Sodium arsenite induces spatial learning and memory impairment associated with oxidative stress and activates the Nrf2/PPARγ pathway against oxidative injury in mice hippocampus

Abstract Arsenic (As) is a ubiquitous environmental and industrial toxin with known correlates of oxidative stress and cognitive deficits in the brain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor that represents a central cellular antioxidant defense mechanism and transcribes many antioxidant genes. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a well-known nuclear receptor to regulate lipid metabolism in many tissues, and it has been also associated with the control of oxidative stress, neuronal death, neurogenesis and differentiation. The role of Nrf2 and PPARγ in As-induced neurotoxicity is still debated. The present study was designed to investigate the neurobehavioral toxic effect of sub-chronic and middle-dose sodium arsenite exposure in mice hippocampus, as well as the response of Nrf2/PPARγ expression and influence on protein expression levels of their downstream antioxidant genes. Our results showed that mice treated with intraperitoneal injection of sodium arsenite (50 mg/kg body wt.) twice a week for 7 weeks resulted in increased generation of reactive oxygen species and impairment of spatial cognitive function. The present study also found a positive association between Nrf2/PPARγ expression in hippocampus of mice, and activation of antioxidant defenses by the evidently upregulated expression of their downstream genes, including superoxide dismutase, heme oxygenase-1 and glutathione peroxidase-3. Therefore, our findings were helpful for further understanding the role of Nrf2/PPARγ feedback loop in As-induced neurobehavioral toxicity.

Download Full-text

The Role of Nrf2-Mediated Pathway in Cardiac Remodeling and Heart Failure

Oxidative Medicine and Cellular Longevity ◽

10.1155/2014/260429 ◽

2014 ◽

Vol 2014 ◽

pp. 1-16 ◽

Cited By ~ 58

Author(s):

Shanshan Zhou ◽

Wanqing Sun ◽

Zhiguo Zhang ◽

Yang Zheng

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Cardiac Remodeling ◽

Target Genes ◽

Cellular Tissue ◽

Antioxidant Defenses ◽

Related Factor ◽

Antioxidant Genes ◽

Endogenous Antioxidant

Heart failure (HF) is frequently the consequence of sustained, abnormal neurohormonal, and mechanical stress and remains a leading cause of death worldwide. The key pathophysiological process leading to HF is cardiac remodeling, a term referring to maladaptation to cardiac stress at the molecular, cellular, tissue, and organ levels. HF and many of the conditions that predispose one to HF are associated with oxidative stress. Increased generation of reactive oxygen species (ROS) in the heart can directly lead to increased necrosis and apoptosis of cardiomyocytes which subsequently induce cardiac remodeling and dysfunction. Nuclear factor-erythroid-2- (NF-E2-) related factor 2 (Nrf2) is a transcription factor that controls the basal and inducible expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes that are ubiquitously expressed in the cardiovascular system. Emerging evidence has revealed that Nrf2 and its target genes are critical regulators of cardiovascular homeostasis via the suppression of oxidative stress, which is the key player in the development and progression of HF. The purpose of this review is to summarize evidence that activation of Nrf2 enhances endogenous antioxidant defenses and counteracts oxidative stress-associated cardiac remodeling and HF.

Download Full-text

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.

Download Full-text

Cytoprotective Effect of Ligustrum robustum Polyphenol Extract against Hydrogen Peroxide-Induced Oxidative Stress via Nrf2 Signaling Pathway in Caco-2 Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/5026458 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Jiayi Chen ◽

Fangting He ◽

Sijing Liu ◽

Tao Zhou ◽

Saira Baloch ◽

...

