{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:45:23Z","timestamp":1791233123276,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,30]],"date-time":"2023-04-30T00:00:00Z","timestamp":1682812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002383","name":"Ministry of Education in Saudi Arabia","doi-asserted-by":"publisher","award":["IFKSURG-2-1303"],"award-info":[{"award-number":["IFKSURG-2-1303"]}],"id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sepsis affects millions of people worldwide and is associated with multiorgan dysfunction that is a major cause of increased morbidity and mortality. Sepsis is associated with several morbidities, such as lung, liver, and central nervous system (CNS) dysfunction. Sepsis-associated CNS dysfunction usually leads to several mental problems including depression. IL-17A is one of the crucial cytokines that is expressed and secreted by Th17 cells. Th17 cells are reported to be involved in the pathogenesis of depression and anxiety in humans and animals. One of the protein tyrosine kinases that plays a key role in controlling the development\/differentiation of Th17 cells is ITK. However, the role of ITK in sepsis-associated neuroinflammation and depression-like symptoms in mice has not been investigated earlier. Therefore, this study investigated the efficacy of the ITK inhibitor, BMS 509744, in sepsis-linked neuroinflammation (ITK, IL-17A, NFkB, iNOS, MPO, lipid peroxides, IL-6, MCP-1, IL-17A) and a battery of depression-like behavioral tests, such as sucrose preference, tail suspension, and the marble burying test. Further, the effect of the ITK inhibitor on anti-inflammatory signaling (Foxp3, IL-10, Nrf2, HO-1, SOD-2) was assessed in the CNS. Our data show that sepsis causes increased ITK protein expression, IL-17A signaling, and neuroinflammatory mediators in the CNS that are associated with a depression-like state in mice. ITK inhibitor-treated mice with sepsis show attenuated IL-17A signaling, which is associated with the upregulation of IL-10\/Nrf2 signaling and the amelioration of depression-like symptoms in mice. Our data show, for the first time, that the ITK inhibition strategy may counteract sepsis-mediated depression through a reduction in IL-17A signaling in the CNS.<\/jats:p>","DOI":"10.3390\/ijms24098101","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T13:54:46Z","timestamp":1682949286000},"page":"8101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Inhibition of ITK Signaling Causes Amelioration in Sepsis-Associated Neuroinflammation and Depression-like State in Mice"],"prefix":"10.3390","volume":"24","author":[{"given":"Mohammad M.","family":"Algahtani","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8452-4789","authenticated-orcid":false,"given":"Samiyah","family":"Alshehri","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2867-0511","authenticated-orcid":false,"given":"Sana S.","family":"Alqarni","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science, College of Applied Medical Sciences, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8282-3726","authenticated-orcid":false,"given":"Sheikh F.","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naif O.","family":"Al-Harbi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saleh A.","family":"Alqarni","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali S.","family":"Alfardan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3617-4876","authenticated-orcid":false,"given":"Khalid E.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabry M.","family":"Attia","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2038-8367","authenticated-orcid":false,"given":"Ahmed","family":"Nadeem","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,30]]},"reference":[{"key":"ref_1","first-page":"580","article-title":"Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock, 2012","volume":"41","author":"Dellinger","year":"2013","journal-title":"Intensive Care Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/S1473-3099(12)70239-6","article-title":"Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: A prospective cohort study","volume":"12","author":"Levy","year":"2012","journal-title":"Lancet Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"325","DOI":"10.21037\/atm.2016.08.59","article-title":"Epidemiologic trends of sepsis in western countries","volume":"4","author":"Gilsanz","year":"2016","journal-title":"Ann. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.jointm.2021.08.002","article-title":"Basic research and clinical progress of sepsis-associated encephalopathy","volume":"1","author":"Huang","year":"2021","journal-title":"J. Intensiv. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1001\/jama.2014.2637","article-title":"Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000\u20132012","volume":"311","author":"Kaukonen","year":"2014","journal-title":"JAMA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12974-020-1701-3","article-title":"Sepsis-associated encephalopathy: A vicious cycle of immunosuppression","volume":"17","author":"Ren","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1586\/eri.12.159","article-title":"Sepsis-induced brain dysfunction","volume":"11","author":"Adam","year":"2013","journal-title":"Expert Rev. Anti-infective Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e2025825118","DOI":"10.1073\/pnas.2025825118","article-title":"Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK","volume":"118","author":"Gallagher","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1007\/s00109-020-01958-z","article-title":"Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis","volume":"98","author":"Lechner","year":"2020","journal-title":"J. Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e625","DOI":"10.1002\/ctm2.625","article-title":"Interleu-kin-2-inducible T-cell kinase (Itk) signaling regulates potent noncanonical regulatory T cells","volume":"11","author":"Mammadli","year":"2021","journal-title":"Clin. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.4049\/jimmunol.1400968","article-title":"IL-2\u2013Inducible T Cell Kinase Tunes T Regulatory Cell Development and Is Required for Suppressive Function","volume":"193","author":"Huang","year":"2014","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"102842","DOI":"10.1016\/j.isci.2021.102842","article-title":"Targeting ITK signaling for T cell-mediated diseases","volume":"24","author":"Weeks","year":"2021","journal-title":"iScience"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"a002287","DOI":"10.1101\/cshperspect.a002287","article-title":"T-Cell Signaling Regulated by the Tec Family Kinase, Itk","volume":"2","author":"Andreotti","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1146\/annurev.immunol.22.012703.104743","article-title":"Tec family kinases in t lymphocyte development and function","volume":"23","author":"Berg","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1111\/j.1742-4658.2011.08072.x","article-title":"Tec family kinases Itk and Rlk \/ Txk in T lymphocytes: Cross-regulation of cytokine production and T-cell fates","volume":"278","author":"Kraus","year":"2011","journal-title":"FEBS J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1523\/JNEUROSCI.1957-14.2015","article-title":"Itk Signals Promote Neuroinflammation by Regulating CD4+T-Cell Activation and Trafficking","volume":"35","author":"Kannan","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.biochi.2020.09.023","article-title":"Inhibition of interleukin-2-inducible T-cell kinase causes reduction in imiquimod-induced psoriasiform inflammation through reduction of Th17 cells and en-hancement of Treg cells in mice","volume":"179","author":"Nadeem","year":"2020","journal-title":"Biochimie"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1038\/s41423-021-00757-x","article-title":"The blood\u2013brain barrier in systemic infection and inflammation","volume":"18","author":"Galea","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41591-020-0752-4","article-title":"An immune-cell signature of bacterial sepsis","volume":"26","author":"Reyes","year":"2020","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.bbi.2014.07.007","article-title":"Lipopolysaccharide-induced sepsis induces long-lasting affective changes in the mouse","volume":"43","author":"Anderson","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3389\/fncel.2015.00028","article-title":"Systemic inflammation and the brain: Novel roles of genetic, molecular, and envi-ronmental cues as drivers of neurodegeneration","volume":"9","author":"Sankowski","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1111\/jcmm.13112","article-title":"Neutrophil dysregulation during sepsis: An overview and update","volume":"21","author":"Shen","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1007\/s00134-011-2151-2","article-title":"Traffic of leukocytes and cytokine up-regulation in the central nervous system in sepsis","volume":"37","author":"Comim","year":"2011","journal-title":"Intensiv. Care Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s12640-020-00270-5","article-title":"Sepsis and Cerebral Dysfunction: BBB Damage, Neuroinflammation, Oxidative Stress, Apoptosis and Autophagy as Key Mediators and the Potential Therapeutic Approaches","volume":"39","author":"Gu","year":"2021","journal-title":"Neurotox. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1186\/cc10334","article-title":"Bench-to-bedside review: Sepsis\u2014From the redox point of view","volume":"15","author":"Andrades","year":"2011","journal-title":"Crit. Care"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1172\/JCI82224","article-title":"Sepsis-induced immune dysfunction: Can immune therapies reduce mortality?","volume":"126","author":"Delano","year":"2016","journal-title":"J. Clin. Invest."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kim, K.S., Jekarl, D.W., Yoo, J., Lee, S., Kim, M., and Kim, Y. (2021). Immune gene expression networks in sepsis: A network biology approach. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0247669"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"636","DOI":"10.2174\/1570159X18666200114125628","article-title":"Evaluation of Anti-inflammatory Nutraceuticals in LPS-induced Mouse Neuroinflammation Model: An Update","volume":"18","author":"Catorce","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.bbi.2019.05.038","article-title":"Caspase-1 inhibitor exerts brain-protective effects against sepsis-associated encephalopathy and cognitive impairments in a mouse model of sepsis","volume":"80","author":"Xu","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1042\/BST20190486","article-title":"Tuning T helper cell differentiation by ITK","volume":"48","author":"Elmore","year":"2020","journal-title":"Biochem. Soc. Trans."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"(2017). Neuroimmune communication. Nat. Neurosci., 20, 127.","DOI":"10.1038\/nn.4496"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1007\/s12640-018-9900-8","article-title":"Dimethyl Fumarate Limits Neu-roinflammation and Oxidative Stress and Improves Cognitive Impairment After Polymicrobial Sepsis","volume":"34","author":"Zarbato","year":"2018","journal-title":"Neurotox. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"25457","DOI":"10.1038\/srep25457","article-title":"Endotoxemia-induced cytokine-mediated re-sponses of hippocampal astrocytes transmitted by cells of the brain-immune interface","volume":"6","author":"Inaba","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"932152","DOI":"10.3389\/fimmu.2022.932152","article-title":"Th17 cells and inflammation in neurological disorders: Possible mechanisms of action","volume":"13","author":"Shi","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3389\/fimmu.2017.00017","article-title":"Histological Architecture Underlying Brain\u2013Immune Cell\u2013Cell Interactions and the Cerebral Response to Systemic Inflammation","volume":"8","author":"Shimada","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.cyto.2017.05.018","article-title":"IL-17A causes depression-like symptoms via NF\u03baB and p38MAPK signaling pathways in mice: Implications for psoriasis associated depression","volume":"97","author":"Nadeem","year":"2017","journal-title":"Cytokine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6693542","DOI":"10.1155\/2021\/6693542","article-title":"Cytokines that Modulate the Differentiation of Th17 Cells in Autoimmune Uveitis","volume":"2021","author":"Guo","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.bbi.2020.11.010","article-title":"Infiltrated regulatory T cells and Th2 cells in the brain contribute to attenuation of sepsis-associated encephalopathy and alleviation of mental impairments in mice with polymicrobial sepsis","volume":"92","author":"Saito","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8461725","DOI":"10.1155\/2019\/8461725","article-title":"Blockade of IL-17A\/IL-17R Pathway Protected Mice from Sep-sis-Associated Encephalopathy by Inhibition of Microglia Activation","volume":"2019","author":"Ye","year":"2019","journal-title":"Mediat. Inflamm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"108703","DOI":"10.1016\/j.intimp.2022.108703","article-title":"Acetyl-11-keto-\u03b2-boswellic acid improves clinical symptoms through modulation of Nrf2 and NF-\u03baB pathways in SJL\/J mouse model of experimental autoimmune encephalomyelitis","volume":"107","author":"Nadeem","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.bbi.2017.08.001","article-title":"Th17 cells in depression","volume":"69","author":"Beurel","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"99364","DOI":"10.1172\/jci.insight.99364","article-title":"Targeting inflammatory monocytes in sep-sis-associated encephalopathy and long-term cognitive impairment","volume":"3","author":"Andonegui","year":"2018","journal-title":"JCI Insight."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/s12974-022-02543-6","article-title":"Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain","volume":"19","author":"Peng","year":"2022","journal-title":"J. Neuroinflammation"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Alhazzani, K., Ahmad, S.F., Al-Harbi, N.O., Attia, S.M., Bakheet, S.A., Sarawi, W., Alqarni, S.A., Algahtani, M., and Nadeem, A. (2021). Pharmacological Inhibition of STAT3 by Stattic Ameliorates Clinical Symptoms and Reduces Autoinflammation in Myeloid, Lymphoid, and Neuronal Tissue Compartments in Relapsing-Remitting Model of Experimental Autoimmune Encephalomyelitis in SJL\/J Mice. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13070925"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1084\/jem.20131459","article-title":"Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells","volume":"211","author":"Wohlfert","year":"2014","journal-title":"J. Exp. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"626193","DOI":"10.3389\/fimmu.2021.626193","article-title":"Function and Role of Regulatory T Cells in Rheumatoid Arthritis","volume":"12","author":"Jiang","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.bbadis.2016.11.005","article-title":"Nrf2 signaling pathway: Pivotal roles in inflammation","volume":"1863","author":"Ahmed","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"101771","DOI":"10.1016\/j.redox.2020.101771","article-title":"Songorine promotes cardiac mitochondrial biogenesis via Nrf2 induction during sepsis","volume":"38","author":"Li","year":"2021","journal-title":"Redox Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.cellsig.2011.01.014","article-title":"Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway","volume":"23","author":"Yu","year":"2011","journal-title":"Cell. Signal."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1042\/BST20150014","article-title":"Dissecting molecular cross-talk between Nrf2 and NF-\u03baB response pathways","volume":"43","author":"Wardyn","year":"2015","journal-title":"Bio-Chem. Soc. Trans."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1164\/rccm.201102-0271OC","article-title":"Enhancing Nrf2 Pathway by Disruption of Keap1 in Myeloid Leukocytes Protects against Sepsis","volume":"184","author":"Kong","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.bbi.2006.11.001","article-title":"Repeated social defeat causes increased anxiety-like behavior and alters splenocyte function in C57BL\/6 and CD-1 mice","volume":"21","author":"Kinsey","year":"2007","journal-title":"Brain Behav. Immun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.intimp.2017.02.018","article-title":"Psoriasis-like inflammation leads to renal dysfunction via upregulation of NADPH oxidases and inducible nitric oxide synthase","volume":"46","author":"Nadeem","year":"2017","journal-title":"Int. Immunopharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.phrs.2015.06.001","article-title":"Imiquimod-induced psoriasis-like skin inflammation is suppressed by BET bromodomain inhibitor in mice through RORC\/IL-17A pathway modulation","volume":"99","author":"Nadeem","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1067\/mai.2003.17","article-title":"Increased oxidative stress and altered levels of antioxidants in asthma","volume":"111","author":"Nadeem","year":"2003","journal-title":"J. Allergy Clin. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/8101\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:27:16Z","timestamp":1760124436000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/8101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,30]]},"references-count":56,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24098101"],"URL":"https:\/\/doi.org\/10.3390\/ijms24098101","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,30]]}}}