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Cuadrado A, Cazalla E, Bach A, Bathish B, Naidu SD, DeNicola GM, Dinkova-Kostova AT, Fernández-Ginés R, Grochot-Przeczek A, Hayes JD, Kensler TW, León R, Liby KT, López MG, Manda G, Shivakumar AK, Hakomäki H, Moerland JA, Motohashi H, Rojo AI, Sykiotis GP, Taguchi K, Valverde ÁM, Yamamoto M, Levonen AL. Health position paper and redox perspectives - Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases. Redox Biol 2025; 81:103569. [PMID: 40059038 PMCID: PMC11970334 DOI: 10.1016/j.redox.2025.103569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 02/13/2025] [Accepted: 02/24/2025] [Indexed: 03/22/2025] Open
Abstract
Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.
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Affiliation(s)
- Antonio Cuadrado
- Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC-UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
| | - Eduardo Cazalla
- Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC-UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Anders Bach
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark
| | - Boushra Bathish
- Jacqui Wood Cancer Centre, Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK
| | - Sharadha Dayalan Naidu
- Jacqui Wood Cancer Centre, Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK
| | - Gina M DeNicola
- Department of Metabolism and Physiology, H. Lee. Moffitt Cancer Center, Tampa, FL, 33612, USA
| | - Albena T Dinkova-Kostova
- Jacqui Wood Cancer Centre, Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK
| | - Raquel Fernández-Ginés
- Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC-UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Anna Grochot-Przeczek
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - John D Hayes
- Jacqui Wood Cancer Centre, Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK
| | - Thomas W Kensler
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
| | - Rafael León
- Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), 28007, Madrid, Spain
| | - Karen T Liby
- Indiana University School of Medicine, Department of Medicine, W. Walnut Street, Indianapolis, IN, 46202, USA
| | - Manuela G López
- Department of Pharmacology, School of Medicine, Universidad Autónoma Madrid, Madrid, Spain; Instituto de Investigación Sanitario (IIS-IP), Hospital Universitario de La Princesa, Madrid, Spain; Instituto Teófilo Hernando, Madrid, Spain
| | - Gina Manda
- Radiobiology Laboratory, Victor Babes National Institute of Pathology, Bucharest, Romania
| | | | - Henriikka Hakomäki
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Jessica A Moerland
- Indiana University School of Medicine, Department of Medicine, W. Walnut Street, Indianapolis, IN, 46202, USA
| | - Hozumi Motohashi
- Department of Medical Biochemistry, Graduate School of Medicine Tohoku University, Sendai, Japan; Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Ana I Rojo
- Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC-UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | | | - Keiko Taguchi
- Laboratory of Food Chemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan; Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Ángela M Valverde
- Instituto de Investigaciones Biomédicas "Sols-Morreale" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain
| | - Masayuki Yamamoto
- Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Anna-Liisa Levonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
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Ulaş N, Üstündağ H, Özkanlar S, Erbaş E, Kara A, Özkanlar Y. D-carvone attenuates LPS-induced acute lung injury via TLR4/NF-κB and Nrf2/HO-1 signaling pathways in rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04024-y. [PMID: 40116872 DOI: 10.1007/s00210-025-04024-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 03/05/2025] [Indexed: 03/23/2025]
Abstract
Acute lung injury (ALI) is a severe respiratory disorder associated with high morbidity and mortality. Lipopolysaccharide (LPS) is widely used to induce ALI in animal models. D-carvone, a natural monoterpene, has been reported to possess anti-inflammatory and antioxidant properties. This study aimed to investigate the protective effects of D-carvone on LPS-induced ALI in rats. Thirty-six male rats were randomly divided into six groups (n = 6): control, D-carvone (10 mg/kg and 20 mg/kg p.o.), LPS (10 mg/kg E. coli lipopolysaccharide i.p.), and LPS + D-carvone (LPS with either 10 or 20 mg/kg D-carvone). D-carvone was administered orally once daily for 10 days. On day 10, sepsis was induced with LPS administration, and samples were collected after 6 h under deep anesthesia. LPS administration caused significant lung injury, as evidenced by increased histopathological scores, upregulation of pro-inflammatory markers (TLR4, IL-1β, TNF-α), and oxidative stress (increased MDA, decreased GSH and SOD). Treatment with D-carvone at both doses significantly attenuated these changes. D-carvone downregulated pro-inflammatory markers, upregulated anti-inflammatory (NRF2) and anti-apoptotic (Bcl-2) proteins, and reduced the levels of pro-inflammatory cytokines (IL-1β, TNF-α, IL-8) in lung tissues. In conclusion, D-carvone protects against LPS-induced ALI in rats, possibly through its anti-inflammatory and antioxidant properties. These findings suggest that D-carvone could be a potential therapeutic candidate for preventing and treating ALI.
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Affiliation(s)
- Nergis Ulaş
- Department of Internal Medicine, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey
| | - Hilal Üstündağ
- Department of Physiology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey.
| | - Seçkin Özkanlar
- Department of Biochemistry, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey
| | - Elif Erbaş
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
| | - Adem Kara
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey
| | - Yunusemre Özkanlar
- Department of Internal Medicine, Faculty of Veterinary, Ondokuz Mayis University, Samsun, Turkey
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Wang T, Liu M, Li X, Zhang S, Gu H, Wei X, Wang X, Xu Z, Shen T. Naturally-derived modulators of the Nrf2 pathway and their roles in the intervention of diseases. Free Radic Biol Med 2024; 225:560-580. [PMID: 39368519 DOI: 10.1016/j.freeradbiomed.2024.09.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 09/19/2024] [Accepted: 09/23/2024] [Indexed: 10/07/2024]
Abstract
Cumulative evidence has verified that persistent oxidative stress is involved in the development of various chronic diseases, including pulmonary, neurodegenerative, kidney, cardiovascular, and liver diseases, as well as cancers. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in regulating cellular oxidative stress and inflammatory reactions, making it a focal point for disease prevention and treatment strategies. Natural products are essential resources for discovering leading molecules for new drug research and development. In this review, we comprehensively outlined the progression of the knowledge on the Nrf2 pathway, Nrf2 activators in clinical trials, the naturally-derived Nrf2 modulators (particularly from 2014-present), as well as their effects on the pathogenesis of chronic diseases.
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Affiliation(s)
- Tian Wang
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Mingjie Liu
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Xinyu Li
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Sen Zhang
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Haoran Gu
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Xuan Wei
- Shandong Center for Food and Drug Evaluation and Inspection, Jinan, Shandong, PR China
| | - Xiaoning Wang
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Zhenpeng Xu
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China.
| | - Tao Shen
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China.
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Yang M, Chen Y, Huang X, Shen F, Meng Y. ETS1 Ameliorates Hyperoxia-Induced Bronchopulmonary Dysplasia in Mice by Activating Nrf2/HO-1 Mediated Ferroptosis. Lung 2023; 201:425-441. [PMID: 37490064 PMCID: PMC10444662 DOI: 10.1007/s00408-023-00639-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 07/13/2023] [Indexed: 07/26/2023]
Abstract
PURPOSE Bronchopulmonary dysplasia (BPD) is associated with hyperoxia-induced oxidative stress-associated ferroptosis. This study examined the effect of E26 oncogene homolog 1 (ETS1) on oxidative stress-associated ferroptosis in BPD. METHODS Hyperoxia-induced A549 cells and neonatal mice were used to establish BPD models. The effects of ETS1 on hyperoxia-induced ferroptosis-like changes in A549 cells were investigated by overexpression of ETS1 plasmid transfection and erastin treatment. Glucose consumption, lactate production, and NADPH levels were assessed by the glucose, lactate, and NADP+/NADPH assay kits, respectively. The potential regulatory relationship between ETS1 and Nrf2/HO-1 was examined by treating hyperoxia-induced A549 cells with the Nrf2 inhibitor ML385. ETS1 effect on the Nrf2 promoter was explored by dual-luciferase reporter and chromatin immunoprecipitation assay. The effect of ETS1 on the symptoms of BPD mice was examined by injecting an adenovirus overexpressing ETS1. RESULTS ETS1 overexpression increased hyperoxia-induced cell viability, glucose consumption, lactate production, and NADPH levels and reduced inflammation and apoptosis in A549 cells. In animal experiments, ETS1 overexpression prevented weight loss, airway enlargement, and reductions in radial alveolar counts in BPD mice, while reducing the mean linear intercept, mean alveolar diameter and inflammation. ETS1 overexpression suppressed PTGS2 and CHAC1 expression, reduced ROS, MDA and ferrous iron (Fe2+) production and increased GSH levels in hyperoxia-induced A549 cells and BPD mice. In addition, ETS1 can bind to the Nrf2 promoter region and thus promote Nrf2 transcription. ETS1 overexpression increased the mRNA and protein levels of Nrf2, HO-1, xCT, and GPX4 in hyperoxia-induced A549 cells and BPD mice. In hyperoxia-induced A549 cells, erastin and ML385 treatment abolished the effect of ETS1 overexpression. CONCLUSION ETS1 is important in oxidative stress-related ferroptosis in a hyperoxia-induced BPD model, and the effect is partially mediated by the Nrf2/HO-1 axis.
