{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T21:52:13Z","timestamp":1783461133787,"version":"3.55.0"},"reference-count":40,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T00:00:00Z","timestamp":1683590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004271","name":"Sapienza University Intramural","doi-asserted-by":"publisher","award":["RM12218161859E20"],"award-info":[{"award-number":["RM12218161859E20"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Primary Sj\u00f6gren\u2019s Syndrome (pSS) is a systemic autoimmune disease that primarily attacks the lacrimal and salivary glands, resulting in impaired secretory function characterized by xerostomia and xerophthalmia. Patients with pSS have been shown to have impaired salivary gland innervation and altered circulating levels of neuropeptides thought to be a cause of decreased salivation, including substance P (SP). Using Western blot analysis and immunofluorescence studies, we examined the expression levels of SP and its preferred G protein-coupled TK Receptor 1 (NK1R) and apoptosis markers in biopsies of the minor salivary gland (MSG) from pSS patients compared with patients with idiopathic sicca syndrome. We confirmed a quantitative decrease in the amount of SP in the MSG of pSS patients and demonstrated a significant increase in NK1R levels compared with sicca subjects, indicating the involvement of SP fibers and NK1R in the impaired salivary secretion observed in pSS patients. Moreover, the increase in apoptosis (PARP-1 cleavage) in pSS patients was shown to be related to JNK phosphorylation. Since there is no satisfactory therapy for the treatment of secretory hypofunction in pSS patients, the SP pathway may be a new potential diagnostic tool or therapeutic target.<\/jats:p>","DOI":"10.3390\/cells12101347","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T01:40:02Z","timestamp":1683682802000},"page":"1347","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Involvement of Substance P (SP) and Its Related NK1 Receptor in Primary Sj\u00f6gren\u2019s Syndrome (pSS) Pathogenesis"],"prefix":"10.3390","volume":"12","author":[{"given":"Pamela","family":"Rosso","sequence":"first","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1730-277X","authenticated-orcid":false,"given":"Elena","family":"Fico","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Colafrancesco","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties, Rheumatology Unit, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario Giuseppe","family":"Bellizzi","sequence":"additional","affiliation":[{"name":"Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Priori","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University, Viale del Policlinico 155, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna","family":"Cerbelli","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnology, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9258-4191","authenticated-orcid":false,"given":"Martina","family":"Leopizzi","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnology, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3716-4303","authenticated-orcid":false,"given":"Carla","family":"Giordano","sequence":"additional","affiliation":[{"name":"Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4824-9871","authenticated-orcid":false,"given":"Antonio","family":"Greco","sequence":"additional","affiliation":[{"name":"Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Tirassa","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6932-704X","authenticated-orcid":false,"given":"Cinzia","family":"Severini","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Fusconi","sequence":"additional","affiliation":[{"name":"Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.2353\/ajpath.2009.090319","article-title":"Systemic and Local Interleukin-17 and Linked Cytokines Associated with Sj\u00f6gren\u2019s Syndrome Immunopathogenesis","volume":"175","author":"Katsifis","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S0140-6736(05)66990-5","article-title":"Sj\u00f6gren\u2019s syndrome","volume":"366","author":"Fox","year":"2005","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s10238-021-00728-6","article-title":"Sj\u00f6gren\u2019s syndrome: A systemic autoimmune disease","volume":"22","author":"Negrini","year":"2022","journal-title":"Clin. Exp. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3088","DOI":"10.1093\/rheumatology\/kez004","article-title":"T cells in primary Sj\u00f6gren\u2019s syndrome: Targets for early intervention","volume":"60","author":"Verstappen","year":"2021","journal-title":"Rheumatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.pharmthera.2017.10.019","article-title":"Cytokines as therapeutic targets in primary Sj\u00f6gren syndrome","volume":"184","author":"Retamozo","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1093\/rheumatology\/kep357","article-title":"Age-related T-cell cytokine profile parallels corneal disease severity in Sjogren\u2019s syndrome-like keratoconjunctivitis sicca in CD25KO mice","volume":"49","author":"Hwang","year":"2010","journal-title":"Rheumatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1136\/ard.61.6.554","article-title":"Classification criteria for Sj\u00f6gren\u2019s syndrome: A revised version of the European criteria proposed by the American-European Consensus Group","volume":"61","author":"Vitali","year":"2002","journal-title":"Ann. Rheum. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/art.39859","article-title":"2016 American College of Rheumatology\/European League Against Rheumatism Classification Criteria for Primary Sj\u00f6gren\u2019s Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts","volume":"69","author":"Shiboski","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/0306-4522(88)90110-8","article-title":"Calcitonin gene-related peptide in rat salivary glands: Neuronal localization, depletion upon nerve stimulation, and effects on salivation in relation to substance P","volume":"26","author":"Ekman","year":"1988","journal-title":"Neuroscience"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.archoralbio.2004.02.001","article-title":"Morphological basis of sensory neuropathy and neuroimmunomodulation in minor salivary glands of patients with Sj\u00f6gren\u2019s syndrome","volume":"49","author":"Batbayar","year":"2004","journal-title":"Arch. Oral Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1002\/art.1780350717","article-title":"Peptide-containing nerves in labial salivary glands in Sj\u00f6gren\u2019s syndrome","volume":"35","author":"Konttinen","year":"1992","journal-title":"Arthritis Rheum."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1053\/sarh.2003.50019","article-title":"Apoptosis and Sj\u00f6gren syndrome","volume":"33","author":"Manganelli","year":"2003","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"199","DOI":"10.4161\/org.25224","article-title":"Interactions between developing nerves and salivary glands","volume":"9","author":"Ferreira","year":"2013","journal-title":"Organogenesis"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1124\/pr.54.2.285","article-title":"The tachykinin peptide family","volume":"54","author":"Severini","year":"2002","journal-title":"Pharmacol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1016\/j.neuropharm.2007.01.020","article-title":"Substance P provides neuroprotection in cerebellar granule cells through Akt and MAPK\/Erk activation: Evidence for the involvement of the delayed rectifier potassium current","volume":"52","author":"Amadoro","year":"2007","journal-title":"Neuropharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1046\/j.1471-4159.2003.02014.x","article-title":"Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca2+-MAPK\/ERK pathways","volume":"87","author":"Lallemend","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1016\/j.neuropharm.2011.12.025","article-title":"Substance P activates ADAM9 mRNA expression and induces \u03b1-secretase-mediated amyloid precursor protein cleavage","volume":"62","author":"Marolda","year":"2012","journal-title":"Neuropharmacology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1124\/mol.105.015453","article-title":"Substance P, neurokinins A and B, and synthetic tachykinin peptides protect mesencephalic dopaminergic neurons in culture via an activity-dependent mechanism","volume":"68","author":"Traver","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"964","DOI":"10.2174\/1567205013666160401114039","article-title":"Substance P and Alzheimer\u2019s Disease: Emerging Novel Roles","volume":"13","author":"Severini","year":"2016","journal-title":"Curr. Alzheimer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0167-0115(93)90026-5","article-title":"Organization of substance P primary sensory neurons: Ultrastructural and physiological correlates","volume":"46","author":"Cuello","year":"1993","journal-title":"Regul. Pept."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Schirinzi, T., Maftei, D., Grillo, P., Bovenzi, R., Bissacco, J., Simonetta, C., Mascioli, D., Zenuni, H., Cerroni, R., and Vincenzi, M. (2023). Olfactory neuron Substance P is overexpressed in Parkinson\u2019s disease reflecting gut dysfunction. Mov. Disord.","DOI":"10.1002\/mds.29433"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1053\/eujp.2000.0171","article-title":"Substance P","volume":"4","author":"Snijdelaar","year":"2000","journal-title":"Eur. J. Pain"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/jcp.20061","article-title":"The role of substance P in inflammatory disease","volume":"201","author":"Goode","year":"2004","journal-title":"J. Cell. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1080\/00016489.1992.11665430","article-title":"Neuropeptides in human salivary (submandibular and parotid) glands","volume":"112","author":"Albegger","year":"1992","journal-title":"Acta Otolaryngol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1136\/annrheumdis-2016-210448","article-title":"Standardisation of labial salivary gland histopathology in clinical trials in primary Sj\u00f6gren\u2019s syndrome","volume":"76","author":"Fisher","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1093\/rheumatology\/kez255","article-title":"CXCL13 as biomarker for histological involvement in Sj\u00f6gren\u2019s syndrome","volume":"59","author":"Colafrancesco","year":"2020","journal-title":"Rheumatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1093\/rheumatology\/41.3.338","article-title":"Activated caspase 3 and cleaved poly(ADP-ribose)polymerase in salivary epithelium suggest a pathogenetic mechanism for Sj\u00f6gren\u2019s syndrome","volume":"41","author":"Jimenez","year":"2002","journal-title":"Rheumatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/371346a0","article-title":"Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE","volume":"371","author":"Lazebnik","year":"1994","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.neubiorev.2021.10.008","article-title":"What substance P might tell us about the prognosis and mechanism of Parkinson\u2019s disease?","volume":"131","author":"Tirassa","year":"2021","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1111\/ger.12353","article-title":"Salivary hypofunction: An update on therapeutic strategies","volume":"35","author":"Salum","year":"2018","journal-title":"Gerodontology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/jcpt.12011","article-title":"Effect of pilocarpine on substance P and calcitonin gene-related peptide releases correlate with salivary secretion in human saliva and plasma","volume":"38","author":"Sato","year":"2013","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_32","first-page":"345","article-title":"Studies on the salivary secretion induced by substance P in perfused submandibular gland of rat","volume":"85","author":"Ueha","year":"1989","journal-title":"Proc. Finn. Dent. Soc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1159\/000305824","article-title":"The treatment of sjoegren\u2019s syndrome with physalaemin","volume":"158","author":"Cordella","year":"1969","journal-title":"Ophthalmologica"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1055\/s-2008-1050096","article-title":"Treatment of severe courses of keratoconjunctivitis sicca with Eledoisin","volume":"192","author":"Jaeger","year":"1988","journal-title":"Klin. Monbl. Augenheilkd."},{"key":"ref_35","first-page":"145","article-title":"[Eledoisin eyedrops in the therapy of keratoconjunctivitis sicca]","volume":"2","author":"Spinelli","year":"1988","journal-title":"Ophtalmologie"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1002\/1529-0131(199801)41:1<150::AID-ART18>3.0.CO;2-T","article-title":"A novel NOD-derived murine model of primary Sj\u00f6gren\u2019s syndrome","volume":"41","author":"Robinson","year":"1998","journal-title":"Arthritis Rheum."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4262","DOI":"10.2337\/db14-0163","article-title":"Substance P promotes diabetic corneal epithelial wound healing through molecular mechanisms mediated via the neurokinin-1 receptor","volume":"63","author":"Yang","year":"2014","journal-title":"Diabetes"},{"key":"ref_38","first-page":"247","article-title":"Salivary gland changes in the NOD mouse model for Sj\u00f6gren\u2019s syndrome: Is there a non-immune genetic trigger?","volume":"36","author":"Yamachika","year":"1998","journal-title":"Eur. J. Morphol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.yexcr.2018.12.027","article-title":"Toll-like receptor 9 signaling promotes autophagy and apoptosis via divergent functions of the p38\/JNK pathway in human salivary gland cells","volume":"375","author":"Fu","year":"2019","journal-title":"Exp. Cell Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.coms.2013.09.003","article-title":"Salivary gland dysfunction and xerostomia in Sj\u00f6gren\u2019s syndrome","volume":"26","author":"Jensen","year":"2014","journal-title":"Oral Maxillofac. Surg. Clin. N. Am."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/10\/1347\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:32:00Z","timestamp":1760124720000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/10\/1347"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,9]]},"references-count":40,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["cells12101347"],"URL":"https:\/\/doi.org\/10.3390\/cells12101347","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,9]]}}}