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NADPH oxidase family proteins: signaling dynamics to disease management

Cellular & Molecular Immunology volume 19, pages 660–686 (2022)Cite this article

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Abstract

Reactive oxygen species (ROS) are pervasive signaling molecules in biological systems. In humans, a lack of ROS causes chronic and extreme bacterial infections, while uncontrolled release of these factors causes pathologies due to excessive inflammation. Professional phagocytes such as neutrophils (PMNs), eosinophils, monocytes, and macrophages use superoxide-generating NADPH oxidase (NOX) as part of their arsenal of antimicrobial mechanisms to produce high levels of ROS. NOX is a multisubunit enzyme complex composed of five essential subunits, two of which are localized in the membrane, while three are localized in the cytosol. In resting phagocytes, the oxidase complex is unassembled and inactive; however, it becomes activated after cytosolic components translocate to the membrane and are assembled into a functional oxidase. The NOX isoforms play a variety of roles in cellular differentiation, development, proliferation, apoptosis, cytoskeletal control, migration, and contraction. Recent studies have identified NOX as a major contributor to disease pathologies, resulting in a shift in focus on inhibiting the formation of potentially harmful free radicals. Therefore, a better understanding of the molecular mechanisms and the transduction pathways involved in NOX-mediated signaling is essential for the development of new therapeutic agents that minimize the hyperproduction of ROS. The current review provides a thorough overview of the various NOX enzymes and their roles in disease pathophysiology, highlights pharmacological strategies, and discusses the importance of computational modeling for future NOX-related studies.

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References

  1. Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxygen species. Mol Cell. 2012;48:158–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Phaniendra A, Jestadi DB, Periyasamy L. Free radicals: properties, sources, targets, and their implication in various diseases. Indian J Clin Biochem. 2015;30:11–26.

    Article  CAS  PubMed  Google Scholar 

  3. Grimsrud PA, Xie H, Griffin TJ, Bernlohr DA. Oxidative stress and covalent modification of protein with bioactive aldehydes. J Biol Chem. 2008;283:21837–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Maraldi T. Natural compounds as modulators of NADPH oxidases. Oxid Med Cell Longev. 2013;2013:271602.

  5. Barua S, Kim JY, Yenari MA, Lee JE. The role of NOX inhibitors in neurodegenerative diseases. IBRO Rep. 2019;7:59–69.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Jarman ER, Khambata VS, Cope C, Jones P, Roger J, Ye LY, et al. An inhibitor of NADPH oxidase-4 attenuates established pulmonary fibrosis in a rodent disease model. Am J Respir Cell Mol Biol. 2014;50:158–69.

    Article  PubMed  Google Scholar 

  7. Cui Y, Wang Y, Li G, Ma W, Zhou XS, Wang J, et al. The Nox1/Nox4 inhibitor attenuates acute lung injury induced by ischemia-reperfusion in mice. PLoS One. 2018;13:e0209444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Santillo M, Colantuoni A, Mondola P, Guida B, Damiano S. NOX signaling in molecular cardiovascular mechanisms involved in the blood pressure homeostasis. Front Physiol. 2015;6:194.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Rastogi R, Geng X, Li F, Ding Y. NOX activation by subunit interaction and underlying mechanisms in disease. Front Cell Neurosci. 2016;10:301.

    PubMed  Google Scholar 

  10. Schroder K, Weissmann N, Brandes RP. Organizers and activators: Cytosolic Nox proteins impacting on vascular function. Free Radic Biol Med. 2017;109:22–32.

    Article  PubMed  CAS  Google Scholar 

  11. Giardino G, Cicalese MP, Delmonte O, Migliavacca M, Palterer B, Loffredo L, et al. NADPH oxidase deficiency: a multisystem approach. Oxid Med Cell Longev. 2017;2017:4590127.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. El-Benna J, Dang PM-C, Gougerot-Pocidalo MA, Marie JC, Braut-Boucher F. p47phox the phagocyte NADPH oxidase/NOX2 organizer: structure phosphorylation and implication in diseases. Exp Mol Med. 2009;41:217–25. https://doi.org/10.3858/emm.2009.41.4.058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ueno N, Takeya R, Miyano K, Kikuchi H, Sumimoto H. The NADPH oxidase Nox3 constitutively produces superoxide in a p22-dependent manner. J Biol Chem. 2005;280:23328–39. https://doi.org/10.1074/jbc.M414548200

    Article  CAS  PubMed  Google Scholar 

  14. Henríquez-Olguín C, Boronat S, Cabello-Verrugio C, Jaimovich E, Hidalgo E, Jensen TE. The emerging roles of nicotinamide adenine dinucleotide phosphate oxidase 2 in skeletal muscle redox signaling and metabolism. Antioxid Redox Signal. 2019;31:1371–4. https://doi.org/10.1089/ars.2018.7678

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Panday A, Sahoo MK, Osorio D, Batra S. NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell Mol Immunol. 2015;12:5–23.

    Article  CAS  PubMed  Google Scholar 

  16. Gimenez M, Schickling BM, Lopes LR, Miller FJ Jr. Nox1 in cardiovascular diseases: regulation and pathophysiology. Clin Sci. 2016;130:151–65.

    Article  CAS  Google Scholar 

  17. Parascandolo A, Laukkanen MO. Carcinogenesis and reactive oxygen species signaling: interaction of the NADPH oxidase NOX1-5 and superoxide dismutase 1-3 signal transduction pathways. Antioxid Redox Signal. 2019;30:443–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87:245–313.

    Article  CAS  PubMed  Google Scholar 

  19. Magnani F, Nenci S, Millana Fananas E, Ceccon M, Romero E, Fraaije MW, et al. Crystal structures and atomic model of NADPH oxidase. Proc Natl Acad Sci. 2017;114:6764–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. van der Vliet A, Danyal K, Heppner DE. Dual oxidase: a novel therapeutic target in allergic disease. Br J Pharm. 2018;175:1401–18.

    Article  CAS  Google Scholar 

  21. Rolas L, Boussif A, Weiss E, Lettéron P, Haddad O, El-Benna J, et al. NADPH oxidase depletion in neutrophils from patients with cirrhosis and restoration via toll-like receptor 7/8 activation. Gut. 2018;67:1505–16.

    Article  CAS  PubMed  Google Scholar 

  22. Yue L, Wang W, Wang Y, Du T, Shen W, Tang H, et al. Bletilla striata polysaccharide inhibits angiotensin II-induced ROS and inflammation via NOX4 and TLR2 pathways. Int J Biol Macromol. 2016;89:376–88.

    Article  CAS  PubMed  Google Scholar 

  23. Carnevale R, Pastori D, Nocella C, Cammisotto V, Bartimoccia S, Novo M, et al. Gut-derived lipopolysaccharides increase post-prandial oxidative stress via Nox2 activation in patients with impaired fasting glucose tolerance: effect of extra-virgin olive oil. Eur J Nutr. 2019;58:843–51.

    Article  CAS  PubMed  Google Scholar 

  24. Kumar H, Kawai T, Akira S. Pathogen recognition by the innate immune system. Int Rev Immunol. 2011;30:16–34.

    Article  CAS  PubMed  Google Scholar 

  25. Vidya MK, Kumar VG, Sejian V, Bagath M, Krishnan G, Bhatta R. Toll-like receptors: Significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol. 2018;37:20–36.

    Article  CAS  PubMed  Google Scholar 

  26. El-Zayat SR, Sibaii H, Mannaa FA. Toll-like receptors activation, signaling, and targeting: an overview. Bull Natl Res Cent. 2019;43:187.

    Article  Google Scholar 

  27. Wang Y, Song E, Bai B, Vanhoutte PM. Toll-like receptors mediating vascular malfunction: Lessons from receptor subtypes. Pharm Ther. 2016;158:91–100.

