{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T03:28:58Z","timestamp":1791430138430,"version":"4.3.3"},"reference-count":52,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T00:00:00Z","timestamp":1693353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004410","name":"Scientific and Technological Research Council of Turkey (TUBITAK)","doi-asserted-by":"publisher","award":["121Z028"],"award-info":[{"award-number":["121Z028"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004410","name":"Scientific and Technological Research Council of Turkey (TUBITAK)","doi-asserted-by":"publisher","award":["44121"],"award-info":[{"award-number":["44121"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Scientific Research Projects Unit (BAP), Istanbul Technical University","award":["121Z028"],"award-info":[{"award-number":["121Z028"]}]},{"name":"Scientific Research Projects Unit (BAP), Istanbul Technical University","award":["44121"],"award-info":[{"award-number":["44121"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Eosinophils function in rapid innate immune responses and allergic reactions. Recent research has raised the possibility that the histone deacetylase inhibitor valproic acid (VPA) may be a promising therapeutic agent for treatment of allergic responses and certain cancers. However, its effects on eosinophils remain unclear. Utilizing the EoL-1 human eosinophil cell line as a model, we investigated the effects of VPA on oxidative stress- and autophagy-mediated immune responses. We found that VPA induced reactive oxidative species (ROS) generation and eosinophil activation without affecting cell viability. Moreover, VPA treatment suppressed the negative regulator of antioxidant transcription factor Nrf2, which is known to activate antioxidant defense. Interestingly, VPA was able to increase autophagic markers, as well as NLRP3 and NLRC4 mRNA activation, in Eol-1 cells in a dose-dependent manner. Collectively, our results indicate that VPA could increase the severity of allergic responses, and if so, it clearly would not be a suitable drug for the treatment of allergic reactions. However, VPA does have the potential to induce autophagy and to regulate the inflammatory responses via inflammasome-driven caspase-1 deactivation in a dose-dependent manner.<\/jats:p>","DOI":"10.3390\/ijms241713446","type":"journal-article","created":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T09:44:46Z","timestamp":1693388686000},"page":"13446","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Duality of Valproic Acid Effects on Inflammation, Oxidative Stress and Autophagy in Human Eosinophilic Cells"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2718-6197","authenticated-orcid":false,"given":"Goksu","family":"Uzel","sequence":"first","affiliation":[{"name":"Molecular Biology and Genetics Department, Istanbul Technical University, 34469 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4234-9086","authenticated-orcid":false,"given":"Ece","family":"Oylumlu","sequence":"additional","affiliation":[{"name":"Molecular Biology and Genetics Department, Istanbul Technical University, 34469 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubeyne","family":"Durmus","sequence":"additional","affiliation":[{"name":"Molecular Biology and Genetics Department, Istanbul Technical University, 34469 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2162-0930","authenticated-orcid":false,"given":"Ceren","family":"Ciraci","sequence":"additional","affiliation":[{"name":"Molecular Biology and Genetics Department, Istanbul Technical University, 34469 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s00441-010-1049-6","article-title":"Eosinophils in innate immunity: An evolving story","volume":"343","author":"Shamri","year":"2011","journal-title":"Cell Tissue Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1007\/s12016-015-8526-3","article-title":"The Role and Immunobiology of Eosinophils in the Respiratory System: A Comprehensive Review","volume":"50","author":"Eng","year":"2016","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3270","DOI":"10.4161\/21645515.2014.979640","article-title":"Mechanisms and pathways of innate immune activation and regulation in health and cancer","volume":"10","author":"Cui","year":"2014","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1159\/000445215","article-title":"A Player and Coordinator: The Versatile Roles of Eosinophils in the Immune System","volume":"43","author":"Long","year":"2016","journal-title":"Transfus. Med. Hemotherapy"},{"key":"ref_5","unstructured":"Robles, H. (2014). Valproic Acid, Elsevier. [3rd ed.]."