{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T19:37:07Z","timestamp":1785872227154,"version":"3.56.0"},"reference-count":48,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,22]],"date-time":"2024-09-22T00:00:00Z","timestamp":1726963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Prince Sattam Bin Abdulaziz University","award":["2023\/03\/29570"],"award-info":[{"award-number":["2023\/03\/29570"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oleuropein (OLP) is a naturally occurring phenolic compound in olive plant with antioxidant and anti-inflammatory potential and can possibly be used in treating pancreatic injuries. This investigation aimed to follow the molecular mechanism behind the potential therapeutic effect of OLP against pancreatic injury persuaded by ischemia\u2013reperfusion (I\/R). Pancreatic I\/R injury was induced by splenic artery occlusion for 60 min followed by reperfusion. Oral administration of OLP (10 and 20 mg\/kg) for 2 days significantly alleviated I\/R-persuaded oxidative damage and inflammatory responses in pancreatic tissue as indicated by the decreased malondialdehyde (MDA) content and increased glutathione peroxidase (GPx) activity, accompanied by the suppression of myeloperoxidase (MPO) activity and reduced levels of interleukin-1beta (IL-1\u03b2), nuclear factor kappa B (NF-\u03baB), and tumor necrosis factor alpha (TNF-\u03b1) in pancreatic tissues. Furthermore, OLP treatment markedly restored the serum levels of amylase, trypsinogen-activated peptide (TAP), and lipase, with concurrent improvement in pancreatic histopathological alterations. Moreover, treatment with OLP regulated the pancreatic expression of inducible nitric oxide synthase (iNOS) and high-mobility group box 1 (HMGB1) relative to rats of the pancreatic IR group. Thus, OLP treatment significantly alleviates the I\/R-induced pancreatic injury by inhibiting oxidative stress and inflammation in rats through downregulation of HMGB1 and its downstream NF-\u03baB signaling pathway.<\/jats:p>","DOI":"10.3390\/ijms251810171","type":"journal-article","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T03:36:38Z","timestamp":1727062598000},"page":"10171","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Oleuropein Relieves Pancreatic Ischemia Reperfusion Injury in Rats by Suppressing Inflammation and Oxidative Stress through HMGB1\/NF-\u03baB Pathway"],"prefix":"10.3390","volume":"25","author":[{"given":"Maged S.","family":"Abdel-Kader","sequence":"first","affiliation":[{"name":"Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia"},{"name":"Department of Pharmacognosy, College of Pharmacy, Alexandria University, Alexandria 21215, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4341-4954","authenticated-orcid":false,"given":"Rehab F.","family":"Abdel-Rahman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, National Research Centre, Giza 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4622-3501","authenticated-orcid":false,"given":"Gamal A.","family":"Soliman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia"},{"name":"Department of Pharmacology, College of Veterinary Medicine, Cairo University, Giza 12613, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0480-5127","authenticated-orcid":false,"given":"Hanan A.","family":"Ogaly","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, College of Veterinary Medicine, Cairo University, Giza 12613, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1534-1388","authenticated-orcid":false,"given":"Mohammed A.","family":"Alamri","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9303-3957","authenticated-orcid":false,"given":"Abdulrahman G.","family":"Alharbi","sequence":"additional","affiliation":[{"name":"Maternity and Children\u2019s Hospital, Ministry of Health, Al-Kharj 11942, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kervella, D., Mesnard, B., Prudhomme, T., Bruneau, S., Masset, C., Cantarovich, D., Blancho, G., and Branchereau, J. (2023). Sterile Pancreas Inflammation during Preservation and after Transplantation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054636"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1016\/j.transproceed.2008.07.093","article-title":"Restrictive Ventilatory Insufficiency and Lung Injury Induced by Ischemia\/reperfusion of the Pancreas in Rats","volume":"40","author":"Chen","year":"2008","journal-title":"Transplant. Proc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/j.1600-079X.2005.00291.x","article-title":"Melatonin Reduces Apoptosis and Necrosis Induced by Ischemia\/Reperfusion Injury of the Pancreas","volume":"40","author":"Padillo","year":"2006","journal-title":"J. Pineal Res."},{"key":"ref_4","unstructured":"Halliwell, B., and Gutteridge, J.M.C. (1999). Free Radicals in Biology and Medicine, Oxford University Press. [3rd ed.]."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1179\/135100007X239261","article-title":"Colonic Healing After Portal Ischemia and Reperfusion: An Experimental Study with Oxidative Stress Biomarkers","volume":"12","author":"Rolim","year":"2007","journal-title":"Redox Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.transproceed.2010.03.017","article-title":"Curcumin Attenuates Airway Hyperreactivity Induced by Ischemia-Reperfusion of the Pancreas in Rats","volume":"42","author":"Chen","year":"2010","journal-title":"Transplant. Proc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s10238-014-0289-2","article-title":"Ischemia\u2013Reperfusion Rat Model of Acute Pancreatitis: Protein Carbonyl as a Putative Early Biomarker of Pancreatic Injury","volume":"15","author":"Schanaider","year":"2015","journal-title":"Clin. Exp. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1073\/pnas.97.4.1772","article-title":"Generation of In Vivo Activating Factors in the Ischemic Intestine by Pancreatic Enzymes","volume":"97","author":"Mitsuoka","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/BF02576782","article-title":"Ischemia Reperfusion of the Pancreas: A New In Vivo Model for Acute Pancreatitis in Rats","volume":"195","author":"Hoffmann","year":"1995","journal-title":"Res. Exp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.jsps.2018.11.015","article-title":"Olive Leaves Extract Attenuates Type II Diabetes Mellitus-Induced Testicular Damage in Rats: Molecular and Biochemical Study","volume":"27","author":"Soliman","year":"2019","journal-title":"Saudi Pharm. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1007\/s10295-016-1841-8","article-title":"A Systems Biology Approach to Investigate the Antimicrobial Activity of Oleuropein","volume":"43","author":"Li","year":"2016","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Polzonetti, V., Natalini, P., Vincenzetti, S., Vita, A., and Pucciarelli, S. (2010). Modulatory Effect of Oleuropein on Digestive Enzymes. Olives and Olive Oil in Health and Disease Prevention, Academic Press.","DOI":"10.1016\/B978-0-12-374420-3.00148-0"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"671","DOI":"10.4103\/jcrt.JCRT_1040_16","article-title":"Therapeutic Effects of Oleuropein on Cisplatin-Induced Pancreas Injury in Rats","volume":"14","author":"Bakir","year":"2018","journal-title":"J. Cancer Res. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1159\/000018793","article-title":"Ischemia\/Reperfusion-Induced Pancreatitis","volume":"17","author":"Sakorafas","year":"2000","journal-title":"Dig. Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1136\/jcp.2002.002923","article-title":"Biochemical Markers of Acute Pancreatitis","volume":"59","author":"Matull","year":"2006","journal-title":"J. Clin. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.foodchem.2004.01.029","article-title":"Involvement of Oleuropein in (some) Digestive Metabolic Pathways","volume":"88","author":"Polzonetti","year":"2004","journal-title":"Food Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1159\/000073652","article-title":"Elevated Protein Carbonyls as Plasma Markers of Oxidative Stress in Acute Pancreatitis","volume":"3","author":"Winterbourn","year":"2003","journal-title":"Pancreatology"},{"key":"ref_18","first-page":"26","article-title":"Variations in the Levels of Oxidative Stress and Antioxidants During Early Acute Pancreatitis","volume":"30","author":"Thareja","year":"2009","journal-title":"Trop. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"563","DOI":"10.4321\/S1130-01082011001100002","article-title":"Malondialdehyde in Early Phase of Acute Pancreatitis","volume":"103","author":"Miranda","year":"2011","journal-title":"Rev. Esp. Enferm. Dig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1097\/00000658-200003000-00008","article-title":"Pathophysiologic Role of Oxygen Free Radicals in Acute Pancreatitis: Initiating Event or Mediator of Tissue Damage?","volume":"231","author":"Rau","year":"2000","journal-title":"Ann. Surg."},{"key":"ref_21","first-page":"185","article-title":"Malondialdehyde and Superoxide Dismutase as Potential Markers of Severity in Acute Pancreatitis","volume":"7","author":"McPhail","year":"2006","journal-title":"JOP"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.copbio.2011.09.006","article-title":"Antimicrobial, Antioxidant and Anti-Inflammatory Phenolic Activities in Extra Virgin Olive Oil","volume":"23","author":"Cicerale","year":"2012","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1006\/bbrc.1998.8735","article-title":"Free Radical-Scavenging Properties of Olive Oil Polyphenols","volume":"247","author":"Visioli","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e22217","DOI":"10.1016\/j.heliyon.2023.e22217","article-title":"Comparative Chemical Composition and Antioxidant Activity of Olive Leaves Olea Europaea L. of Tunisian and Algerian Varieties","volume":"16","author":"Khelouf","year":"2023","journal-title":"Heliyon"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1016\/j.phymed.2013.05.002","article-title":"Oleuropein and Oleacein May Restore Biological Functions of Endothelial Progenitor Cells Impaired by Angiotensin II via Activation of Nrf2\/heme Oxygenase-1 Pathway","volume":"20","author":"Parzonko","year":"2013","journal-title":"Phytomedicine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1016\/j.lfs.2005.07.029","article-title":"Hypoglycemic and antioxidant effect of oleuropein in alloxan-diabetic rabbits","volume":"78","author":"Alhamdani","year":"2006","journal-title":"Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.jep.2014.03.070","article-title":"Inhibition of Myeloperoxidase Activity by the Alkaloids of Peganum harmala L. (Zygophyllaceae)","volume":"154","author":"Bensalem","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Prudhomme, T., Mulvey, J.F., Young, L.A.J., Mesnard, B., Lo Faro, M.L., Ogbemudia, A.E., Dengu, F., Friend, P.J., Ploeg, R., and Hunter, J.P. (2021). Ischemia-Reperfusion Injuries Assessment During Pancreas Preservation. Int. J. Mol. Sci., 13.","DOI":"10.3390\/ijms22105172"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1080\/713609331","article-title":"The Usefulness of Laboratory Tests in the Early Assessment of Severity of Acute Pancreatitis","volume":"40","author":"Rettally","year":"2003","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1159\/000082796","article-title":"Laboratory Markers of Severe Acute Pancreatitis","volume":"22","author":"Rau","year":"2004","journal-title":"Dig. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12882","DOI":"10.1021\/jf203715m","article-title":"Oleuropein Ameliorates Acute Colitis in Mice","volume":"59","author":"Giner","year":"2011","journal-title":"J. Agric. Food Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.drudis.2013.11.002","article-title":"NF-k\u03b2 Signaling and Chronic Inflammatory Diseases: Exploring the Potential of Natural Products to Drive New Therapeutic Opportunities","volume":"19","author":"Killeen","year":"2013","journal-title":"Drug Discov. Today"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.phrs.2012.10.018","article-title":"Beneficial Effects of Polyphenols on Cardiovascular Disease","volume":"68","author":"Miguel","year":"2013","journal-title":"Pharmacol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.phrs.2011.12.005","article-title":"Preventive and Therapeutic Effects of Oleuropein Against Carbon Tetrachloride-Induced Liver Damage in Mice","volume":"65","author":"Jakovac","year":"2012","journal-title":"Pharmacol. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.clnu.2011.02.004","article-title":"The Effects of Oleuropein Aglycone, an Olive Oil Compound, in a Mouse Model of Carrageenan-Induced Pleurisy","volume":"30","author":"Impellizzeri","year":"2011","journal-title":"Clin. Nutr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1002\/JLB.3MIR1218-497R","article-title":"Location is the Key to Function: HMGB1 in Sepsis and Trauma-Induced Inflammation","volume":"106","author":"Deng","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s12276-022-00736-w","article-title":"The Mechanism of HMGB1 Secretion and Release","volume":"54","author":"Chen","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nature00858","article-title":"Release of Chromatin Protein HMGB1 by Necrotic Cells Triggers Inflammation","volume":"418","author":"Scaffidi","year":"2002","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2543268","DOI":"10.1155\/2016\/2543268","article-title":"The Role of HMGB1 in the Pathogenesis of Type 2 Diabetes","volume":"2016","author":"Wang","year":"2016","journal-title":"J. Diabetes Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Yu, Y., Tang, D., and Kang, R. (2015). Oxidative Stress-Mediated HMGB1 Biology. Front. Physiol., 6.","DOI":"10.3389\/fphys.2015.00093"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1006\/jsre.1997.5151","article-title":"Ischemia\u2013Reperfusion Injury on the Pancreas in Rats: Identification of Acinar Cell Apoptosis","volume":"71","author":"Fujimoto","year":"1997","journal-title":"J. Surg. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1016\/j.ajpath.2019.07.008","article-title":"A New Role for the Spleen: Aggravation of the Systemic Inflammatory Response in Rats with Severe Acute Pancreatitis","volume":"189","author":"Zhou","year":"2019","journal-title":"Am. J. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6066","DOI":"10.3748\/wjg.v13.45.6066","article-title":"Protective Effect of Inducible Nitric Oxide Synthase Inhibitor on Pancreas Transplantation in Rats","volume":"13","author":"Li","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.yjmcc.2006.11.016","article-title":"Acute Doxorubicin Cardiotoxicity is Successfully Treated with the Phytochemical Oleuropein Through Suppression of Oxidative and Nitrosative Stress","volume":"42","author":"Andreadou","year":"2007","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1016\/j.jff.2014.09.001","article-title":"Biological Activities of the Natural Antioxidant Oleuropein: Exceeding the Expectation\u2014A Mini-Review","volume":"18","author":"Hassen","year":"2015","journal-title":"J. Funct. Foods"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Warzecha, Z., Sendur, P., Ceranowicz, P., Cieszkowski, J., Dembi\u0144ski, M., Sendur, R., Bonior, J., Jaworek, J., Ambro\u017cy, T., and Olszanecki, R. (2017). Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia\/Reperfusion-Induced Acute Pancreatitis in Rats. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040882"},{"key":"ref_47","unstructured":"Bancroft, J.D., and Gamble, M. (2008). Theory and Practice of Histological Techniques, Elsevier Health Sciences."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"101798","DOI":"10.1016\/j.jsps.2023.101798","article-title":"Amentoflavone Attenuates Oxidative Stress and Neuroinflammation Induced by Cerebral Ischemia\/Reperfusion in Rats by Targeting HMGB1-Mediated TLR4\/NF-\u03baB Signaling Pathway","volume":"26","author":"Saeedan","year":"2023","journal-title":"Saudi Pharm. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/10171\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:02:04Z","timestamp":1760112124000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/10171"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,22]]},"references-count":48,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms251810171"],"URL":"https:\/\/doi.org\/10.3390\/ijms251810171","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,22]]}}}