{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T02:35:49Z","timestamp":1790908549705,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T00:00:00Z","timestamp":1722556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Salud Carlos III","award":["PI18\/01287"],"award-info":[{"award-number":["PI18\/01287"]}]},{"name":"Instituto de Salud Carlos III","award":["PI22\/01718"],"award-info":[{"award-number":["PI22\/01718"]}]},{"name":"Instituto de Salud Carlos III","award":["PI-0123-2018"],"award-info":[{"award-number":["PI-0123-2018"]}]},{"name":"Instituto de Salud Carlos III","award":["PI-0012-2019"],"award-info":[{"award-number":["PI-0012-2019"]}]},{"name":"Consejer\u00eda de Salud de la Junta de Andaluc\u00eda","award":["PI18\/01287"],"award-info":[{"award-number":["PI18\/01287"]}]},{"name":"Consejer\u00eda de Salud de la Junta de Andaluc\u00eda","award":["PI22\/01718"],"award-info":[{"award-number":["PI22\/01718"]}]},{"name":"Consejer\u00eda de Salud de la Junta de Andaluc\u00eda","award":["PI-0123-2018"],"award-info":[{"award-number":["PI-0123-2018"]}]},{"name":"Consejer\u00eda de Salud de la Junta de Andaluc\u00eda","award":["PI-0012-2019"],"award-info":[{"award-number":["PI-0012-2019"]}]},{"name":"Convocatoria de Subvenciones para la Financiaci\u00f3n de la Investigaci\u00f3n y la Innovaci\u00f3n Biom\u00e9dica y en Ciencias de la Salud en el Marco de la Iniciativa Territorial Integrada 2014\u20132020 para la Provincia de C\u00e1diz, Fondos ITIFEDER","award":["PI18\/01287"],"award-info":[{"award-number":["PI18\/01287"]}]},{"name":"Convocatoria de Subvenciones para la Financiaci\u00f3n de la Investigaci\u00f3n y la Innovaci\u00f3n Biom\u00e9dica y en Ciencias de la Salud en el Marco de la Iniciativa Territorial Integrada 2014\u20132020 para la Provincia de C\u00e1diz, Fondos ITIFEDER","award":["PI22\/01718"],"award-info":[{"award-number":["PI22\/01718"]}]},{"name":"Convocatoria de Subvenciones para la Financiaci\u00f3n de la Investigaci\u00f3n y la Innovaci\u00f3n Biom\u00e9dica y en Ciencias de la Salud en el Marco de la Iniciativa Territorial Integrada 2014\u20132020 para la Provincia de C\u00e1diz, Fondos ITIFEDER","award":["PI-0123-2018"],"award-info":[{"award-number":["PI-0123-2018"]}]},{"name":"Convocatoria de Subvenciones para la Financiaci\u00f3n de la Investigaci\u00f3n y la Innovaci\u00f3n Biom\u00e9dica y en Ciencias de la Salud en el Marco de la Iniciativa Territorial Integrada 2014\u20132020 para la Provincia de C\u00e1diz, Fondos ITIFEDER","award":["PI-0012-2019"],"award-info":[{"award-number":["PI-0012-2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetic retinopathy (DR) is one of the most prevalent secondary complications associated with diabetes. Specifically, Type 1 Diabetes Mellitus (T1D) has an immune component that may determine the evolution of DR by compromising the immune response of the retina, which is mediated by microglia. In the early stages of DR, the permeabilization of the blood\u2013retinal barrier allows immune cells from the peripheral system to interact with the retinal immune system. The use of new bioactive molecules, such as 3-(2,4-dihydroxyphenyl)phthalide (M9), with powerful anti-inflammatory activity, might represent an advance in the treatment of diseases like DR by targeting the immune systems responsible for its onset and progression. Our research aimed to investigate the molecular mechanisms involved in the interaction of specific cells of the innate immune system during the progression of DR and the reduction in inflammatory processes contributing to the pathology. In vitro studies were conducted exposing Bv.2 microglial and Raw264.7 macrophage cells to proinflammatory stimuli for 24 h, in the presence or absence of M9. Ex vivo and in vivo approaches were performed in BB rats, an animal model for T1D. Retinal explants from BB rats were cultured with M9. Retinas from BB rats treated for 15 days with M9 via intraperitoneal injection were analyzed to determine survival, cellular signaling, and inflammatory markers using qPCR, Western blot, or immunofluorescence approaches. Retinal structure images were acquired via Spectral-Domain\u2013Optical Coherence Tomography (SD-OCT). Our results show that the treatment with M9 significantly reduces inflammatory processes in in vitro, ex vivo, and in vivo models of DR. M9 works by inhibiting the proinflammatory responses during DR progression mainly affecting immune cell responses. It also induces an anti-inflammatory response, primarily mediated by microglial cells, leading to the synthesis of Arginase-1 and Hemeoxygenase-1(HO-1). Ultimately, in vivo administration of M9 preserves the retinal integrity from the degeneration associated with DR progression. Our findings demonstrate a specific interaction between both retinal and systemic immune cells in the progression of DR, with a differential response to treatment, mainly driven by microglia in the anti-inflammatory action. In vivo treatment with M9 induces a switch in immune cell phenotypes and functions that contributes to delaying the DR progression, positioning microglial cells as a new and specific therapeutic target in DR.