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Affiliation(s)
- Min Yang
- Respiratory Department, Hunan Children's Hospital, Changsha, 410007, China.
| | - Yanping Chen
- Respiratory Department, Hunan Children's Hospital, Changsha, 410007, China
| | | | - Fang Shen
- Research Institute of Children, Hunan Children's Hospital, Changsha, 410007, China
| | - Yanni Meng
- Respiratory Department, Hunan Children's Hospital, Changsha, 410007, China
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Zhang J, Zhang M, Zhang WH, Zhu QM, Ning J, Huo XK, Xiao HT, Sun CP. Total terpenoids of Inula japonica activated the Nrf2 receptor to alleviate the inflammation and oxidative stress in LPS-induced acute lung injury. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 107:154377. [PMID: 36116200 DOI: 10.1016/j.phymed.2022.154377] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/15/2022] [Accepted: 08/01/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Acute lung injury (ALI) is a life-threatening lung disease and characterized by pulmonary edema and atelectasis. Inula japonica Thunb. is a commonly used traditional Chinese medicine for the treatment of lung diseases. However, the potential effect and mechanism of total terpenoids of I. japonica (TTIJ) on ALI remain obscure. PURPOSE This study focused on the protective effect of TTIJ on lipopolysaccharide (LPS)-induced ALI in mice and its potential mechanism. STUDY DESIGN AND METHODS A mouse model of ALI was established by intratracheal instillation of LPS to investigate the protective effect of TTIJ. RNA-seq and bioinformatics were then performed to reveal the underlying mechanism. Finally, western blot and real-time qPCR were used to verify the effects of TTIJ on the inflammation and oxidative stress. RESULTS TTIJ notably attenuated LPS-induced histopathological changes of lung. The RNA-seq result suggested that the protective effect of TTIJ on LPS-induced ALI were associated with the Toll-like receptor 4 (TLR4) and nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathways. Pretreatment with TTIJ significantly reduced the inflammation and oxidative stress via regulating levels of pro-inflammatory and anti-oxidative cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD), and glutathione (GSH), in LPS-induced ALI mice. TTIJ treatment could suppress the cyclooxygenase-2 (COX-2) expression level and the phosphorylation of p65, p38, ERK, and JNK through the inactivation of the MAPK/NF-κB signaling pathway in a TLR4-independent manner. Meanwhile, TTIJ treatment upregulated expression levels of proteins involved in the Nrf2 signaling pathway, such as heme oxygenase-1 (HO-1), NAD(P)H: quinoneoxidoreductase-1 (NQO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and glutamate-cysteine ligase modifier subunit (GCLM), via activating the Nrf2 receptor, which was confirmed by the luciferase assay. CONCLUSION TTIJ could activate the Nrf2 receptor to alleviate the inflammatory response and oxidative stress in LPS-induced ALI mice, which suggested that TTIJ could serve as the potential agent in the treatment of ALI.
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Affiliation(s)
- Juan Zhang
- College of Civil and Transportation Engineering, Shenzhen University, Shenzhen, China; School of pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China; Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Min Zhang
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Wen-Hao Zhang
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Qi-Meng Zhu
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Jing Ning
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Xiao-Kui Huo
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China.
| | - Hai-Tao Xiao
- School of pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China.
| | - Cheng-Peng Sun
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China.
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Melatonin ameliorates bleomycin-induced pulmonary fibrosis via activating NRF2 and inhibiting galectin-3 expression. Acta Pharmacol Sin 2022; 44:1029-1037. [PMID: 36333557 PMCID: PMC9638373 DOI: 10.1038/s41401-022-01018-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 10/19/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022]
Abstract
Pulmonary fibrosis (PF) is a chronic interstitial lung disease with no effective therapies. Galectin-3 (Gal-3), a marker of oxidative stress, plays a key role in the pathogenesis of PF. Fibroblast-myofibroblast differentiation (FMD) is an important source of fibrotic cells in PF. Previous studies showed that melatonin (MT) exerted anti-fibrotic effect in many diseases including PF through its antioxidant activity. In the present study we investigated the relationships among Gal-3, NRF2, ROS in FMD and their regulation by MT. We established an in vitro model of FMD in TGF-β1-treated human fetal lung fibroblast1 (HFL1) cells and a PF mouse model via bleomycin (BLM) intratracheal instillation. We found that Gal-3 expression was significantly increased both in vitro and in vivo. Knockdown of Gal-3 in HFL1 cells markedly attenuated TGF-β1-induced FMD process and ROS accumulation. In TGF-β1-treated HFL1 cells, pretreatment with NRF2-specific inhibitor ML385 (5 μM) significantly increased the levels of Gal-3, α-SMA and ROS, suggesting that the expression of Gal-3 was regulated by NRF2. Treatment with NRF2-activator MT (250 μM) blocked α-SMA and ROS accumulation accompanied by reduced Gal-3 expression. In BLM-induced PF model, administration of MT (5 mg·kg−1·d−1, ip for 14 or 28 days) significantly attenuated the progression of lung fibrosis through up-regulating NRF2 and down-regulating Gal-3 expression in lung tissues. These results suggest that Gal-3 regulates TGF-β1-induced pro-fibrogenic responses and ROS production in FMD, and MT activates NRF2 to block FMD process by down-regulating Gal-3 expression. This study provides a useful clue for a clinical strategy to prevent PF.
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Network-based toxicogenomic approach to explore oral benzo(a)pyrene exposure effect on respiratory system. Mol Cell Toxicol 2022. [DOI: 10.1007/s13273-022-00223-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Huang T, Tong H, Zhou H, Wang J, Hu L, Wang Y, Huang Z. ADSC-Exosomes Alleviate MTX-induced Rat Neuronal Damage by Activating Nrf2-ARE Pathway. J Mol Neurosci 2022; 72:1334-1344. [PMID: 35322376 PMCID: PMC9170627 DOI: 10.1007/s12031-022-01996-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 03/01/2022] [Indexed: 01/31/2023]
Abstract
The aim of this study was to analyze the efficacy and underlying mechanism of adipose-derived mesenchymal stem cell exosome (ADSC-exosomes)-mediated protection on methotrexate (MTX)-induced neuronal damage. We established a H2O2-induced oxidative stress model in vitro, as well as an MTX-induced neuronal damage rat model in vivo. We analyzed the effects of ADSC-exosomes on neuronal damage and Nrf2-ARE signaling pathway in rats and related mechanisms. The morphological and functional recovery of rat hippocampal neurons by ADSC-exosomes was examined by Nissl staining and modified neurological severity score (mNSS) score. The activation of Nrf2-ARE pathway effectively inhibited H2O2-induced oxidative stress. ADSC-exosomes treatment restored the activity of hippocampal neuronal cells, reduced ROS production, and inhibited hippocampal neuronal cells apoptosis. In in vivo experiments, ADSC-exosomes ameliorates MTX-induced hippocampal neuron damage by triggering Nrf2-ARE pathway, decreasing IL-6, IFN-, and TNF-a levels and TUNEL positive cells in hippocampus, and repairing hippocampal neuronal cell damage. ADSC-exosomes ameliorated MTX-induced neuronal damage and suppressed oxidative stress induced by neuronal damage through the activation of Nrf2-ARE signaling pathway.
