scholarly journals An Update on the Role of Nrf2 in Respiratory Disease: Molecular Mechanisms and Therapeutic Approaches

2021 ◽  
Vol 22 (16) ◽  
pp. 8406
Author(s):  
Jooyeon Lee ◽  
Jimin Jang ◽  
Sung-Min Park ◽  
Se-Ran Yang
Keyword(s):  
Oxidative Stress ◽  
Respiratory Diseases ◽  
Molecular Mechanisms ◽  
Antioxidant Response ◽  
Atmospheric Environment ◽  
Chronic Obstructive ◽  
Related Factor ◽  
Protective Effects ◽  
Cell Protection ◽  
Obstructive Pulmonary Disease

Nuclear factor erythroid 2-related factor (Nrf2) is a transcriptional activator of the cell protection gene that binds to the antioxidant response element (ARE). Therefore, Nrf2 protects cells and tissues from oxidative stress. Normally, Kelch-like ECH-associated protein 1 (Keap1) inhibits the activation of Nrf2 by binding to Nrf2 and contributes to Nrf2 break down by ubiquitin proteasomes. In moderate oxidative stress, Keap1 is inhibited, allowing Nrf2 to be translocated to the nucleus, which acts as an antioxidant. However, under unusually severe oxidative stress, the Keap1-Nrf2 mechanism becomes disrupted and results in cell and tissue damage. Oxide-containing atmospheric environment generally contributes to the development of respiratory diseases, possibly leading to the failure of the Keap1-Nrf2 pathway. Until now, several studies have identified changes in Keap1-Nrf2 signaling in models of respiratory diseases, such as acute respiratory distress syndrome (ARDS)/acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and asthma. These studies have confirmed that several Nrf2 activators can alleviate symptoms of respiratory diseases. Thus, this review describes how the expression of Keap1-Nrf2 functions in different respiratory diseases and explains the protective effects of reversing this expression.

scholarly journals Role of Nrf2 and Its Activators in Respiratory Diseases

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Qinmei Liu ◽  
Yun Gao ◽  
Xinxin Ci
Keyword(s):  
Respiratory Diseases ◽  
Respiratory Infections ◽  
Redox Balance ◽  
Antioxidant Response ◽  
Experimental Models ◽  
26S Proteasome ◽  
Chronic Obstructive ◽  
Related Factor ◽  
Protective Effects ◽  
Obstructive Pulmonary Disease

Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidant response element- (ARE-) driven cytoprotective protein expression. The activation of Nrf2 signaling plays an essential role in preventing cells and tissues from injury induced by oxidative stress. Under the unstressed conditions, natural inhibitor of Nrf2, Kelch-like ECH-associated protein 1 (Keap1), traps Nrf2 in the cytoplasm and promotes the degradation of Nrf2 by the 26S proteasome. Nevertheless, stresses including highly oxidative microenvironments, impair the ability of Keap1 to target Nrf2 for ubiquitination and degradation, and induce newly synthesized Nrf2 to translocate to the nucleus to bind with ARE. Due to constant exposure to external environments, including diverse pollutants and other oxidants, the redox balance maintained by Nrf2 is fairly important to the airways. To date, researchers have discovered that Nrf2 deletion results in high susceptibility and severity of insults in various models of respiratory diseases, including bronchopulmonary dysplasia (BPD), respiratory infections, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and lung cancer. Conversely, Nrf2 activation confers protective effects on these lung disorders. In the present review, we summarize Nrf2 involvement in the pathogenesis of the above respiratory diseases that have been identified by experimental models and human studies and describe the protective effects of Nrf2 inducers on these diseases.

scholarly journals Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches – Pulmonary Disease/Asthma

2021 ◽  
Vol 12 ◽  
Author(s):  
Camille Audousset ◽  
Toby McGovern ◽  
James G. Martin
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Protective Role ◽  
Experimental Models ◽  
Chronic Obstructive ◽  
Related Factor ◽  
Obstructive Pulmonary Disease

