{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T08:25:04Z","timestamp":1787214304834,"version":"build-2736575974"},"reference-count":29,"publisher":"Walter de Gruyter GmbH","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec id=\"j_jbcpp-2026-0178_abs_001\">\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This study investigated the protective and therapeutic effects of hexarelin (HEX) against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced lung injury in mice by evaluating oxidative stress, IL-6\u2013mediated inflammation, and Caspase-3\u2013dependent apoptosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_jbcpp-2026-0178_abs_002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Fifty male Balb\/C mice were randomly assigned to five groups (n=10): control, MPTP, PREHEX, POSTHEX, and HEX. Parkinson-like neurotoxicity was induced by a single intranasal dose of MPTP (1\u202fmg\/kg). Hexarelin (10\u202f\u03bcg\/kg, i.p.) was administered twice at 4-h intervals before or after MPTP exposure. Lung tissues were examined histopathologically using hematoxylin\u2013eosin staining, and immunohistochemically for Caspase-3, IL-6, and SOD expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_jbcpp-2026-0178_abs_003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MPTP caused severe pulmonary injury, including alveolar wall thickening, edema, hyperemia, and inflammatory infiltration, with increased Caspase-3 (p&lt;0.001) and IL-6 (p=0.002) expression and reduced SOD immunoreactivity compared with controls (p&lt;0.001). Both HEX regimens significantly reduced histopathological damage and improved immunohistochemical parameters (p&lt;0.05). POSTHEX showed greater recovery than PREHEX, with lower apoptotic (p=0.005) and inflammatory (p=0.050) marker expression and higher SOD (p=0.007) levels. The enhanced efficacy of therapeutic post-treatment over prophylactic pretreatment is likely attributable to the active engagement of cytoprotective pathways during ongoing severe oxidative and inflammatory cascades, optimizing hexarelin\u2019s receptor-mediated cellular rescue mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_jbcpp-2026-0178_abs_004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Hexarelin demonstrated significant protective and therapeutic effects against MPTP-induced lung injury by mitigating oxidative stress, suppressing inflammation, and limiting apoptosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1515\/jbcpp-2026-0178","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T08:03:53Z","timestamp":1787213033000},"source":"Crossref","is-referenced-by-count":0,"title":["Protective and restorative effects of hexarelin on MPTP-induced lung injury in mice"],"prefix":"10.1515","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2743-7424","authenticated-orcid":false,"given":"Onur","family":"Celikoglu","sequence":"first","affiliation":[{"name":"Faculty of Veterinary Medicine Department of Pathology , Burdur Mehmet Akif Ersoy University , Burdur , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8544-3598","authenticated-orcid":false,"given":"Elif S.","family":"Karanfil","sequence":"additional","affiliation":[{"name":"Medical Faculty, Department of Physiology , Suleyman Demirel University , Isparta , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1835-1082","authenticated-orcid":false,"given":"Ozlem","family":"Ozmen","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary Medicine Department of Pathology , Burdur Mehmet Akif Ersoy University , Burdur , T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_001","unstructured":"Pajares, M, Rojo, AI, Cuadrado, A. Inflammation and oxidative stress in Parkinson\u2019s disease: the peripheral connection. Free Radic Biol Med 2020;155:120\u201335."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_002","unstructured":"Liu, Y, Guo, T, Chen, Z. Systemic oxidative stress and peripheral tissue degeneration in experimental models of Parkinsonian pathology. J\u00a0Basic Clin Physiol Pharmacol 2026;37:45\u201356."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_003","doi-asserted-by":"crossref","unstructured":"Schiller, M, Ben-Shaanan, TL, Rolls, A. Neuronal regulation of peripheral immunity and acute tissue injury. Nat Rev Immunol 2021;21:487\u201399.","DOI":"10.1038\/s41577-020-0387-1"},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_004","unstructured":"Guo, T, Liu, Y, Wang, X. Deciphering the lung\u2013brain axis: peripheral immune responses in neurodegenerative disorders. Front Immunol 2026;17:884\u201395."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_005","unstructured":"Ceriello, A, Prasad, KB, Martinez, J. Systemic manifestations of neurotoxic agents: emphasis on peripheral organ involvement. J\u00a0Neurotox Res 2022;40:112\u201325."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_006","unstructured":"Mondal, S, Firdous, SM. Extraneural toxicity of MPTP: evaluating the pathways of acute organ injury. Toxicology 2025;512:153\u201362."