Resveratrol Regulates Nrf2-Mediated Expression of Antioxidant and Xenobiotic Metabolizing Enzymes in Pesticides-Induced Parkinsonism

2020 ◽  
Vol 27 (10) ◽  
pp. 1038-1045
Author(s):  
Mohd Sami Ur Rasheed ◽  
Manish Kumar Tripathi ◽  
Devendra Kumar Patel ◽  
Mahendra Pratap Singh
Keyword(s):  
Nuclear Translocation ◽  
Neuroblastoma Cells ◽  
Related Factor ◽  
Quinone Oxidoreductase ◽  
Metabolizing Enzymes ◽  
Cyp2d6 Activity ◽  
Xenobiotic Metabolizing Enzymes ◽  
Dopamine Content ◽  
Nrf2 Activation ◽  
Induced Changes

Background: Combined maneb (MB) and paraquat (PQ), two widely used pesticides, increases oxidative stress leading to Parkinsonism. Xenobiotic metabolizing enzymes, cytochrome P450 (CYP) 2D6 and its mouse ortholog Cyp2d22 protect against Parkinsonism. Resveratrol, an antioxidant, restores antioxidant defense system through the activation of nuclear factor erythroid 2- related factor 2 (Nrf2). However, a crosstalk between Cyp2d22/CYP2D6-mediated protection and resveratrol-induced Nrf2 activation leading to neuroprotection is not yet elucidated. Objective: The study aimed to decipher the effect of resveratrol on Nrf2 activation and expression of its downstream mediators, nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1 (NQO1) and thioredoxin 1 (Trx1) along with Cyp2d22/CYP2D6 activity in combined MB and PQ mouse model of Parkinsonism and differentiated neuroblastoma cells. Results: MB and PQ reduced the dopamine content (mouse) and Cyp2d22/CYP2D6 activity (mouse/neuroblastoma cells) and increased the nuclear translocation of Nrf2 and expression of NQO1 and Trx1 (both). Resveratrol ameliorated pesticides-induced changes in dopamine content and Cyp2d22/CYP2D6 activity. It was found to promote nuclear translocation of Nrf2 and expression of NQO1 and Trx1 proteins. Since Cyp2d22/CYP2D6 inhibitor (ketoconazole/quinidine) per se reduced Cyp2d22/CYP2D6 activity and dopamine content, it was found to substantially increase the pesticides-induced reduction in Cyp2d22/CYP2D6 activity and dopamine content. Inhibitors normalized the pesticides induced changes in Nrf2 translocation and NQO1 and Trx1 levels in pesticides treated groups. Conclusion: The results suggest that resveratrol promotes the catalytic activity of xenobiotic metabolizing enzyme, Cyp2d22/CYP2D6, which partially contributes to Nrf2 activation in pesticides- induced Parkinsonism.

scholarly journals Allyl Isothiocyanate Protects Acetaminophen-Induced Liver Injury via NRF2 Activation by Decreasing Spontaneous Degradation in Hepatocyte

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3585
Author(s):  
Min Woo Kim ◽  
Ju-Hee Kang ◽  
Hyun Jin Jung ◽  
Se Yong Park ◽  
Thu Han Le Phan ◽  
...  
Keyword(s):  
Target Genes ◽  
Nuclear Translocation ◽  
Biological Effects ◽  
Allyl Isothiocyanate ◽  
Heme Oxygenase 1 ◽  
Toxic Metabolite ◽  
Related Factor ◽  
Dependent Manner ◽  
Nrf2 Activation ◽  
Nrf2 Target Gene

Acetaminophen (APAP) is one of the most frequently prescribed analgesic and anti-pyretic drugs. However, APAP-induced hepatotoxicity is a major cause of acute liver failure globally. While the therapeutic dose is safe, an overdose of APAP produces an excess of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), subsequently resulting in hepatotoxicity. Allyl isothiocyanate (AITC), a bioactive molecule in cruciferous plants, is reported to exert various biological effects, including anti-inflammatory, anti-cancer, and anti-microbial effects. Notably, AITC is known for activating nuclear factor erythroid 2-related factor 2 (NRF2), but there is limited evidence supporting the beneficial effects on hepatocytes and liver, where AITC is mainly metabolized. We applied a mouse model in the current study to investigate whether AITC protects the liver against APAP-induced injury, wherein we observed the protective effects of AITC. Furthermore, NRF2 nuclear translocation and the increase of target genes by AITC treatment were confirmed by in vitro experiments. APAP-induced cell damage was attenuated by AITC via an NRF2-dependent manner, and rapid NRF2 activation by AITC was attributed to the elevation of NRF2 stability by decreasing its spontaneous degradation. Moreover, liver tissues from our mouse experiment revealed that AITC increases the expression of heme oxygenase-1 (HO-1), an NRF2 target gene, confirming the potential of AITC as a hepatoprotective agent that induces NRF2 activation. Taken together, our results indicate the potential of AITC as a natural-product-derived NRF2 activator targeting the liver.

