{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:16:03Z","timestamp":1790046963665,"version":"4.0.1"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T00:00:00Z","timestamp":1622073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Minister of Science and Higher Education in the range of the program entitled \u201cRegional Initiative of Excellence\u201d for the years 2019\u20132022, Project No. 010\/RID\/2018\/19, amount of funding 12.000.000 PLN.","award":["010\/RID\/2018\/19"],"award-info":[{"award-number":["010\/RID\/2018\/19"]}]},{"name":"the University of Warmia and Mazury in Olsztyn","award":["No 15.610.003-300 (statutory research)"],"award-info":[{"award-number":["No 15.610.003-300 (statutory research)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetic gastroenteropathy is a common complication, which develops in patients with long-term diabetes. The pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide known for its cytoprotective properties and plays an important role in neuronal development, neuromodulation and neuroprotection. The present study was designed to elucidate, for the first time, the impact of prolonged hyperglycaemia conditions on a population of PACAP-like immunoreactive neurons in selected parts of the porcine gastrointestinal tract. The experiment was conducted on 10 juvenile female pigs assigned to two experimental groups: The DM group (pigs with streptozocin-induced diabetes) and the C group (control pigs). Diabetes conditions were induced by a single intravenous injection of streptozocin. Six weeks after the induction of diabetes, all animals were euthanised and further collected, and fixed fragments of the stomach, duodenum, jejunum, ileum and descending colon were processed using the routine double-labelling immunofluorescence technique. Streptozotocin-induced hyperglycaemia caused a significant increase in the population of PACAP-containing enteric neurons in the porcine stomach, small intestines and descending colon. The recorded changes may result from the direct toxic effect of hyperglycaemia on the ENS neurons, oxidative stress or inflammatory conditions accompanying hyperglycaemia and suggest that PACAP is involved in regulatory processes of the GIT function in the course of diabetes.<\/jats:p>","DOI":"10.3390\/ijms22115727","type":"journal-article","created":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T11:07:02Z","timestamp":1622113622000},"page":"5727","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Diabetes Affects the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)-Like Immunoreactive Enteric Neurons in the Porcine Digestive Tract"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7593-9552","authenticated-orcid":false,"given":"Katarzyna","family":"Palus","sequence":"first","affiliation":[{"name":"Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego Str. 13, 10-718 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1402-5423","authenticated-orcid":false,"given":"Micha\u0142","family":"Bulc","sequence":"additional","affiliation":[{"name":"Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego Str. 13, 10-718 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaros\u0142aw","family":"Ca\u0142ka","sequence":"additional","affiliation":[{"name":"Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego Str. 13, 10-718 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0983-5592","authenticated-orcid":false,"given":"\u0141ukasz","family":"Zielonka","sequence":"additional","affiliation":[{"name":"Department of Veterinary Prevention and Feed Hygiene, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego Str. 13, 10-719 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"Nowicki","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, University of Leipzig, Liebigstra\u00dfe 13, D-04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,27]]},"reference":[{"key":"ref_1","unstructured":"International Diabetes Federation (2017). IDF Diabetes Atlas, International Diabetes Federation. [8th ed.]."},{"key":"ref_2","first-page":"263","article-title":"Diabetic Gastroenteropathy: A Complication of Diabetes Mellitus","volume":"51","author":"Kurniawan","year":"2019","journal-title":"Acta Med. Indones"},{"key":"ref_3","first-page":"V6200462","article-title":"Symptoms of diabetic gastroenteropathy in patients with diabetes","volume":"182","author":"Kornum","year":"2020","journal-title":"Ugeskr. Laeger"},{"key":"ref_4","first-page":"CD007543","article-title":"Enhanced glucose control for preventing and treating diabetic neuropathy","volume":"6","author":"Callaghan","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1007\/s11894-010-0129-9","article-title":"Enteric nervous system in the small intestine: Pathophysiology and clinical implications","volume":"12","author":"Nezami","year":"2010","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1007\/s12031-012-9838-x","article-title":"Changes in pituitary adenylate cyclase-activating Peptide 27-like immunoreactive nervous structures in the porcine descending colon during selected pathological processes","volume":"48","author":"Gonkowski","year":"2012","journal-title":"J. Mol. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.neuro.2018.09.002","article-title":"Changes in VIP-, SP- and CGRP- like immunoreactivity in intramural neurons within the pig stomach following supplementation with low and high doses of acrylamide","volume":"69","author":"Palus","year":"2018","journal-title":"Neurotoxicology"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bulc, M., Palus, K., D\u0105browski, M., and Ca\u0142ka, J. (2019). Hyperglycaemia-induced downregulation in expression of nNOS intramural neurons of the small intestine in the pig. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071681"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/0006-291X(90)92140-U","article-title":"Isolation of a neuropeptide corresponding to the N-terminal 27 residues of the pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38)","volume":"170","author":"Miyata","year":"1990","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Horvath, G., Opper, B., and Reglodi, D. (2019). The Neuropeptide Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is Protective in Inflammation and Oxidative Stress-Induced Damage in the Kidney. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194944"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1124\/pr.109.001370","article-title":"Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery","volume":"61","author":"Vaudry","year":"2009","journal-title":"Pharmacol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/BF00319630","article-title":"A novel neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), in human intestine: Evidence for reduced content in Hirschsprung\u2019s disease","volume":"269","author":"Shen","year":"1992","journal-title":"Cell Tissue Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s004410050980","article-title":"Pituitary adenylate cyclase activating polypeptide (PACAP) in the gastrointestinal tract of the rat: Distribution and effects of capsaicin or denervation","volume":"291","author":"Hannibal","year":"1998","journal-title":"Cell Tissue Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/0167-0115(91)90074-Q","article-title":"PACAP, a VIP-like peptide, in neurons of the esophagus","volume":"36","author":"Uddman","year":"1991","journal-title":"Regul. Pept."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/0306-4522(92)90064-9","article-title":"Pituitary adenylate cyclase activating peptide: A novel vasoactive intestinal peptide-like neuropeptide in the gut","volume":"46","author":"Sundler","year":"1992","journal-title":"Neuroscience"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.14336\/AD.2020.0626","article-title":"Pituitary Adenylate Cyclase-Activating Polypeptide: A Promising Neuroprotective Peptide in Stroke","volume":"11","author":"Fang","year":"2020","journal-title":"Aging Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"221","DOI":"10.3389\/fncel.2020.00221","article-title":"Protective Effects of Pituitary Adenylate Cyclase-Activating Polypeptide and Vasoactive Intestinal Peptide against Cognitive Decline in Neurodegenerative Diseases","volume":"14","author":"Vaudry","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"160928","DOI":"10.1155\/2015\/160928","article-title":"Emerging Role of PACAP as a New Potential Therapeutic Target in Major Diabetes Complications","volume":"2015","author":"Marzagalli","year":"2015","journal-title":"Int. J. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s12031-015-0621-7","article-title":"PACAP Modulates Expression of Hypoxia-Inducible Factors in Streptozotocin-Induced Diabetic Rat Retina","volume":"57","author":"Maugeri","year":"2015","journal-title":"Mol. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1002\/pmic.201000320","article-title":"Recent advances in the use of Sus scrofa (pig) as a model system for proteomic studies","volume":"11","author":"Verma","year":"2011","journal-title":"Proteomics"},{"key":"ref_21","first-page":"485e518","article-title":"Drugs producing diabetes through damage of the insulin secreting cells","volume":"22","author":"Rerup","year":"1970","journal-title":"Pharmacol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"375","DOI":"10.3109\/00365529209000091","article-title":"Pituitary adenylate cyclase-activating polypeptide relaxes rat gastrointestinal smooth muscle","volume":"27","author":"Mungan","year":"1992","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_23","first-page":"G901","article-title":"Chief cells possess a receptor with high affinity for PACAP and VIP that stimulates pepsinogen release","volume":"263 Pt 1","author":"Felley","year":"1992","journal-title":"Am. J. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"G16","DOI":"10.1152\/ajpgi.00081.2017","article-title":"Expression and localization of VPAC1, the major receptor of vasoactive intestinal peptide along the length of the intestine","volume":"313","author":"Jayawardena","year":"2017","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0167-0115(02)00003-4","article-title":"Expression of pituitary adenylate cyclase-activating polypeptide and PACAP type 1 receptor in the rat gastric and colonic myenteric neurons","volume":"105","author":"Miampamba","year":"2002","journal-title":"Regul. Pept."