{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:26:00Z","timestamp":1779927960755,"version":"3.53.1"},"reference-count":36,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T00:00:00Z","timestamp":1703116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Improving clinical outcomes and delaying disease recrudescence in Ulcerative Colitis (UC) patients is crucial for clinicians. In addition to traditional and new pharmacological therapies that utilize biological drugs, the development of medical devices that can ameliorate UC and facilitate the remission phase should not be overlooked. Drug-based therapy requires time to be personalized and to evaluate the benefit\/risk ratio. However, the increasing number of diagnosed UC cases worldwide necessitates the exploration of new strategies to enhance clinical outcomes. By incorporating medical devices alongside pharmacological treatments, clinicians can provide additional support to UC patients, potentially improving their condition and slowing down the recurrence of symptoms. Chemically identified as an azelaic acid derivative and palmitoylethanolamide (PEA) analog, adelmidrol is a potent anti-inflammatory and antioxidant compound. In this study, we aimed to evaluate the effect of an intrarectal administration of 2% adelmidrol (Ade) and 0.1% hyaluronic acid (HA) gel formulation in both the acute and resolution phase of a mouse model of colitis induced via DNBS enema. We also investigated its activity in cultured human colon biopsies isolated from UC patients in the remission phase at follow-up when exposed in vitro to a cytomix challenge. Simultaneously, with its capacity to effectively alleviate chronic painful inflammatory cystitis when administered intravesically to urological patients such as Vessilen, the intrarectal administration of Ade\/HA gel has shown remarkable potential in improving the course of colitis. This treatment approach has demonstrated a reduction in the histological damage score and an increase in the expression of ZO-1 and occludin tight junctions in both in vivo studies and human specimens. By acting independently on endogenous PEA levels and without any noticeable systemic absorption, the effectiveness of Ade\/HA gel is reliant on a local antioxidant mechanism that functions as a \u201cbarrier effect\u201d in the inflamed gut. Building on the findings of this preliminary study, we are confident that the Ade\/HA gel medical device holds promise as a valuable adjunct in supporting traditional anti-UC therapies.<\/jats:p>","DOI":"10.3390\/ijms25010165","type":"journal-article","created":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T01:19:42Z","timestamp":1703207982000},"page":"165","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Intrarectal Administration of Adelmidrol plus Hyaluronic Acid Gel Ameliorates Experimental Colitis in Mice and Inhibits Pro-Inflammatory Response in Ex Vivo Cultured Biopsies Derived from Ulcerative Colitis-Affected Patients"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5019-653X","authenticated-orcid":false,"given":"Irene","family":"Palenca","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology \u201cV. Erspamer\u201d, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2346-9912","authenticated-orcid":false,"given":"Luisa","family":"Seguella","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology \u201cV. Erspamer\u201d, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora","family":"Zilli","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology \u201cV. Erspamer\u201d, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7114-9089","authenticated-orcid":false,"given":"Silvia","family":"Basili Franzin","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology \u201cV. Erspamer\u201d, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Del Re","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology \u201cV. Erspamer\u201d, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6617-8192","authenticated-orcid":false,"given":"Federico","family":"Pepi","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Drug Technologies, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6412-9407","authenticated-orcid":false,"given":"Anna","family":"Troiani","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Drug Technologies, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5996-4259","authenticated-orcid":false,"given":"Marcella","family":"Pesce","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Rurgo","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6109-2768","authenticated-orcid":false,"given":"Fatima Domenica Elisa","family":"De Palma","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, Centro Ingegneria Genetica-Biotecnologie Avanzate s.c.a rl, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Luglio","sequence":"additional","affiliation":[{"name":"Endoscopic Surgery Unit, Department of Medical and Surgical Gastrointestinal Disease, Federico II University of Naples, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca Paola","family":"Tropeano","sequence":"additional","affiliation":[{"name":"Endoscopic Surgery Unit, Department of Medical and Surgical Gastrointestinal Disease, Federico II University of Naples, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1467-1134","authenticated-orcid":false,"given":"Giovanni","family":"Sarnelli","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8080-8218","authenticated-orcid":false,"given":"Giuseppe","family":"Esposito","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology \u201cV. Erspamer\u201d, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/S2468-1253(18)30159-6","article-title":"Differential diagnosis of inflammatory bowel disease: Imitations and complications","volume":"3","author":"Gecse","year":"2018","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/nrgastro.2017.136","article-title":"Environmental triggers in IBD: A review of progress and evidence","volume":"15","author":"Ananthakrishnan","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3748\/wjg.v20.i1.91","article-title":"Inflammatory bowel disease: Pathogenesis","volume":"20","author":"Zhang","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_4","first-page":"147","article-title":"Patients Perception of Risks and Benefits of Biologic Therapy","volume":"26","year":"2020","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/j.1365-2036.2010.04489.x","article-title":"Review article: Explaining risks of inflammatory bowel disease therapy to patients","volume":"33","author":"Siegel","year":"2011","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Fusco, R., Cordaro, M., Genovese, T., Impellizzeri, D., Siracusa, R., Gugliandolo, E., Peritore, A.F., D\u2019Amico, R., Crupi, R., and Cuzzocrea, S. (2020). Adelmidrol: A New Promising Antioxidant and Anti-Inflammatory Therapeutic Tool in Pulmonary Fibrosis. Antioxidants, 9.","DOI":"10.3390\/antiox9070601"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1124\/mol.116.105668","article-title":"Adelmidrol, a Palmitoylethanolamide Analogue, as a New Pharmacological Treatment for the Management of Inflammatory Bowel Disease","volume":"90","author":"Cordaro","year":"2016","journal-title":"Mol. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.tvjl.2015.10.060","article-title":"Adelmidrol increases the endogenous concentrations of palmitoylethanolamide in canine keratinocytes and down-regulates an inflammatory reaction in an in vitro model of contact allergic dermatitis","volume":"207","author":"Petrosino","year":"2016","journal-title":"Vet. J."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Del Re, A., Palenca, I., Seguella, L., Pesce, M., Corpetti, C., Steardo, L., Rurgo, S., Sarnelli, G., and Esposito, G. (2022). Oral Adelmidrol Administration Up-Regulates Palmitoylethanolamide Production in Mice Colon and Duodenum through a PPAR-\u03b3 Independent Action. Metabolites, 12.","DOI":"10.3390\/metabo12050457"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.2174\/092986709788186138","article-title":"Role, metabolism, chemical modifications and applications of hyaluronan","volume":"16","author":"Volpi","year":"2009","journal-title":"Curr. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1186\/s13075-016-1189-5","article-title":"Adelmidrol, in combination with hyaluronic acid, displays increased anti-inflammatory and analgesic effects against monosodium iodoacetate-induced osteoarthritis in rats","volume":"18","author":"Fusco","year":"2016","journal-title":"Arthritis Res. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Campolo, M., Siracusa, R., Cordaro, M., Filippone, A., Gugliandolo, E., Peritore, A.F., Impellizzeri, D., Crupi, R., Paterniti, I., and Cuzzocrea, S. (2019). The association of adelmidrol with sodium hyaluronate displays beneficial properties against bladder changes following spinal cord injury in mice. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0208730"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.phrs.2018.05.013","article-title":"Adelmidrol + sodium hyaluronate in IC\/BPS or conditions associated to chronic urothelial inflammation. A translational study","volume":"134","author":"Ostardo","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1093\/ecco-jcc\/jjac102","article-title":"Numbers Do Not Lie: The Dire Need for New Directions in IBD","volume":"16","author":"Fiocchi","year":"2022","journal-title":"J. Crohns Colitis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1111\/j.1582-4934.2008.00353.x","article-title":"Adelmidrol, a palmitoylethanolamide analogue, reduces chronic inflammation in a carrageenin-granuloma model in rats","volume":"13","author":"Cinelli","year":"2009","journal-title":"J. Cell. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.bcp.2016.09.001","article-title":"Adelmidrol, a palmitoylethanolamide analogue, as a new pharmacological treatment for the management of acute and chronic inflammation","volume":"119","author":"Impellizzeri","year":"2016","journal-title":"Biochem. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1111\/jgh.14872","article-title":"The epidemiology of inflammatory bowel disease: East meets west","volume":"35","author":"Mak","year":"2020","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1093\/ecco-jcc\/jjv231","article-title":"Dimethyl Fumarate Reduces Inflammatory Responses in Experimental Colitis","volume":"10","author":"Casili","year":"2016","journal-title":"J. Crohns Colitis"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6482","DOI":"10.1039\/D2FO03644D","article-title":"A comparative study of the ameliorative effects of hyaluronic acid oligosaccharides and hyaluronic acid on DSS-induced colitis in mice and research on relevant mechanisms","volume":"14","author":"Liu","year":"2023","journal-title":"Food Funct."