scholarly journals 2-Methoxy-7-Acetonyljuglone Isolated from Reynoutria japonica Increases the Activity of Nuclear Factor Erythroid 2-Related Factor-2 through Inhibition of Ubiquitin Degradation in HeLa Cells

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 398 ◽  
Author(s):  
Jung-Hwan Kim ◽  
Atif Ali Khan Khalil ◽  
Hye-Jin Kim ◽  
Sung-Eun Kim ◽  
Mi-Jeong Ahn
Keyword(s):  
Hela Cells ◽  
Target Genes ◽  
Proteasomal Degradation ◽  
Degradation Pathway ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Signaling Mechanism ◽  
Reynoutria Japonica

The nuclear factor erythroid-derived 2-related factor 2 (NRF2) is a key transcription factor for the activation of genes responsible for oxidative stress and drug detoxification. Thus, it is important to identify NRF2 activators, which can be used to protect the cells from oxidative damage. Here, we investigated the effect of juglone derivatives isolated from Reynoutria japonica on the activity of NRF2 in HeLa cells. We demonstrated that among the juglone derivatives, 2-methoxy-7-acetonyljuglone (MA) strongly stimulated the antioxidant response element (ARE)-luciferase activity in a dose-dependent manner. In addition, MA significantly increased the nuclear localization of NRF2 and, consequently, increased the expression of NRF2 target genes, including heme oxygenase-1(HO-1), NAD(P)H: quinine oxidoreductase-1 (NQO-1), and glutamate-cysteine ligase catalytic (GCLC). To gain insights into the NRF2 signaling mechanism by MA, we measured the activities of RAC-alpha serine/threonine-protein kinase (AKT) and mitogen-activated protein (MAP) kinase family proteins, including extracellular signal-regulated kinase (ERK) and p38. Our results showed that MA induced NRF2 activity through p38 and AKT signaling. Subsequently, we found that MA significantly enhanced NRF2 stability by inhibiting ubiquitin-dependent proteasomal degradation. Thus, MA might protect cells by enhancing the activity and stability of NRF2 through inhibition of the proteasomal degradation pathway.

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.

Nuclear factor erythroid 2-related factor 2 rescues the oxidative stress induced by di-N-butylphthalate in testicular Leydig cells

2014 ◽  
Vol 34 (2) ◽  
pp. 145-152 ◽  
Author(s):  
B Shen ◽  
W Wang ◽  
L Ding ◽  
Y Sao ◽  
Y Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Leydig Cells ◽  
Target Genes ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Quinone Oxidoreductase ◽  
Antioxidant Genes ◽  
Protein Levels

Aim: This study aimed to determine whether nuclear factor erythroid 2-related factor 2 antagonized the oxidative stress induced by di- N-butylphthalate (DBP) in testicular Leydig cells. Methods: Mouse TM3 testicular Leydig cells were treated with Nrf2 knockdown (KD) or overexpression in the presence and absence of DBP. Oxidative profiles were examined. Nrf2 target antioxidant genes were studied, and the effects of Nrf2 inducer sulphoraphane (SFN) were tested. Results: DBP induced intracellular oxidative stress to a similar extent with Nrf2 KD. Expression and protein levels of Nrf2 were increased together with its target genes, namely heme oxygenase 1, nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1 and peroxiredoxin 6, following DBP stimulation. Use of SFN not only restored the intracellular oxidative toxicity but also cell proliferation and testosterone secretion in response to DBP. Conclusion: Increased Nrf2 activity, for example, by SFN can effectively antagonize the oxidative stress in testicular Leydig cells caused by DBP.

scholarly journals Degradation of Promoter-bound p65/RelA Is Essential for the Prompt Termination of the Nuclear Factor κB Response

2004 ◽  
Vol 200 (1) ◽  
pp. 107-113 ◽  
Author(s):  
Simona Saccani ◽  
Ivan Marazzi ◽  
Amer A. Beg ◽  
Gioacchino Natoli
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Target Genes ◽  
Proteasomal Degradation ◽  
Nuclear Factor Κb ◽  
Proteasome Activity ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Transcriptional Termination

