{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T02:36:13Z","timestamp":1789439773144,"version":"build-2803163510"},"reference-count":60,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,21]],"date-time":"2020-11-21T00:00:00Z","timestamp":1605916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["SAF2016-81063"],"award-info":[{"award-number":["SAF2016-81063"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Oxidative stress and proinflammatory cytokines are factors affecting multiple sclerosis (MS) disease progression. Oleacein (OLE), an olive secoiridoid, possesses powerful antioxidant and anti-inflammatory activities, which suggests its potential application to treat neuroinflammatory disorders. Herein, we investigated the impact of OLE on the main clinic-pathological features of experimental autoimmune encephalomyelitis (EAE), an animal model for MS, including paralysis, demyelination, central nervous system (CNS) inflammation\/oxidative stress and blood-brain barrier (BBB) breakdown. Methods: Mice were immunized with the myelin oligodendrocyte glycoprotein peptide, MOG35-55, to induce EAE, and OLE was administrated from immunization day. Serum, optic nerve, spinal cord and cerebellum were collected to evaluate immunomodulatory activities at a systemic level, as well as within the CNS. Additionally, BV2 microglia and the retinal ganglion cell line RGC-5 were used to confirm the direct effect of OLE on CNS-resident cells. Results: We show that OLE treatment effectively reduced clinical score and histological signs typical of EAE. Histological evaluation confirmed a decrease in leukocyte infiltration, demyelination, BBB disruption and superoxide anion accumulation in CNS tissues of OLE-treated EAE mice compared to untreated ones. OLE significantly decreased expression of proinflammatory cytokines (IL-13, TNF\u03b1, GM-CSF, MCP-1 and IL-1\u03b2), while it increased the anti-inflammatory cytokine IL-10. Serum levels of anti-MOG35-55 antibodies were also lower in OLE-treated EAE mice. Further, OLE significantly diminished the presence of oxidative system parameters, while upregulated the ROS disruptor, Sestrin-3. Mechanistically, OLE prevented NLRP3 expression, phosphorylation of p65-NF-\u03baB and reduced the synthesis of proinflammatory mediators induced by relevant inflammatory stimuli in BV2 cells. OLE did not affect viability or the phagocytic capabilities of BV2 microglia. In addition, apoptosis of RGC-5 induced by oxidative stressors was also prevented by OLE. Conclusion: Altogether, our results show that the antioxidant and anti-inflammatory OLE has neuroprotective effects in the CNS of EAE mice, pointing out this natural product as a candidate to consider for research on MS treatments.<\/jats:p>","DOI":"10.3390\/antiox9111161","type":"journal-article","created":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T01:28:48Z","timestamp":1606094928000},"page":"1161","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Oleacein Attenuates the Pathogenesis of Experimental Autoimmune Encephalomyelitis through Both Antioxidant and Anti-Inflammatory Effects"],"prefix":"10.3390","volume":"9","author":[{"given":"Beatriz","family":"Guti\u00e9rrez-Miranda","sequence":"first","affiliation":[{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (IBGM-CSIC\/UVa), 47001 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Gallardo","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (IBGM-CSIC\/UVa), 47001 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Melliou","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Cabero","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (IBGM-CSIC\/UVa), 47001 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (IBGM-CSIC\/UVa), 47001 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0399-5344","authenticated-orcid":false,"given":"Prokopios","family":"Magiatis","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marita","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (IBGM-CSIC\/UVa), 47001 Valladolid, Spain"},{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Medicina, Universidad de Valladolid, 47001 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6842-799X","authenticated-orcid":false,"given":"Mar\u00eda Luisa","family":"Nieto","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (IBGM-CSIC\/UVa), 47001 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1248\/cpb.55.689","article-title":"Naturally Occurring Secoiridoids and Bioactivity of Naturally Occurring Iridoids and Secoiridoids: A Review, Part 2","volume":"55","author":"Dinda","year":"2007","journal-title":"Chem. Pharm. Bull. (Tokyo)"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Castej\u00f3n, M.L., Montoya, T., Alarc\u00f3n-De-La-Lastra, C., and S\u00e1nchez-Hidalgo, M. (2020). Potential Protective Role Exerted by Secoiridoids from Olea europaea L. in Cancer, Cardiovascular, Neurodegenerative, Aging-Related, and Immunoinflammatory Diseases. Antioxidants, 9.","DOI":"10.3390\/antiox9020149"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lepore, S.M., Maggisano, V., Bulotta, S., Mignogna, C., Arcidiacono, B., Procopio, A., Brunetti, A., Russo, D., and Celano, M. (2019). Oleacein Prevents High Fat Diet-Induced A Diposity and Ameliorates Some Biochemical Parameters of Insulin Sensitivity in Mice. Nutrients, 11.","DOI":"10.3390\/nu11081829"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"116","DOI":"10.3389\/fendo.2018.00116","article-title":"Effects of Oleacein on High-Fat Diet-Dependent Steatosis, Weight Gain, and Insulin Resistance in Mice","volume":"9","author":"Lombardo","year":"2018","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/B978-0-444-63916-5.00015-X","article-title":"Balance, gait, and falls in multiple sclerosis","volume":"159","author":"Cameron","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/labinvest.3780235","article-title":"Multiple Sclerosis: Current Pathophysiological Concepts","volume":"81","author":"Wingerchuk","year":"2001","journal-title":"Lab. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.bbadis.2010.06.011","article-title":"Radical changes in multiple sclerosis pathogenesis","volume":"1812","author":"Witte","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1159\/000363515","article-title":"Oxidative Stress Induced by Lipid Peroxidation Is Related with Inflammation of Demyelination and Neurodegeneration in Multiple Sclerosis","volume":"72","author":"Wang","year":"2014","journal-title":"Eur. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.pathophys.2010.04.004","article-title":"The relevance of animal models in multiple sclerosis research","volume":"18","author":"Denic","year":"2011","journal-title":"Pathophysiology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.ejphar.2015.03.042","article-title":"Animal models of Multiple Sclerosis","volume":"759","author":"Procaccini","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Carpi, S., Scoditti, E., Massaro, M., Polini, B., Manera, C., Digiacomo, M., Salsano, J.E., Poli, G., Tuccinardi, T., and Doccini, S. (2019). The Extra-Virgin Olive Oil Polyphenols Oleocanthal and Oleacein Counteract Inflammation-Related Gene and miRNA Expression in Adipocytes by Attenuating NF-\u03baB Activation. Nutrients, 11.","DOI":"10.3390\/nu11122855"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1006\/abio.1996.0292","article-title":"The ferric reducing ability of plasma (FRAP) as a measure of \u201cantioxidant power\u201d: The FRAP assay","volume":"239","author":"Benzie","year":"1996","journal-title":"Anal. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0076-6879(99)99005-5","article-title":"Ferric reducing\/antioxidant power assay: Direct measure of total antioxidant activity of biological fluids and modified version for simultaneous measurement of total antioxidant power and ascorbic acid concentration","volume":"299","author":"Benzie","year":"1999","journal-title":"Methods Enzymol."},{"key":"ref_14","first-page":"41","article-title":"Modification of the method of determining lipid peroxidation in a test using thiobarbituric acid","volume":"11","author":"Andreeva","year":"1988","journal-title":"Lab. Delo"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0003-2697(79)90738-3","article-title":"Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction","volume":"95","author":"Ohkawa","year":"1979","journal-title":"Anal. Biochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1002\/jnr.490310405","article-title":"An immortalized cell line expresses properties of activated microglial cells","volume":"31","author":"Bocchini","year":"1992","journal-title":"J. Neurosci. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1167\/iovs.04-0883","article-title":"The Molecular Basis of Oxidative Stress-Induced Cell Death in an Immortalized Retinal Ganglion Cell Line","volume":"46","author":"Maher","year":"2005","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Diamantakos, P., Giannara, T., Skarkou, M., Melliou, E., and Magiatis, P. (2020). Influence of Harvest Time and Malaxation Conditions on the Concentration of Individual Phenols in Extra Virgin Olive Oil Related to Its Healthy Properties. Molecules, 25.","DOI":"10.3390\/molecules25102449"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11696","DOI":"10.1021\/jf3032765","article-title":"Direct Measurement of Oleocanthal and Oleacein Levels in Olive Oil by Quantitative1H NMR. Establishment of a New Index for the Characterization of Extra Virgin Olive Oils","volume":"60","author":"Karkoula","year":"2012","journal-title":"J. Agric. Food Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1016\/j.jnutbio.2012.12.011","article-title":"Effect of olive oil phenols on the production of inflammatory mediators in freshly isolated human monocytes","volume":"24","author":"Rosignoli","year":"2013","journal-title":"J. Nutr. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Papanikolaou, C., Melliou, E., and Magiatis, P. (2019, April 03). Olive Oil Phenols, Functional Foods, Vasiliki Lagouri, IntechOpen. Available online: https:\/\/www.intechopen.com\/books\/functional-foods\/olive-oil-phenols.","DOI":"10.5772\/intechopen.81394"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1111\/j.1476-5381.2012.01869.x","article-title":"Natural triterpenes modulate immune-inflammatory markers of experimental autoimmune encephalomyelitis: therapeutic implications for multiple sclerosis","volume":"166","author":"Cordova","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.bcp.2009.08.002","article-title":"Beneficial actions of oleanolic acid in an experimental model of multiple sclerosis: A potential therapeutic role","volume":"79","author":"Nieto","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Conde, C., Escribano, B.M., Luque, E., Feij\u00f3o, M., Caballero-Villarraso, J., Valdelvira, M.E., Ochoa-Sep\u00falveda, J.J., Lillo, R., Paz, E., and Santamar\u00eda, A. (2019). Extra-Virgin Olive Oil Modifies the Changes Induced in Non-Nervous Organs and Tissues by Experimental Autoimmune Encephalomyelitis Models. Nutrients, 11.","DOI":"10.3390\/nu11102448"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.clim.2011.11.007","article-title":"Interleukin-33 upregulation in peripheral leukocytes and CNS of multiple sclerosis patients","volume":"142","author":"Christophi","year":"2012","journal-title":"Clin. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1189\/jlb.1207830","article-title":"Induction of IL-33 expression and activity in central nervous system glia","volume":"84","author":"Hudson","year":"2008","journal-title":"J. Leukoc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1177\/1352458518763094","article-title":"Cytokine signaling in multiple sclerosis: Lost in translation","volume":"24","author":"Ruck","year":"2018","journal-title":"Mult. Scler."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.cyto.2014.09.011","article-title":"T cell subsets and their signature cytokines in autoimmune and inflammatory diseases","volume":"74","author":"Raphael","year":"2015","journal-title":"Cytokine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.neuroscience.2015.09.019","article-title":"Interleukin-33 is released in spinal cord and suppresses experimental autoimmune encephalomyelitis in mice","volume":"308","author":"Chen","year":"2015","journal-title":"Neuroscience"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.jneuroim.2018.02.012","article-title":"The therapeutic effect of anti-CD52 treatment in murine experimental autoimmune encephalomyelitis is associated with altered IL-33 and ST2 expression levels","volume":"318","author":"Barbour","year":"2018","journal-title":"J. Neuroimmunol."},{"key":"ref_31","first-page":"35","article-title":"Vitamin D Modulates the Expression of IL-27 and IL-33 in the Central Nervous System in Experimental Autoimmune Encephalomyelitis (EAE)","volume":"12","author":"Azizi","year":"2015","journal-title":"Iran J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jneuroim.2012.03.016","article-title":"IL-33 blockade suppresses the development of experimental autoimmune encephalomyelitis in C57BL\/6 mice","volume":"247","author":"Li","year":"2012","journal-title":"J. Neuroimmunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1001\/jamaneurol.2015.3977","article-title":"Effect of Multiple Sclerosis Disease-Modifying Therapies on B Cells and Humoral Immunity","volume":"73","author":"Longbrake","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1172\/JCI85113","article-title":"Human regulatory B cells in health and disease: therapeutic potential","volume":"127","author":"Mauri","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0165-5728(00)00351-9","article-title":"Modulation of experimental autoimmune encephalomyelitis: effect of altered peptide ligand on chemokine and chemokine receptor expression","volume":"110","author":"Fischer","year":"2000","journal-title":"J. Neuroimmunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.4049\/jimmunol.161.6.2667","article-title":"Cutting edge commentary: Chemokine regulation of experimental autoimmune encephalomyelitis: Temporal and spatial expression patterns govern disease pathogenesis","volume":"161","author":"Karpus","year":"1998","journal-title":"J Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S1044-5323(02)00125-2","article-title":"The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE)","volume":"15","author":"Mahad","year":"2003","journal-title":"Semin. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"577281","DOI":"10.1016\/j.jneuroim.2020.577281","article-title":"Glatiramer acetate increases T- and B -regulatory cells and decreases granulocyte-macrophage colony-stimulating factor (GM-CSF) in an animal model of multiple sclerosis","volume":"345","author":"Aharoni","year":"2020","journal-title":"J. Neuroimmunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s40120-018-0120-1","article-title":"Granulocyte-Macrophage Colony-Stimulating Factor as a Therapeutic Target in Multiple Sclerosis","volume":"8","author":"Aram","year":"2019","journal-title":"Neurol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Monaghan, K.L., and Wan, E.C.K. (2020). The Role of Granulocyte-Macrophage Colony-Stimulating Factor in Murine Models of Multiple Sclerosis. Cells, 9.","DOI":"10.3390\/cells9030611"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e729","DOI":"10.1212\/NXI.0000000000000729","article-title":"Dimethyl fumarate suppresses granulocyte macrophage colony-stimulating factor\u2013producing Th1 cells in CNS neuroinflammation","volume":"7","author":"Safavi","year":"2020","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Oreja-Guevara, C., Ramos-Cejudo, J., Aroeira, L.S., Chamorro, B., and Diez-Tejedo, E. (2012). TH1\/TH2 cytokine profile in relapsing-remitting multiple sclerosis patients treated with Glatiramer acetate or Natalizumab. BMC Neurol., 12.","DOI":"10.1186\/1471-2377-12-95"},{"key":"ref_43","first-page":"1","article-title":"Mechanisms of Oxidative Damage in Multiple Sclerosis and a Cell Therapy Approach to Treatment","volume":"2011","author":"Witherick","year":"2010","journal-title":"Autoimmune Dis."