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Affiliation(s)
- Tingting Huang
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hongfei Tong
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Haixia Zhou
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Juxiang Wang
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Linglong Hu
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yao Wang
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhen Huang
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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Mishra R, Nawas AF, Mendelson CR. Role of NRF2 in immune modulator expression in developing lung. FASEB J 2021; 35:e21758. [PMID: 34245611 DOI: 10.1096/fj.202100129rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 06/07/2021] [Accepted: 06/11/2021] [Indexed: 11/11/2022]
Abstract
After birth, the alveolar epithelium is exposed to environmental pathogens and high O2 tensions. The alveolar type II cells may protect this epithelium through surfactant production. Surfactant protein, SP-A, an immune modulator, is developmentally upregulated in fetal lung with surfactant phospholipid synthesis. Herein, we observed that the redox-regulated transcription factor, NRF2, and co-regulated C/EBPβ and PPARγ, were markedly induced during cAMP-mediated differentiation of cultured human fetal lung (HFL) epithelial cells. This occurred with enhanced expression of immune modulators, SP-A, TDO2, AhR, and NQO1. Like SP-A, cAMP induction of NRF2 was prevented when cells were exposed to hypoxia. NRF2 knockdown inhibited induction of C/EBPβ, PPARγ, and immune modulators. Binding of endogenous NRF2 to promoters of SP-A and other immune modulator genes increased during HFL cell differentiation. In mouse fetal lung (MFL), a developmental increase in Nrf2, SP-A, Tdo2, Ahr, and Nqo1 and decrease in Keap1 occurred from 14.5 to 18.5 dpc. Developmental induction of Nrf2 in MFL was associated with increased nuclear localization of NF-κB p65, a decline in p38 MAPK phosphorylation, increase in the MAPK phosphatase, DUSP1, induction of the histone acetylase, CBP, and decline in the histone deacetylase, HDAC4. Thus, together with surfactant production, type II cells protect the alveolar epithelium through increased expression of NRF2 and immune modulators to prevent inflammation and oxidative stress. Our findings further suggest that lung cancer cells have usurped this developmental pathway to promote immune tolerance and enhance survival.
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Affiliation(s)
- Ritu Mishra
- Department of Biochemistry, North Texas March of Dimes Birth Defects Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Afshan Fathima Nawas
- Department of Biochemistry, North Texas March of Dimes Birth Defects Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Carole R Mendelson
- Department of Biochemistry, North Texas March of Dimes Birth Defects Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA.,Department of Obstetrics & Gynecology, North Texas March of Dimes Birth Defects Center, The University of Texas Southwestern Med Center, Dallas, TX, USA
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Jia L, Hao H, Wang C, Wei J. Etomidate attenuates hyperoxia-induced acute lung injury in mice by modulating the Nrf2/HO-1 signaling pathway. Exp Ther Med 2021; 22:785. [PMID: 34055084 PMCID: PMC8145798 DOI: 10.3892/etm.2021.10217] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 05/04/2021] [Indexed: 12/15/2022] Open
Abstract
The present study aimed to investigate the protective effects of etomidate on hyperoxia-induced acute lung injury in mice, particularly on the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. Fifty specific pathogen-free mice were randomly divided into the blank control, model, high oxygen exposure + low etomidate dose (0.3 mg·kg-1), a high oxygen exposure + moderate etomidate dose (3 mg·kg-1), and a high oxygen exposure + high etomidate dose (10 mg·kg-1) groups, with ten mice allotted per group. After 72 h, the mice were sacrificed and the lung tissues were harvested, and the wet-to-dry (W/D) ratio of the tissues was calculated. Hematoxylin-eosin staining was performed to observe the pathological changes in the lung tissues, and the lung injury score (LIS) was calculated. The mRNA and protein expression levels of Nrf2 and HO-1 were measured. The malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD) and catalase (CAT) levels were also measured, and interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNF-α) and IL-10 concentrations in the bronchoalveolar lavage fluid were determined. At low and moderate doses, etomidate decreased pathological damage in the lung tissue, decreased the LIS and W/D ratio, upregulated Nrf2 and HO-1 mRNA and protein expression, decreased IL-1β, IL-6, and TNF-α concentrations, increased MPO activity and IL-10 levels, suppressed the production of the oxidation product MDA, and enhanced the activities of the antioxidant enzymes CAT and SOD. Within a certain dose range, etomidate enhanced antioxidant and anti-inflammatory effects in mice, thereby decreasing lung injury induced by the chronic inhalation of oxygen at high concentrations. Furthermore, the underlying mechanism may be associate with the upregulation of the Nrf2/HO-1 signaling pathway.
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Affiliation(s)
- Liming Jia
- Department of Anesthesiology, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
| | - Hongzhong Hao
- Department of Anesthesiology, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
| | - Chunyu Wang
- Department of Anesthesiology, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
| | - Jianfeng Wei
- Department of Anesthesiology, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
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Rana AK, Rahmatkar SN, Kumar A, Singh D. Glycogen synthase kinase-3: A putative target to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Cytokine Growth Factor Rev 2020; 58:92-101. [PMID: 32948440 PMCID: PMC7446622 DOI: 10.1016/j.cytogfr.2020.08.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 08/20/2020] [Indexed: 02/07/2023]
Abstract
The coronavirus disease 19 (COVID-19) outbreak caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) had turned out to be highly pathogenic and transmittable. Researchers throughout the globe are still struggling to understand this strain's aggressiveness in search of putative therapies for its control. Crosstalk between oxidative stress and systemic inflammation seems to support the progression of the infection. Glycogen synthase kinase-3 (Gsk-3) is a conserved serine/threonine kinase that mainly participates in cell proliferation, development, stress, and inflammation in humans. Nucleocapsid protein of SARS-CoV-2 is an important structural protein responsible for viral replication and interferes with the host defence mechanism by the help of Gsk-3 protein. The viral infected cells show activated Gsk-3 protein that degrades the Nuclear factor erythroid 2-related factor (Nrf2) protein, resulting in excessive oxidative stress. Activated Gsk-3 also modulates CREB-DNA activity, phosphorylates NF-κB, and degrades β-catenin, thus provokes systemic inflammation. Interaction between these two pathophysiological events, oxidative stress, and inflammation enhance mucous secretion, coagulation cascade, and hypoxia, which ultimately leads to multiple organs failure, resulting in the death of the infected patient. The present review aims to highlight the pathogenic role of Gsk-3 in viral replication, initiation of oxidative stress, and inflammation during SARS-CoV-2 infection. The review also summarizes the potential Gsk-3 pathway modulators as putative therapeutic interventions in combating the COVID-19 pandemic.
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Affiliation(s)
- Anil Kumar Rana
- Pharmacology and Toxicology Laboratory, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, Himachal Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, Himachal Pradesh, India
| | - Shubham Nilkanth Rahmatkar
- Pharmacology and Toxicology Laboratory, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, Himachal Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, Himachal Pradesh, India
| | - Amit Kumar
- Pharmacology and Toxicology Laboratory, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, Himachal Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, Himachal Pradesh, India
| | - Damanpreet Singh
- Pharmacology and Toxicology Laboratory, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, Himachal Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, Himachal Pradesh, India.
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Pardo M, Qiu X, Zimmermann R, Rudich Y. Particulate Matter Toxicity Is Nrf2 and Mitochondria Dependent: The Roles of Metals and Polycyclic Aromatic Hydrocarbons. Chem Res Toxicol 2020; 33:1110-1120. [PMID: 32302097 PMCID: PMC7304922 DOI: 10.1021/acs.chemrestox.0c00007] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
![]()
Particulate matter
(PM), an important component of air pollution,
induces significant adverse health effects. Many of the observed health
effects caused by inhaled PM are associated with oxidative stress
and inflammation. This association has been linked in particular to
the particles’ chemical components, especially the inorganic/metal
and the organic/polycyclic aromatic hydrocarbon (PAH) fractions, and
their ability to generate reactive oxygen species in biological systems.
The transcription factor NF-E2 nuclear factor erythroid-related factor
2 (Nrf2) is activated by redox imbalance and regulates the expression
of phase II detoxifying enzymes. Nrf2 plays a key role in preventing
PM-induced toxicity by protecting against oxidative damage and inflammation.
This review focuses on specific PM fractions, particularly the dissolved
metals and PAH fractions, and their roles in inducing oxidative stress
and inflammation in cell and animal models with respect to Nrf2 and
mitochondria.
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Affiliation(s)
- Michal Pardo
- Department of Earth and Planetary Sciences, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Xinghua Qiu
- State Key Joint Laboratory for Environmental Simulation and Pollution Control, College of Environmental Sciences and Engineering, and Center for Environment and Health, Peking University, Beijing 100871, P.R. China
| | - Ralf Zimmermann
- Joint Mass Spectrometry Centre, University of Rostock, 18055 Rostock, Germany.,Joint Mass Spectrometry Centre, Comprehensive Molecular Analytics (CMA) Cooperation Group Helmholtz Zentrum, 81379 München, Germany
| | - Yinon Rudich
- Department of Earth and Planetary Sciences, Weizmann Institute of Science, Rehovot 76100, Israel
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Zhang J, Cui H, Namani A, Yao J, Deng H, Tang X, Wang XJ. Transcriptomic profiling identifies a critical role of Nrf2 in regulating the inflammatory response to fly ash particles in mouse lung. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2020; 190:110132. [PMID: 31918253 DOI: 10.1016/j.ecoenv.2019.110132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 12/17/2019] [Accepted: 12/23/2019] [Indexed: 06/10/2023]
Abstract
Exposure to combustion-derived nanoparticles is recognized as a major health hazard, but the molecular responses are still insufficiently described. The transcription factor erythroid 2-related factor 2 (Nrf2, also known as NFE2L2) is a master regulator of the pulmonary defense system against insults by particulate matter. However, its downstream molecular processes are not fully characterized. In the current study, BALB/c wild-type (WT) and Nrf2-/- mice were exposed by intranasal administration to fly ash particles (F3-S; 20 mg/kg BW), which were collected from a municipal waste incinerator in China, for three consecutive days. Using a comparative transcriptomics approach, the pulmonary global gene expression profiles to F3-S exposure were characterized for both genotypes. The preponderance of the differentially-expressed genes (DEGs) in WT mice induced by the fly ash particles, was related to inflammation. Functional enrichment and molecular pathway mapping of the DEGs specific to Nrf2-/- mice exposed to the particles revealed that all of the top 10 perturbed molecular pathways were associated with the inflammatory response. Our study identified a transcriptional signature related to the initial pulmonary injury in mouse upon fly ash exposure, and suggests an anti-inflammatory role of Nrf2 in protecting the lung against such exposure.