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/j.1749-6632.1998.tb11173.x","article-title":"The pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1-R) is expressed on gastric ECL cells: Evidence by immunocytochemistry and RT-PCR","volume":"865","author":"Zeng","year":"1998","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/j.1365-2982.2009.01365.x","article-title":"Association of the status of interstitial cells of Cajal and electrogastrogram parameters, gastric emptying and symptoms in patients with gastroparesis","volume":"22","author":"Lin","year":"2010","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4881","DOI":"10.3748\/wjg.v13.i36.4881","article-title":"Impaired contractility and remodeling of the upper gastrointestinal tract in diabetes mellitus type-1","volume":"13","author":"Frokjaer","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s12640-017-9727-8","article-title":"PACAP Protects Against Ethanol and Nicotine Toxicity in SH-SY5Y Cells: Implications for Drinking-Smoking Co-morbidity","volume":"32","author":"Manavalan","year":"2017","journal-title":"Neurotox. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1196\/annals.1317.002","article-title":"Microiontophoretically applied PACAP blocks excitatory effects of kainic acid in vivo","volume":"1070","author":"Atlasz","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1046\/j.1460-9568.2002.01981.x","article-title":"PACAP protects cerebellar granule neurons against oxidative stress-induced apoptosis","volume":"15","author":"Vaudry","year":"2002","journal-title":"Eur. J. Neurosci."},{"key":"ref_32","first-page":"42","article-title":"Pituitary adenylate cyclase activating polypeptide protects neuro-2a cells from beta amyloid protein cytotoxicity by modulating intracellular calcium","volume":"55","author":"Gui","year":"2003","journal-title":"Sheng Li Xue Bao"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3066","DOI":"10.1167\/iovs.16-19285","article-title":"VEGF as a Survival Factor in Ex Vivo Models of Early Diabetic Retinopathy","volume":"57","author":"Amato","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1556\/maseb.66.2013.5.4","article-title":"Examination of cytoprotective and anti-inflammatory effect of PACAP-38 on small bowel autotransplantation","volume":"66","author":"Nedvig","year":"2013","journal-title":"Magy. Seb."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"564457","DOI":"10.3389\/fphar.2020.564457","article-title":"Neurochemistry of Enteric Neurons Following Prolonged Indomethacin Administration in the Porcine Duodenum","volume":"11","author":"Czajkowska","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1007\/s12031-015-0537-2","article-title":"The Influence of Low Doses of Zearalenone on Distribution of Selected Active Substances in Nerve Fibers within the Circular Muscle Layer of Porcine Ileum","volume":"56","author":"Gonkowski","year":"2015","journal-title":"J. Mol. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s13300-016-0182-y","article-title":"A Practical Approach to Gastrointestinal Complications of Diabetes","volume":"7","author":"Maisey","year":"2016","journal-title":"Diabetes Ther."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Sadanandan, N., Cozene, B., Park, Y.J., Farooq, J., Kingsbury, C., Wang, Z.J., Moscatello, A., Saft, M., Cho, J., and Gonzales-Portillo, B. (2021). Pituitary Adenylate Cyclase-Activating Polypeptide: A Potent Therapeutic Agent in Oxidative Stress. Antioxidants, 10.","DOI":"10.3390\/antiox10030354"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s12640-016-9659-8","article-title":"Protective Effects of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Against Oxidative Stress in Zebrafish Hair Cells","volume":"30","author":"Kasica","year":"2016","journal-title":"Neurotox. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.npep.2017.07.002","article-title":"Effects of pituitary adenylate cyclase activating polypeptide on small intestinal INT 407 cells","volume":"65","author":"Illes","year":"2017","journal-title":"Neuropeptides"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Heimesaat, M.M., Dunay, I.R., Schulze, S., Fischer, A., Grundmann, U., Alutis, M., K\u00fchl, A.A., Tamas, A., Toth, G., and Dunay, M.P. (2014). Pituitary adenylate cyclase-activating polypeptide ameliorates experimental acute ileitis and extra-intestinal sequelae. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0108389"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/jcp.21381","article-title":"PACAP provides colonic protection against dextran sodium sulfate induced colitis","volume":"216","author":"Azuma","year":"2008","journal-title":"J. Cell. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0167-0115(99)00024-5","article-title":"Biological relevance of pituitary adenylate cyclase-activating polypeptide (PACAP) in the gastrointestinal tract","volume":"84","author":"Modlin","year":"1999","journal-title":"Regul. Pept."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9037476","DOI":"10.1155\/2017\/9037476","article-title":"Changes in Somatostatin-Like Immunoreactivity in the Sympathetic Neurons Projecting to the Prepyloric Area of the Porcine Stomach Induced by Selected Pathological Conditions","volume":"2017","author":"Palus","year":"2017","journal-title":"BioMed Res. Int."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5727\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:09:08Z","timestamp":1760162948000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5727"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,27]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22115727"],"URL":"https:\/\/doi.org\/10.3390\/ijms22115727","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,27]]}}}