scholarly journals Fucoxanthinol from the Diatom Nitzschia Laevis Ameliorates Neuroinflammatory Responses in Lipopolysaccharide-Stimulated BV-2 Microglia

Marine Drugs ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 116 ◽  
Author(s):  
Yuelian Li ◽  
Lu Liu ◽  
Peipei Sun ◽  
Yifeng Zhang ◽  
Tao Wu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nuclear Translocation ◽  
Mitogen Activated Protein Kinase ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Quinone Oxidoreductase ◽  
Necrosis Factor Alpha ◽  
Food Ingredients ◽  
Nitzschia Laevis ◽  
Pre Treatment

In recent years, microalgae have drawn increasing attention as a valuable source of functional food ingredients. Intriguingly, Nitzschia laevis is rich in fucoxanthinol that is seldom found in natural sources. Fucoxanthinol, a marine xanthophyll carotenoid, possesses various beneficial bioactivities. Nevertheless, it’s not clear whether fucoxanthinol could exert anti-neuroinflammatory function. In light of these premises, the aim of the present study was to investigate the anti-inflammatory role of fucoxanthinol purified from Nitzschia laevis in Lipopolysaccharide (LPS)-stimulated microglia. The results showed that pre-treatment of fucoxanthinol remarkably attenuated the expression of LPS-induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and the production of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), prostaglandin E2 (PGE-2), nitric oxide (NO) and reactive oxygen species (ROS) induction. Modulation mechanism studies revealed that fucoxanthinol hampered nuclear factor-kappa B (NF-κB), Akt, and mitogen-activated protein kinase (MAPK) pathways. Meanwhile, fucoxanthinol led to the enhancement of nuclear translocation of NF-E2-related factor 2 (Nrf2), and the upregulation of heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO-1). Taken together, the results indicated that fucoxanthinol obtained from Nitzschia laevis had great potential as a neuroprotective agent in neuroinflammation and neurodegenerative disorders.

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

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.

scholarly journals Sevoflurane preconditioning reduces brain inflammation after experimental stroke by enhancing glycogen synthesis kinase-3 β/ nuclear factor erythroid 2-related factor - dependent microglial M2 polarization

2019 ◽  
Author(s):  
Min Cai ◽  
Sisi Sun ◽  
Shiquan Wang ◽  
Beibei Dong ◽  
Li Tian ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Glycogen Synthesis ◽  
Ischemic Tolerance ◽  
Inflammatory Factors ◽  
Related Factor ◽  
Nuclear Factor ◽  
M2 Polarization ◽  
Nrf2 Activation ◽  
Sevoflurane Preconditioning ◽  
Gsk 3Β

Abstract Background: Sevoflurane preconditioning (SPC) results in cerebral ischemic tolerance; however, the mechanism remains unclear. In current study, we aimed to assess the M1/M2 shift in the brain induced by SPC and whether glycogen synthesis kinase-3β (GSK-3β)-regulated nuclear factor erythroid 2-related factor (Nrf2) activation was involved in the M2 polarization mediated by SPC. Methods: Mouse primary microglia with SPC were challenged by oxygen-glucose deprivation (OGD) or lipopolysaccharide (LPS), and mice with SPC were subjected to middle cerebral artery occlusion (MCAO). Then, the mRNA and protein levels of proinflammatory/anti-inflammatory factors were analysed. GSK-3β phosphorylation and Nrf2 nuclear translocation were measured. The mRNA and protein expression of proinflammatory/anti-inflammatory factors, neurological scores, infarct volume, cellular apoptosis, the proportion of M1/M2-positive cells, and the generation of super-oxidants were examined after SPC or GSK-3β inhibitor TDZD treatment with or without Nrf2 deficiency. Results: SPC promoted M2 phenotype polarization both in vitro and in vivo . GSK-3β phosphorylation at Ser9 was increased after SPC. Both SPC and TDZD administration enhanced Nrf2 nuclear translocation, promoted M2 phenotype polarization and elicited a neuroprotective effect. Nrf2 deficiency abolished the promoted M2 polarization and ischemic tolerance induced by TDZD treatment. The reduced percentage of M1-positive cells and super-oxidants generation induced by SFC or TDZD was also reversed by Nrf2 knockdown. Conclusions: Our results indicated that SPC exerts brain ischemic tolerance and enhances M2 polarization by GSK-3β-dependent Nrf2 activation, which provides a novel mechanism for SPC-induced neuroprotection.

