{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:51:24Z","timestamp":1790790684220,"version":"4.1.0"},"reference-count":61,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T00:00:00Z","timestamp":1677196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The intestinal barrier is the main contributor to gut homeostasis. Perturbations of the intestinal epithelium or supporting factors can lead to the development of intestinal hyperpermeability, termed \u201cleaky gut\u201d. A leaky gut is characterized by loss of epithelial integrity and reduced function of the gut barrier, and is associated with prolonged use of Non-Steroidal Anti-Inflammatories. The harmful effect of NSAIDs on intestinal and gastric epithelial integrity is considered an adverse effect that is common to all drugs belonging to this class, and it is strictly dependent on NSAID properties to inhibit cyclo-oxygenase enzymes. However, different factors may affect the specific tolerability profile of different members of the same class. The present study aims to compare the effects of distinct classes of NSAIDs, such as ketoprofen (K), Ibuprofen (IBU), and their corresponding lysine (Lys) and, only for ibuprofen, arginine (Arg) salts, using an in vitro model of leaky gut. The results obtained showed inflammatory-induced oxidative stress responses, and related overloads of the ubiquitin-proteasome system (UPS) accompanied by protein oxidation and morphological changes to the intestinal barrier, many of these effects being counteracted by ketoprofen and ketoprofen lysin salt. In addition, this study reports for the first time a specific effect of R-Ketoprofen on the NFkB pathway that sheds new light on previously reported COX-independent effects, and that may account for the observed unexpected protective effect of K on stress-induced damage on the IEB.<\/jats:p>","DOI":"10.3390\/cells12050728","type":"journal-article","created":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T04:05:40Z","timestamp":1677470740000},"page":"728","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Differential Effects of Nonsteroidal Anti-Inflammatory Drugs in an In Vitro Model of Human Leaky Gut"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3693-840X","authenticated-orcid":false,"given":"Michele","family":"d\u2019Angelo","sequence":"first","affiliation":[{"name":"Dept. of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5959-4443","authenticated-orcid":false,"given":"Laura","family":"Brandolini","sequence":"additional","affiliation":[{"name":"Domp\u00e9 Farmaceutici S.p.A., via Campo di Pile snc, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariano","family":"Catanesi","sequence":"additional","affiliation":[{"name":"Dept. of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7005-3218","authenticated-orcid":false,"given":"Vanessa","family":"Castelli","sequence":"additional","affiliation":[{"name":"Dept. of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Giorgio","sequence":"additional","affiliation":[{"name":"Domp\u00e9 Farmaceutici S.p.A., via De Amicis 95, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0261-3148","authenticated-orcid":false,"given":"Margherita","family":"Alfonsetti","sequence":"additional","affiliation":[{"name":"Dept. of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Tomassetti","sequence":"additional","affiliation":[{"name":"Domp\u00e9 Farmaceutici S.p.A., via De Amicis 95, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3749-1176","authenticated-orcid":false,"given":"Mara","family":"Zippoli","sequence":"additional","affiliation":[{"name":"Domp\u00e9 Farmaceutici S.p.A., via De Amicis 95, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6740-7724","authenticated-orcid":false,"given":"Elisabetta","family":"Benedetti","sequence":"additional","affiliation":[{"name":"Dept. of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4847-2985","authenticated-orcid":false,"given":"Maria Candida","family":"Cesta","sequence":"additional","affiliation":[{"name":"Domp\u00e9 Farmaceutici S.p.A., via Campo di Pile snc, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandro","family":"Colagioia","sequence":"additional","affiliation":[{"name":"Domp\u00e9 Farmaceutici S.p.A., via Campo di Pile snc, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6436-2399","authenticated-orcid":false,"given":"Pasquale","family":"Cocchiaro","sequence":"additional","affiliation":[{"name":"Domp\u00e9 Farmaceutici S.p.A., via De Amicis 95, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2737-7970","authenticated-orcid":false,"given":"Annamaria","family":"Cimini","sequence":"additional","affiliation":[{"name":"Dept. of