Response of Cytoprotective and Detoxifying Proteins to Vanadate and/or Magnesium in the Rat Liver: The Nrf2-Keap1 System

Oxidative stress (OS) is a mechanism underlying metal-induced toxicity. As a redox-active element, vanadium (V) can act as a strong prooxidant and generate OS at certain levels. It can also attenuate the antioxidant barrier and intensify lipid peroxidation (LPO). The prooxidant potential of V reflected in enhanced LPO, demonstrated by us previously in the rat liver, prompted us to analyze the response of the nuclear factor erythroid-derived 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2-Keap1) system involved in cellular regulation of OS to administration of sodium metavanadate (SMV, 0.125 mg V/mL) and/or magnesium sulfate (MS, 0.06 mg Mg/mL). The levels of some Nrf2-dependent cytoprotective and detoxifying proteins, i.e., glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), glutamate cysteine ligase catalytic subunit (GCLC), glutathione synthetase (GSS), NAD(P) H dehydrogenase quinone 1 (NQO1), UDP-glucumno-syltransferase 1 (UGT1), and heme oxygenase 1 (HO-1); glutathione (GSH); metallothionein (MT1); and glutamate-cysteine ligase (GCL) mRNA were measured. We also focused on the V-Mg interactive effects and trends toward interactive action as well as relationships between the examined indices. The elevated levels of Nrf2, GCL mRNA, and GCL catalytic subunit (GCLC) confirm OS in response to SMV and point to the capacity to synthesize GSH. The results also suggest a limitation of the second step in GSH synthesis reflected by the unchanged glutathione synthetase (GSS) and GSH levels. The positive correlations between certain cytoprotective/detoxifying proteins (which showed increasing trends during the SMV and/or MS administration, compared to the control) and between them and malondialdehyde (MDA), the hepatic V concentration/total content, and/or V dose (discussed by us previously) point to cooperation between the components of antioxidant defense in the conditions of the hepatic V accumulation and SMV-induced LPO intensification. The V-Mg interactive effect and trend are involved in changes in Nrf2 and UGT1, respectively. The p62 protein has to be determined in the context of potential inhibition of degradation of Keap1, which showed a visible upward trend, in comparison with the control. The impact of Mg on MT1 deserves further exploration.

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Hepatoprotective Effect of Polysaccharides Isolated from Dendrobium officinale against Acetaminophen-Induced Liver Injury in Mice via Regulation of the Nrf2-Keap1 Signaling Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/6962439 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Guosheng Lin ◽

Dandan Luo ◽

Jingjing Liu ◽

Xiaoli Wu ◽

Jinfen Chen ◽

...

Keyword(s):

Liver Injury ◽

Signaling Pathway ◽

Nuclear Translocation ◽

Hepatoprotective Effect ◽

Dendrobium Officinale ◽

Regulatory Subunit ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Glutamate Cysteine Ligase ◽

Nrf2 Signaling Pathway

The effect of polysaccharides isolated from Dendrobium officinale (DOP) on acetaminophen- (APAP-) induced hepatotoxicity and the underlying mechanisms involved are investigated. Male Institute of Cancer Research (ICR) mice were randomly assigned to six groups: (1) control, (2) vehicle (APAP, 230 mg/kg), (3) N-acetylcysteine (100 mg/kg), (4) 50 mg/kg DOP, (5) 100 mg/kg DOP, and (6) 200 mg/kg DOP. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the serum and glutathione (GSH), malondialdehyde (MDA), catalase (CAT), total antioxidant capacity (T-AOC), myeloperoxidase (MPO), and reactive oxygen species (ROS) levels in the liver were determined after the death of the mice. The histological examination of the liver was also performed. The effect of DOP on the Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was evaluated using Western blot analysis and real-time polymerase chain reaction (PCR). The results showed that DOP treatment significantly alleviated the hepatic injury. The decrease in ALT and AST levels in the serum and ROS, MDA, and MPO contents in the liver, as well as the increases in GSH, CAT, and T-AOC in the liver, were observed after DOP treatment. DOP treatment significantly induced the dissociation of Nrf2 from the Nrf2−Keap1 complex and promoted the Nrf2 nuclear translocation. Subsequently, DOP-mediated Nrf2 activation triggered the transcription and expressions of the glutamate–cysteine ligase catalytic (GCLC) subunit, glutamate–cysteine ligase regulatory subunit (GCLM), heme oxygenase-1 (HO-1), and NAD(P)H dehydrogenase quinone 1 (NQO1) in APAP-treated mice. The present study revealed that DOP treatment exerted potentially hepatoprotective effects against APAP-induced liver injury. Further investigation about mechanisms indicated that DOP exerted the hepatoprotective effect by suppressing the oxidative stress and activating the Nrf2−Keap1 signaling pathway.