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_007","unstructured":"Tansey, MG, Wallings, RL, Houser, MC. Inflammation and immune dysfunction in Parkinson\u2019s disease: from central to peripheral mechanisms. Lancet Neurol 2022;21:654\u201366."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_008","unstructured":"Park, S, Lee, JH. The lung\u2013brain axis: structural and functional pulmonary injury following neurotoxic insults. Physiol Res 2024;73:501\u201312."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_009","unstructured":"Ribeiro, FM, Silva, GC, Santos, RA. Pulmonary manifestations of systemic neurotoxin exposure: morphological and biochemical analyses. Toxicon 2023;224:78\u201389."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_010","unstructured":"Pokharel, S, Khan, A, Thapa, R. Attenuating the destructive triad: antioxidant, anti-inflammatory, and anti-apoptotic strategies in tissue protection. Life Sci 2024;338:122\u201334."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_011","unstructured":"Sarman, H, Asci, A. Cytoprotective agents in experimental organ damage: a comprehensive review of recent pharmacological interventions. Pharmacol Rep 2026;78:210\u201325."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_012","unstructured":"Zambelli, V, Passoni, L, Locatelli, V. Hexarelin as a therapeutic tool: anti-inflammatory and cytoprotective properties of a stable ghrelin analogue. Front Endocrinol 2021;12:698\u2013709."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_013","unstructured":"Guan, R, Wang, H, Zhang, L. Hexarelin attenuates oxidative stress and apoptotic signaling in acute tissue injury models through Nrf2 upregulation. Eur J Pharmacol 2023;942:175\u201384."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_014","unstructured":"Dluzen, DE, Kefalas, GG. An intranasal MPTP model for Parkinson\u2019s disease in mice. Neurosci Lett 1996;206:141\u20134."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_015","unstructured":"Lopez, A, Garcia, M, Smith, R. Prophylactic regimens of growth hormone secretagogues in experimental models of metabolic and oxidative stress. Endocrinology 2012;153:3712\u201323."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_016","unstructured":"Ozmen, O, Dogan, M, Aslan, R. A standardized semi-quantitative scoring system for experimental acute lung injury in rodent models. Vet Pathol 2024;61:412\u201321."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_017","unstructured":"Tansey, MG, Romero, EM. Peripheral inflammation in Parkinson\u2019s disease: open questions and clinical implications. Trends Neurosci 2019;42:584\u201395."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_018","unstructured":"Lickteig, AJ, Wimalasena, K. Kinetics and mechanism of MPTP-induced mitochondrial complex I inhibition in peripheral cells. Biochim Biophys Acta Bioenerg 2019;1860:392\u2013401."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_019","unstructured":"Risiglione, P, Leggio, GM, Drago, F. Mitochondrial dysfunction induced by MPTP in peripheral tissues: focus on respiration and ROS generation. Neurochem Int 2020;134:104\u201315."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_020","doi-asserted-by":"crossref","unstructured":"Sagliocchi, S, Restolfer, F, Cossidente, A, Dentice, M. 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Cell Death Dis 2010;1:e41."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_024","unstructured":"Marra, AM, Egenlauf, B, Bossone, E. Molecular signaling and inflammatory pathways in systemic organ degeneration. J\u00a0Basic Clin Physiol Pharmacol 2023. https:\/\/doi.org\/10.1515\/jbcpp-2023-0314."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_025","unstructured":"Meanti, R, Licata, M, Locatelli, V. Anti-apoptotic mechanisms of hexarelin: role of the PI3K\/Akt pathway and Bcl-2 family proteins. Growth Hormone IGF Res 2021;58:101\u201312."},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_026","doi-asserted-by":"crossref","unstructured":"Marra, AM, Egenlauf, B, Bossone, E, Eichstaedt, C, Gr\u00fcnig, E, Ehlken, N. Principles of rehabilitation and reactivation: pulmonary hypertension. Respiration 2015;89:265\u201373. https:\/\/doi.org\/10.1159\/000371855.","DOI":"10.1159\/000371855"},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_027","doi-asserted-by":"crossref","unstructured":"Marra, AM, Halank, M, Egenlauf, B, Bossone, E, Cittadini, A, Eichstaedt, CA, et al.. Right ventricular size and function under riociguat in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (the RIVER study). Respir Res 2018;19:258. https:\/\/doi.org\/10.1186\/s12931-018-0957-y.","DOI":"10.1186\/s12931-018-0957-y"},{"key":"2026082008032309823_j_jbcpp-2026-0178_ref_028","doi-asserted-by":"crossref","unstructured":"Marra, AM, Attanasio, U, Cuomo, A, Salzano, A, Sirico, D, Bobbio, E, et al.. Mildly elevated pulmonary hypertension: gray zone or already a disease. 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