Transcription factors of the nuclear factor (NF)-κB/Rel family translocate into the nucleus upon degradation of the IκBs. Postinduction repression of NF-κB activity depends on NF-κB–regulated resynthesis of IκBα, which dissociates NF-κB from DNA and exports it to the cytosol. We found that after activation, p65/RelA is degraded by the proteasome in the nucleus and in a DNA binding–dependent manner. If proteasome activity is blocked, NF-κB is not promptly removed from some target genes in spite of IκBα resynthesis and sustained transcription occurs. These results indicate that proteasomal degradation of p65/RelA does not merely regulate its stability and abundance, but also actively promotes transcriptional termination.

scholarly journals Antineuroinflammatory and Neuroprotective Effects of Gyejibokryeong-Hwan in Lipopolysaccharide-Stimulated BV2 Microglia

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Bo-Kyung Park ◽  
Young Hwa Kim ◽  
Yu Ri Kim ◽  
Jeong June Choi ◽  
Changsop Yang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mitogen Activated Protein Kinase ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Neuroprotective Effects ◽  
Bv2 Cells ◽  
Bv2 Microglia ◽  
Anti Inflammatory

Microglia, the central nervous system’s innate immune cells, mediate neuroinflammation and are implicated in a variety of neuropathologies. The present study investigated the antineuroinflammatory and neuroprotective effects of Gyejibokryeong-hwan (GBH), a traditional Korean medicine, in lipopolysaccharide- (LPS-) stimulated murine BV2 microglia. BV2 cells were pretreated with GBH, fluoxetine (FXT), or amitriptyline (AMT) for 1 h and then stimulated with LPS (100 ng/mL). The expression levels of nitric oxide (NO), cytokines, and chemokines were determined by the Griess method, ELISA, or real-time PCR. Western blotting was used to measure various transcription factors and mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt activity. GBH significantly reduced the levels of NO, inducible nitric oxide synthase (iNOS), cyclooxygenase- (COX-) 2, tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, macrophage inhibitory protein- (MIP-) 1α, macrophage chemoattractant protein- (MCP-) 1, and IFN-γ inducible protein- (IP-) 10, regulated upon activation normal T cell expressed sequence (RANTES) in a dose-dependent manner. Expression of nuclear factor- (NF-) κB p65 was significantly decreased and phosphorylation of extracellular signal-regulated kinase (Erk), c-Jun NH2-terminal kinase (JNK), and PI3K/Akt by GBH, but not p38 MAPK, was decreased. Furthermore, production of anti-inflammatory cytokine IL-10 was increased and Heme oxygenase-1 (HO-1) was upregulated via the nuclear factor-E2-related factor 2 (NRF2)/cAMP response element-binding protein (CREB) pathway, collectively indicating the neuroprotective effects of GBH. We concluded that GBH may suppress neuroinflammatory responses by inhibiting NF-κB activation and upregulating the neuroprotective factor, HO-1. These results suggest that GBH has potential as anti-inflammatory and neuroprotective agents against microglia-mediated neuroinflammatory disorders.

Mifepristone-inducible recombinant adenovirus attenuates paraquat-induced lung injury in rats

2014 ◽  
Vol 34 (1) ◽  
pp. 32-43 ◽  
Author(s):  
G-L Hong ◽  
Q-Q Cai ◽  
J-P Tan ◽  
X-Z Jiang ◽  
G-J Zhao ◽  
...  
Keyword(s):  
Lung Injury ◽  
Recombinant Adenovirus ◽  
Antioxidant Response ◽  
Nuclear Factor Κb ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Quinone Oxidoreductase ◽  
Protein Levels