<\/jats:p>","DOI":"10.3390\/ijms25158440","type":"journal-article","created":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T13:14:42Z","timestamp":1722604482000},"page":"8440","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Arylphthalide Delays Diabetic Retinopathy via Immunomodulating the Early Inflammatory Response in an Animal Model of Type 1 Diabetes Mellitus"],"prefix":"10.3390","volume":"25","author":[{"given":"Francisco","family":"Mart\u00edn-Loro","sequence":"first","affiliation":[{"name":"Diabetes Mellitus Laboratory, Instituto de Investigaci\u00f3n e Innovaci\u00f3n en Ciencias Biom\u00e9dicas de la Provincia de C\u00e1diz (INiBICA), Hospital Universitario Puerta del Mar, 11009 C\u00e1diz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7290-0812","authenticated-orcid":false,"given":"F\u00e1tima","family":"Cano-Cano","sequence":"additional","affiliation":[{"name":"Diabetes Mellitus Laboratory, Instituto de Investigaci\u00f3n e Innovaci\u00f3n en Ciencias Biom\u00e9dicas de la Provincia de C\u00e1diz (INiBICA), Hospital Universitario Puerta del Mar, 11009 C\u00e1diz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda J.","family":"Ortega","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Ciencias del Mar y Ambientales, Universidad de C\u00e1diz, 11510 Puerto Real, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7667-0751","authenticated-orcid":false,"given":"Bel\u00e9n","family":"Cuevas","sequence":"additional","affiliation":[{"name":"Diabetes Mellitus Laboratory, Instituto de Investigaci\u00f3n e Innovaci\u00f3n en Ciencias Biom\u00e9dicas de la Provincia de C\u00e1diz (INiBICA), Hospital Universitario Puerta del Mar, 11009 C\u00e1diz, Spain"},{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Ciencias del Mar y Ambientales, Universidad de C\u00e1diz, 11510 Puerto Real, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"G\u00f3mez-Jaramillo","sequence":"additional","affiliation":[{"name":"Diabetes Mellitus Laboratory, Instituto de Investigaci\u00f3n e Innovaci\u00f3n en Ciencias Biom\u00e9dicas de la Provincia de C\u00e1diz (INiBICA), Hospital Universitario Puerta del Mar, 11009 C\u00e1diz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2332-6153","authenticated-orcid":false,"given":"Mar\u00eda del Carmen","family":"Gonz\u00e1lez-Montelongo","sequence":"additional","affiliation":[{"name":"Diabetes Mellitus Laboratory, Instituto de Investigaci\u00f3n e Innovaci\u00f3n en Ciencias Biom\u00e9dicas de la Provincia de C\u00e1diz (INiBICA), Hospital Universitario Puerta del Mar, 11009 C\u00e1diz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Cedric","family":"Freisenhausen","sequence":"additional","affiliation":[{"name":"Dermatology and Venereology Division, Department of Medicine, Karolinska Institute, SE-171 77 Solna, Sweden"},{"name":"Center for Molecular Medicine, Karolinska University Hospital, SE-171 76 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8478-5156","authenticated-orcid":false,"given":"Almudena","family":"Lara-Barea","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, University Hospital Puerta del Mar, 11009 C\u00e1diz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8532-2153","authenticated-orcid":false,"given":"Antonio","family":"Campos-Caro","sequence":"additional","affiliation":[{"name":"\u00c1rea Gen\u00e9tica, Departamento Biomedicina Biotecnolog\u00eda y Salud P\u00fablica, Universidad de C\u00e1diz, 11510 Puerto Real, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Zub\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Ciencias del Mar y Ambientales, Universidad de C\u00e1diz, 11510 Puerto Real, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9657-5949","authenticated-orcid":false,"given":"Manuel","family":"Aguilar-Diosdado","sequence":"additional","affiliation":[{"name":"Diabetes Mellitus Laboratory, Instituto de Investigaci\u00f3n e Innovaci\u00f3n en Ciencias Biom\u00e9dicas de la Provincia de C\u00e1diz (INiBICA), Hospital Universitario Puerta del Mar, 11009 C\u00e1diz, Spain"},{"name":"Department of Endocrinology and Metabolism, University Hospital Puerta del Mar, 11009 C\u00e1diz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5136-1725","authenticated-orcid":false,"given":"Ana I.","family":"Arroba","sequence":"additional","affiliation":[{"name":"Diabetes