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

Biomolecules ◽

10.3390/biom9080380 ◽

2019 ◽

Vol 9 (8) ◽

pp. 380 ◽

Cited By ~ 4

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.

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Lico A Enhances Nrf2-Mediated Defense Mechanisms againstt-BHP-Induced Oxidative Stress and Cell Death via Akt and ERK Activation in RAW 264.7 Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/709845 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 22

Author(s):

Hongming Lv ◽

Hua Ren ◽

Lidong Wang ◽

Wei Chen ◽

Xinxin Ci

Keyword(s):

Oxidative Damage ◽

Nuclear Translocation ◽

Antioxidant Activities ◽

Biological Properties ◽

Raw 264.7 Cells ◽

Ros Generation ◽

Heme Oxygenase 1 ◽

Raw 264.7 ◽

Related Factor ◽

Glutamate Cysteine Ligase

Licochalcone A (Lico A) exhibits various biological properties, including anti-inflammatory and antioxidant activities. In this study, we investigated the antioxidative potential and mechanisms of Lico A againsttert-butyl hydroperoxide- (t-BHP-) induced oxidative damage in RAW 264.7 cells. Our results indicated that Lico A significantly inhibitedt-BHP-induced cytotoxicity, apoptosis, and reactive oxygen species (ROS) generation and reduced glutathione (GSH) depletion but increased the glutamate-cysteine ligase modifier (GCLM) subunit and the glutamate-cysteine ligase catalytic (GCLC) subunit genes expression. Additionally, Lico A dramatically upregulated the antioxidant enzyme heme oxygenase 1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2), which were associated with inducing Nrf2 nuclear translocation, decreasing Keap1 protein expression and increasing antioxidant response element (ARE) promoter activity. Lico A also obviously induced the activation of serine/threonine kinase (Akt) and extracellular signal-regulated kinase (ERK), but PI3K/Akt and ERK inhibitors treatment displayed clearly decreased levels of LicoA-induced Nrf2 nuclear translocation and HO-1 expression, respectively. Furthermore, Lico A treatment markedly attenuatedt-BHP-induced oxidative damage, which was reduced by treatment with PI3K/Akt, ERK, and HO-1 inhibitors. Therefore, Lico A might have a protective role againstt-BHP-induced cytotoxicity by modulating HO-1 and by scavenging ROS via the activation of the PI3K/Akt and ERK/Nrf2 signaling pathways.

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Polygonatum sibiricum Polysaccharides Protect against MPP-Induced Neurotoxicity via the Akt/mTOR and Nrf2 Pathways

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/8843899 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Si Huang ◽

Haiyan Yuan ◽

Wenqun Li ◽

Xinyi Liu ◽

Xiaojie Zhang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Neuronal Loss ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Dependent Manner ◽