scholarly journals Nrf2 is activated by disruption of mitochondrial thiol homeostasis but not by enhanced mitochondrial superoxide production

2020 ◽  
pp. jbc.RA120.016551
Author(s):  
Filip Cvetko ◽  
Stuart T. Caldwell ◽  
Maureen Higgins ◽  
Takafumi Suzuki ◽  
Masayuki Yamamoto ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Nuclear Translocation ◽  
Antioxidant Defenses ◽  
Glutathione Metabolism ◽  
Related Factor ◽  
Hydrogen Peroxide Production ◽  
Mitochondrial Superoxide ◽  
Nrf2 Activation ◽  
Thioredoxin System ◽  
Thiol Homeostasis

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of genes involved in antioxidant defenses to modulate fundamental cellular processes such as mitochondrial function and glutathione metabolism. Previous reports proposed that mitochondrial ROS production and disruption of the glutathione pool activate the Nrf2 pathway, suggesting that Nrf2 senses mitochondrial redox signals and/or oxidative damage and signals to the nucleus to respond appropriately. However, until now it has not been possible to disentangle the overlapping effects of mitochondrial superoxide/ hydrogen peroxide production as a redox signal from changes to mitochondrial thiol homeostasis on Nrf2. Recently, we developed mitochondria-targeted reagents that can independently induce mitochondrial superoxide and hydrogen peroxide production (MitoPQ), or selectively disrupt mitochondrial thiol homeostasis (MitoCDNB). Using these reagents, here we have determined how enhanced generation of mitochondrial superoxide and hydrogen peroxide, or disruption of mitochondrial thiol homeostasis affect activation of the Nrf2 system in cells, which was assessed by Nrf2 protein level, nuclear translocation and expression of its target genes. We found that selective disruption of the mitochondrial glutathione pool and inhibition of its thioredoxin system by MitoCDNB led to Nrf2 activation, while using MitoPQ to enhance production of mitochondrial superoxide and hydrogen peroxide alone did not. We further showed that Nrf2 activation by MitoCDNB requires cysteine sensors of Kelch-like ECH-associated protein 1 (Keap1). These findings provide important information on how disruption to mitochondrial redox homeostasis is sensed in the cytoplasm and signaled to the nucleus.

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

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.

scholarly journals Aurothioglucose does not improve alveolarization or elicit sustained Nrf2 activation in C57BL/6 models of bronchopulmonary dysplasia

2018 ◽  
Vol 314 (5) ◽  
pp. L736-L742 ◽  
Author(s):  
Qian Li ◽  
Rui Li ◽  
Stephanie B. Wall ◽  
Katelyn Dunigan ◽  
Changchun Ren ◽  
...  
Keyword(s):  
Lung Development ◽  
Inbred Mouse ◽  
Thioredoxin Reductase ◽  
Differential Sensitivity ◽  
Mouse Strains ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Protective Effects ◽  
Quinone Oxidoreductase ◽  
Nrf2 Activation

We previously showed that the thioredoxin reductase-1 (TrxR1) inhibitor aurothioglucose (ATG) improves alveolarization in hyperoxia-exposed newborn C3H/HeN mice. Our data supported a mechanism by which the protective effects of ATG are mediated via sustained nuclear factor E2-related factor 2 (Nrf2) activation in hyperoxia-exposed C3H/HeN mice 72 h after ATG administration. Given that inbred mouse strains have differential sensitivity and endogenous Nrf2 activation by hyperoxia, the present studies utilized two C57BL/6 exposure models to evaluate the effects of ATG on lung development and Nrf2 activation. The first model (0–14 days) was used in our C3H/HeN studies and the 2nd model (4–14 days) is well characterized in C57BL/6 mice. ATG significantly inhibited lung TrxR1 activity in both models; however, there was no effect on parameters of alveolarization in C57BL/6 mice. In sharp contrast to C3H/HeN mice, there was no effect of ATG on pulmonary NADPH quinone oxidoreductase-1 ( Nqo1) and heme oxygenase-1 ( Hmox1) at 72 h in either C57BL/6 model. In conclusion, although ATG inhibited TrxR1 activity in the lungs of newborn C57BL/6 mice, effects on lung development and sustained Nrf2-dependent pulmonary responses were blunted. These findings also highlight the importance of strain-dependent hyperoxic sensitivity in evaluation of potential novel therapies.

scholarly journals Organic synthesis and anti-influenza A virus activity of cyclobakuchiols A, B, C, and D