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Affiliation(s)
- Jingwen Zhang
- Department of Pharmacology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China
| | - Huiling Cui
- Department of Pharmacology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China
| | - Akhileshwar Namani
- Department of Biochemistry, Zhejiang University School of Medicine, Hangzhou, 310058, PR China
| | - Jun Yao
- Department of Pharmacology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China
| | - Hong Deng
- Department of Pathology, Zhejiang University School of Medicine, Hangzhou, 310058, PR China
| | - Xiuwen Tang
- Department of Biochemistry and Department of Thoracic Surgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China
| | - Xiu Jun Wang
- Department of Pharmacology and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China.
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Tanshinone IIA attenuates silica-induced pulmonary fibrosis via Nrf2-mediated inhibition of EMT and TGF-β1/Smad signaling. Chem Biol Interact 2020; 319:109024. [PMID: 32097614 DOI: 10.1016/j.cbi.2020.109024] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 01/09/2020] [Accepted: 02/21/2020] [Indexed: 12/28/2022]
Abstract
Silicosis is an occupational pulmonary fibrosis that is caused by inhalation of silica (SiO2), and there are no effective drugs to treat this disease. Tanshinone IIA (Tan IIA), a natural product, has been reported to possess antioxidant and anti-fibrotic properties in various diseases. The purpose of the current study was to examine Tan IIA's protective effects against silica-induced pulmonary fibrosis and to explore the underlying mechanisms. We found that in vivo treatment with Tan IIA significantly relieved silica-induced lung fibrosis in a silicosis rat model by histological and immunohistochemical analyses. Further, in vitro mechanistic investigations, mainly using western blot and immunofluorescence analyses, revealed that Tan IIA administration markedly inhibited the silica-induced epithelial-mesenchymal transition (EMT) and transforming growth factor-β1 (TGF-β1)/Smad signaling pathway and also reduced silica-induced oxidative stress and activated the nuclear factor erythroid 2-related factor-2 (Nrf2) signaling pathway in A549 and human bronchial epithelial (HBE) cells. Furthermore, through transfection with siRNA, we demonstrate that Nrf2 activation partially mediates the suppression effects of Tan IIA on EMT and TGF-β1/Smad signaling pathway activation induced by silica exposure, thus mediating the anti-fibrotic effects of Tan IIA against silica-induced pulmonary fibrosis. In our study, Tan IIA has been identified as a possible anti-oxidative and anti-fibrotic drug for silicosis.
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Feng F, Cheng P, Zhang H, Li N, Qi Y, Wang H, Wang Y, Wang W. The Protective Role of Tanshinone IIA in Silicosis Rat Model via TGF-β1/Smad Signaling Suppression, NOX4 Inhibition and Nrf2/ARE Signaling Activation. DRUG DESIGN DEVELOPMENT AND THERAPY 2019; 13:4275-4290. [PMID: 31908414 PMCID: PMC6930391 DOI: 10.2147/dddt.s230572] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 11/14/2019] [Indexed: 12/12/2022]
Abstract
Purpose Silicosis is an occupational disease caused by inhalation of silica and there are no effective drugs to treat this disease. Tanshinone IIA (Tan IIA), a traditional natural component, has been reported to possess anti-inflammatory, antioxidant, and anti-fibrotic properties. The current study’s purpose was to examine Tan IIA’s protective effects against silica-induced pulmonary fibrosis and to explore the underlying mechanisms. Methods 48 male SD rats were randomly divided into four groups (n=12): i) Control group; ii) Silicosis group; iii) Tan IIA group; iv) Silicosis +Tan IIA group. Two days after modeling, the rats of Tan IIA group and Silicosis +Tan IIA group were given intraperitoneal administration 25 mg/kg/d Tan IIA for 40 days. Then, the four groups of rats were sacrificed and the lung inflammatory responses were measured by ELISA, lung damage and fibrosis were analyzed by hematoxylin and eosin (H&E) staining and Masson staining, the expression levels of collagen I, fibronectin and α-smooth muscle actin (α-SMA) were measured by immunohistochemistry. The markers of oxidative stress were measured by commercial kits, and the activity of the TGF-β1/Smad and NOX4, Nrf2/ARE signaling pathways were measured by RT-PCR and Western blotting. Results The silica-induced pulmonary inflammtory responses, structural damage and fibrosis were significantly attenuated by Tan IIA treatment. In addition, treatment with Tan IIA decreased collagen I, fibronectin and α-SMA expression, and inhibited TGF-β1/Smad signaling in the lung tissue. The upregulated levels of oxidative stress markers in silicosis rats were also markedly restored following Tan IIA treatment. Furthermore, treatment with Tan IIA reduced NOX4 expression and enhanced activation of the Nrf2/ARE pathway in the lung tissue of silicosis rats. Conclusion These findings suggest that Tan IIA may protect lung from silica damage via the suppression of TGF-β1/Smad signaling, inhibition of NOX4 expression and activation of the Nrf2/ARE pathway. ![]()
Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/kPjjBxXCkyc
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Affiliation(s)
- Feifei Feng
- Department of Respiratory Medicine, The Second Hospital of Shandong University, Jinan, Shandong 250033, People's Republic of China
| | - Peng Cheng
- Department of Neural Medicine, The Second Hospital of Shandong University, Jinan, Shandong 250033, People's Republic of China
| | - Huanan Zhang
- Department of Respiratory Medicine, The Second Hospital of Shandong University, Jinan, Shandong 250033, People's Republic of China
| | - Nannan Li
- Department of Respiratory Medicine, The Second Hospital of Shandong University, Jinan, Shandong 250033, People's Republic of China
| | - Yuxin Qi
- Department of Respiratory Medicine, Jinan People's Hospital, Jinan, Shandong 250033, People's Republic of China
| | - Hui Wang
- Department of Respiratory Medicine, The Second Hospital of Shandong University, Jinan, Shandong 250033, People's Republic of China
| | - Yongbin Wang
- Department of Respiratory Medicine, The Second Hospital of Shandong University, Jinan, Shandong 250033, People's Republic of China
| | - Wei Wang
- Department of Respiratory Medicine, The Second Hospital of Shandong University, Jinan, Shandong 250033, People's Republic of China
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Abstract
Significance: Redox homeostasis is finely tuned and governed by distinct intracellular mechanisms. The dysregulation of this either by external or internal events is a fundamental pathophysiologic base for many pulmonary diseases. Recent Advances: Based on recent discoveries, it is increasingly clear that cellular redox state and oxidation of signaling molecules are critical modulators of lung disease and represent a final common pathway that leads to poor respiratory outcomes. Critical Issues: Based on the wide variety of stimuli that alter specific redox signaling pathways, improved understanding of the disease and patient-specific alterations are needed for the development of therapeutic targets. Further Directions: For the full comprehension of redox signaling in pulmonary disease, it is essential to recognize the role of reactive oxygen intermediates in modulating biological responses. This review summarizes current knowledge of redox signaling in pulmonary development and pulmonary vascular disease.