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor involved in redox homeostasis and in the response induced by oxidative injury. Nrf2 is present in an inactive state in the cytoplasm of cells. Its activation by internal or external stimuli, such as infections or pollution, leads to the transcription of more than 500 elements through its binding to the antioxidant response element. The lungs are particularly susceptible to factors that generate oxidative stress such as infections, allergens and hyperoxia. Nrf2 has a crucial protective role against these ROS. Oxidative stress and subsequent activation of Nrf2 have been demonstrated in many human respiratory diseases affecting the airways, including asthma and chronic obstructive pulmonary disease (COPD), or the pulmonary parenchyma such as acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. Several compounds, both naturally occurring and synthetic, have been identified as Nrf2 inducers and enhance the activation of Nrf2 and expression of Nrf2-dependent genes. These inducers have proven particularly effective at reducing the severity of the oxidative stress-driven lung injury in various animal models. In humans, these compounds offer promise as potential therapeutic strategies for the management of respiratory pathologies associated with oxidative stress but there is thus far little evidence of efficacy through human trials. The purpose of this review is to summarize the involvement of Nrf2 and its inducers in ARDS, COPD, asthma and lung fibrosis in both human and in experimental models.

scholarly journals Oregano Essential Oil Induces SOD1 and GSH Expression through Nrf2 Activation and Alleviates Hydrogen Peroxide-Induced Oxidative Damage in IPEC-J2 Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Yi Zou ◽  
Jun Wang ◽  
Jian Peng ◽  
Hongkui Wei
Keyword(s):  
Hydrogen Peroxide ◽  
Essential Oil ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Cell Damage ◽  
Antioxidant Response ◽  
Related Factor ◽  
Protective Effects ◽  
Oregano Essential Oil ◽  
Protein Levels

Oregano essential oil (OEO) has long been used to improve the health of animals, particularly their intestinal health. The health benefits of OEO are generally attributed to antioxidative actions, but the mechanisms remain unclear. Here, we investigate the antioxidative effects of OEO and their underlying molecular mechanisms in porcine small intestinal epithelial (IPEC-J2) cells. We found that OEO treatment prior to hydrogen peroxide (H2O2) exposure increased cell viability and prevented lactate dehydrogenase (LDH) release into the medium. H2O2-induced reactive oxygen species (ROS) and malondialdehyde (MDA) were remarkably suppressed by OEO. OEO dose-dependently increased mRNA and protein levels of the nuclear factor-erythroid 2-related factor-2 (Nrf2) target genes Cu/Zn-superoxide dismutase (SOD1) and g-glutamylcysteine ligase (GCLC, GLCM), as well as intracellular concentrations of SOD1 and glutathione. OEO also increased intranuclear expression of Nrf2 and the activity of an antioxidant response element reporter plasmid in IPEC-J2 cells. The OEO-induced expression of Nrf2-regulated genes and increased SOD1 and glutathione concentrations in IPEC-J2 cells were reduced by Nrf2 small interfering (si) RNAs, counteracting the protective effects of OEO against oxidative stress in IPEC-J2 cells. Our results suggest that OEO protects against H2O2-induced IPEC-J2 cell damage by inducing Nrf2 and related antioxidant enzymes.

scholarly journals The role of nuclear factor-erythroid 2 related factor 2 (Nrf-2) in the protection against lung injury

2017 ◽  
Vol 312 (2) ◽  
pp. L155-L162 ◽  
Author(s):  
Hailin Zhao ◽  
Shiori Eguchi ◽  
Azeem Alam ◽  
Daqing Ma
Keyword(s):  
Lung Injury ◽  
Therapeutic Potential ◽  
Antioxidant Response ◽  
Protective Role ◽  
Chronic Obstructive ◽  
Related Factor ◽  
Nuclear Factor ◽  
Obstructive Pulmonary Disease ◽  
Antioxidant Response Elements

Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a ubiquitous master transcription factor that upregulates antioxidant response elements (AREs)-mediated expression of antioxidant enzyme and cytoprotective proteins. Activation of Nrf2 has been shown to be protective against lung injury. In the lung, diverse stimuli including environmental oxidants, medicinal agents, and pathogens can activate Nrf2. Nrf2 translocates to the nucleus and binds to an ARE. Through transcriptional induction of ARE-bearing genes encoding antioxidant-detoxifying proteins, Nrf2 induces cellular rescue pathways against oxidative pulmonary injury, abnormal inflammatory and immune responses, and apoptosis. The Nrf2-antioxidant pathway has been shown to be important in the protection against various lung injuries including acute lung injury/acute respiratory distress syndrome and bronchopulmonary dysplasia, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, and allergy and was widely examined for new therapeutic targets. The present review explores the protective role of Nrf-2 against lung injury and the therapeutic potential in targeting Nrf-2.