Objective: To investigate the effects of overexpression of nuclear factor E2-related factor-2 (NRF2) on lung injury in rats exposed to paraquat (PQ) poisoning. Methods: A mifepristone (RU486)-inducible recombinant adenoviral vector carrying the human NRF2 gene (Ad-RUNRF2) was constructed and transfected via airway into the rats 7 days before the administration of RU486. Rats were orally challenged with PQ at 20 mg/kg 24 h after the injection of RU486. On days 0.5, 3 and 21 after PQ poisoning, the expressions of NRF2 and cytokines related to inflammation and oxidation in lung tissue were examined. Results: RU486 remarkably enhanced NRF2 mRNA and NRF2 protein levels in Ad-RUNRF2-transfected rats in a dose-dependent manner ( p < 0.01). PQ stimulated compensatory overexpression of NRF2, heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO-1) in lungs on days 0.5 and 3 after exposure ( p < 0.05), but depleted the expression of catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione (GSH), with an increased malondialdehyde (MDA) ( p < 0.05). However, pretreatment with Ad-RUNRF2 and RU486 strongly enhanced the expression levels of NRF2, HO-1, NQO-1, CAT and GSH-Px in the lungs of PQ intoxicated rats, with increased GSH and decreased MDA ( p < 0.05). Pretreatment with Ad-RUNRF2 and RU486 also strongly suppressed the PQ-induced activation of nuclear factor κB (NF-κB) and decreased the levels of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). In addition, Ad-RUNRF2 and RU486 induction significantly reduced PQ-induced pathological changes in lungs and attenuated lung oedema and protein leakage caused by PQ ( p < 0.05). Conclusion: RU486-induced overexpression of NRF2 in lungs transfected with Ad-RUNRF2 can ameliorate PQ-induced lung injury by the activation of the NRF2-antioxidant response element (ARE) pathway.

scholarly journals Leishmania Parasites Differently Regulate Antioxidant Genes in Macrophages Derived From Resistant and Susceptible Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Haifa Bichiou ◽  
Sameh Rabhi ◽  
Cherif Ben Hamda ◽  
Cyrine Bouabid ◽  
Meriam Belghith ◽  
...  
Keyword(s):  
Target Genes ◽  
Parasite Growth ◽  
Mouse Strains ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Detoxifying Enzymes ◽  
Antioxidant Genes ◽  
Enhance Cell Survival ◽  
Leishmania Parasites

Macrophage–Leishmania interactions are central to parasite growth and disease outcome. Macrophages have developed various strategies to fight invaders, including oxidative burst. While some microorganisms seem to survive and even thrive in an oxidative environment, others are susceptible and get killed. To counter oxidative stress, macrophages switch the expressions of cytoprotective and detoxifying enzymes, which are downstream targets of the nuclear factor erythroid 2-related factor 2 (Nrf2), to enhance cell survival. We have explored the transcription of NRF2 and of its target genes and compared the effect of the parasite on their transcription in bone marrow-derived macrophages (BMdMs) from Leishmania-resistant and Leishmania-susceptible mice. While heme oxygenase 1 (HO-1) transcription is independent of the genetic background, the transcription of glutathione reductase (Gsr) and of cysteine/glutamate exchange transporter (Slc7a11), involved in glutathione accumulation, was differentially regulated in BMdMs from both mouse strains. We also show that, except for HO-1, known to favor the survival of the parasite, the transcription of the selected genes, including Gsr, CD36, and catalase (CAT), was actively repressed, if not at all time points at least at the later ones, by the parasite, especially in Balb/c BMdMs. Consistent with these results, we found that the silencing of NRF2 in this study increases the survival and multiplication of the parasite.

scholarly journals Anti-Inflammatory and Anti-Oxidative Effects of luteolin-7-O-glucuronide in LPS-Stimulated Murine Macrophages through TAK1 Inhibition and Nrf2 Activation

2020 ◽  
Vol 21 (6) ◽  
pp. 2007 ◽  
Author(s):  
Young-Chang Cho ◽  
Jiyoung Park ◽  
Sayeon Cho
Keyword(s):  
Heme Oxygenase 1 ◽  
No Production ◽  
Related Factor ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Quinone Oxidoreductase ◽  
Murine Macrophages ◽  
Nrf2 Activation ◽  
Anti Inflammatory ◽  
Oxidative Effects