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Affiliation(s)
- Gaston Ofman
- Redox Biology Laboratory, Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Trent E Tipple
- Redox Biology Laboratory, Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama
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Helou DG, Braham S, De Chaisemartin L, Granger V, Damien MH, Pallardy M, Kerdine-Römer S, Chollet-Martin S. Nrf2 downregulates zymosan-induced neutrophil activation and modulates migration. PLoS One 2019; 14:e0216465. [PMID: 31419224 PMCID: PMC6697320 DOI: 10.1371/journal.pone.0216465] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 07/09/2019] [Indexed: 12/23/2022] Open
Abstract
Polymorphonuclear neutrophils (PMNs) are the first line of defense against pathogens and their activation needs to be tightly regulated in order to limit deleterious effects. Nrf2 (Nuclear factor (erythroïd-derived 2)-like 2) transcription factor regulates oxidative stress and/or represses inflammation in various cells such as dendritic cells or macrophages. However, its involvement in PMN biology is still unclear. Using Nrf2 KO mice, we thus aimed to investigate the protective role of Nrf2 in various PMN functions such as oxidative burst, netosis, migration, cytokine production and phagocytosis, mainly in response to zymosan. We found that zymosan induced Nrf2 accumulation in PMNs leading to the upregulation of some target genes including Hmox-1, Nqo1 and Cat. Nrf2 was able to decrease zymosan-induced PMN oxidative burst; sulforaphane-induced Nrf2 hyperexpression confirmed its implication. Tnfα, Ccl3 and Cxcl2 gene transcription was decreased in zymosan-stimulated Nrf2 KO PMNs, suggesting a role for Nrf2 in the regulation of proinflammatory cytokine production. However, Nrf2 was not involved in phagocytosis. Finally, spontaneous migration of Nrf2 KO PMNs was lower than that of WT PMNs. Moreover, in response to low concentrations of CXCL2 or CXCL12, Nrf2 KO PMN migration was decreased despite similar CXCR2 and CXCR4 expression and ATP levels in PMNs from both genotypes. Nrf2 thus seems to be required for an optimal migration. Altogether these results suggest that Nrf2 has a protective role in several PMN functions. In particular, it downregulates their activation in response to zymosan and is required for an adequate migration.
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Affiliation(s)
- Doumet Georges Helou
- Inflammation, Chimiokines et Immunopathologie, INSERM UMR996, Univ. Paris-Sud, Université Paris-Saclay,Châtenay-Malabry, France
| | - Sarah Braham
- Inflammation, Chimiokines et Immunopathologie, INSERM UMR996, Univ. Paris-Sud, Université Paris-Saclay,Châtenay-Malabry, France
| | - Luc De Chaisemartin
- Inflammation, Chimiokines et Immunopathologie, INSERM UMR996, Univ. Paris-Sud, Université Paris-Saclay,Châtenay-Malabry, France
- Laboratoire d'immunologie, « Autoimmunité et Hypersensibilités », Hôpital Bichat-Claude Bernard, AP-HP, Paris, France
| | - Vanessa Granger
- Inflammation, Chimiokines et Immunopathologie, INSERM UMR996, Univ. Paris-Sud, Université Paris-Saclay,Châtenay-Malabry, France
- Laboratoire d'immunologie, « Autoimmunité et Hypersensibilités », Hôpital Bichat-Claude Bernard, AP-HP, Paris, France
| | - Marie-Hélène Damien
- Inflammation, Chimiokines et Immunopathologie, INSERM UMR996, Univ. Paris-Sud, Université Paris-Saclay,Châtenay-Malabry, France
| | - Marc Pallardy
- Inflammation, Chimiokines et Immunopathologie, INSERM UMR996, Univ. Paris-Sud, Université Paris-Saclay,Châtenay-Malabry, France
| | - Saadia Kerdine-Römer
- Inflammation, Chimiokines et Immunopathologie, INSERM UMR996, Univ. Paris-Sud, Université Paris-Saclay,Châtenay-Malabry, France
| | - Sylvie Chollet-Martin
- Inflammation, Chimiokines et Immunopathologie, INSERM UMR996, Univ. Paris-Sud, Université Paris-Saclay,Châtenay-Malabry, France
- Laboratoire d'immunologie, « Autoimmunité et Hypersensibilités », Hôpital Bichat-Claude Bernard, AP-HP, Paris, France
- * E-mail:
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Qin Y, Cao L, Hu L. Sirtuin 6 mitigated LPS-induced human umbilical vein endothelial cells inflammatory responses through modulating nuclear factor erythroid 2-related factor 2. J Cell Biochem 2019; 120:11305-11317. [PMID: 30784091 DOI: 10.1002/jcb.28407] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 12/05/2018] [Accepted: 12/10/2018] [Indexed: 01/24/2023]
Abstract
BACKGROUND Nuclear factor erythroid 2-related factor 2 (Nrf2) protects the lung from sepsis-induced injury through activating Nrf2-regulated multiple phase 2 detoxification genes, including NAD(P)H: quinine oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO1). Based on the positive effect of Sirtuin 6 on Nrf2, we aim to explore the potential role of SIRT6 in the mechanism of sepsis-induced acute lung injury (ALI). METHODS Mouse models of sepsis were constructed by instilling intratracheal of lipopolysaccharide (LPS; 4 ml/kg). After 48-hour treatment, lung tissues were collected to measure the degree of lung injury. The SIRT6, siSIRT6, and siNrf2 plasmids were cotransfected into various concentrations of LPS-treated human umbilical vein endothelial cells (HUVECs; 0, 1, 5, 10, and 50 μg/ml) using Lipofectamine 2000. Tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 levels were determined by enzyme-linked immunosorbent assay. Expression levels of SIRT6, Nrf2, NQO1, and HO1 was measured by quantitative polymerase chain reaction and Western blot analysis. Cell apoptosis was determined by flow cytometry. RESULTS Lung tissues in the model group already had basic characteristics of ALI. Compared with the control model, TNF-α and IL-6 levels were much higher (P < 0.01), the levels of SIRT6, Nrf2, and Nrf2-modulated detoxification factors were downregulated (P < 0.01). SIRT6 overexpression decreased the apoptosis below to 10% (P < 0.01), significantly increased the Nrf2 expression, effectively inhibited TNF-α and IL-6 releases, and enhanced NQO1 and HO1 levels (P < 0.01). siNrf2 abolished the protective effects of SIRT6 overexpression, including increasing apoptosis and inhibiting anti-inflammatory and antioxidative genes expressions (P < 0.01). CONCLUSIONS Our study suggested SIRT6 positively regulated Nrf2 expression and activated Nrf2-regulated anti-inflammatory and antioxidative enzymes, which could effectively mitigate LPS-induced HUVECs inflammatory responses. This might reflect the mechanism of ALI induced by sepsis.
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Affiliation(s)
- Yi Qin
- ICU, Jingzhou Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Jingzhou, China
| | - Lirong Cao
- Medical Department, Hubei College of Chinese Medicine, Jingzhou, China
| | - Lili Hu
- ICU, Shenzhen Hospital, Southern Medical University, Shenzhen, China
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Waterpipe Smoke Exposure Triggers Lung Injury and Functional Decline in Mice: Protective Effect of Gum Arabic. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:8526083. [PMID: 31178975 PMCID: PMC6501418 DOI: 10.1155/2019/8526083] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 01/08/2019] [Accepted: 03/04/2019] [Indexed: 12/12/2022]
Abstract
The prevalence of waterpipe (shisha) tobacco smoking has recently seen a substantial increase worldwide and is becoming a public health problem. Both human and animal studies have established that waterpipe smoke (WPS) increases airway reactivity and inflammation. Gum Arabic (GA) is a prebiotic agent that possesses antioxidant and anti-inflammatory properties. However, its effects on lung toxicity induced by WPS exposure are unknown. Thus, the aim of this study was to investigate the possible salutary effects and underlying mechanisms of GA on WPS-induced pulmonary pathophysiologic effects. C57BL/6 mice were exposed to air or WPS (30 minutes/day for one month) with or without GA treatment in drinking water (15%, w/v). Exposure to WPS induced an influx of neutrophil polymorphs in the peribronchiolar and interstitial spaces and an increase of tumor necrosis factor-α and 8-isoprostane, a marker of lipid peroxidation, concentrations in lung homogenates. The latter effects were significantly mitigated by GA treatment. Likewise, the lung DNA damage induced by WPS exposure was prevented by GA administration. Western blot analysis of the lung showed that GA inhibited nuclear factor kappa-B (NF-κB) expression caused by WPS and augmented that of nuclear factor erythroid 2-related factor 2 (Nrf2). Similarly, immunohistochemical analysis of bronchial epithelial cells and alveolar cells showed a parallel and significant increase in the nuclear expression of Nrf2 and cytoplasmic expression of glutathione in mice treated with GA and exposed to WPS. Moreover, GA administration has significantly prevented airway hyperreactivity to methacholine induced by WPS. We conclude that GA administration significantly declined the physiological, histological, biochemical, and molecular indices of lung toxicity caused by WPS exposure, indicating its beneficial respiratory impact. Considering that GA is a safe agent with health benefits in humans, our data suggest its potential usage in waterpipe smokers.