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Signaling Pathway ◽

Total Phenolic ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Cytoprotective Effect ◽

Quinone Oxidoreductase ◽

Antioxidant Genes ◽

Nrf2 Signaling Pathway

Ligustrum robustum is a traditional herbal tea that is widely distributed in southwest China. The health effects of L. robustum are characteristics of clearing heat, antioxidant, inducing resurgence, and improving digestion. However, the molecular mechanisms related to these effects, particularly the antioxidant mechanism, have been seldom reported. The objective of this study was to assess antioxidative capacity of L. robustum, and its protective effects and mechanisms against hydrogen peroxide (H2O2) - induced toxicity in Caco-2 cells. Total phenolic contents, free radical scavenging activity, and reducing capacity of L. robustum were measured. The effects of L. robustum on the cell viability and antioxidant defense system were explored. The expression of nuclear factor E2 related factor 2 (Nrf2) and antioxidant genes: quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and glutamate cysteine ligase (GCL) were analyzed by western blot and qPCR. Pretreatment of L. robustum could significantly reduce H2O2-induced toxicity, decrease the level of reactive oxygen species (ROS) and malondialdehyde (MDA), and increase the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR). By activating the expression of Nrf2 and antioxidant genes (NQO1, HO-1, and GCL), L. robustum exerts cytoprotective effect in Caco-2 cells dealt with H2O2. Therefore, the well-established model of Caco-2 cells demonstrates that L. robustum may modulate the cytoprotective effect against the H2O2-induced oxidative stress through the Nrf2 signaling pathway.

Download Full-text

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

Human & Experimental Toxicology ◽

10.1177/0960327114530744 ◽

2014 ◽

Vol 34 (2) ◽

pp. 145-152 ◽

Cited By ~ 10

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.

Download Full-text

The effects of quercetin on oxidative stress and fibrosis markers in chronic kidney disease rat model

Medical Journal of Indonesia ◽

10.13181/mji.v26i3.1462 ◽

2017 ◽

Vol 26 (3) ◽

pp. 169-77 ◽

Cited By ~ 1

Author(s):

Kamalia Layal ◽

Ika S. Perdhana ◽

Melva Louisa ◽

Ari Estuningtyas ◽

Vivian Soetikno

Keyword(s):

Oxidative Stress ◽

Fruits And Vegetables ◽

Defense Mechanism ◽

Plasma Creatinine ◽

Control Group ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Sprague Dawley ◽

Cell Defense ◽

Gpx Activity

Background: Oxidative stress may play a role in the pathogenesis of (CKD), Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor involved in cell defense mechanism against oxidative stress. In this study, we examined the effect of quercetin, a polyphenplic antioxidant anti fibrosis compund in fruits and vegetables, on the 5/6 nephrectomy-induced CKD progression model rats through modulation of Nrf2 expression.Methods: Male Sprague-Dawley rats were randomly divided into normal control group (C), untreated 5/6 nephrectomy (Nx), quercetin-treated 5/6 nephrectomy (100 mg/kgBW/day orally) (NxQ), and captopril-treated 5/6 nephrectomy (10 mg/kgBW/day orally) (NxK) for 8 weeks. At the end of study, all animals were sacrified. Urine, blood, and kidney tissues were taken for examination of proteinuria, plasma creatinine, urea, malondialdehyde (MDA), glutathione peroxidase (GPx) activity, Nrf2, Keap1, heme oxygenase-1 (HO-1) expressions, and renal fibrosis.Results: Quercetin administration did not affect the level of protein in urine, plasma creatinine, and urea. However, it tended to reduce the level of MDA, increase GPx activity, Nrf2, Keap1, and HO-1 expression as well as the degree of fibrosis.Conclusion: In 5/6 nephrectomized rats, quercetin tended to ameliorate the level of MDA, GPx activity, Nrf2, Keap1, and HO-1 expression. In addition, quercetin tended to decrease the degree of fibrosis in the remnant kidney.

Download Full-text

Zebrafish Oxr1a Knockout Reveals Its Role in Regulating Antioxidant Defenses and Aging

Genes ◽

10.3390/genes11101118 ◽

2020 ◽

Vol 11 (10) ◽

pp. 1118 ◽

Cited By ~ 1

Author(s):

Hao Xu ◽

Yu Jiang ◽

Sheng Li ◽

Lang Xie ◽

Yi-Xi Tao ◽

...