Various herbal extracts containing luteolin-7-O-glucuronide (L7Gn) have been traditionally used to treat inflammatory diseases. However, systemic studies aimed at elucidating the anti-inflammatory and anti-oxidative mechanisms of L7Gn in macrophages are insufficient. Herein, the anti-inflammatory and anti-oxidative effects of L7Gn and their underlying mechanisms of action in macrophages were explored. L7Gn inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages by transcriptional regulation of inducible NO synthase (iNOS) in a dose-dependent manner. The mRNA expression of inflammatory mediators, including cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α), was inhibited by L7Gn treatment. This suppression was mediated through transforming growth factor beta-activated kinase 1 (TAK1) inhibition that leads to reduced activation of nuclear factor-κB (NF-κB), p38, and c-Jun N-terminal kinase (JNK). L7Gn also enhanced the radical scavenging effect and increased the expression of anti-oxidative regulators, including heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and NAD(P)H quinone oxidoreductase 1 (NQO1), by nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) activation. These results indicate that L7Gn exhibits anti-inflammatory and anti-oxidative properties in LPS-stimulated murine macrophages, suggesting that L7Gn may be a suitable candidate to treat severe inflammation and oxidative stress.

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

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.

scholarly journals Association of Nuclear Factor-Erythroid 2-Related Factor 2, Thioredoxin Interacting Protein, and Heme Oxygenase-1 Gene Polymorphisms with Diabetes and Obesity in Mexican Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Angélica Saraí Jiménez-Osorio ◽  
Susana González-Reyes ◽  
Wylly Ramsés García-Niño ◽  
Hortensia Moreno-Macías ◽  
Martha Eunice Rodríguez-Arellano ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Protective Factor ◽  
Target Genes ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Diabetes And Obesity ◽  
Mexican Patients

The nuclear factor-erythroid 2- (NF-E2-) related factor 2 (Nrf2) is abated and its ability to reduce oxidative stress is impaired in type 2 diabetes and obesity. Thus, the aim of this study was to explore if polymorphisms in Nrf2 and target genes are associated with diabetes and obesity in Mexican mestizo subjects. The rs1800566 of NAD(P)H:quinone oxidoreductase 1 (NQO1) gene, rs7211 of thioredoxin interacting protein (TXNIP) gene, rs2071749 of heme oxygenase-1 (HMOX1) gene, and the rs6721961 and the rs2364723 from Nrf2 gene were genotyped in 627 diabetic subjects and 1020 controls. The results showed that the rs7211 polymorphism is a protective factor against obesity in nondiabetic subjects (CC + CT versus TT, OR = 0.40,P=0.005) and in women (CC versus CT + TT, OR = 0.7,P=0.016). TT carriers had lower high-density lipoprotein cholesterol levels and lower body mass index. The rs2071749 was positively associated with obesity (AA versus AG + GG, OR = 1.25,P=0.026). Finally, the rs6721961 was negatively associated with diabetes in men (CC versus CA + AA, OR = 0.62,P=0.003). AA carriers showed lower glucose concentrations. No association was found for rs1800566 and rs2364723 polymorphisms. In conclusion, the presence of Nrf2 and related genes polymorphisms are associated with diabetes and obesity in Mexican patients.

Trilobatin Protects Cardiomyocytes from Hypoxia/ Reperfusion Injury by Regulating the Nuclear Factor Erythroid 2-Related Factor 2/Heme Oxygenase-1 Pathway

2020 ◽  
Vol 19 (2) ◽  
pp. 133-138
Author(s):  
Wenyu Chen ◽  
Hui He
Keyword(s):  
Heme Oxygenase ◽  
Molecular Mechanisms ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Cellular Injury ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
H9c2 Cells ◽  
Natural Plant ◽  
Induced Changes

Trilobatin is a natural plant-derived glycosylated flavonoid that has been shown to exhibit multiple beneficial pharmacologic activities including protection of heart against H/R-induced cardiomyocyte injury. However, the molecular mechanisms underlying protection from H/R-induced cardiomyocyte injury remain unknown. Using H9C2 cells as a model, we examined the effect of trilobatin on H/R-induced cellular injury, apoptosis, and generation of reactive oxygen species. The results showed that trilobatin protected H9C2 cells not only from cell death and apoptosis, but also counteracted H/R-induced changes in malondialdehyde, superoxide dismutase, glutathione, and glutathione peroxidase. The evaluation of the mechanism underlying the effect of trilobatin on protection from H/R-induced cellular injury suggested changes in the regulation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway.

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