Mellitus Laboratory, Instituto de Investigaci\u00f3n e Innovaci\u00f3n en Ciencias Biom\u00e9dicas de la Provincia de C\u00e1diz (INiBICA), Hospital Universitario Puerta del Mar, 11009 C\u00e1diz, Spain"},{"name":"Department of Endocrinology and Metabolism, University Hospital Puerta del Mar, 11009 C\u00e1diz, 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Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1152\/physrev.00045.2011","article-title":"Mechanisms of diabetic complications","volume":"93","author":"Forbes","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Mrugacz, M., Bryl, A., and Zorena, K. (2021). Retinal vascular endothelial cell dysfunction and neuroretinal degeneration in diabetic patients. J. Clin. Med., 10.","DOI":"10.3390\/jcm10030458"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Marium, R., Khan, M., Jia, Z., Chua, Y., Tan, J.C., Yang, Y., Liao, Z., and Zhao, Y. (2019). From Pre-Diabetes to Diabetes: Diagnosis, Treatments and Translational Research. Medicina, 55.","DOI":"10.3390\/medicina55090546"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ophtha.2008.09.037","article-title":"Association of Vitreous Inflammatory Factors with Diabetic Macular Edema","volume":"116","author":"Funatsu","year":"2009","journal-title":"Ophthalmology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.2337\/diabetes.54.5.1559","article-title":"Minocycline reduces proinflammatory cytokine expression, microglial activation, and Caspase-3 activation in a rodent model of diabetic retinopathy","volume":"54","author":"Krady","year":"2005","journal-title":"Diabetes"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"95103","DOI":"10.1155\/2007\/95103","article-title":"Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy","volume":"2007","author":"Kern","year":"2007","journal-title":"Exp. Diabetes Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"582060","DOI":"10.1155\/2015\/582060","article-title":"Diabetic retinopathy: Vascular and inflammatory disease","volume":"2015","author":"Semeraro","year":"2015","journal-title":"J. Diabetes Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.cell.2010.02.029","article-title":"Nonresolving Inflammation","volume":"140","author":"Nathan","year":"2010","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1189\/jlb.0207114","article-title":"Microglia activation in retinal degeneration","volume":"81","author":"Langmann","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.tins.2020.03.012","article-title":"Microglia versus Monocytes: Distinct Roles in Degenerative Diseases of the Retina","volume":"43","author":"Yu","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1016\/j.immuni.2022.09.005","article-title":"Differential plasticity and fate of brain-resident and recruited macrophages during the onset and resolution of neuroinflammation","volume":"55","author":"Kancheva","year":"2022","journal-title":"Immunity"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s00401-023-02629-2","article-title":"Microglial contribution to the pathology of neurodevelopmental disorders in humans","volume":"146","author":"Matuleviciute","year":"2023","journal-title":"Acta Neuropathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/nri2448","article-title":"Exploring the full spectrum of macrophage activation","volume":"8","author":"Mosser","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1146\/annurev.immunol.021908.132532","article-title":"Alternative activation of macrophages: An immunologic functional perspective","volume":"27","author":"Martinez","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2170","DOI":"10.1007\/s00125-023-05995-4","article-title":"Retinal inflammation in murine models of type 1 and type 2 diabetes with diabetic retinopathy","volume":"66","author":"Dharmarajan","year":"2023","journal-title":"Diabetologia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6213","DOI":"10.1021\/cr400524q","article-title":"Phthalides and phthalans: Synthetic methodologies and their applications in the total synthesis","volume":"114","author":"Karmakar","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Le\u00f3n, A., Del-\u00c1ngel, M., \u00c1vila, J.L., and Delgado, G. (2017). Phthalides: Distribution in Nature, Chemical Reactivity, Synthesis, and Biological Activity, Springer.","DOI":"10.1007\/978-3-319-45618-8_2"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ortega, M.J., Parra-Torrej\u00f3n, B., Cano-Cano, F., G\u00f3mez-Jaramillo, L., Gonz\u00e1lez-Montelongo, M.C., and Zub\u00eda, E. (2022). Synthesis and Antioxidant\/Anti-Inflammatory Activity of 3-Arylphthalides. Pharmaceuticals, 15.","DOI":"10.3390\/ph15050588"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1016\/j.bbadis.2016.05.024","article-title":"Modulation of microglia polarization dynamics during diabetic retinopathy in db\/db mice","volume":"1862","author":"Arroba","year":"2016","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.fct.2017.11.050","article-title":"The sp2-iminosugar glycolipid 1-dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin (DSO2-ONJ) as selective anti-inflammatory agent by modulation of hemeoxygenase-1 in Bv.2 microglial cells and retinal explants","volume":"111","author":"Arroba","year":"2018","journal-title":"Food Chem. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e130845","DOI":"10.1172\/jci.insight.130845","article-title":"Autoimmune inner ear disease patient\u2013associated 28-kDa proinflammatory IL-1\u03b2 fragment results from caspase-7\u2013mediated cleavage in vitro","volume":"5","author":"Pathak","year":"2020","journal-title":"JCI Insight"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"465","DOI":"10.2174\/138161208783597362","article-title":"Carbon Monoxide-Releasing Molecules: A Pharmacological Expedient to Counteract Inflammation","volume":"14","author":"Alcaraz","year":"2008","journal-title":"Curr. Pharm. Des."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1016\/j.bcp.2009.03.009","article-title":"Heme oxygenase-1 induction modulates microsomal prostaglandin E synthase-1 expression and prostaglandin E2 production in osteoarthritic chondrocytes","volume":"77","author":"Rojo","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Cano-Cano, F., Alcalde-Est\u00e9vez, E., G\u00f3mez-Jaramillo, L., Iturregui, M., S\u00e1nchez-Fern\u00e1ndez, E.M., Garc\u00eda Fern\u00e1ndez, J.M., Ortiz Mellet, C., Campos-Caro, A., L\u00f3pez-Tinoco, C., and Aguilar-Diosdado, M. (2021). Anti-Inflammatory (M2) Response Is Induced by a sp2-Iminosugar Glycolipid Sulfoxide in Diabetic Retinopathy. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.632132"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"115390","DOI":"10.1016\/j.ejmech.2023.115390","article-title":"Fluoro-labelled sp2-iminoglycolipids with immunomodulatory properties","volume":"255","author":"Puerta","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/372739a0","article-title":"A protein kinase involved in the regulation of inflammatory cytokine biosynthesis","volume":"372","author":"Lee","year":"1994","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1016\/j.bcp.2010.07.014","article-title":"Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential","volume":"80","author":"Paine","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Tanaka, H., Hasebe, R., Murakami, K., Sugawara, T., Yamasaki, T., and Murakami, M. (2023). Gateway reflexes describe novel neuro-immune communications that establish immune cell gateways at specific vessels. Bioelectron. Med., 9.","DOI":"10.1186\/s42234-023-00126-1"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1038\/nn.3469","article-title":"M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination","volume":"16","author":"Miron","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.intimp.2014.02.017","article-title":"Hemin inhibits NLRP3 inflammasome activation in sepsis-induced acute lung injury, involving heme oxygenase-1","volume":"20","author":"Luo","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4184","DOI":"10.1039\/C8FO00650D","article-title":"Targeting heme oxygenase-1 by quercetin ameliorates alcohol-induced acute liver injury via inhibiting NLRP3 inflammasome activation","volume":"9","author":"Liu","year":"2018","journal-title":"Food Funct."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1002\/jnr.23448","article-title":"Lipopolysaccharide preconditioning facilitates M2 activation of resident microglia after spinal cord injury","volume":"92","author":"Hayakawa","year":"2014","journal-title":"J. Neurosci. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s13195-015-0139-9","article-title":"Immune phenotypes of microglia in human neurodegenerative disease: Challenges to detecting microglial polarization in human brains","volume":"7","author":"Walker","year":"2015","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e35331","DOI":"10.1097\/MD.0000000000035331","article-title":"Identification of differential immune cells and related diagnostic genes in patients with diabetic retinopathy","volume":"102","author":"Yuan","year":"2023","journal-title":"Medicine"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ramos, H., Hern\u00e1ndez, C., Sim\u00f3, R., and Sim\u00f3-Servat, O. (2023). Inflammation: The Link between Neural and Vascular Impairment in the Diabetic Retina and Therapeutic Implications. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108796"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"VI1","DOI":"10.1093\/rheumatology\/kez387","article-title":"The innate immune perspective of autoimmune and autoinflammatory conditions","volume":"58","author":"Frizinsky","year":"2019","journal-title":"Rheumatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1242\/dmm.026344","article-title":"Autophagy resolves early retinal inflammation in Igf1-deficient mice","volume":"9","author":"Arroba","year":"2016","journal-title":"DMM Dis. Model. Mech."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez, C., Arroba, A.I., Bogdanov, P., Ramos, H., Sim\u00f3-Servat, O., Sim\u00f3, R., and Valverde, A.M. (2020). Effect of topical administration of somatostatin on retinal inflammation and neurodegeneration in an experimental model of diabetes. J. Clin. Med., 9.","DOI":"10.3390\/jcm9082579"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.preteyeres.2015.08.001","article-title":"The progress in understanding and treatment of diabetic retinopathy","volume":"51","author":"Stitt","year":"2016","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_41","first-page":"3561","article-title":"Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes","volume":"41","author":"Barber","year":"2000","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1007\/s10384-007-0471-0","article-title":"Involvement of the Rho\/Rho kinase signaling pathway in platelet-derived growth factor BB-induced vascular endothelial growth factor expression in diabetic rat retina","volume":"51","author":"Yokota","year":"2007","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/glia.10154","article-title":"Microglia as neuroprotective, immunocompetent cells of the CNS","volume":"40","author":"Streit","year":"2002","journal-title":"Glia"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.exer.2009.02.013","article-title":"Systemic Administration of HMG CoA Reductase Inhibitor Protects the Blood-retinal Barrier and Ameliorates Retinal Inflammation in Type 2 diabetes","volume":"89","author":"Li","year":"2009","journal-title":"Exp. Eye Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Lypka, K.R., Carmy-Bennun, T., Garces, K.N., Venanzi, A.W., and Hackam, A.S. (2022). Assessment of outer retinal thickness and function in mice after experimental optic nerve trauma. BMC Ophthalmol., 22.","DOI":"10.1186\/s12886-022-02737-9"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ramos, H., Bogdanov, P., Sabater, D., Huerta, J., Valeri, M., Hern\u00e1ndez, C., and Sim\u00f3, R. (2021). Neuromodulation induced by sitagliptin: A new strategy for treating diabetic retinopathy. Biomedicines, 9.","DOI":"10.3390\/biomedicines9121772"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5793","DOI":"10.1016\/j.bmcl.2010.07.134","article-title":"Switch control pocket inhibitors of p38-MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region","volume":"20","author":"Ahn","year":"2010","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1007\/s00125-012-2789-5","article-title":"The role of arginase i in diabetes-induced retinal vascular dysfunction in mouse and rat models of diabetes","volume":"56","author":"Elms","year":"2013","journal-title":"Diabetologia"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4843","DOI":"10.1073\/pnas.0735876100","article-title":"Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox","volume":"100","author":"Lee","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s00726-019-02719-0","article-title":"The role of polyamines in the regulation of macrophage polarization and function","volume":"52","author":"Latour","year":"2020","journal-title":"Amino Acids"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/0003-2697(82)90118-X","article-title":"Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids","volume":"126","author":"Green","year":"1982","journal-title":"Anal. Biochem."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Yamauchi, K., Tanabu, R., Monai, N., Gonome, T., Xie, Y., Takahashi, S., Ishiguro, S.I., and Nakazawa, M. (2018). The Spectral-Domain Optical Coherence Tomography Findings Associated with the Morphological and Electrophysiological Changes in a Rat Model of Retinal Degeneration, Rhodopsin S334ter-4 Rats. Biomed Res. Int., 2018.","DOI":"10.1155\/2018\/5174986"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/15\/8440\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:28:43Z","timestamp":1760110123000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/15\/8440"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,2]]},"references-count":52,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["ijms25158440"],"URL":"https:\/\/doi.org\/10.3390\/ijms25158440","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,2]]}}}