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Youness ER, Shady M, Nassar MS, Mostafa R, Abuelhamd W. The role of serum nuclear factor erythroid 2-related factor 2 in childhood bronchial asthma. J Asthma 2019; 57:347-352. [PMID: 30729848 DOI: 10.1080/02770903.2019.1571081] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background: Asthma is one of the most common chronic airway disease of childhood. Poor asthma control has been associated with antioxidant deficiencies. Objective: To assess the association of bronchial asthma in Egyptian children with serum nuclear factor erythroid 2-related factor2 (NRF2) and its relation to disease severity. Subjects and methods: The study included 60 asthmatic children with comparable 60 controls (age ranged from 6-16 years). Subjects were classified according to the severity of asthma into mild or moderate asthma in group I, and severe asthma in group II. Antioxidant markers including superoxide-dismutase (SOD), glutathione peroxidase (GPX) and NRF2 were assessed once in blood and serum of both subjects and controls. Results: Mean serum NRF2 and GPX were significantly lower in asthmatic group than controls group (26.36 ± 4.18 pg/mL and 5.76 ± 0.81 mU/mL vs 29.05 ± 3.87 and 6.23 ± 0.97 respectively, p < 0.05). No significant difference was detected regarding SOD (p > 0.05). In severe bronchial asthma, mean serum NRF2 and GPX were significantly lower than in mild and moderate asthma (24.29 ± 1.86 pg/mL and 5.56 ± 0.67 mU/mL vs 27.95 ± 4.77 and 6.03 ± 0.90 respectively, p < 0.05). No significant difference was found in SOD regarding severity of bronchial asthma. Low NRF2 was the only predictor of the severity of bronchial asthma (OR = 0.749 and 95% CI 0.595 - 0.942). Conclusion: The pathogenesis of childhood bronchial asthma may be associated with low serum NRF2 which may be a strong predictor of the disease severity.
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Affiliation(s)
| | - Mones Shady
- Child Health, National Research Centre, Cairo, Egypt
| | | | - Rehab Mostafa
- Child Health, National Research Centre, Cairo, Egypt
| | - Walaa Abuelhamd
- Neonatology, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt
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Role of Nrf2 and Its Activators in Respiratory Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:7090534. [PMID: 30728889 PMCID: PMC6341270 DOI: 10.1155/2019/7090534] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/22/2018] [Accepted: 12/03/2018] [Indexed: 02/07/2023]
Abstract
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.
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Suojalehto H, Lindström I, Wolff H, Puustinen A. Nasal protein profiles in work-related asthma caused by different exposures. Allergy 2018; 73:653-663. [PMID: 28960398 DOI: 10.1111/all.13325] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND The mechanisms of work-related asthma (WRA) are incompletely delineated. Nasal cell samples may be informative about processes in the lower airways. Our aim was to determine the nasal protein expression profiles of WRA caused by different kind of exposures. METHODS We collected nasal brush samples from 82 nonsmoking participants, including healthy controls and WRA patients exposed to (i) protein allergens, (ii) isocyanates and (iii) welding fumes the day after relevant exposure. The proteome changes in samples were analysed by two-dimensional difference gel electrophoresis, and the differentially regulated proteins found were identified by mass spectrometry. Immunological comparison was carried out using Western blot. RESULTS We detected an average of 2500 spots per protein gel. Altogether, 228 protein spots were chosen for identification, yielding 77 different proteins. Compared to the controls, exposure to protein allergens had the largest effects on the proteome. Hierarchical clustering revealed that protein allergen- and isocyanate-related asthma had similar profiles, whereas asthma related to welding fumes differed. The highly overrepresented functional categories in the asthma groups were defence response, protease inhibitor activity, inflammatory and calcium signalling, complement activation and cellular response to oxidative stress. Immunological analysis confirmed the found abundance differences in galectin 10 and protein S100-A9 between the groups. CONCLUSIONS Work-related asthma patients exposed to protein allergens and isocyanates elicit similar nasal proteome responses and the profiles of welders and healthy controls were alike. Revealed biological activities of the protein expression changes are associated with allergic inflammation and asthma.
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Affiliation(s)
- H. Suojalehto
- Occupational Medicine; Finnish Institute of Occupational Health; Helsinki Finland
| | - I. Lindström
- Occupational Medicine; Finnish Institute of Occupational Health; Helsinki Finland
| | - H. Wolff
- Work Environment Laboratories; Finnish Institute of Occupational Health; Helsinki Finland
| | - A. Puustinen
- Unit of Systems Toxicology; Finnish Institute of Occupational Health; Helsinki Finland
- Verifin; Department of Chemistry; University of Helsinki; Helsinki Finland
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Abstract
Intestinal fibrosis, a common complication of inflammatory bowel diseases, becomes clinically apparent in ~ 40% of patients with Crohn's disease and ~ 5% of those with ulcerative colitis. Fibrosis, a consequence of local chronic inflammation, is characterized by excessive deposition of extracellular matrix (ECM) proteins by activated myofibroblasts, which are modulated by pro-fibrotic and anti-fibrotic factors. Fibrosis depends on the balance between production and degradation of ECM proteins. Although the transforming growth factor (TGF)-β1/Smad pathway is the major driving force of fibrosis, several pro-fibrogenic and anti-fibrogenic endogenous factors appear to interact directly with this pathway such as reactive oxygen species (ROS) and nuclear factor-erythroid 2-related factor 2 (Nrf2), which are connected with TGF-β1 during fibrosis development in several organs, including the intestine. Nrf2 is a ubiquitous master transcription factor that upregulates the expression of antioxidant enzymes and cytoprotective proteins mediated by antioxidant response elements (AREs). Here, I describe and discuss the links among TGF-β1, ROS, and Nrf2-AREs in the pathogenesis of intestinal fibrosis.
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Affiliation(s)
- Giovanni Latella
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi n.1, Coppito, 67100, L'Aquila, Italy.
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Mondal NK, Saha H, Mukherjee B, Tyagi N, Ray MR. Inflammation, oxidative stress, and higher expression levels of Nrf2 and NQO1 proteins in the airways of women chronically exposed to biomass fuel smoke. Mol Cell Biochem 2018; 447:63-76. [DOI: 10.1007/s11010-018-3293-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2017] [Accepted: 01/19/2018] [Indexed: 11/24/2022]
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Role of the Nrf2/HO-1 axis in bronchopulmonary dysplasia and hyperoxic lung injuries. Clin Sci (Lond) 2017; 131:1701-1712. [PMID: 28667068 DOI: 10.1042/cs20170157] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 05/11/2017] [Accepted: 05/16/2017] [Indexed: 12/23/2022]
Abstract
Bronchopulmonary dysplasia (BPD) is a chronic illness that usually originates in preterm newborns. Generally, BPD is a consequence of respiratory distress syndrome (RDS) which, in turn, comes from the early arrest of lung development and the lack of pulmonary surfactant. The need of oxygen therapy to overcome premature newborns' compromised respiratory function generates an increasing amount of reactive oxygen species (ROS), the onset of sustained oxidative stress (OS) status, and inflammation in the pulmonary alveoli deputies to respiratory exchanges. BPD is a severe and potentially life-threatening disorder that in the most serious cases, can open the way to neurodevelopmental delay. More importantly, there is no adequate intervention to hamper or treat BPD. This perspective article seeks to review the most recent and relevant literature describing the very early stages of BPD and hyperoxic lung injuries focussing on nuclear factor erythroid derived 2 (Nrf2)/heme oxygenase-1 (HO-1) axis. Indeed, Nrf2/HO1 activation in response to OS induced lung injury in preterm concurs to the induction of certain number of antioxidant, anti-inflammatory, and detoxification pathways that seem to be more powerful than the activation of one single antioxidant gene. These elicited protective effects are able to counteract/mitigate all multifaceted aspects of the disease and may support novel approaches for the management of BPD.
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Duan L, Li J, Ma P, Yang X, Xu S. Vitamin E antagonizes ozone-induced asthma exacerbation in Balb/c mice through the Nrf2 pathway. Food Chem Toxicol 2017. [PMID: 28624471 DOI: 10.1016/j.fct.2017.06.025] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Millions of people are regularly exposed to ozone, a gas known to contribute significantly to worsening the symptoms of patients with asthma. However, the mechanisms underlying these ozone exacerbation effects are not fully understood. In this study, we examined the exacerbation effect of ozone in OVA-induced asthma mice and tried to demonstrate the protective mechanism of vitamin E (VE). An asthma mouse model was established, and used to identify the exacerbating effects of ozone by assessing cytokine and serum immunoglobulin concentrations, airway leukocyte infiltration, histopathological changes in lung tissues, and airway hyper-responsiveness. We then determined the amount of reactive oxygen species (ROS) accumulated, the extent to which VE induced ROS elimination, and examined the antagonistic effects of VE on the ozone-induced exacerbating effects. This study showed that 1-ppm ozone exposure could exacerbate OVA-induced asthma in mice. More importantly we found that ozone induced oxidative stress in asthmatic airways may lead to the inhibition of Nuclear factor-erythroid 2-related factor 2 (Nrf2), and may subsequently induce even more exaggerated oxidative stress associated with asthma exacerbation. Through VE induced Nrf2 activation and the subsequent increase in Nrf2 target protein expression, this study suggests a novel mechanism for alleviating ozone exacerbated asthma symptoms.