    Article  CAS  Google Scholar 

  28. Singh A, Koduru B, Carlisle C, Akhter H, Liu R-M, Schroder K, et al. NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-4. Sci Rep. 2017;7:14346.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Huang H, Tohme S, Al-Khafaji AB, Tai S, Loughran P, Chen L, et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology. 2015;62:600–14.

    Article  CAS  PubMed  Google Scholar 

  30. Lorne E, Zmijewski JW, Zhao X, Liu G, Tsuruta Y, Park YJ, et al. Role of extracellular superoxide in neutrophil activation: interactions between xanthine oxidase and TLR4 induce proinflammatory cytokine production. Am J Physiol Cell Physiol. 2008;294:C985–93.

    Article  CAS  PubMed  Google Scholar 

  31. Nguyen GT, Green ER, Mecsas J. Neutrophils to the ROScue: Mechanisms of NADPH oxidase activation and bacterial resistance. Front Cell Infect Microbiol. 2017;7:373.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Al-Khafaji AB, Tohme S, Yazdani HO, Miller D, Huang H, Tsung A. Superoxide induces neutrophil extracellular trap formation in a TLR-4 and NOX-dependent mechanism. Mol Med. 2016;22:621–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Platnich JM, Muruve DA. NOD-like receptors and inflammasomes: A review of their canonical and non-canonical signaling pathways. Arch Biochem Biophys. 2019;670:4–14.

    Article  CAS  PubMed  Google Scholar 

  34. Sharma D, Kanneganti TD. The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation. J Cell Biol. 2016;213:617–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int J Mol Sci. 2019;20:3328.

  36. Zhen Y, Zhang H. NLRP3 inflammasome and inflammatory bowel disease. Front Immunol. 2019;10:276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fangxiao M, Yifan K, Jihong Z, Yan S, Yingchao L. Effect of tripterygium wilfordii polycoride on the NOXs-ROS-NLRP3 inflammasome signaling pathway in mice with ulcerative colitis. Evid Based Complement Altern Med. 2019;2019:9306283.

    Article  Google Scholar 

  38. Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Disco. 2018;17:588–606.

    Article  CAS  Google Scholar 

  39. Kasper L, König A, Koenig PA, Gresnigt MS, Westman J, Drummond RA, et al. The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes. Nat Commun. 2018;9:4260.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Rogiers O, Frising UC, Kucharíková S, Jabra-Rizk MA, van Loo G, Van Dijck P, et al. Candidalysin crucially contributes to nlrp3 inflammasome activation by Candida albicans hyphae. mBio. 2019;10:e02221–18.

  41. Mathur A, Feng S, Hayward JA, Ngo C, Fox D, Atmosukarto II, et al. A multicomponent toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome. Nat Microbiol. 2019;4:362–74.

    Article  CAS  PubMed  Google Scholar 

  42. You Y, Huang Y, Wang D, Li Y, Wang G, Jin S, et al. Angiotensin (1-7) inhibits arecoline-induced migration and collagen synthesis in human oral myofibroblasts via inhibiting NLRP3 inflammasome activation. J Cell Physiol. 2019;234:4668–80.

    Article  CAS  PubMed  Google Scholar 

  43. Chen Y, Ding SX, Zhang H, Sun ZH, Shen XY, Sun LL, et al. Protective effects of ginsenoside Rg1 on neuronal senescence due to inhibition of NOX2 and NLRP1 inflammasome activation in SAMP8 mice. J Funct Foods. 2020;65:103713.

  44. Wang X, Chu G, Yang Z, Sun Y, Zhou H, Li M. et al. Ethanol directly induced HMGB1 release through NOX2/NLRP1 inflammasome in neuronal cells. Toxicology. 2015;334:104–10.

    Article  CAS  PubMed  Google Scholar 

  45. Sun D, Gao G, Zhong B, Zhang H, Ding S, Sun Z, et al. NLRP1 inflammasome involves in learning and memory impairments and neuronal damages during aging process in mice. Behav Brain Funct. 2021;17:11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Xu T, Sun L, Shen X, Chen Y, Yin Y, Zhang J, et al. NADPH oxidase 2-mediated NLRP1 inflammasome activation involves in neuronal senescence in hippocampal neurons in vitro. Int Immunopharmacol. 2019;69:60–70.

    Article  CAS  PubMed  Google Scholar 

  47. Sun L, Chen Y, Shen X, Xu T, Yin Y, Zhang H, et al. Inhibition of NOX2-NLRP1 signaling pathway protects against chronic glucocorticoids exposure-induced hippocampal neuronal damage. Int Immunopharmacol. 2019;74:105721.

    Article  CAS  PubMed  Google Scholar 

  48. Cheng L, Chen L, Wei X, Wang Y, Ren Z, Zeng S, et al. NOD2 promotes dopaminergic degeneration regulated by NADPH oxidase 2 in 6-hydroxydopamine model of Parkinson’s disease. J Neuroinflammation. 2018;15:243.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Kong LJ, Liu XQ, Xue Y, Gao W, Lv QZ. Muramyl dipeptide induces reactive oxygen species generation through the NOD2/COX-2/NOX4 signaling pathway in human umbilical vein endothelial cells. J Cardiovasc Pharm. 2018;71:352–8.

    Article  CAS  Google Scholar 

  50. Lipinski S, Petersen BS, Barann M, Piecyk A, Tran F, Mayr G, et al. Missense variants in NOX1 and p22phox in a case of very-early-onset inflammatory bowel disease are functionally linked to NOD2. Cold Spring Harb Mol Case Stud. 2019;5:a002428.

  51. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18:459–80.

  52. Hou L, Zhang L, Hong JS, Zhang D, Zhao J, Wang Q. Nicotinamide adenine dinucleotide phosphate oxidase and neurodegenerative diseases: mechanisms and therapy. Antioxid Redox Signal. 2020;33:374–93.

    Article  CAS  PubMed  Google Scholar 

  53. Esteras N, Kundel F, Amodeo GF, Pavlov EV, Klenerman D, Abramov AY. Insoluble tau aggregates induce neuronal death through modification of membrane ion conductance, activation of voltage-gated calcium channels and NADPH oxidase. Febs J. 2021;288:127–41.

    Article  CAS  PubMed  Google Scholar 

  54. Russo R, Cattaneo F, Lippiello P, Cristiano C, Zurlo F, Castaldo M, et al. Motor coordination and synaptic plasticity deficits are associated with increased cerebellar activity of NADPH oxidase, CAMKII, and PKC at preplaque stage in the TgCRND8 mouse model of Alzheimer’s disease. Neurobiol Aging. 2018;68:123–33.

    Article  CAS  PubMed  Google Scholar 

  55. Rabie MA, Abd El Fattah MA, Nassar NN, El-Abhar HS, Abdallah DM. Angiotensin 1-7 ameliorates 6-hydroxydopamine lesions in hemiparkinsonian rats through activation of MAS receptor/PI3K/Akt/BDNF pathway and inhibition of angiotensin II type-1 receptor/NF-kappaB axis. Biochem Pharm. 2018;151:126–34.

    Article  CAS  PubMed  Google Scholar 

  56. Wu G, Li L, Li HM, Zeng Y, Wu WC. Electroacupuncture ameliorates spatial learning and memory impairment via attenuating NOX2-related oxidative stress in a rat model of Alzheimer’s disease induced by Abeta1-42. Cell Mol Biol. 2017;63:38–45.

    Article  CAS  PubMed  Google Scholar 

  57. Sorce S, Stocker R, Seredenina T, Holmdahl R, Aguzzi A, Chio A, et al. NADPH oxidases as drug targets and biomarkers in neurodegenerative diseases: What is the evidence? Free Radic Biol Med. 2017;112:387–96.