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Miller, E.D., Dziedzic, A., Saluk-Bijak, J., and Bijak, M. (2019). A Review of Various Antioxidant Compounds and their Potential Utility as Complementary Therapy in Multiple Sclerosis. Nutrients, 11.","DOI":"10.3390\/nu11071528"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7191080","DOI":"10.1155\/2020\/7191080","article-title":"Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development","volume":"2020","author":"Pegoretti","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s12974-015-0325-5","article-title":"Inhibition of NADPH oxidase activation reduces EAE-induced white matter damage in mice","volume":"12","author":"Choi","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.tins.2005.01.006","article-title":"Multiple sclerosis: Novel perspectives on newly forming lesions","volume":"28","author":"Matute","year":"2005","journal-title":"Trends Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/j.1750-3639.2007.00110.x","article-title":"Elevated Activity and Microglial Expression of Myeloperoxidase in Demyelinated Cerebral Cortex in Multiple Sclerosis","volume":"18","author":"Gray","year":"2008","journal-title":"Brain Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.biopha.2003.11.004","article-title":"Neurodegenerative diseases and oxidative stress","volume":"58","author":"Emerit","year":"2004","journal-title":"Biomed. Pharmacother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1096\/fj.00-0881fje","article-title":"Reactive oxygen species enhance the migration of monocytes across the blood-brain barrier in vitro","volume":"15","author":"Wouters","year":"2001","journal-title":"FASEB J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1111\/j.1750-3639.1999.tb00212.x","article-title":"Demyelination: The Role of Reactive Oxygen and Nitrogen Species","volume":"9","author":"Smith","year":"2006","journal-title":"Brain Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1007\/s12031-019-01468-9","article-title":"Gypenosides Prevent H2O2-Induced Retinal Ganglion Cell Apoptosis by Concurrently Suppressing the Neuronal Oxidative Stress and Inflammatory Response","volume":"70","author":"Zhang","year":"2020","journal-title":"J. Mol. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.tibs.2016.04.005","article-title":"Biochemical Basis of Sestrin Physiological Activities","volume":"41","author":"Ho","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1126\/science.1095569","article-title":"Regeneration of Peroxiredoxins by p53-Regulated Sestrins, Homologs of Bacterial AhpD","volume":"304","author":"Budanov","year":"2004","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.cmet.2012.12.002","article-title":"Sestrins Activate Nrf2 by Promoting p62-Dependent Autophagic Degradation of Keap1 and Prevent Oxidative Liver Damage","volume":"17","author":"Bae","year":"2013","journal-title":"Cell Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4671","DOI":"10.1158\/0008-5472.CAN-06-2466","article-title":"Repression of Sestrin Family Genes Contributes to Oncogenic Ras-Induced Reactive Oxygen Species Up-regulation and Genetic Instability","volume":"67","author":"Kopnin","year":"2007","journal-title":"Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"G58","DOI":"10.1152\/ajpgi.00373.2013","article-title":"The inhibitory effect of ethanol on Sestrin3 in the pathogenesis of ethanol-induced liver injury","volume":"307","author":"Kang","year":"2014","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Gallardo-Fern\u00e1ndez, M., Hornedo-Ortega, R., Alonso-Bellido, I.M., Rodr\u00edguez-G\u00f3mez, J.A., Troncoso, A.M., Garc\u00eda-Parrilla, M.C., Venero, J.L., Espinosa-Oliva, A.M., and De Pablos, R.M. (2019). Hydroxytyrosol Decreases LPS- and \u03b1-Synuclein-Induced Microglial Activation In Vitro. Antioxidants, 9.","DOI":"10.3390\/antiox9010036"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"948976","DOI":"10.1155\/2013\/948976","article-title":"The Benefits and Detriments of Macrophages\/Microglia in Models of Multiple Sclerosis","volume":"2013","author":"Rawji","year":"2013","journal-title":"Clin. Dev. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Kronenberg, J., Pars, K., Brieskorn, M., Prajeeth, C.K., Heckers, S., Schwenkenbecher, P., Skripuletz, T., Pul, R., Pavlou, A., and Stangel, M. (2019). Fumaric Acids Directly Influence Gene Expression of Neuroprotective Factors in Rodent Microglia. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20020325"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/11\/1161\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:35:26Z","timestamp":1760178926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/11\/1161"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,21]]},"references-count":60,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["antiox9111161"],"URL":"https:\/\/doi.org\/10.3390\/antiox9111161","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,21]]}}}