Quinone Oxidoreductase ◽

Glutamate Cysteine Ligase ◽

Dopaminergic Neuronal Loss

Polygonatum sibiricum, a well-known life-prolonging tonic in Chinese medicine, has been widely used for nourishing nerves in the orient, but the underlying molecular mechanisms remain unclear. In this study, we found that P. sibiricum polysaccharides (PSP) ameliorated 1-methyl-4-phenyl-1,2.3,6-tetrahydropyridine- (MPTP-) induced locomotor activity deficiency and dopaminergic neuronal loss in an in vivo Parkinson’s disease (PD) mouse model. Additionally, PSP pretreatment inhibited N-methyl-4-phenylpyridine (MPP+) induced the production of reactive oxygen species, increasing the ratio of reduced glutathione/oxidized glutathione. In vitro experiments showed that PSP promoted the proliferation of N2a cells in a dose-dependent manner, while exhibiting effects against oxidative stress and neuronal apoptosis elicited by MPP+. These effects were found to be associated with the activation of Akt/mTOR-mediated p70S6K and 4E-BP1 signaling pathways, as well as nuclear factor erythroid 2-related factor 2- (Nrf2-) mediated NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (Gclc), and glutamate-cysteine ligase modulatory subunit (Gclm), resulting in antiapoptotic and antioxidative effects. Meanwhile, PSP exhibited no chronic toxicity in C57BJ/6 mice. Together, our results suggest that PSP can serve as a promising therapeutic candidate with neuroprotective properties in preventing PD.

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Glutathione synthetase overexpression in Acidithiobacillus ferrooxidans improves halotolerance of iron oxidation

Applied and Environmental Microbiology ◽

10.1128/aem.01518-21 ◽

2021 ◽

Author(s):

Yuta Inaba ◽

Alan C. West ◽

Scott Banta

Keyword(s):

Acidithiobacillus Ferrooxidans ◽

Iron Oxidation ◽

Glutathione Synthetase ◽

Wild Type ◽

Glutamate Cysteine Ligase ◽

Acidophilic Bacteria ◽

Hydrometallurgical Processing ◽

Intracellular Ros ◽

Sulfur Oxidizing ◽

The Impact

Acidithiobacillus ferrooxidans are well-studied iron- and sulfur-oxidizing acidophilic chemolithoautotrophs that are exploited for their ability to participate in the bioleaching of metal sulfides. Here, we overexpressed the endogenous glutamate–cysteine ligase and glutathione synthetase genes in separate strains and found that glutathione synthetase overexpression increased intracellular glutathione levels. We explored the impact of pH on the halotolerance of iron oxidation in wild type and engineered cultures. The increase in glutathione allowed the modified cells to grow under salt concentrations and pH conditions that are fully inhibitory to wild type cells. Furthermore, we found that improved iron oxidation ability in the presence of chloride also resulted in higher levels of intracellular ROS in the strain. These results indicate that glutathione overexpression can be used to increase halotolerance in A. ferrooxidans and would likely be a useful strategy on other acidophilic bacteria. Importance The use of acidophilic bacteria in the hydrometallurgical processing of sulfide ores can enable many benefits including the potential reduction of environmental impacts. The cells involved in bioleaching tend to have limited halotolerance, and increased halotolerance could enable several benefits, including a reduction in the need for the use of fresh water resources. We show that the genetic modification of A. ferrooxidans for the overproduction of glutathione is a promising strategy to enable cells to resist the oxidative stress that can occur during growth in the presence of salt.

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Glutathione synthetase overexpression in Acidithiobacillus ferrooxidans improves halotolerance of iron oxidation

10.1101/2021.06.29.450459 ◽

2021 ◽

Author(s):

Yuta Inaba ◽

Alan C. West ◽

Scott Banta

Keyword(s):

Acidithiobacillus Ferrooxidans ◽

Iron Oxidation ◽

Metal Sulfides ◽

Glutathione Synthetase ◽

Wild Type ◽

Glutamate Cysteine Ligase ◽

Acidophilic Bacteria ◽

Sulfur Oxidizing ◽

Ph Conditions ◽

The Impact

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Nrf2 Regulation by Curcumin: Molecular Aspects for Therapeutic Prospects

Molecules ◽

10.3390/molecules27010167 ◽

2021 ◽

Vol 27 (1) ◽

pp. 167

Author(s):

Seyed Hossein Shahcheraghi ◽

Fateme Salemi ◽

Niloufar Peirovi ◽

Jamshid Ayatollahi ◽

Waqas Alam ◽

...