    Article  CAS  PubMed  Google Scholar 

  58. Hemmati-Dinarvand M, Taher-Aghdam AA, Mota A, Zununi Vahed S, Samadi N. Dysregulation of serum NADPH oxidase1 and ferritin levels provides insights into diagnosis of Parkinson’s disease. Clin Biochem. 2017;50:1087–92.

    Article  CAS  PubMed  Google Scholar 

  59. Jiang T, Sun Q, Chen S. Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson’s disease and Alzheimer’s disease. Prog Neurobiol. 2016;147:1–19.

    Article  CAS  PubMed  Google Scholar 

  60. Zhang C, Hou L, Yang J, Che Y, Sun F, Li H, et al. 2,5-Hexanedione induces dopaminergic neurodegeneration through integrin α(M)β2/NADPH oxidase axis-mediated microglial activation. Cell Death Dis. 2018;9:60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chung YC, Baek JY, Kim SR, Ko HW, Bok E, Shin WH, et al. Capsaicin prevents degeneration of dopamine neurons by inhibiting glial activation and oxidative stress in the MPTP model of Parkinson’s disease. Exp Mol Med. 2017;49:e298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. González-Reyes RE, Nava-Mesa MO, Vargas-Sánchez K, Ariza-Salamanca D, Mora-Muñoz L. Involvement of astrocytes in alzheimer’s disease from a neuroinflammatory and oxidative stress perspective. Front Mol Neurosci. 2017;10:427.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Chay KO, Nam Koong KY, Hwang S, Kim JK, Bae CS. NADPH oxidase mediates β-amyloid peptide-induced neuronal death in mouse cortical cultures. Chonnam Med J. 2017;53:196–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wyssenbach A, Quintela T, Llavero F, Zugaza JL, Matute C, Alberdi E. Amyloid β-induced astrogliosis is mediated by β1-integrin via NADPH oxidase 2 in Alzheimer’s disease. Aging Cell. 2016;15:1140–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Joseph E, Villalobos-Acosta D, Torres-Ramos MA, Farfán-García ED, Gómez-López M, Miliar-García Á, et al. Neuroprotective effects of apocynin and galantamine during the chronic administration of scopolamine in an alzheimer’s disease model. J Mol Neurosci. 2020;70:180–93.

    Article  CAS  PubMed  Google Scholar 

  66. Nortley R, Korte N, Izquierdo P, Hirunpattarasilp C, Mishra A, Jaunmuktane Z, et al. Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science. 2019;365:eaav9518.

  67. Sharma N, Kapoor M, Nehru B. Apocyanin, NADPH oxidase inhibitor prevents lipopolysaccharide induced α-synuclein aggregation and ameliorates motor function deficits in rats: Possible role of biochemical and inflammatory alterations. Behav Brain Res. 2016;296:177–90.

    Article  CAS  PubMed  Google Scholar 

  68. Gallardo-Fernández M, Hornedo-Ortega R, Alonso-Bellido IM, Rodríguez-Gómez JA, Troncoso AM, García-Parrilla MC, et al. Hydroxytyrosol decreases LPS- and α-synuclein-induced microglial activation in vitro. Antioxidants. 2019;9:36.

  69. Hou L, Bao X, Zang C, Yang H, Sun F, Che Y, et al. Integrin CD11b mediates alpha-synuclein-induced activation of NADPH oxidase through a Rho-dependent pathway. Redox Biol. 2018;14:600–8.

    Article  CAS  PubMed  Google Scholar 

  70. Che Y, Hou L, Sun F, Zhang C, Liu X, Piao F, et al. Taurine protects dopaminergic neurons in a mouse Parkinson’s disease model through inhibition of microglial M1 polarization. Cell Death Dis. 2018;9:435.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Jiang T, Hoekstra J, Heng X, Kang W, Ding J, Liu J, et al. P2X7 receptor is critical in α-synuclein-mediated microglial NADPH oxidase activation. Neurobiol Aging. 2015;36:2304–18.

    Article  CAS  PubMed  Google Scholar 

  72. Rodriguez-Perez AI, Sucunza D, Pedrosa MA, Garrido-Gil P, Kulisevsky J, Lanciego JL, et al. Angiotensin type 1 receptor antagonists protect against alpha-synuclein-induced neuroinflammation and dopaminergic neuron death. Neurotherapeutics. 2018;15:1063–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hou L, Sun F, Sun W, Zhang L, Wang Q. Lesion of the locus coeruleus damages learning and memory performance in paraquat and maneb-induced mouse parkinson’s disease model. Neuroscience. 2019;419:129–40.

    Article  CAS  PubMed  Google Scholar 

  74. Hou L, Che Y, Sun F, Wang Q. Taurine protects noradrenergic locus coeruleus neurons in a mouse Parkinson’s disease model by inhibiting microglial M1 polarization. Amino Acids. 2018;50:547–56.

    Article  CAS  PubMed  Google Scholar 

  75. Hou L, Zhou X, Zhang C, Wang K, Liu X, Che Y, et al. NADPH oxidase-derived H(2)O(2) mediates the regulatory effects of microglia on astrogliosis in experimental models of Parkinson’s disease. Redox Biol. 2017;12:162–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Dang DK, Shin EJ, Kim DJ, Tran HQ, Jeong JH, Jang CG, et al. PKCdelta-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity. Free Radic Biol Med. 2018;115:318–37.

    Article  CAS  PubMed  Google Scholar 

  77. Morrice JR, Gregory-Evans CY, Shaw CA. Animal models of amyotrophic lateral sclerosis: A comparison of model validity. Neural Regeneration Res. 2018;13:2050–4.

    Article  CAS  Google Scholar 

  78. Apolloni S, Fabbrizio P, Parisi C, Amadio S, Volonté C. Clemastine confers neuroprotection and induces an anti-inflammatory phenotype in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Mol Neurobiol. 2016;53:518–31.

    Article  CAS  PubMed  Google Scholar 

  79. Wang T, Cheng J, Wang S, Wang X, Jiang H, Yang Y, et al. α-Lipoic acid attenuates oxidative stress and neurotoxicity via the ERK/Akt-dependent pathway in the mutant hSOD1 related Drosophila model and the NSC34 cell line of amyotrophic lateral sclerosis. Brain Res Bull. 2018;140:299–310.

    Article  CAS  PubMed  Google Scholar 

  80. Harraz MM, Marden JJ, Zhou W, Zhang Y, Williams A, Sharov VS, et al. SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Invest. 2008;118:659–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Seredenina T, Nayernia Z, Sorce S, Maghzal GJ, Filippova A, Ling SC, et al. Evaluation of NADPH oxidases as drug targets in a mouse model of familial amyotrophic lateral sclerosis. Free Radic Biol Med. 2016;97:95–108.

    Article  CAS  PubMed  Google Scholar 

  82. Kato K, Hecker L. NADPH oxidases: Pathophysiology and therapeutic potential in age-associated pulmonary fibrosis. Redox. Biology 2020;33:101541.

    CAS  Google Scholar 

  83. Kurundkar A, Thannickal VJ. Redox mechanisms in age-related lung fibrosis. Redox Biol. 2016;9:67–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Liu B, Rong Y, Sun D, Li W, Chen H, Cao B, et al. Costunolide inhibits pulmonary fibrosis via regulating NF-kB and TGF-beta1/Smad2/Nrf2-NOX4 signaling pathways. Biochem Biophys Res Commun. 2019;510:329–33.

    Article  CAS  PubMed  Google Scholar 

  85. Wu YC, Wang WT, Lee SS, Kuo YR, Wang YC, Yen SJ, et al. Glucagon-like peptide-1 receptor agonist attenuates autophagy to ameliorate pulmonary arterial hypertension through Drp1/NOX- and Atg-5/Atg-7/Beclin-1/LC3beta pathways. Int J Mol Sci. 2019;20:3435.