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Affiliation(s)
- Liju Duan
- Key Laboratory of Environment and Health (Huazhong University of Science and Technology), Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; College of Public Health, Zhengzhou University, Zhengzhou 450001, China
| | - Jinquan Li
- Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan 430079, China
| | - Ping Ma
- Research Center of Basic Medical Sciences, School of Basic Medical Sciences, Hubei University of Science and Technology, Xianning 437100, China
| | - Xu Yang
- Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan 430079, China
| | - Shunqing Xu
- Key Laboratory of Environment and Health (Huazhong University of Science and Technology), Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Lin L, Yin Y, Hou G, Han D, Kang J, Wang Q. Ursolic acid attenuates cigarette smoke-induced emphysema in rats by regulating PERK and Nrf2 pathways. Pulm Pharmacol Ther 2017; 44:111-121. [PMID: 28347799 DOI: 10.1016/j.pupt.2017.03.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 02/28/2017] [Accepted: 03/23/2017] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Ursolic acid (UA) is widely distributed in natural plants to against oxidation, virus, inflammation, tumor, and has been widely used in the pharmaceutical and cosmetics. However, its effect on emphysema of chronic obstructive pulmonary disease (COPD) is unknown. Unfolded protein response is involved in pathogenesis of COPD through PERK pathway. Nuclear erythroid-related factor 2 (Nrf2) regulates antioxidant defensive mechanism in COPD. This study was to explore effect and mechanism of UA on cigarette smoke (CS)-induced rat emphysema. MATERIALS AND METHODS 50 Wistar rats were divided into 5 groups (n = 10 each): rats were exposed to CS for 12 weeks in absence (CS group) or presence of UA at different doses. Control group was treated with UA vehicle only. Histopathology, apoptosis, key protein expression of PERK and Nrf2 pathway were determined in lung tissues. Oxidative stress levels in lung were represented by 8-OHdG, MDA and GSH levels. RESULTS Emphysema-related pathology, based on inter-alveolar wall distance and alveolar density, was less severe in UA groups than in CS group. Compared with CS group, UA treatment down-regulated PERK pathway protein expression, up-regulated expression of Bcl-2 and down-regulated expression of Bax, Cleaved-Caspase3 and Cleaved-Caspase12. Moreover, UA decreased number of apoptotic cells in rat lungs. UA also up-regulated protein expression of Nrf2/ARE pathway and GSH level, decreased expression of oxidant stress factor 8-OHdG and MDA. These improvements were in accordance with attenuation of severity of emphysema. CONCLUSIONS UA attenuates CS-induced rat emphysema by down-regulating PERK pathway to alleviate CS-induced apoptosis in lung, and up-regulating Nrf2 pathway to improve cigarette smoke-induced oxidant stress in rat lungs.
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Affiliation(s)
- Li Lin
- Institute of Respiratory Disease, The First Hospital of China Medical University, Shenyang 110001, China
| | - Yan Yin
- Institute of Respiratory Disease, The First Hospital of China Medical University, Shenyang 110001, China
| | - Gang Hou
- Institute of Respiratory Disease, The First Hospital of China Medical University, Shenyang 110001, China
| | - Dan Han
- Institute of Respiratory Disease, The First Hospital of China Medical University, Shenyang 110001, China
| | - Jian Kang
- Institute of Respiratory Disease, The First Hospital of China Medical University, Shenyang 110001, China
| | - Qiuyue Wang
- Institute of Respiratory Disease, The First Hospital of China Medical University, Shenyang 110001, China.
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Nrf2 Regulates the Risk of a Diesel Exhaust Inhalation-Induced Immune Response during Bleomycin Lung Injury and Fibrosis in Mice. Int J Mol Sci 2017; 18:ijms18030649. [PMID: 28304344 PMCID: PMC5372661 DOI: 10.3390/ijms18030649] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 03/03/2017] [Accepted: 03/09/2017] [Indexed: 01/09/2023] Open
Abstract
The present study investigated the effects of diesel exhaust (DE) on an experimental model of bleomycin (BLM)-induced lung injury and fibrosis in mice. BLM was intravenously administered to both Nrf2+/+ and Nrf2−/− C57BL/6J mice on day 0. The mice were exposed to DE for 56 days from 28 days before the BLM injection to 28 days after the BLM injection. Inhalation of DE induced significant inhibition of airway clearance function and the proinflammatory cytokine secretion in macrophages, an increase in neutrophils, and severe lung inflammatory injury, which were greater in Nrf2−/− mice than in Nrf2+/+ mice. In contrast, inhalation of DE was observed to induce a greater increase of hydroxyproline content in the lung tissues and significantly higher pulmonary antioxidant enzyme mRNA expression in the Nrf2+/+ mice than in Nrf2−/− mice. DE is an important risk factor, and Nrf2 regulates the risk of a DE inhalation induced immune response during BLM lung injury and fibrosis in mice.
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Yang J, Wang T, Li Y, Yao W, Ji X, Wu Q, Han L, Han R, Yan W, Yuan J, Ni C. Earthworm extract attenuates silica-induced pulmonary fibrosis through Nrf2-dependent mechanisms. J Transl Med 2016; 96:1279-1300. [PMID: 27775689 DOI: 10.1038/labinvest.2016.101] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 08/05/2016] [Accepted: 08/25/2016] [Indexed: 12/15/2022] Open
Abstract
Silicosis is an occupational pulmonary fibrosis caused by inhalation of silica (SiO2) and there are no ideal drugs to treat this disease. Earthworm extract (EE), a natural nutrient, has been reported to have anti-inflammatory, antioxidant, and anti-apoptosis effects. The purpose of the current study was to test the protective effects of EE against SiO2-induced pulmonary fibrosis and to explore the underlying mechanisms using both in vivo and in vitro models. We found that treatment with EE significantly reduced lung inflammation and fibrosis and improved lung structure and function in SiO2-instilled mice. Further mechanistic investigations revealed that EE administration markedly inhibited SiO2-induced oxidative stress, mitochondrial apoptotic pathway, and epithelial-mesenchymal transition in HBE and A549 cells. Furthermore, we demonstrate that Nrf2 activation partly mediates the interventional effects of EE against SiO2-induced pulmonary fibrosis. Our study has identified EE to be a potential anti-oxidative, anti-inflammatory, and anti-fibrotic drug for silicosis.
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Affiliation(s)
- Jingjin Yang
- Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ting Wang
- Department of Pathology, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Yan Li
- Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Wenxi Yao
- Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xiaoming Ji
- Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qiuyun Wu
- Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Lei Han
- Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ruhui Han
- Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Weiwen Yan
- Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jiali Yuan
- Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Chunhui Ni
- Department of Occupational Medicine and Environmental Health and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
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Manti S, Marseglia L, D'Angelo G, Cuppari C, Cusumano E, Arrigo T, Gitto E, Salpietro C. "Cumulative Stress": The Effects of Maternal and Neonatal Oxidative Stress and Oxidative Stress-Inducible Genes on Programming of Atopy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:8651820. [PMID: 27504149 PMCID: PMC4967692 DOI: 10.1155/2016/8651820] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 05/27/2016] [Accepted: 06/22/2016] [Indexed: 12/16/2022]
Abstract
Although extensive epidemiological and laboratory studies have been performed to identify the environmental and immunological causes of atopy, genetic predisposition seems to be the biggest risk factor for allergic diseases. The onset of atopic diseases may be the result of heritable changes of gene expression, without any alteration in DNA sequences occurring in response to early environmental stimuli. Findings suggest that the establishment of a peculiar epigenetic pattern may also be generated by oxidative stress (OS) and perpetuated by the activation of OS-related genes. Analyzing the role of maternal and neonatal oxidative stress and oxidative stress-inducible genes, the purpose of this review was to summarize what is known about the relationship between maternal and neonatal OS-related genes and the development of atopic diseases.