scholarly journals Lactate and pyruvate promote oxidative stress resistance through hormetic ROS signaling

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Arnaud Tauffenberger ◽  
Hubert Fiumelli ◽  
Salam Almustafa ◽  
Pierre J. Magistretti
Keyword(s):  
Oxidative Stress ◽  
Cell Survival ◽  
Stress Resistance ◽  
Molecular Mechanisms ◽  
Antioxidant Defenses ◽  
Related Factor ◽  
Cell Protection ◽  
Unfolded Protein ◽  
Ros Burst

Abstract L-lactate was long considered a glycolytic by-product but is now being recognized as a signaling molecule involved in cell survival. In this manuscript, we report the role of L-lactate in stress resistance and cell survival mechanisms using neuroblastoma cells (SH-SY5Y) as well as the C. elegans model. We observed that L-lactate promotes cellular defense mechanisms, including Unfolded Protein Response (UPR) and activation of nuclear factor erythroid 2–related factor 2 (NRF2), by promoting a mild Reactive Oxygen Species (ROS) burst. This increase in ROS triggers antioxidant defenses and pro-survival pathways, such as PI3K/AKT and Endoplasmic Reticulum (ER) chaperones. These results contribute to the understanding of the molecular mechanisms involved in beneficial effects of L-lactate, involving mild ROS burst, leading to activation of unfolded protein responses and detoxification mechanisms. We present evidence that this hormetic mechanism induced by L-lactate protects against oxidative stress in vitro and in vivo. This work contributes to the identification of molecular mechanisms, which could serve as targets for future therapeutic approaches for cell protection and aging-related disorders.

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

Marine Drugs ◽  
2019 ◽  
Vol 17 (12) ◽  
pp. 673 ◽  
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.

scholarly journals LncRNA Nqo1-AS1 Attenuates Cigarette Smoke-Induced Oxidative Stress by Upregulating its Natural Antisense Transcript Nqo1

2021 ◽  
Vol 12 ◽  
Author(s):  
Haiyun Zhang ◽  
Ruijuan Guan ◽  
Zili Zhang ◽  
Defu Li ◽  
Jingyi Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cigarette Smoke ◽  
Mrna Stability ◽  
Molecular Mechanisms ◽  
Antisense Transcript ◽  
Alveolar Epithelium ◽  
Chronic Obstructive ◽  
Protein Coding ◽  
Obstructive Pulmonary Disease ◽  
Coding Potential

Evidence of the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of chronic obstructive pulmonary disease (COPD) is growing but still largely unknown. This study aims to explore the expression, functions and molecular mechanisms of Fantom3_F830212L20, a lncRNA that transcribes in an antisense orientation to Nqo1.We name this lncRNA as Nqo1 antisense transcript 1 (Nqo1-AS1). The distribution, expression level and protein coding potential of Nqo1-AS1 were determined. The effects of Nqo1-AS1 on cigarette smoke (CS)-induced oxidative stress were also evaluated. The results showed that Nqo1-AS1 were mainly located in the cytoplasm of mouse alveolar epithelium and had a very low protein coding potential. Nqo1-AS1 (or its human homologue) was increased with the increase of CS exposure. Nqo1-AS1 overexpression enhanced the mRNA and protein levels of Nqo1 and Serpina1 mRNA expression, and attenuated CS-induced oxidative stress, whereas knockdown of Nqo1-AS1 significantly decreased Nqo1 and Serpina1 mRNA expressions, and aggravated CS-induced oxidative stress. Nqo1-AS1 increased Nqo1 mRNA stability and upregulated Nqo1 expression through antisense pairing with Nqo1 3′UTR. In conclusion, these results suggest that Nqo1-AS1 attenuates CS-induced oxidative stress by increasing Nqo1 mRNA stability and upregulating Nqo1 expression, which might serve as a novel approach for the treatment of COPD.