  86. Kracun D, Klop M, Knirsch A, Petry A, Kanchev I, Chalupsky K, et al. NADPH oxidases and HIF1 promote cardiac dysfunction and pulmonary hypertension in response to glucocorticoid excess. Redox Biol. 2020;34:101536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hollins F, Sutcliffe A, Gomez E, Berair R, Russell R, Szyndralewiez C, et al. Airway smooth muscle NOX4 is upregulated and modulates ROS generation in COPD. Respir Res. 2016;17:84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Hsu PS, Lin CM, Chang JF, Wu CS, Sia KC, Lee IT, et al. Participation of NADPH oxidase-related reactive oxygen species in leptin-promoted pulmonary inflammation: regulation of cPLA2alpha and COX-2 expression. Int J Mol Sci. 2019;20:1078.

  89. Zhang Y, Shan P, Srivastava A, Jiang G, Zhang X, Lee PJ. An endothelial Hsp70-TLR4 axis limits Nox3 expression and protects against oxidant injury in lungs. Antioxid Redox Signal. 2016;24:991–1012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wieczfinska J, Sokolowska M, Pawliczak R. NOX modifiers-just a step away from application in the therapy of airway inflammation? Antioxid Redox Signal. 2015;23:428–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Martinez FJ, Collard HR, Pardo A, Raghu G, Richeldi L, Selman M, et al. Idiopathic pulmonary fibrosis. Nat Rev Dis Prim. 2017;3:17074.

    Article  PubMed  Google Scholar 

  92. Waters DW, Blokland KEC, Pathinayake PS, Burgess JK, Mutsaers SE, Prele CM, et al. Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2018;315:L162–L72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Veith C, Boots AW, Idris M, van Schooten F-J, van der Vliet A. Redox imbalance in idiopathic pulmonary fibrosis: a role for oxidant cross-talk between NADPH oxidase enzymes and mitochondria. Antioxid Redox Signal. 2019;31:1092–115. https://doi.org/10.1089/ars.2019.7742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Li L, Cai L, Zheng L, Hu Y, Yuan W, Guo Z, et al. Gefitinib inhibits bleomycin-induced pulmonary fibrosis via alleviating the oxidative damage in mice. Oxid Med Cell Longev. 2018;2018:1–12. https://doi.org/10.1155/2018/8249693

    Article  CAS  Google Scholar 

  95. Wang CL, Kang J, Li ZH. [Increased expression of NADPH oxidase p47-PHOX and p67-PHOX factor in idiopathic pulmonary fibrosis]. Zhonghua Jie He He Hu Xi Za Zhi. 2007;30:265–8.

    PubMed  Google Scholar 

  96. Jarman ER, Khambata VS, Yun Ye L, Cheung K, Thomas M, Duggan N, et al. A translational preclinical model of interstitial pulmonary fibrosis and pulmonary hypertension: mechanistic pathways driving disease pathophysiology. Physiol Rep. 2014;2:e12133.

  97. Liu RM, Desai LP. Reciprocal regulation of TGF-β and reactive oxygen species: A perverse cycle for fibrosis. Redox Biol. 2015;6:565–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Carnesecchi S, Deffert C, Donati Y, Basset O, Hinz B, Preynat-Seauve O, et al. A key role for NOX4 in epithelial cell death during development of lung fibrosis. Antioxid Redox Signal. 2011;15:607–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Maximillian R, Richter T. Acute lung injury and acute respiratory distress syndrome. J Emerg Trauma Shock. 2010;3:43–51. https://doi.org/10.4103/0974-2700.58663

    Article  Google Scholar 

  100. Wu F, Szczepaniak WS, Shiva S, Liu H, Wang Y, Wang L, et al. Nox2-dependent glutathionylation of endothelial NOS leads to uncoupled superoxide production and endothelial barrier dysfunction in acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2014;307:L987–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Whitmore LC, Hilkin BM, Goss KL, Wahle EM, Colaizy TT, Boggiatto PM, et al. NOX2 protects against prolonged inflammation, lung injury, and mortality following systemic insults. J Innate Immun. 2013;5:565–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Huang W, Xiong YQ, Chen YL, Cheng Y, Wang RR. NOX2 is involved in CB2-mediated protection against lung ischemia-reperfusion injury in mice. Int J Clin Exp Pathol. 2020;13:277–85.

    PubMed  PubMed Central  Google Scholar 

  103. Stanton RC. Glucose-6-phosphate dehydrogenase NADPH and cell survival. IUBMB Life. 2012;64:362–9. https://doi.org/10.1002/iub.1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Nadeem A, Al-Harbi NO, Ahmad SF, Ibrahim KE, Siddiqui N, Al-Harbi MM. Glucose-6-phosphate dehydrogenase inhibition attenuates acute lung injury through reduction in NADPH oxidase-derived reactive oxygen species. Clin Exp Immunol. 2018;191:279–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Chen W, Chen YY, Tsai CF, Chen SC, Lin MS, Ware LB, et al. Incidence and outcomes of acute respiratory distress syndrome: a nationwide registry-based study in Taiwan, 1997 to 2011. Medicine. 2015;94:e1849.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Jensen JS, Itenov TS, Thormar KM, Hein L, Mohr TT, Andersen MH, et al. Prediction of non-recovery from ventilator-demanding acute respiratory failure, ARDS and death using lung damage biomarkers: data from a 1200-patient critical care randomized trial. Ann Intensive Care. 2016;6:114.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Kellner M, Noonepalle S, Lu Q, Srivastava A, Zemskov E, Black SM. ROS signaling in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Adv Exp Med Biol. 2017;967:105–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wells JM, Iyer AS, Rahaghi FN, Bhatt SP, Gupta H, Denney TS, et al. Pulmonary artery enlargement is associated with right ventricular dysfunction and loss of blood volume in small pulmonary vessels in chronic obstructive pulmonary disease. Circ Cardiovasc Imaging. 2015;8:e002546.

  109. Boukhenouna S, Wilson MA, Bahmed K, Kosmider B. Reactive oxygen species in chronic obstructive pulmonary disease. Oxid Med Cell Longev. 2018;2018:1–9. https://doi.org/10.1155/2018/5730395

    Article  CAS  Google Scholar 

  110. Guo X, Fan Y, Cui J, Hao B, Zhu L, Sun X, et al. NOX4 expression and distal arteriolar remodeling correlate with pulmonary hypertension in COPD. BMC Pulm Med. 2018;18:111.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Liu X, Hao B, Ma A, He J, Liu X, Chen J. The expression of NOX4 in smooth muscles of small airway correlates with the disease severity of COPD. Biomed Res Int. 2016;2016:2891810.

    PubMed  PubMed Central  Google Scholar 

  112. Seimetz M, Sommer N, Bednorz M, Pak O, Veith C, Hadzic S, et al. NADPH oxidase subunit NOXO1 is a target for emphysema treatment in COPD. Nat Metab. 2020;2:532–46.

    Article  CAS  PubMed  Google Scholar 

  113. Li H, Han X, Hu Z, Huang J, Chen J, Hixson JE, et al. Associations of NADPH oxidase-related genes with blood pressure changes and incident hypertension: The GenSalt Study. J Hum Hypertens. 2018;32:287–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Lu W, Kang J, Hu K, Tang S, Zhou X, Xu L, et al. The role of the Nox4-derived ROS-mediated RhoA/Rho kinase pathway in rat hypertension induced by chronic intermittent hypoxia. Sleep Breath. 2017;21:667–77.

    Article  PubMed  Google Scholar 

  115. Song Q, Zhang Y, Han X, Zhang X, Gao Y, Zhang J, et al. Potential mechanisms underlying the protective effects of salvianic acid A against atherosclerosis in vivo and vitro. Biomed Pharmacother. 2019;109:945–56.