Keyword(s):

Oxidative Stress ◽

Stress Response ◽

Antioxidant Defenses ◽

Transcriptional Networks ◽

Antioxidant Genes ◽

Apoptosis Pathway ◽

P53 Signaling ◽

Cellular Reactive Oxygen Species ◽

Prolonged Observation

Oxidation resistance gene 1 (OXR1) is essential for protection against oxidative stress in mammals, but its functions in non-mammalian vertebrates, especially in fish, remain uncertain. Here, we created a homozygous oxr1a-knockout zebrafish via the CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9) system. Compared with wild-type (WT) zebrafish, oxr1a−/− mutants exhibited higher mortality and more apoptotic cells under oxidative stress, and multiple antioxidant genes (i.e., gpx1b, gpx4a, gpx7 and sod3a) involved in detoxifying cellular reactive oxygen species were downregulated significantly. Based on these observations, we conducted a comparative transcriptome analysis of early oxidative stress response. The results show that oxr1a mutation caused more extensive changes in transcriptional networks compared to WT zebrafish, and several stress response and pro-inflammatory pathways in oxr1a−/− mutant zebrafish were strongly induced. More importantly, we only observed the activation of the p53 signaling and apoptosis pathway in oxr1a−/− mutant zebrafish, revealing an important role of oxr1a in regulating apoptosis via the p53 signaling pathway. Additionally, we found that oxr1a mutation displayed a shortened lifespan and premature ovarian failure in prolonged observation, which may be caused by the loss of oxr1a impaired antioxidant defenses, thereby increasing pro-apoptotic events. Altogether, our findings demonstrate that oxr1a is vital for antioxidant defenses and anti-aging in zebrafish.

Download Full-text

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.

Download Full-text

Rutaecarpine Inhibits Doxorubicin-Induced Oxidative Stress and Apoptosis by Activating AKT Signaling Pathway

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.809689 ◽

2022 ◽

Vol 8 ◽

Author(s):

Zi-Qi Liao ◽

Yi-Nong Jiang ◽

Zhuo-Lin Su ◽

Hai-Lian Bi ◽

Jia-Tian Li ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Fibrosis ◽

Heart Function ◽

Underlying Mechanism ◽

Protective Role ◽

Pcr Analysis ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Akt Inhibitor

Patients with cancer who receive doxorubicin (DOX) treatment can experience cardiac dysfunction, which can finally develop into heart failure. Oxidative stress is considered the most important mechanism for DOX-mediated cardiotoxicity. Rutaecarpine (Rut), a quinazolinocarboline alkaloid extracted from Evodia rutaecarpa was shown to have a protective effect on cardiac disease. The purpose of this study is to investigate the role of Rut in DOX-induced cardiotoxicity and explore the underlying mechanism. Intravenous injection of DOX (5 mg/kg, once a week) in mice for 4 weeks was used to establish the cardiotoxic model. Echocardiography and pathological staining analysis were used to detect the changes in structure and function in the heart. Western blot and real-time PCR analysis were used to detect the molecular changes. In this study, we found that DOX time-dependently decreased cardiac function with few systemic side effects. Rut inhibited DOX-induced cardiac fibrosis, reduction in heart size, and decrease in heart function. DOX-induced reduction in superoxide dismutase (SOD) and glutathione (GSH), enhancement of malondialdehyde (MDA) was inhibited by Rut administration. Meanwhile, Rut inhibited DOX-induced apoptosis in the heart. Importantly, we further found that Rut activated AKT or nuclear factor erythroid 2-related factor 2 (Nrf-2) which further upregulated the antioxidant enzymes such as heme oxygenase-1 (HO-1) and GSH cysteine ligase modulatory subunit (GCLM) expression. AKT inhibitor (AKTi) partially inhibited Nrf-2, HO-1, and GCLM expression and abolished the protective role of Rut in DOX-induced cardiotoxicity. In conclusion, this study identified Rut as a potential therapeutic agent for treating DOX-induced cardiotoxicity by activating AKT.