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Affiliation(s)
- Sara Manti
- Unit of Pediatric Genetics and Immunology, Department of Pediatrics, University of Messina, 98125 Messina, Italy
| | - Lucia Marseglia
- Neonatal and Pediatric Intensive Care Unit, Department of Pediatrics, University of Messina, 98125 Messina, Italy
| | - Gabriella D'Angelo
- Neonatal and Pediatric Intensive Care Unit, Department of Pediatrics, University of Messina, 98125 Messina, Italy
| | - Caterina Cuppari
- Unit of Pediatric Genetics and Immunology, Department of Pediatrics, University of Messina, 98125 Messina, Italy
| | - Erika Cusumano
- Neonatal and Pediatric Intensive Care Unit, Department of Pediatrics, University of Messina, 98125 Messina, Italy
| | - Teresa Arrigo
- Unit of Pediatric Genetics and Immunology, Department of Pediatrics, University of Messina, 98125 Messina, Italy
| | - Eloisa Gitto
- Neonatal and Pediatric Intensive Care Unit, Department of Pediatrics, University of Messina, 98125 Messina, Italy
| | - Carmelo Salpietro
- Unit of Pediatric Genetics and Immunology, Department of Pediatrics, University of Messina, 98125 Messina, Italy
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Rojo de la Vega M, Dodson M, Gross C, Mansour HM, Lantz RC, Chapman E, Wang T, Black SM, Garcia JGN, Zhang DD. Role of Nrf2 and Autophagy in Acute Lung Injury. ACTA ACUST UNITED AC 2016; 2:91-101. [PMID: 27313980 DOI: 10.1007/s40495-016-0053-2] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the clinical manifestations of severe lung damage and respiratory failure. Characterized by severe inflammation and compromised lung function, ALI/ARDS result in very high mortality of affected individuals. Currently, there are no effective treatments for ALI/ARDS, and ironically, therapies intended to aid patients (specifically mechanical ventilation, MV) may aggravate the symptoms. Key events contributing to the development of ALI/ARDS are: increased oxidative and proteotoxic stresses, unresolved inflammation, and compromised alveolar-capillary barrier function. Since the airways and lung tissues are constantly exposed to gaseous oxygen and airborne toxicants, the bronchial and alveolar epithelial cells are under higher oxidative stress than other tissues. Cellular protection against oxidative stress and xenobiotics is mainly conferred by Nrf2, a transcription factor that promotes the expression of genes that regulate oxidative stress, xenobiotic metabolism and excretion, inflammation, apoptosis, autophagy, and cellular bioenergetics. Numerous studies have demonstrated the importance of Nrf2 activation in the protection against ALI/ARDS, as pharmacological activation of Nrf2 prevents the occurrence or mitigates the severity of ALI/ARDS. Another promising new therapeutic strategy in the prevention and treatment of ALI/ARDS is the activation of autophagy, a bulk protein and organelle degradation pathway. In this review, we will discuss the strategy of concerted activation of Nrf2 and autophagy as a preventive and therapeutic intervention to ameliorate ALI/ARDS.
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Affiliation(s)
| | - Matthew Dodson
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA
| | - Christine Gross
- Department of Medicine, Division of Translational and Regenerative Medicine, University of Arizona, Tucson, AZ, USA
| | - Heidi M Mansour
- Skaggs Pharmaceutical Sciences Center, University of Arizona, Tucson, AZ, USA
| | - R Clark Lantz
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
| | - Eli Chapman
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA; Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
| | - Ting Wang
- Arizona Respiratory Center and Department of Medicine, University of Arizona, Tucson, AZ
| | - Stephen M Black
- Department of Medicine, Division of Translational and Regenerative Medicine, University of Arizona, Tucson, AZ, USA
| | - Joe G N Garcia
- Arizona Respiratory Center and Department of Medicine, University of Arizona, Tucson, AZ
| | - Donna D Zhang
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA; Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
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Abstract
Maintaining cellular redox status to allow cell signalling to occur requires modulation of both the controlled production of oxidants and the thiol-reducing networks to allow specific regulatory post-translational modification of protein thiols. The oxidative stress hypothesis captured the concept that overproduction of oxidants can be proteotoxic, but failed to predict the recent finding that hyperactivation of the KEAP1-NRF2 system also leads to proteotoxicity. Furthermore, sustained activation of thiol redox networks by KEAP1-NRF2 induces a reductive stress, by decreasing the lifetime of necessary oxidative post-translational modifications required for normal metabolism or cell signalling. In this context, it is now becoming clear why antioxidants or hyperactivation of antioxidant pathways with electrophilic therapeutics can be deleterious. Furthermore, it suggests that the autophagy-lysosomal pathway is particularly important in protecting the cell against redox-stress-induced proteotoxicity, since it can degrade redox-damaged proteins without causing aberrant changes to the redox network needed for metabolism or signalling. In this context, it is important to understand: (i) how NRF2-mediated redox signalling, or (ii) the autophagy-mediated antioxidant/reductant pathways sense cellular damage in the context of cellular pathogenesis. Recent studies indicate that the modification of protein thiols plays an important role in the regulation of both the KEAP1-NRF2 and autophagy pathways. In the present review, we discuss evidence demonstrating that the KEAP1-NRF2 pathway and autophagy act in concert to combat the deleterious effects of proteotoxicity. These findings are discussed with a special emphasis on their impact on cardiovascular disease and neurodegeneration.
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Ci X, Zhong W, Ren H, Wen Z, Li D, Peng L. Esculentoside A Attenuates Allergic Airway Inflammation via Activation of the Nrf-2 Pathway. Int Arch Allergy Immunol 2015; 167:280-90. [PMID: 26496193 DOI: 10.1159/000441061] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 09/14/2015] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The role of airway inflammation and inflammation-induced oxidative stress in the pathogenesis and progression of chronic inflammatory airway diseases has received increasing attention in recent years. We investigated the potential anti-inflammatory and antioxidative effects of esculentoside A (EsA), a saponin isolated from the Chinese herb Phytolacca esculenta, in comparison to dexamethasone, a potent corticosteroid, in a murine model of allergic asthma. METHODS EsA was added to cultures of A549 cells at different concentrations or for different lengths of time, and nuclear factor erythroid 2-related factor 2 (Nrf-2) translocation and heme oxygenase 1 expression were monitored. Mice treated with or without EsA and Nrf-2 siRNA were sensitized and challenged with ovalbumin (OVA) and developed airway inflammation and oxidative lung damage. The Th2-type cytokine levels and inflammatory cells in bronchoalveolar lavage fluid (BALF) and the serum immunoglobulin production and adhesion molecule expression in the lung tissues were measured. The activities of related antioxidases and glutathione were measured using assay kits. RESULTS EsA enhanced nuclear Nrf-2 translocation in both A549 cells and the lungs of OVA-challenged mice. Airway inflammation induced by OVA was reduced. Additionally, EsA increased mRNA expression of antioxidant enzymes regulated by Nrf-2, leading to a reduction in Th2 cytokines and the expression of adhesion molecule mRNA in the BALF and lung tissues. Inhibition of Nrf-2 by siRNA abrogated the regulatory effects of EsA on inflammation and oxidant stress. CONCLUSIONS This is the first study to illustrate that EsA acts as a novel Nrf-2 activator, which modulates the oxidative stress pathway to improve lung injury and ameliorate the development of airway inflammation.
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Affiliation(s)
- Xinxin Ci
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
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Kong M, Mao J, Luo B, Qin Z. Role of transcriptional factor Nrf2 in the acute lung injury of mice. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:10929-34. [PMID: 26617809 PMCID: PMC4637624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 08/26/2015] [Indexed: 06/05/2023]
Abstract
OBJECTIVE This study aimed to investigate the expression and role of Nrf2 in the acute lung injury (ALI) of mice. METHODS A total of 60 BABL/c mice were randomly divided into 2 groups: ALI group and control group. In ALI group, ALI was introduced by injection of LPS. Immunohistochemistry was performed to detect Nrf2 expression in the lung; Western blot assay was employed to detect the expression of Nrf2 in the lung homogenate; ELISA was conducted to detect the expression of Nrf2 in the lung homogenate and BALF. RESULTS As compared to control group, ALI mice had a high Nrf2 expression in the lung as shown in immunohistochemistry, and the Nrf2 expression in the lung homogenate and BALF also increased markedly (P<0.05). CONCLUSION The Nrf2 expression increases in the lung and BALF of ALI mice, suggesting that Nrf2 is involved in the inflammation during ALI and may serve as a new target in the therapy of ALI.
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Affiliation(s)
| | | | - Bijun Luo
- Department of Emergency, Shanghai Tenth People’s Hospital, Tongji University School of MedicineShanghai 20072, China
| | - Zonghao Qin
- Department of Emergency, Shanghai Tenth People’s Hospital, Tongji University School of MedicineShanghai 20072, China
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