    Article  CAS  PubMed  Google Scholar 

  116. Lu Z, Wang F, Yu P, Wang X, Wang Y, Tang ST, et al. Inhibition of miR-29b suppresses MAPK signaling pathway through targeting SPRY1 in atherosclerosis. Vasc Pharm. 2018;102:29–36.

    Article  CAS  Google Scholar 

  117. Simplicio JA, do Vale GT, Gonzaga NA, Leite LN, Hipolito UV, Pereira CA, et al. Reactive oxygen species derived from NAD(P)H oxidase play a role on ethanol-induced hypertension and endothelial dysfunction in rat resistance arteries. J Physiol Biochem. 2017;73:5–16.

    Article  CAS  PubMed  Google Scholar 

  118. Shin YK, Han AY, Hsieh YS, Kwon S, Kim J, Lee KW, et al. Lancemaside A from Codonopsis lanceolata prevents hypertension by inhibiting NADPH oxidase 2-mediated MAPK signalling and improving NO bioavailability in rats. J Pharm Pharm. 2019;71:1458–68.

    Article  CAS  Google Scholar 

  119. Zhang Y, Murugesan P, Huang K, Cai H. NADPH oxidases and oxidase crosstalk in cardiovascular diseases: novel therapeutic targets. Nat Rev Cardiol. 2020;17:170–94.

    Article  CAS  PubMed  Google Scholar 

  120. Knock GA. NADPH oxidase in the vasculature: Expression, regulation and signalling pathways; role in normal cardiovascular physiology and its dysregulation in hypertension. Free Radic Biol Med. 2019;145:385–427.

    Article  CAS  PubMed  Google Scholar 

  121. Li Y, Pagano PJ. Microvascular NADPH oxidase in health and disease. Free Radic Biol Med. 2017;109:33–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Li WJ, Liu Y, Wang JJ, Zhang YL, Lai S, Xia YL, et al. “Angiotensin II memory” contributes to the development of hypertension and vascular injury via activation of NADPH oxidase. Life Sci. 2016;149:18–24.

    Article  CAS  PubMed  Google Scholar 

  123. Liang YF, Zhang DD, Yu XJ, Gao HL, Liu KL, Qi J, et al. Hydrogen sulfide in paraventricular nucleus attenuates blood pressure by regulating oxidative stress and inflammatory cytokines in high salt-induced hypertension. Toxicol Lett. 2017;270:62–71.

    Article  CAS  PubMed  Google Scholar 

  124. Marchi KC, Ceron CS, Muniz JJ, De Martinis BS, Tanus-Santos JE, Tirapelli CR. NADPH oxidase plays a role on ethanol-induced hypertension and reactive oxygen species generation in the vasculature. Alcohol Alcohol. 2016;51:522–34.

    Article  CAS  PubMed  Google Scholar 

  125. Huang YP, Jin HY, Yu HP. Inhibitory effects of alpha-lipoic acid on oxidative stress in the rostral ventrolateral medulla in rats with salt-induced hypertension. Int J Mol Med. 2017;39:430–6.

    Article  CAS  PubMed  Google Scholar 

  126. Qi J, Yu XJ, Shi XL, Gao HL, Yi QY, Tan H, et al. NF-kappaB blockade in hypothalamic paraventricular nucleus inhibits high-salt-induced hypertension through NLRP3 and caspase-1. Cardiovasc Toxicol. 2016;16:345–54.

    Article  CAS  PubMed  Google Scholar 

  127. Niazi ZR, Silva GC, Ribeiro TP, León-González AJ, Kassem M, Mirajkar A, et al. EPA:DHA 6:1 prevents angiotensin II-induced hypertension and endothelial dysfunction in rats: role of NADPH oxidase- and COX-derived oxidative stress. Hypertens Res. 2017;40:966–75.

    Article  CAS  PubMed  Google Scholar 

  128. Ma MM, Gao M, Guo KM, Wang M, Li XY, Zeng XL, et al. TMEM16A contributes to endothelial dysfunction by facilitating Nox2 NADPH oxidase-derived reactive oxygen species generation in hypertension. Hypertension. 2017;69:892–901.

    Article  CAS  PubMed  Google Scholar 

  129. Helfinger V, Palfi K, Weigert A, Schröder K. The NADPH oxidase nox4 controls macrophage polarization in an NFκB-dependent manner. Oxid Med Cell Longev. 2019;2019:3264858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Li X, Lin Y, Zhou H, Li Y, Wang A, Wang H, et al. Puerarin protects against endothelial dysfunction and end-organ damage in Ang II-induced hypertension. Clin Exp Hypertens. 2017;39:58–64.

    Article  PubMed  CAS  Google Scholar 

  131. Liang GZ, Cheng LM, Chen XF, Li YJ, Li XL, Guan YY, et al. ClC-3 promotes angiotensin II-induced reactive oxygen species production in endothelial cells by facilitating Nox2 NADPH oxidase complex formation. Acta Pharm Sin. 2018;39:1725–34.

    Article  CAS  Google Scholar 

  132. Ling WC, Mustafa MR, Vanhoutte PM, Murugan DD. Chronic administration of sodium nitrite prevents hypertension and protects arterial endothelial function by reducing oxidative stress in angiotensin II-infused mice. Vasc Pharm. 2018;102:11–20.

    Article  CAS  Google Scholar 

  133. Kang Y, Ding L, Dai H, Wang F, Zhou H, Gao Q, et al. Intermedin in paraventricular nucleus attenuates ang II-induced sympathoexcitation through the inhibition of NADPH oxidase-dependent ROS generation in obese rats with hypertension. Int J Mol Sci. 2019;20:4217.

  134. Radwan E, Mali V, Haddox S, El-Noweihi A, Mandour M, Ren J, et al. Treg cells depletion is a mechanism that drives microvascular dysfunction in mice with established hypertension. Biochim Biophys Acta Mol Basis Dis. 2019;1865:403–12.

    Article  CAS  PubMed  Google Scholar 

  135. Camargo LL, Harvey AP, Rios FJ, Tsiropoulou S, Da Silva RNO, Cao Z, et al. Vascular nox (NADPH Oxidase) compartmentalization, protein hyperoxidation, and endoplasmic reticulum stress response in hypertension. Hypertension. 2018;72:235–46.

    Article  CAS  PubMed  Google Scholar 

  136. Sciarretta S, Yee D, Ammann P, Nagarajan N, Volpe M, Frati G, et al. Role of NADPH oxidase in the regulation of autophagy in cardiomyocytes. Clin Sci. 2014;128:387–403.

    Article  CAS  Google Scholar 

  137. Mei Y, Thompson MD, Cohen RA, Tong X. Autophagy and oxidative stress in cardiovascular diseases. Biochim Biophys Acta. 2015;1852:243–51.

    Article  CAS  PubMed  Google Scholar 

  138. Mo J, Yang R, Li F, Zhang X, He B, Zhang Y, et al. Scutellarin protects against vascular endothelial dysfunction and prevents atherosclerosis via antioxidation. Phytomedicine. 2018;42:66–74.

    Article  CAS  PubMed  Google Scholar 

  139. Kim J, Seo M, Kim SK, Bae YS. Flagellin-induced NADPH oxidase 4 activation is involved in atherosclerosis. Sci Rep. 2016;6:25437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Sfyri P, Matsakas A. Crossroads between peripheral atherosclerosis, western-type diet and skeletal muscle pathophysiology: emphasis on apolipoprotein E deficiency and peripheral arterial disease. J Biomed Sci. 2017;24:42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Liang W, Wang Q, Ma H, Yan W, Yang J. Knockout of low molecular weight FGF2 attenuates atherosclerosis by reducing macrophage infiltration and oxidative stress in mice. Cell Physiol Biochem. 2018;45:1434–43.