Download Full-text

Abstract 15037: Novel Role of Kelch-like ECH-associated Protein 1/NF-E2-related Factor 2 System in Vascular Smooth Muscle Cell Apoptosis Following Vascular Injury

Circulation ◽

10.1161/circ.130.suppl_2.15037 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Takashi Ashino ◽

Masayuki Yamamoto ◽

Satoshi Numazawa

Keyword(s):

Oxidative Stress ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Vascular Injury ◽

Neointimal Hyperplasia ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Neointimal Formation ◽

Quinone Oxidoreductase

Abnormal increases in vascular smooth muscle cells (VSMCs) in the intimal region after vascular injury are a key event in the neointimal hyperplasia followed by vascular occlusive diseases. To maintain vascular functions, the number of VSMCs is tightly controlled by those proliferation and apoptosis during vascular remodeling. Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system plays a critical role in the oxidative stress response. While Keap1 ubiquitinates Nrf2 for degradation under unstressed conditions, this Keap1 function is abrogated in response to oxidative stress, leading to Nrf2 stabilization and coordinated up-regulation of antioxidant genes. We have previously found that Nrf2 plays an important role in neointimal hyperplasia after vascular injury via regulating platelet-derived growth factor-induced reactive oxygen species-dependent VSMC migration; however, the role of Keap1-Nrf2 system in VSMC apoptosis has not been established. Here we show that TUNEL-positive cells are detected in both the layers of neointima and media, both of which observe alpha-smooth muscle actin positive and high Nrf2-expressed cells, 14 days after transluminal arterial injury in mice. Nrf2 deficient mice show decreased TUNEL-positive cells in neointimal and medial areas (60%) and enhanced neointimal formation (I/M ratio: 152%) 14 days after vascular injury compared with the wild-type mice. In VSMCs isolated from the thoracic aorta of rats, depletion of Keap1 with siRNA increases nuclear Nrf2 (685%) and induces its target genes, including NAD(P)H: quinone oxidoreductase-1 (664%) and heme oxygenase-1 (230%). Functionally, Keap1 depletion increase apoptotic morphological features such as cell shrinkage and nuclear condensation (4114%), annexin V binding (512%), and positive TUNEL staining in VSMCs, which is associated with caspase-3/7 activation (576%). Pretransfection of VSMCs with Nrf2 siRNA inhibits apotosis mediated by Keap1 siRNA. In summary, Keap1-Nrf2 system regulates VSMC apoptosis in the process of neointimal formation, thereby inhibiting VSMC hyperproliferation, which may contribute to the development of neointimal hyperplasia after vascular injury.

Download Full-text

Astaxanthin Suppresses Cigarette Smoke-Induced Emphysema through Nrf2 Activation in Mice

Marine Drugs ◽

10.3390/md17120673 ◽

2019 ◽

Vol 17 (12) ◽

pp. 673 ◽

Cited By ~ 8

Author(s):

Hiroaki Kubo ◽

Kazuhisa Asai ◽

Kazuya Kojima ◽

Arata Sugitani ◽

Yohkoh Kyomoto ◽

...

Keyword(s):

Oxidative Stress ◽

Cigarette Smoke ◽

Defense Mechanism ◽

Inflammatory Cells ◽

Lavage Fluid ◽

Chronic Obstructive ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Obstructive Pulmonary Disease ◽

Suppression Effect

Oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key cellular defense mechanism against oxidative stress. Recent studies have shown that astaxanthin protects against oxidative stress via Nrf2. In this study, we investigated the emphysema suppression effect of astaxanthin via Nrf2 in mice. Mice were divided into four groups: control, smoking, astaxanthin, and astaxanthin + smoking. The mice in the smoking and astaxanthin + smoking groups were exposed to cigarette smoke for 12 weeks, and the mice in the astaxanthin and astaxanthin + smoking groups were fed a diet containing astaxanthin. Significantly increased expression levels of Nrf2 and its target gene, heme oxygenase-1 (HO-1), were found in the lung homogenates of astaxanthin-fed mice. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was significantly decreased, and emphysema was significantly suppressed. In conclusion, astaxanthin protects against oxidative stress via Nrf2 and ameliorates cigarette smoke-induced emphysema. Therapy with astaxanthin directed toward activating the Nrf2 pathway has the potential to be a novel preventive and therapeutic strategy for COPD.

Download Full-text