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.exer.2014.01.021","article-title":"Valproic acid suppresses Nrf2\/Keap1 dependent antioxidant protection through induction of endoplasmic reticulum stress and Keap1 promoter DNA demethylation in human lens epithelial cells","volume":"121","author":"Palsamy","year":"2014","journal-title":"Exp. Eye Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"479364","DOI":"10.1155\/2010\/479364","article-title":"Molecular and Therapeutic Potential and Toxicity of Valproic Acid","volume":"2010","author":"Chateauvieux","year":"2010","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.3892\/ol.2016.4880","article-title":"Valproic acid induces autophagy by suppressing the Akt\/mTOR pathway in human prostate cancer cells","volume":"12","author":"Xia","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1093\/neuonc\/nop005","article-title":"Autophagy induced by valproic acid is associated with oxidative stress in glioma cell lines","volume":"12","author":"Fu","year":"2009","journal-title":"Neuro-Oncology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1002\/JLB.3AB0320-547RR","article-title":"The histone deacetylase inhibitor valproic acid attenuates phospholipase C\u03b32 and IgE-mediated mast cell activation","volume":"108","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1203\/PDR.0b013e3181a9eafb","article-title":"The Role of Oxygen in Health and Disease\u2014A Series of Reviews Oxygen Toxicity and Reactive Oxygen Species: The Devil Is in the Details","volume":"66","author":"Auten","year":"2009","journal-title":"Pediatr. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7915","DOI":"10.1073\/pnas.90.17.7915","article-title":"Oxidants, antioxidants, and the degenerative diseases of aging","volume":"90","author":"Ames","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"R453","DOI":"10.1016\/j.cub.2014.03.034","article-title":"ROS Function in Redox Signaling and Oxidative Stress","volume":"24","author":"Schieber","year":"2014","journal-title":"Curr. Biol."},{"key":"ref_14","first-page":"7090534","article-title":"Role of Nrf2 and Its Activators in Respiratory Diseases","volume":"2019","author":"Liu","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2090813","DOI":"10.1155\/2018\/2090813","article-title":"Interplay of Oxidative Stress, Inflammation, and Autophagy: Their Role in Tissue Injury of the Heart, Liver, and Kidney","volume":"2018","author":"Mukhopadhyay","year":"2018","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/all.12761","article-title":"Autophagy in airway diseases: A new frontier in human asthma?","volume":"71","author":"Zeki","year":"2015","journal-title":"Allergy"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s12943-020-1138-4","article-title":"Autophagy and autophagy-related proteins in cancer","volume":"19","author":"Li","year":"2020","journal-title":"Mol. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3389\/fonc.2017.00051","article-title":"Autophagy and the Cell Cycle: A Complex Landscape","volume":"7","author":"Mathiassen","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"313","DOI":"10.4110\/in.2015.15.6.313","article-title":"Comparative Analysis of Dibutyric cAMP and Butyric Acid on the Differentiation of Human Eosinophilic Leukemia EoL-1 Cells","volume":"15","author":"Jung","year":"2015","journal-title":"Immune Netw."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3109\/10428199209053629","article-title":"EoL-1, A Human Eosinophilic Cell Line","volume":"7","author":"Mayumi","year":"1992","journal-title":"Leuk. Lymphoma"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.redox.2016.12.035","article-title":"Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress","volume":"11","author":"Sies","year":"2017","journal-title":"Redox Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7718","DOI":"10.1002\/jcp.27890","article-title":"Serum-reduced media impacts on cell viability and protein expression in human lung epithelial cells","volume":"234","author":"Rashid","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1007\/s10495-009-0396-9","article-title":"Serum deprivation induced autophagy and predominantly an AIF-dependent apoptosis in hippocampal HT22 neurons","volume":"14","author":"Rami","year":"2009","journal-title":"Apoptosis"},{"key":"ref_24","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_25","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1042\/BJ20130282","article-title":"ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors","volume":"454","author":"Halasi","year":"2013","journal-title":"Biochem. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8416763","DOI":"10.1155\/2017\/8416763","article-title":"Oxidative Stress: Harms and Benefits for Human Health","volume":"2017","author":"Pizzino","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Yun, H.R., Jo, Y.H., Kim, J., Shin, Y., Kim, S.S., and Choi, T.G. (2020). Roles of Autophagy in Oxidative Stress. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093289"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.1038\/ncomms3799","article-title":"Autophagy proteins regulate ERK phosphorylation","volume":"4","author":"Athonvarangkul","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhu, Z., Yang, C., Iyaswamy, A., Krishnamoorthi, S., Sreenivasmurthy, S.G., Liu, J., Wang, Z., Tong, B.C.-K., Song, J., and Lu, J. (2019). Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson\u2019s Disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030728"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s00253-019-10257-8","article-title":"Targeting PI3K\/AKT\/mTOR-mediated autophagy for tumor therapy","volume":"104","author":"Xu","year":"2019","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Karim, R., Fisher, C.R., Kapphahn, R.J., Polanco, J.R., and Ferrington, D.A. (2020). Investigating AKT activation and autophagy in immunoproteasome-deficient retinal cells. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0231212"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.cell.2017.03.035","article-title":"mTOR Signaling in Growth, Metabolism, and Disease","volume":"169","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.neuropharm.2015.04.035","article-title":"mTOR plays an important role in cow\u2019s milk allergy-associated behavioral and immunological deficits","volume":"97","author":"Wu","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_34","first-page":"598","article-title":"PI3K-AKT-MTOR Signaling Pathway: The Intersection of Allergic Asthma and Cataract","volume":"74","author":"Zhao","year":"2019","journal-title":"Die Pharm.-Int. J. Pharm. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Koukourakis, M.I., Kalamida, D., Giatromanolaki, A., Zois, C.E., Sivridis, E., Pouliliou, S., Mitrakas, A., Gatter, K.C., and Harris, A.L. (2015). Autophagosome Proteins LC3A, LC3B and LC3C Have Distinct Subcellular Distribution Kinetics and Expression in Cancer Cell Lines. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0137675"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/cdd.2010.191","article-title":"The Beclin 1 network regulates autophagy and apoptosis","volume":"18","author":"Kang","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s12943-019-0944-z","article-title":"The relationship between autophagy and the immune system and its applications for tumor immunotherapy","volume":"18","author":"Jiang","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e42","DOI":"10.4110\/in.2021.21.e42","article-title":"NLRC4 Inflammasome-Mediated Regulation of Eosinophilic Functions","volume":"21","author":"Akkaya","year":"2021","journal-title":"Immune Netw."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1083\/jcb.201602089","article-title":"The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation","volume":"213","author":"Sharma","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1084\/jem.20141388","article-title":"Small intestinal eosinophils regulate Th17 cells by producing IL-1 receptor antagonist","volume":"213","author":"Sugawara","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ctrv.2007.11.003","article-title":"Valproic acid as epigenetic cancer drug: Preclinical, clinical and transcriptional effects on solid tumors","volume":"34","author":"Candelaria","year":"2008","journal-title":"Cancer Treat. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1124\/mol.111.072314","article-title":"Valproic Acid Increases Formation of Reactive Oxygen Species and Induces Apoptosis in Postimplantation Embryos: A Role for Oxidative Stress in Valproic Acid-Induced Neural Tube Defects","volume":"80","author":"Tung","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1182\/blood.V66.6.1233.1233","article-title":"Establishment and characterization of a new human eosinophilic leukemia cell line","volume":"66","author":"Saito","year":"1985","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1182\/blood.V81.5.1193.1193","article-title":"Cooperative effects of interleukin-3 (IL-3), IL-5, and granulocyte- macrophage colony-stimulating factor: A new myeloid cell line inducible to eosinophils","volume":"81","author":"Paul","year":"1993","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/jlb.56.1.74","article-title":"Cytokine induction of granule protein synthesis in an eosinophil-inducible human myeloid cell line, AML14","volume":"56","author":"Paul","year":"1994","journal-title":"J. Leukoc. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3737","DOI":"10.1182\/blood.V86.10.3737.bloodjournal86103737","article-title":"Changing the differentiation program of hematopoietic cells: Retinoic acid-induced shift of eosinophil-committed cells to neutrophils","volume":"86","author":"Paul","year":"1995","journal-title":"Blood"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.molcel.2014.03.030","article-title":"Stress, Inflammation, and Defense of Homeostasis","volume":"54","author":"Chovatiya","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3389\/fmed.2017.00101","article-title":"Homeostatic Eosinophils: Characteristics and Functions","volume":"4","author":"Marichal","year":"2017","journal-title":"Front. Med."},{"key":"ref_49","first-page":"269","article-title":"Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis","volume":"17","author":"Cai","year":"2015","journal-title":"Thromb. Haemost."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/cdd.2014.150","article-title":"Oxidative stress and autophagy: The clash between damage and metabolic needs","volume":"22","author":"Filomeni","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1421795","DOI":"10.1155\/2020\/1421795","article-title":"Adenosine-Induced NLRP11 in B Lymphoblasts Suppresses Human CD4+ T Helper Cell Responses","volume":"2020","author":"Ozel","year":"2020","journal-title":"J. Immunol. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.dci.2010.11.012","article-title":"Avian-specific TLRs and downstream effector responses to CpG-induction in chicken macrophages","volume":"35","author":"Ciraci","year":"2011","journal-title":"Dev. Comp. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13446\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:42:54Z","timestamp":1760128974000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13446"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,30]]},"references-count":52,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241713446"],"URL":"https:\/\/doi.org\/10.3390\/ijms241713446","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,30]]}}}