    Article  CAS  PubMed  Google Scholar 

  142. Sfyri PP, Yuldasheva NY, Tzimou A, Giallourou N, Crispi V, Aburima A, et al. Attenuation of oxidative stress-induced lesions in skeletal muscle in a mouse model of obesity-independent hyperlipidaemia and atherosclerosis through the inhibition of Nox2 activity. Free Radic Biol Med. 2018;129:504–19.

    Article  CAS  PubMed  Google Scholar 

  143. Peng Y, Xu J, Zeng Y, Chen L, Xu XL. Polydatin attenuates atherosclerosis in apolipoprotein E-deficient mice: Role of reverse cholesterol transport. Phytomedicine. 2019;62:152935.

    Article  CAS  PubMed  Google Scholar 

  144. Shu Q, Lai S, Wang XM, Zhang YL, Yang XL, Bi HL, et al. Administration of ubiquitin-activating enzyme UBA1 inhibitor PYR-41 attenuates angiotensin II-induced cardiac remodeling in mice. Biochem Biophys Res Commun. 2018;505:317–24.

    Article  CAS  PubMed  Google Scholar 

  145. Charbonneau M-E, Passalacqua KD, Hagen SE, Showalter HD, Wobus CE, O’Riordan MXD. Perturbation of ubiquitin homeostasis promotes macrophage oxidative defenses. Sci Rep. 2019;9:10245.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Liao J, Yang X, Lin Q, Liu S, Xie Y, Xia Y, et al. Inhibition of the ubiquitin-activating enzyme UBA1 suppresses diet-induced atherosclerosis in apolipoprotein E-knockout mice. J Immunol Res. 2020;2020:7812709.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Manea SA, Vlad ML, Fenyo IM, Lazar AG, Raicu M, Muresian H, et al. Pharmacological inhibition of histone deacetylase reduces NADPH oxidase expression, oxidative stress and the progression of atherosclerotic lesions in hypercholesterolemic apolipoprotein E-deficient mice; potential implications for human atherosclerosis. Redox Biol. 2020;28:101338.

    Article  CAS  PubMed  Google Scholar 

  148. Vlad ML, Manea SA, Lazar AG, Raicu M, Muresian H, Simionescu M, et al. Histone acetyltransferase-dependent pathways mediate upregulation of NADPH oxidase 5 in human macrophages under inflammatory conditions: a potential mechanism of reactive oxygen species overproduction in atherosclerosis. Oxid Med Cell Longev. 2019;2019:3201062.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Cheng Y, Zhou M, Zhou W. MicroRNA-30e regulates TGF-β-mediated NADPH oxidase 4-dependent oxidative stress by Snai1 in atherosclerosis. Int J Mol Med. 2019;43:1806–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Pejenaute Á, Cortés A, Marqués J, Montero L, Beloqui Ó, Fortuño A, et al. NADPH oxidase overactivity underlies telomere shortening in human atherosclerosis. Int J Mol Sci. 2020;21:1434.

  151. Shi Q, Viswanadhapalli S, Friedrichs WE, Velagapudi C, Szyndralewiez C, Bansal S, et al. Nox4 is a target for tuberin deficiency syndrome. Sci Rep. 2018;8:3781.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Jeong BY, Park SR, Cho S, Yu SL, Lee HY, Park CG, et al. TGF-beta-mediated NADPH oxidase 4-dependent oxidative stress promotes colistin-induced acute kidney injury. J Antimicrob Chemother. 2018;73:962–72.

    Article  CAS  PubMed  Google Scholar 

  153. Jeong BY, Lee HY, Park CG, Kang J, Yu SL, Choi DR, et al. Oxidative stress caused by activation of NADPH oxidase 4 promotes contrast-induced acute kidney injury. PLoS One. 2018;13:e0191034.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Meng XM, Ren GL, Gao L, Yang Q, Li HD, Wu WF, et al. NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation. Lab Invest. 2018;98:63–78.

    Article  CAS  PubMed  Google Scholar 

  155. Cha JJ, Min HS, Kim KT, Kim JE, Ghee JY, Kim HW, et al. APX-115, a first-in-class pan-NADPH oxidase (Nox) inhibitor, protects db/db mice from renal injury. Lab Invest. 2017;97:419–31.

    Article  CAS  PubMed  Google Scholar 

  156. Sureshbabu A, Patino E, Ma KC, Laursen K, Finkelsztein EJ, Akchurin O, et al. RIPK3 promotes sepsis-induced acute kidney injury via mitochondrial dysfunction. JCI Insight. 2018;3:e98411.

  157. Al-Harbi NO, Nadeem A, Ahmad SF, Alanazi MM, Aldossari AA, Alasmari F. Amelioration of sepsis-induced acute kidney injury through inhibition of inflammatory cytokines and oxidative stress in dendritic cells and neutrophils respectively in mice: Role of spleen tyrosine kinase signaling. Biochimie. 2019;158:102–10.

    Article  CAS  PubMed  Google Scholar 

  158. Sawhney S, Fraser SD. Epidemiology of AKI: utilizing large databases to determine the burden of AKI. Adv Chronic Kidney Dis. 2017;24:194–204.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Cho S, Yu SL, Kang J, Jeong BY, Lee HY, Park CG, et al. NADPH oxidase 4 mediates TGF-β1/Smad signaling pathway induced acute kidney injury in hypoxia. PLoS One. 2019;14:e0219483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Gyurászová M, Gurecká R, Bábíčková J, Tóthová Ľ. Oxidative Stress in the Pathophysiology of Kidney Disease: Implications for Noninvasive Monitoring and Identification of Biomarkers. Oxid Med Cell Longev. 2020;2020:5478708.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Galvan DL, Green NH, Danesh FR. The hallmarks of mitochondrial dysfunction in chronic kidney disease. Kidney Int. 2017;92:1051–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Karanovic D, Grujic-Milanovic J, Miloradovic Z, Ivanov M, Jovovic D, Vajic UJ, et al. Effects of single and combined losartan and tempol treatments on oxidative stress, kidney structure and function in spontaneously hypertensive rats with early course of proteinuric nephropathy. PLoS One. 2016;11:e0161706.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Djamali A, Wilson NA, Sadowski EA, Zha W, Niles D, Hafez O, et al. Nox2 and cyclosporine-induced renal hypoxia. Transplantation. 2016;100:1198–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Vodosek Hojs N, Bevc S, Ekart R, Hojs R. Oxidative stress markers in chronic kidney disease with emphasis on diabetic nephropathy. Antioxidants. 2020;9:925.

  165. Kuchta A, Pacanis A, Kortas-Stempak B, Cwiklinska A, Zietkiewicz M, Renke M, et al. Estimation of oxidative stress markers in chronic kidney disease. Kidney Blood Press Res. 2011;34:12–9.

    Article  CAS  PubMed  Google Scholar 

  166. Duni A, Liakopoulos V, Roumeliotis S, Peschos D, Dounousi E. Oxidative stress in the pathogenesis and evolution of chronic kidney disease: untangling ariadne’s thread. Int J Mol Sci. 2019;20:3711.

  167. Bondi CD, Manickam N, Lee DY, Block K, Gorin Y, Abboud HE, et al. NAD(P)H oxidase mediates TGF-β1–induced activation of kidney myofibroblasts. J Am Soc Nephrol. 2010;21:93–102. https://doi.org/10.1681/ASN.2009020146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Nezu M, Suzuki N, Yamamoto M. Targeting the KEAP1-NRF2 system to prevent kidney disease progression. Am J Nephrol. 2017;45:473–83.

    Article  CAS  PubMed  Google Scholar 

  169. Lee JH, Kim D, Oh YS, Jun HS. Lysophosphatidic acid signaling in diabetic nephropathy. Int J Mol Sci. 2019;20:2850.

  170. Zhang J, Yang S, Li H, Chen F, Shi J. Naringin ameliorates diabetic nephropathy by inhibiting NADPH oxidase 4. Eur J Pharm. 2017;804:1–6.

