of Inflammation ◽

10.1155/2020/3164239 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Yea-Jin Park ◽

Se-Yun Cheon ◽

Dong-Sung Lee ◽

Divina C. Cominguez ◽

Zhiyun Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Methanolic Extract ◽

Raw 264.7 Cells ◽

Heme Oxygenase 1 ◽

Prostaglandin E ◽

Raw 264.7 ◽

Related Factor ◽

Dependent Manner ◽

Nuclear Factor ◽

Anti Inflammatory

A hypernomic reaction or an abnormal inflammatory process could cause a series of diseases, such as cardiovascular disease, neurodegeneration, and cancer. Additionally, oxidative stress has been identified to induce severe tissue injury and inflammation. Carpesium cernuum L. (C. cernuum) is a Chinese folk medicine used for its anti-inflammatory, analgesic, and detoxifying properties. However, the underlying molecular mechanism of C. cernuum in inflammatory and oxidative stress conditions remains largely unknown. The aim of this study was to examine the effects of a methanolic extract of C. cernuum (CLME) on lipopolysaccharide- (LPS-) induced RAW 264.7 mouse macrophages and a sepsis mouse model. The data presented in this study indicated that CLME inhibited LPS-induced production of proinflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7 cells. CLME treatment also reduced reactive oxygen species (ROS) generation and enhanced the expression of heme oxygenase-1 (HO-1) protein in a dose-dependent manner in the LPS-stimulated RAW 264.7 cells. Moreover, CLME treatment abolished the nuclear translocation of nuclear factor-κB (NF-κB), enhanced the activation of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), and reduced the expression of extracellular signal-related kinase (ERK) and ERK kinase (MEK) phosphorylation in LPS-stimulated RAW 264.7 cells. These outcomes implied that CLME could be a potential antioxidant and anti-inflammatory agent.

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