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248960
Author(s):  
Masaki Shoji ◽  
Tomoyuki Esumi ◽  
Narue Tanaka ◽  
Misa Takeuchi ◽  
Saki Yamaji ◽  
...  
Keyword(s):  
Host Cell ◽  
Influenza A Virus ◽  
Influenza A ◽  
Related Factor ◽  
Mrna Levels ◽  
Isopropyl Group ◽  
Quinone Oxidoreductase ◽  
Virus Activity ◽  
Nrf2 Activation ◽  
Infected Cells

Novel antiviral agents for influenza, which poses a substantial threat to humans, are required. Cyclobakuchiols A and B have been isolated from Psoralea glandulosa, and cyclobakuchiol C has been isolated from P. corylifolia. The structural differences between cyclobakuchiol A and C arise due to the oxidation state of isopropyl group, and these compounds can be derived from (+)-(S)-bakuchiol, a phenolic isoprenoid compound present in P. corylifolia seeds. We previously reported that bakuchiol induces enantiospecific anti-influenza A virus activity involving nuclear factor erythroid 2-related factor 2 (Nrf2) activation. However, it remains unclear whether cyclobakuchiols A–C induce anti-influenza A virus activity. In this study, cyclobakuchiols A, B, and C along with cyclobakuchiol D, a new artificial compound derived from cyclobakuchiol B, were synthesized and examined for their anti-influenza A virus activities using Madin-Darby canine kidney cells. As a result, cyclobakuchiols A–D were found to inhibit influenza A viral infection, growth, and the reduction of expression of viral mRNAs and proteins in influenza A virus-infected cells. Additionally, these compounds markedly reduced the mRNA expression of the host cell influenza A virus-induced immune response genes, interferon-β and myxovirus-resistant protein 1. In addition, cyclobakuchiols A–D upregulated the mRNA levels of NAD(P)H quinone oxidoreductase 1, an Nrf2-induced gene, in influenza A virus-infected cells. Notably, cyclobakuchiols A, B, and C, but not D, induced the Nrf2 activation pathway. These findings demonstrate that cyclobakuchiols have anti-influenza viral activity involving host cell oxidative stress response. In addition, our results suggest that the suitably spatial configuration between oxidized isopropyl group and phenol moiety in the structure of cyclobakuchiols is required for their effect.

scholarly journals Effects of Pyrene on Human Liver HepG2 Cells: Cytotoxicity, Oxidative Stress, and Transcriptomic Changes in Xenobiotic Metabolizing Enzymes and Inflammatory Markers with Protection Trial Using Lycopene

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Jin-Kui Ma ◽  
Walaa Fathy Saad Eldin ◽  
Waleed Rizk El-Ghareeb ◽  
Abdelazim Elsayed Elhelaly ◽  
Mariam H. E. Khedr ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Mrna Expression ◽  
Hepg2 Cells ◽  
Inflammatory Markers ◽  
Human Liver ◽  
Regulatory Elements ◽  
Related Factor ◽  
Dependent Manner ◽  
Metabolizing Enzymes ◽  
Xenobiotic Metabolizing Enzymes

Pyrene is one of the major polycyclic aromatic hydrocarbons formed during heat treatment of meat and in car exhausts; however, few studies have investigated pyrene-induced adverse effects on human cell lines. This study aimed at the investigation of pyrene-induced cytotoxicity and oxidative damage in human liver HepG2 cells at environmentally relevant concentrations. Pyrene-induced changes in mRNA expression of xenobiotic metabolizing enzymes (XMEs), xenobiotic transporters, antioxidant enzymes, and inflammatory markers were investigated using real-time PCR. As a protection trial, the ameliorative effects of lycopene, a carotenoid abundantly found in tomato, were investigated. The possible mechanisms behind such effects were examined via studying the co exposure effects of pyrene and lycopene on regulatory elements including the aryl hydrocarbon receptor (Air) and elytroid 2-related factor 2 (RF). The achieved results indicated that pyrene caused significant cytotoxicity at 50 n, with a clear production of reactive oxygen species (ROS) in a dose-dependent manner. Pyrene upregulated mRNA expression of phase I enzymes including CYP1A1, 1A2, and CYP1B1 and inflammatory markers including TNFα and Cox2. However, pyrene significantly downregulated phase II enzymes, xenobiotic transporters, and antioxidant enzymes. Interestingly, lycopene significantly reduced pyrene-induced cytotoxicity and ROS production. Moreover, lycopene upregulated detoxification and antioxidant enzymes, probably via its regulatory effects on Air- and RF-dependent pathways.

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