    Article  CAS  Google Scholar 

  171. Lopez-Sanz L, Bernal S, Recio C, Lazaro I, Oguiza A, Melgar A, et al. SOCS1-targeted therapy ameliorates renal and vascular oxidative stress in diabetes via STAT1 and PI3K inhibition. Lab Invest. 2018;98:1276–90.

    Article  CAS  PubMed  Google Scholar 

  172. Cheng YS, Chao J, Chen C, Lv LL, Han YC, Liu BC. The PKCbeta-p66shc-NADPH oxidase pathway plays a crucial role in diabetic nephropathy. J Pharm Pharm. 2019;71:338–47.

    Article  CAS  Google Scholar 

  173. Papadopoulou-Marketou N, Chrousos GP, Kanaka-Gantenbein C. Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis. Diabetes Metab Res Rev. 2017;33:e2841.

  174. Jha JC, Banal C, Okabe J, Gray SP, Hettige T, Chow BSM, et al. NADPH oxidase Nox5 accelerates renal injury in diabetic nephropathy. Diabetes. 2017;66:2691–703.

    Article  CAS  PubMed  Google Scholar 

  175. Holterman CE, Read NC, Kennedy CR. Nox and renal disease. Clin Sci. 2015;128:465–81.

    Article  CAS  Google Scholar 

  176. Stinghen AE, Massy ZA, Vlassara H, Striker GE, Boullier A. Uremic toxicity of advanced glycation end products in CKD. J Am Soc Nephrol. 2016;27:354–70.

    Article  CAS  PubMed  Google Scholar 

  177. Matsui T, Higashimoto Y, Nishino Y, Nakamura N, Fukami K, Yamagishi SI. RAGE-aptamer blocks the development and progression of experimental diabetic nephropathy. Diabetes. 2017;66:1683–95.

    Article  CAS  PubMed  Google Scholar 

  178. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114:597–605.

    Article  CAS  PubMed  Google Scholar 

  179. Yao M, Gao F, Wang X, Shi Y, Liu S, Duan H. Nox4 is involved in high glucose-induced apoptosis in renal tubular epithelial cells via Notch pathway. Mol Med Rep. 2017;15:4319–25.

    Article  CAS  PubMed  Google Scholar 

  180. Cui Y, Shi Y, Bao Y, Wang S, Hua Q, Liu Y. Zingerone attenuates diabetic nephropathy through inhibition of nicotinamide adenine dinucleotide phosphate oxidase 4. Biomed Pharmacother. 2018;99:422–30.

    Article  CAS  PubMed  Google Scholar 

  181. Reis J, Massari M, Marchese S, Ceccon M, Aalbers FS, Corana F, et al. A closer look into NADPH oxidase inhibitors: Validation and insight into their mechanism of action. Redox Biology. 2020;32:101466.

  182. Kovacic H. 2020, A decisive decade for NADPH oxidases inhibitors. Antioxid Redox Signal. 2020;33:329–31.

    Article  CAS  PubMed  Google Scholar 

  183. Chocry M, Leloup L. The NADPH oxidase family and its inhibitors. Antioxid Redox Signal. 2020;33:332–53.

    Article  CAS  PubMed  Google Scholar 

  184. Li Y, Cifuentes-Pagano E, DeVallance ER, de Jesus DS, Sahoo S, Meijles DN, et al. NADPH oxidase 2 inhibitors CPP11G and CPP11H attenuate endothelial cell inflammation & vessel dysfunction and restore mouse hind-limb flow. Redox Biology. 2019;22:101143.

  185. de Jesus DS, DeVallance E, Li Y, Falabella M, Guimaraes D, Shiva S, et al. Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration. Redox Biol. 2019;22:101138.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Levy C. Novel therapies for cholestatic liver disease. Gastroenterol Hepatol. 2019;15:493–6.

    Google Scholar 

  187. Galoosian A, Hanlon C, Zhang J, Holt EW, Yimam KK. Clinical updates in primary biliary cholangitis: trends, epidemiology, diagnostics, and new therapeutic approaches. J Clin Transl Hepatol. 2020;8:49–60.

    PubMed  PubMed Central  Google Scholar 

  188. Petronio MS, Zeraik ML, da Fonseca LM, Ximenes VF. Apocynin: chemical and biophysical properties of a NADPH oxidase inhibitor. Molecules. 2013;18:2821–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Augsburger F, Filippova A, Rasti D, Seredenina T, Lam M, Maghzal G, et al. Pharmacological characterization of the seven human NOX isoforms and their inhibitors. Redox Biol. 2019;26:101272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Wingler K, Hermans JJ, Schiffers P, Moens A, Paul M, Schmidt HHNOX1. 2, 4, 5: counting out oxidative stress. Br J Pharm. 2011;164:866–83.

    Article  CAS  Google Scholar 

  191. ten Freyhaus H, Huntgeburth M, Wingler K, Schnitker J, Baumer AT, Vantler M, et al. Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation. Cardiovasc Res. 2006;71:331–41.

    Article  PubMed  CAS  Google Scholar 

  192. Zhao J, Sun T, Wu JJ, Cao YF, Fang ZZ, Sun HZ, et al. Inhibition of human CYP3A4 and CYP3A5 enzymes by gomisin C and gomisin G, two lignan analogs derived from Schisandra chinensis. Fitoterapia. 2017;119:26–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Yang J, Li J, Wang Q, Xing Y, Tan Z, Kang Q. Novel NADPH oxidase inhibitor VAS2870 suppresses TGFbetadependent epithelialtomesenchymal transition in retinal pigment epithelial cells. Int J Mol Med. 2018;42:123–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Kleinschnitz C, Grund H, Wingler K, Armitage ME, Jones E, Mittal M, et al. Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol. 2010;8:e1000479 https://doi.org/10.1371/journal.pbio.1000479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Szilagyi JT, Mishin V, Heck DE, Jan YH, Aleksunes LM, Richardson JR, et al. Selective targeting of heme protein in cytochrome P450 and nitric oxide synthase by diphenyleneiodonium. Toxicol Sci. 2016;151:150–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Sun J, Ming L, Shang F, Shen L, Chen J, Jin Y. Apocynin suppression of NADPH oxidase reverses the aging process in mesenchymal stem cells to promote osteogenesis and increase bone mass. Sci Rep. 2015;5:18572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Lu J, Risbood P, Kane CT Jr, Hossain MT, Anderson L, Hill K, et al. Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases. Biochem Pharm. 2017;143:25–38.

    Article  CAS  PubMed  Google Scholar 

  198. Nagel S, Genius J, Heiland S, Horstmann S, Gardner H, Wagner S. Diphenyleneiodonium and dimethylsulfoxide for treatment of reperfusion injury in cerebral ischemia of the rat. Brain Res. 2007;1132:210–7.

    Article  CAS  PubMed  Google Scholar 

  199. Byrnes KR, Washington PM, Knoblach SM, Hoffman E, Faden AI. Delayed inflammatory mRNA and protein expression after spinal cord injury. J Neuroinflammation. 2011;8:130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. He YF, Chen HJ, Qian LH, He LF, Buzby JS. Diphenyleneiodonium protects preoligodendrocytes against endotoxin-activated microglial NADPH oxidase-generated peroxynitrite in a neonatal rat model of periventricular leukomalacia. Brain Res. 2013;1492:108–21.

    Article  CAS  PubMed  Google Scholar 

  201. Wang Q, Qian L, Chen SH, Chu CH, Wilson B, Oyarzabal E, et al. Post-treatment with an ultra-low dose of NADPH oxidase inhibitor diphenyleneiodonium attenuates disease progression in multiple Parkinson’s disease models. Brain. 2015;138:1247–62.