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"536","DOI":"10.4062\/biomolther.2020.227","article-title":"Hyaluronic Acid Increases Anti-Inflammatory Efficacy of Rectal 5-Amino Salicylic Acid Administration in a Murine Colitis Model","volume":"29","author":"Jhundoo","year":"2021","journal-title":"Biomol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Hlaing, S.P., Cao, J., Lee, J., Kim, J., Saparbayeva, A., Kwak, D., Kim, H., Hwang, S., Yun, H., and Moon, H.R. (2022). Hyaluronic Acid-Conjugated PLGA Nanoparticles Alleviate Ulcerative Colitis via CD44-Mediated Dual Targeting to Inflamed Colitis Tissue and Macrophages. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14102118"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/978-981-13-7709-9_12","article-title":"Clinical Applications of Hyaluronidase","volume":"1148","author":"Weber","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1097\/00054725-200108000-00007","article-title":"Measurement of colonic mucosal concentrations of 5-aminosalicylic acid is useful for estimating its therapeutic efficacy in distal ulcerative colitis: Comparison of orally administered mesalamine and sulfasalazine","volume":"7","author":"Naganuma","year":"2001","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/nprot.2007.41","article-title":"Chemically induced mouse models of intestinal inflammation","volume":"2","author":"Wirtz","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.1111\/jcmm.14943","article-title":"Pentamidine niosomes thwart S100B effects in human colon carcinoma biopsies favouring wtp53 rescue","volume":"24","author":"Seguella","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"De Palma, G.D., Colavita, I., Zambrano, G., Giglio, M.C., Maione, F., Luglio, G., Sarnelli, G., Rispo, A., Schettino, P., and D\u2019Armiento, F.P. (2017). Detection of colonic dysplasia in patients with ulcerative colitis using a targeted fluorescent peptide and confocal laser endomicroscopy: A pilot study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0180509"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1006\/cyto.2000.0813","article-title":"Influence of glutamine on cytokine production by human gut in vitro","volume":"13","author":"Lalaude","year":"2001","journal-title":"Cytokine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1209-e112","DOI":"10.1111\/j.1365-2982.2009.01346.x","article-title":"Increased mucosal nitric oxide production in ulcerative colitis is mediated in part by the enteroglial-derived S100B protein","volume":"21","author":"Cirillo","year":"2009","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2900","DOI":"10.1038\/nprot.2006.446","article-title":"High resolution colonoscopy in live mice","volume":"1","author":"Becker","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_30","first-page":"238","article-title":"Clinicopathologic study of dextran sulfate sodium experimental murine colitis","volume":"69","author":"Cooper","year":"1993","journal-title":"Lab. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1021\/acs.jafc.6b03806","article-title":"Muscadine Grape (Vitis rotundifolia) or Wine Phytochemicals Reduce Intestinal Inflammation in Mice with Dextran Sulfate Sodium-Induced Colitis","volume":"65","author":"Li","year":"2017","journal-title":"J. Agric. Food Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1007\/s00011-007-7216-x","article-title":"Phenotype of exogenous microparticle-containing pigment cells of the human Peyer\u2019s patch in inflamed and normal ileum","volume":"57","author":"Thoree","year":"2008","journal-title":"Inflamm. Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"D\u2019Amico, R., Siracusa, R., Fusco, R., Cordaro, M., Genovese, T., Peritore, A.F., Gugliandolo, E., Crupi, R., Impellizzeri, D., and Cuzzocrea, S. (2020). Protective effects of Colomast\u00ae, A New Formulation of Adelmidrol and Sodium Hyaluronate, in A Mouse Model of Acute Restraint Stress. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218136"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Cassini-Vieira, P., Moreira, C.F., da Silva, M.F., and da Silva Barcelos, L. (2015). Estimation of Wound Tissue Neutrophil and Macrophage Accumulation by Measuring Myeloperoxidase (MPO) and N-Acetyl-\u03b2-D-glucosaminidase (NAG) Activities. Bio-Protocol, 5.","DOI":"10.21769\/BioProtoc.1662"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1186\/1742-2094-9-277","article-title":"The antiprotozoal drug pentamidine ameliorates experimentally induced acute colitis in mice","volume":"9","author":"Esposito","year":"2012","journal-title":"J. Neuroinflammation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.jchromb.2014.11.001","article-title":"A quantitiative LC-MS\/MS method for the measurement of arachidonic acid, prostanoids, endocannabinoids, N-acylethanolamines and steroids in human plasma","volume":"976\u2013977","author":"Gachet","year":"2015","journal-title":"J. Chromatogr. B"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/1\/165\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:39:58Z","timestamp":1760132398000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/1\/165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,21]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["ijms25010165"],"URL":"https:\/\/doi.org\/10.3390\/ijms25010165","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,21]]}}}