Protective effects of curcumin against mercury-induced hepatic injuries in rats, involvement of oxidative stress antagonism, and Nrf2-ARE pathway activation

2016 ◽  
Vol 36 (9) ◽  
pp. 949-966 ◽  
Author(s):  
W Liu ◽  
Z Xu ◽  
H Li ◽  
M Guo ◽  
T Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Radical Scavenging ◽  
Antioxidant Response ◽  
Serum Lactate ◽  
Serum Lactate Dehydrogenase ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Protective Effects ◽  
Glutamylcysteine Synthetase ◽  
Subunit Expression

Mercury (Hg) represents a ubiquitous environmental heavy metal that could lead to severe toxic effects in a variety of organs usually at a low level. The present study focused on the liver oxidative stress, one of the most important roles playing in Hg hepatotoxicity, by evaluation of different concentrations of mercuric chloride (HgCl2) administration. Moreover, the protective potential of curcumin against Hg hepatotoxic effects was also investigated. Eighty-four rats were randomly divided into six groups for a three-days experiment: control, dimethyl sulfoxide control, HgCl2 treatment (0.6, 1.2, and 2.4 mg kg−1 day−1), and curcumin pretreatment (100 mg kg−1 day−1) groups. Exposure of HgCl2 resulted in acute dose-dependent hepatotoxic effects. Administration of 2.4 mg kg−1 HgCl2 significantly elevated total Hg, nonprotein sulfhydryl, reactive oxygen species formation, malondialdehyde, apoptosis levels, serum lactate dehydrogenase, and alanine transaminase activities, with an impairment of superoxide dismutase and glutathione peroxidase in the liver. Moreover, HgCl2 treatment activated nuclear factor-E2-related factor 2-antioxidant response element (Nrf2-ARE) signaling pathway in further investigation, with a significant upregulation of Nrf2, heme oxygenase-1, and γ-glutamylcysteine synthetase heavy subunit expression, relative to control. Pretreatment with curcumin obviously prevented HgCl2-induced liver oxidative stress, which may be due to its free radical scavenging or Nrf2-ARE pathway-inducing properties. Taking together these data suggest that curcumin counteracts HgCl2 hepatotoxicity through antagonizing liver oxidative stress.

Dexamethasone and losartan combination treatment protected cigarette smoke-induced COPD in rats

2020 ◽  
pp. 096032712095001
Author(s):  
Samia S Sokar ◽  
Esraa H Afify ◽  
Enass Y Osman
Keyword(s):  
Oxidative Stress ◽  
Lung Injury ◽  
Cigarette Smoke ◽  
Lavage Fluid ◽  
Control Group ◽  
Chronic Obstructive ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Obstructive Pulmonary Disease ◽  
Sprague Dawley Rats

Chronic Obstructive Pulmonary Disease (COPD) is a dangerous prevalent smoking-related disease characterized by abnormal inflammation and oxidative stress and expected to be the third cause of death in the world next decade. Corticosteroids have low effects in decreasing numbers of inflammatory mediators specifically in long-term use. Our study designed to investigate the possible protective effects of combined dexamethasone (Dex) (2mg/kg) and losartan (Los) (30mg/kg angiotensin receptor blocker, it possesses antioxidant and anti-inflammatory properties in lung injury in mice) against cigarette -smoke (CS) induced COPD in rats compared with dexamethasone and losartan. Male Sprague Dawley rats (N = 40) divided into five groups (n = 8): control group, CS group, Dex group, Los group, and Dex +Los group. COPD induced in rats by CS exposure twice daily for 10 weeks. After the specified treatment period, bronchoalveolar lavage fluid (BALF) and lung tissue were collected for measurement of SOD, NO, MDA, ICAM-, MMP-9, CRP, NF-κB and histopathology scoring. Our results indicated that Los+Dex significantly prevent CS-induced COPD emphysema, congested alveoli, and elevation of lung injury parameters in BALF. They also showed a significant decrease in MDA, ICAM-1, MMP-9, CRP, and NF-κB and a significant increase in SOD and NO. In conclusion, adding Los to Dex potentiating their activity in inhibition the progression of COPD based on its activity on oxidative stress, inflammation, and NF-κB protein expression.

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