    Article  PubMed  PubMed Central  Google Scholar 

  202. Kim SK, Rho SJ, Kim SH, Kim SY, Song SH, Yoo JY, et al. Protective effects of diphenyleneiodonium, an NADPH oxidase inhibitor, on lipopolysaccharide-induced acute lung injury. Clin Exp Pharm Physiol. 2019;46:153–62.

    Article  CAS  Google Scholar 

  203. Lapchak PA, Zivin JA. Ebselen, a seleno-organic antioxidant, is neuroprotective after embolic strokes in rabbits: synergism with low-dose tissue plasminogen activator. Stroke. 2003;34:2013–8.

    Article  CAS  PubMed  Google Scholar 

  204. Cifuentes-Pagano ME, Meijles DN, Pagano PJ. Nox inhibitors & therapies: rational design of peptidic and small molecule inhibitors. Curr Pharm Des. 2015;21:6023–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  205. Solbak SMO, Zang J, Narayanan D, Hoj LJ, Bucciarelli S, Softley C, et al. Developing inhibitors of the p47phox-p22phox protein-protein interaction by fragment-based drug discovery. J Med Chem. 2020;63:1156–77.

    Article  CAS  PubMed  Google Scholar 

  206. Unsal C, Oran M, Albayrak Y, Aktas C, Erboga M, Topcu B, et al. Neuroprotective effect of ebselen against intracerebroventricular streptozotocin-induced neuronal apoptosis and oxidative stress in rats. Toxicol Ind Health. 2016;32:730–40.

    Article  CAS  PubMed  Google Scholar 

  207. Jia ZQ, Li SQ, Qiao WQ, Xu WZ, Xing JW, Liu JT, et al. Ebselen protects mitochondrial function and oxidative stress while inhibiting the mitochondrial apoptosis pathway after acute spinal cord injury. Neurosci Lett. 2018;678:110–7.

    Article  CAS  PubMed  Google Scholar 

  208. Park C, Choi SH, Jeong J-W, Han MH, Lee H, Hong SH, et al. Honokiol ameliorates oxidative stress[1]induced DNA damage and apoptosis of c2c12 myoblasts by ROS generation and mitochondrial pathway. Anim Cells Syst (Seoul). 2019;24:60–8. https://doi.org/10.1080/19768354.2019.1706634

    Article  CAS  Google Scholar 

  209. Wang M, Li Y, Ni C, Song G. Honokiol attenuates oligomeric amyloid beta1-42-induced alzheimer’s disease in mice through attenuating mitochondrial apoptosis and inhibiting the nuclear factor kappa-B signaling pathway. Cell Physiol Biochem. 2017;43:69–81.

    Article  CAS  PubMed  Google Scholar 

  210. Kim HJ, Yoo HY, Zhang YH, Kim WK, Kim SJ. Biphasic augmentation of alpha-adrenergic contraction by plumbagin in rat systemic arteries. Korean J Physiol Pharm. 2017;21:687–94.

    Article  CAS  Google Scholar 

  211. Kim JY, Park J, Lee JE, Yenari MA. NOX inhibitors - a promising avenue for ischemic stroke. Exp Neurobiol. 2017;26:195–205.

    Article  PubMed  PubMed Central  Google Scholar 

  212. Csanyi G, Cifuentes-Pagano E, Al Ghouleh I, Ranayhossaini DJ, Egana L, Lopes LR, et al. Nox2 B-loop peptide, Nox2ds, specifically inhibits the NADPH oxidase Nox2. Free Radic Biol Med. 2011;51:1116–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Kumar A, Barrett JP, Alvarez-Croda DM, Stoica BA, Faden AI, Loane DJ. NOX2 drives M1-like microglial/macrophage activation and neurodegeneration following experimental traumatic brain injury. Brain Behav Immun. 2016;58:291–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Pal R, Bajaj L, Sharma J, Palmieri M, Di Ronza A, Lotfi P, et al. NADPH oxidase promotes Parkinsonian phenotypes by impairing autophagic flux in an mTORC1-independent fashion in a cellular model of Parkinson’s disease. Sci Rep. 2016;6:22866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Saw S, Kale SL, Arora N. Serine protease inhibitor attenuates ovalbumin induced inflammation in mouse model of allergic airway disease. PLoS One. 2012;7:e41107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Wang L, Yang T, Wang C. Are statins beneficial for the treatment of pulmonary hypertension? Chronic Dis Transl Med. 2017;3:213–20.

    PubMed  PubMed Central  Google Scholar 

  217. Banfi C, Baetta R, Gianazza E, Tremoli E. Technological advances and proteomic applications in drug discovery and target deconvolution: identification of the pleiotropic effects of statins. Drug Disco Today. 2017;22:848–69.

    Article  CAS  Google Scholar 

  218. Chen IC, Tan MS, Wu BN, Chai CY, Yeh JL, Chou SH, et al. Statins ameliorate pulmonary hypertension secondary to left ventricular dysfunction through the Rho-kinase pathway and NADPH oxidase. Pediatr Pulmonol. 2017;52:443–57.

    Article  PubMed  Google Scholar 

  219. Tong H, Zhang X, Meng X, Lu L, Mai D, Qu S. Simvastatin inhibits activation of NADPH oxidase/p38 MAPK pathway and enhances expression of antioxidant protein in parkinson disease models. Front Mol Neurosci. 2018;11:165.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Soni N, Madhusudhan MS. Computational modeling of protein assemblies. Curr Opin Struct Biol. 2017;44:179–89.

    Article  CAS  PubMed  Google Scholar 

  221. Kaur G, Guruprasad K, Temple BRS, Shirvanyants DG, Dokholyan NV, Pati PK. Structural complexity and functional diversity of plant NADPH oxidases. Amino Acids. 2018;50:79–94.

    Article  CAS  PubMed  Google Scholar 

  222. Meijles DN, Howlin BJ, Li JM. Consensus in silico computational modelling of the p22phox subunit of the NADPH oxidase. Comput Biol Chem. 2012;39:6–13.

    Article  CAS  PubMed  Google Scholar 

  223. Yadav DK, Adhikari M, Kumar S, Ghimire B, Han I, Kim MH, et al. Cold atmospheric plasma generated reactive species aided inhibitory effects on human melanoma cells: an in vitro and in silico study. Sci Rep. 2020;10:3396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Bosco EE, Kumar S, Marchioni F, Biesiada J, Kordos M, Szczur K, et al. Rational design of small molecule inhibitors targeting the Rac GTPase-p67(phox) signaling axis in inflammation. Chem Biol. 2012;19:228–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Macias-Perez ME, Martinez-Ramos F, Padilla M, II, Correa-Basurto J, Kispert L, Mendieta-Wejebe JE, et al. Ethers and esters derived from apocynin avoid the interaction between p47phox and p22phox subunits of NADPH oxidase: evaluation in vitro and in silico. Biosci Rep. 2013;33:e00055.

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Acknowledgements

This work was supported by the Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (FAMRI- 123253_YCSA_Faculty) and by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant numbers 5P20 GM103424-18 and 3 P20 GM103424-15S1.

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  1. Gagandeep Kaur

    Present address: Department of Environmental Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, NY, 14642, USA

  2. Prathyusha Bagam

    Present address: Division of Systems Biology, National Center for Toxicological Research, Jefferson, AR, 72079, USA

Authors and Affiliations

  1. Laboratory of Pulmonary Immunotoxicology, Department of Environmental Toxicology, Southern University and A&M College, Baton Rouge, LA, 70813, USA

    Rizwana Begum, Shilpa Thota, Abubakar Abdulkadir, Gagandeep Kaur, Prathyusha Bagam & Sanjay Batra

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  1. Rizwana Begum
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Correspondence to Sanjay Batra.

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Begum, R., Thota, S., Abdulkadir, A. et al. NADPH oxidase family proteins: signaling dynamics to disease management. Cell Mol Immunol 19, 660–686 (2022). https://doi.org/10.1038/s41423-022-00858-1

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