Keyword(s):

Molecular Mechanisms ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Glutamate Cysteine Ligase ◽

Response Elements ◽

Nrf2 Signaling Pathway ◽

Anti Inflammatory ◽

Molecular Aspects

Nuclear factor erythroid 2 p45-related factor (2Nrf2) is an essential leucine zipper protein (bZIP) that is primarily located in the cytoplasm under physiological conditions. Nrf2 principally modulates endogenous defense in response to oxidative stress in the brain.In this regard, Nrf2 translocates into the nucleus and heterodimerizes with the tiny Maf or Jun proteins. It then attaches to certain DNA locations in the nucleus, such as electrophile response elements (EpRE) or antioxidant response elements (ARE), to start the transcription of cytoprotective genes. Many neoplasms have been shown to have over activated Nrf2, strongly suggesting that it is responsible for tumors with a poor prognosis. Exactly like curcumin, Zinc–curcumin Zn (II)–curc compound has been shown to induce Nrf2 activation. In the cancer cell lines analyzed, Zinc–curcumin Zn (II)–curc compound can also display anticancer effects via diverse molecular mechanisms, including markedly increasing heme oxygenase-1 (HO-1) p62/SQSTM1 and the Nrf2 protein levels along with its targets. It also strikingly decreases the levels of Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1) protein.As a result, the crosstalk between p62/SQSTM1 and Nrf2 could be used to improve cancer patient response to treatments. The interconnected anti-inflammatory and antioxidative properties of curcumin resulted from its modulatory effects on Nrf2 signaling pathway have been shown to improve insulin resistance. Curcumin exerts its anti-inflammatory impact through suppressing metabolic reactions and proteins such as Keap1 that provoke inflammation and oxidation. A rational amount of curcumin-activated antioxidant Nrf2 HO-1 and Nrf2-Keap1 pathways and upregulated the modifier subunit of glutamate-cysteine ligase involved in the production of the intracellular antioxidant glutathione. Enhanced expression of glutamate-cysteine ligase, a modifier subunit (GLCM), inhibited transcription of glutamate-cysteine ligase, a catalytic subunit (GCLC). A variety of in vivo, in vitro and clinical studies has been done so far to confirm the protective role of curcumin via Nrf2 regulation. This manuscript is designed to provide a comprehensive review on the molecular aspects of curcumin and its derivatives/analogs via regulation of Nrf2 regulation.

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How to make use of team knowledge variety? The role of power disparity

Journal of Knowledge Management ◽

10.1108/jkm-08-2020-0620 ◽

2021 ◽

Vol ahead-of-print (ahead-of-print) ◽

Author(s):

Jin Yao ◽

Xinmei Liu ◽

Wenxin He

Keyword(s):

Positive Impact ◽

Interactive Effect ◽

Underlying Mechanism ◽

Interactive Effects ◽

Open Communication ◽

Team Creativity ◽

Content Type ◽

Team Members ◽

Power Disparity ◽

The Impact

Purpose Based on the social dominance theory, this study aims to theorize the moderating effect of power disparity in the impact of team knowledge variety on team creativity and further to verify team open communication as the mediating mechanism of the aforementioned interactive effect. Design/methodology/approach The multisource (team members and their team leaders) and longitudinal (separated by four months) survey data were collected from 67 research and development teams in China to test the research model. The authors used multiple regression analyses to validate all the proposed hypotheses. Findings Results reveal that team knowledge variety has a more positive impact on team creativity when teams have lower power disparity. Besides, team open communication is significantly and positively related to team creativity and mediates the interactive effect of team knowledge variety and team power disparity on team creativity. Originality/value This study reconciles the mixed findings in the previous study and provides new insights regarding the functionality of team knowledge variety. By identifying team power disparity as a moderator in shaping the effects of team knowledge variety, the authors extend the research that explores the moderators of the team knowledge variety–team creativity relationship, and make comprehensive consideration of the coexistence of multiple diversities within teams (i.e. knowledge variety and power disparity) and their joint effects on team creativity. Besides, this research identifies team open communication as an important underlying mechanism in transmitting the interactive effects of two different types of diversities on team creativity, thus offering new insights on how teams can perform creatively.

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