Life, Health and Environmental Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"},{"name":"Sbarro Institute for Cancer Research and Molecular Medicine, Dept. of Biology, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0617-0233","authenticated-orcid":false,"given":"Marcello","family":"Allegretti","sequence":"additional","affiliation":[{"name":"Domp\u00e9 Farmaceutici S.p.A., via Campo di Pile snc, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1080\/17474124.2017.1343143","article-title":"The Intestinal Barrier: A Fundamental Role in Health and Disease","volume":"11","author":"Vancamelbeke","year":"2017","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"717925","DOI":"10.3389\/fnut.2021.717925","article-title":"The Role of Intestinal Permeability in Gastrointestinal Disorders and Current Methods of Evaluation","volume":"8","author":"Vanuytsel","year":"2021","journal-title":"Front. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/labinvest.3700050","article-title":"A Porous Defense: The Leaky Epithelial Barrier in Intestinal Disease","volume":"84","author":"Clayburgh","year":"2004","journal-title":"Lab. Investig."},{"key":"ref_4","first-page":"902","article-title":"Normalization of Leaky Gut in Chronic Fatigue Syndrome (CFS) Is Accompanied by a Clinical Improvement: Effects of Age, Duration of Illness and the Translocation of LPS from Gram-Negative Bacteria","volume":"29","author":"Maes","year":"2008","journal-title":"Neuroendocrinol. Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nrgastro.2015.15","article-title":"NAFLD. Leaky Guts: Intestinal Permeability and NASH","volume":"12","author":"Ray","year":"2015","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14788","DOI":"10.1073\/pnas.1909224116","article-title":"Autoimmune Diabetes Mellitus and the Leaky Gut","volume":"116","author":"Peters","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kirby, T.O., and Ochoa-Rep\u00e1raz, J. (2018). The Gut Microbiome in Multiple Sclerosis: A Potential Therapeutic Avenue. Med. Sci., 6.","DOI":"10.3390\/medsci6030069"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1136\/gutjnl-2019-318427","article-title":"Leaky Gut: Mechanisms, Measurement and Clinical Implications in Humans","volume":"68","author":"Camilleri","year":"2019","journal-title":"Gut"},{"key":"ref_9","first-page":"1635","article-title":"Role of Snail Activation in Alcohol-Induced INOS-Mediated Disruption of Intestinal Epithelial Cell Permeability","volume":"35","author":"Forsyth","year":"2011","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.bbr.2017.01.049","article-title":"Drunk Bugs: Chronic Vapour Alcohol Exposure Induces Marked Changes in the Gut Microbiome in Mice","volume":"323","author":"Peterson","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7125","DOI":"10.3168\/jds.2021-21768","article-title":"Induction of Leaky Gut by Repeated Intramuscular Injections of Indomethacin to Preweaning Holstein Calves","volume":"105","author":"Cangiano","year":"2022","journal-title":"J. Dairy Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"818877","DOI":"10.3389\/fphar.2022.818877","article-title":"NSAID-Associated Small Intestinal Injury: An Overview From Animal Model Development to Pathogenesis, Treatment, and Prevention","volume":"13","author":"Zhang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jaci.2009.05.038","article-title":"Intestinal Barrier Function: Molecular Regulation and Disease Pathogenesis","volume":"124","author":"Groschwitz","year":"2009","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1136\/gut.27.11.1292","article-title":"Effect of Non-Steroidal Anti-Inflammatory Drugs and Prostaglandins on the Permeability of the Human Small Intestine","volume":"27","author":"Bjarnason","year":"1986","journal-title":"Gut"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/BF03220020","article-title":"A Comparative Experimental Study of the Effects of Diclofenac and Ketoprofen on the Small-Bowel Mucosa of Canines","volume":"200","author":"Baltoyiannis","year":"2001","journal-title":"Res. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"821","DOI":"10.18433\/J3VW2F","article-title":"Adverse Effects of Nonsteroidal Antiinflammatory Drugs: An Update of Gastrointestinal, Cardiovascular and Renal Complications","volume":"16","author":"Harirforoosh","year":"2014","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1002\/jcp.24809","article-title":"Gastroprotective Effects of L-Lysine Salification of Ketoprofen in Ethanol-Injured Gastric Mucosa","volume":"230","author":"Cimini","year":"2015","journal-title":"J. Cell. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Castelli, V., Catanesi, M., Alfonsetti, M., Laezza, C., Lombardi, F., Cinque, B., Cifone, M.G., Ippoliti, R., Benedetti, E., and Cimini, A. (2021). PPAR\u03b1-Selective Antagonist GW6471 Inhibits Cell Growth in Breast Cancer Stem Cells Inducing Energy Imbalance and Metabolic Stress. Biomedicines, 9.","DOI":"10.3390\/biomedicines9020127"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Catanesi, M., Brandolini, L., d\u2019Angelo, M., Tupone, M.G., Benedetti, E., Alfonsetti, M., Quintiliani, M., Fratelli, M., Iaconis, D., and Cimini, A. (2021). S-Carboxymethyl Cysteine Protects against Oxidative Stress and Mitochondrial Impairment in a Parkinson\u2019s Disease In Vitro Model. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101467"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"18337","DOI":"10.1038\/s41598-020-75394-x","article-title":"NSAIDs-Dependent Adaption of the Mitochondria-Proteasome System in Immortalized Human Cardiomyocytes","volume":"10","author":"Brandolini","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16820","DOI":"10.1021\/acs.jmedchem.1c01647","article-title":"Discovery of Novel TRPM8 Blockers Suitable for the Treatment of Somatic and Ocular Painful Conditions: A Journey through p Ka and LogD Modulation","volume":"64","author":"Bianchini","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Aramini, A., Bianchini, G., Lillini, S., Bordignon, S., Tomassetti, M., Novelli, R., Mattioli, S., Lvova, L., Paolesse, R., and Chierotti, M.R. (2021). Unexpected Salt\/Cocrystal Polymorphism of the Ketoprofen\u2013Lysine System: Discovery of a New Ketoprofen\u2013l-Lysine Salt Polymorph with Different Physicochemical and Pharmacokinetic Properties. Pharmaceuticals, 14.","DOI":"10.3390\/ph14060555"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7563","DOI":"10.1073\/pnas.96.13.7563","article-title":"Nonsteroid Drug Selectivities for Cyclo-Oxygenase-1 Rather than Cyclo-Oxygenase-2 Are Associated with Human Gastrointestinal Toxicity: A Full in Vitro Analysis","volume":"96","author":"Warner","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0002-9343(98)00091-6","article-title":"Cyclooxygenase-1 and Cyclooxygenase-2 Selectivity of Widely Used Nonsteroidal Anti-Inflammatory Drugs","volume":"104","author":"Cryer","year":"1998","journal-title":"Am. J. Med."},{"key":"ref_25","first-page":"172","article-title":"Pain and Ketoprofen: What Is Its Role in Clinical Practice?","volume":"62","author":"Atzeni","year":"2011","journal-title":"Reumatismo"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/SHK.0b013e31815abe80","article-title":"Acute alcohol intoxication potentiates neutrophil-mediated intestinal tissue damage after burn injury","volume":"29","author":"Li","year":"2008","journal-title":"Shock"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1097\/BCR.0b013e3182223c9e","article-title":"Inflammatory Response in Multiple Organs in a Mouse Model of Acute Alcohol Intoxication and Burn Injury","volume":"32","author":"Li","year":"2011","journal-title":"J. Burn Care Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"495","DOI":"10.2174\/1566524020666201026162343","article-title":"Critical Role of NF\u03baB in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Widespread Key Regulator","volume":"21","author":"Franceschetti","year":"2021","journal-title":"CMM"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/978-981-13-9367-9_10","article-title":"NF-\u039aB, I\u03baB, and IKK: Integral Components of Immune System Signaling","volume":"1172","author":"Mulero","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1038\/emboj.2008.73","article-title":"NF-\u039aB Dictates the Degradation Pathway of I\u03baB\u03b1","volume":"27","author":"Mathes","year":"2008","journal-title":"EMBO J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1172\/JCI7145","article-title":"A Novel Therapy for Colitis Utilizing PPAR-\u03b3 Ligands to Inhibit the Epithelial Inflammatory Response","volume":"104","author":"Su","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"36703","DOI":"10.1074\/jbc.M004045200","article-title":"Induction of I\u03baB\u03b1 Expression as a Mechanism Contributing to the Anti-Inflammatory Activities of Peroxisome Proliferator-Activated Receptor-\u03b1 Activators","volume":"275","author":"Gervois","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1080\/07388551.2017.1375890","article-title":"Recent Advances in Protein Engineering and Biotechnological Applications of Glutathione Transferases","volume":"38","author":"Perperopoulou","year":"2018","journal-title":"Crit. Rev. Biotechnol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"165","DOI":"10.3109\/03602532.2011.558092","article-title":"Interactions of Glutathione Transferases with 4-Hydroxynonenal","volume":"43","author":"Balogh","year":"2011","journal-title":"Drug Metab. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s002329900072","article-title":"Na+-Independent Lysine Transport in Human Intestinal Caco-2 Cells","volume":"151","author":"Thwaites","year":"1996","journal-title":"J. Membr. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1093\/jn\/127.6.1183","article-title":"The Efflux of Lysine from the Basolateral Membrane of Human Cultured Intestinal Cells (Caco-2) Occurs by Different Mechanisms Depending on the Extracellular Availability of Amino Acids","volume":"127","author":"Ferruzza","year":"1997","journal-title":"J. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/j.1552-4604.1992.tb04643.x","article-title":"Pure Enantiomers of 2-Arylpropionic Acids: Tools in Pain Research and Improved Drugs in Rheumatology","volume":"32","author":"Brune","year":"1992","journal-title":"J. Clin. Pharmacol."},{"key":"ref_38","first-page":"969","article-title":"Differential Contribution of R and S Isomers in Ketoprofen Anti-Inflammatory Activity: Role of Cytokine Modulation","volume":"287","author":"Ghezzi","year":"1998","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"181","DOI":"10.3727\/107156999819565829","article-title":"Analgesic Effect of Ketoprofen Is Mainly Associated to Its R -Enantiomer: Role of Cytokine Modulation","volume":"4","author":"Bertini","year":"1999","journal-title":"Analgesia"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/BF00342469","article-title":"Non-Steroidal Anti-Inflammatory Drug-Induced Colitis","volume":"11","author":"Faucheron","year":"1996","journal-title":"Int. J. Colorectal Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5073","DOI":"10.2174\/1381612821666150915105738","article-title":"Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Induced Dyspepsia","volume":"21","author":"Yap","year":"2015","journal-title":"CPD"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6704","DOI":"10.3748\/wjg.14.6704","article-title":"Endoscopic and Histopathological Evaluation of Acute Gastric Injury in High-Dose Acetaminophen and Nonsteroidal Anti-Inflammatory Drug Ingestion with Suicidal Intent","volume":"14","author":"Soylu","year":"2008","journal-title":"WJG"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"131","DOI":"10.7861\/clinmed.2021-0039","article-title":"Non-Steroidal Anti-Inflammatory Drugs and the Gastrointestinal Tract","volume":"21","author":"Tai","year":"2021","journal-title":"Clin. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/nrm.2016.80","article-title":"Tight Junctions: From Simple Barriers to Multifunctional Molecular Gates","volume":"17","author":"Zihni","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e1187325","DOI":"10.1080\/21688370.2016.1187325","article-title":"Indomethacin Induces Increase in Gastric Epithelial Tight Junction Permeability via Redistribution of Occludin and Activation of P38 MAPK in MKN-28 Cells","volume":"4","author":"Blikslager","year":"2016","journal-title":"Tissue Barriers"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Stolfi, C., Maresca, C., Monteleone, G., and Laudisi, F. (2022). Implication of Intestinal Barrier Dysfunction in Gut Dysbiosis and Diseases. Biomedicines, 10.","DOI":"10.3390\/biomedicines10020289"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Usuda, H., Okamoto, T., and Wada, K. (2021). Leaky Gut: Effect of Dietary Fiber and Fats on Microbiome and Intestinal Barrier. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147613"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Elamin, E., Masclee, A., Troost, F., Pieters, H.-J., Keszthelyi, D., Aleksa, K., Dekker, J., and Jonkers, D. (2014). Ethanol Impairs Intestinal Barrier Function in Humans through Mitogen Activated Protein Kinase Signaling: A Combined In Vivo and In Vitro Approach. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107421"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.mrfmmm.2009.09.009","article-title":"Role of PPAR-Gamma in Inflammation. Prospects for Therapeutic Intervention by Food Components","volume":"690","author":"Martin","year":"2010","journal-title":"Mutat. Res. Fundam. Mol. Mech. Mutagen."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"641087","DOI":"10.1155\/2012\/641087","article-title":"PPAR\u03b3 and Oxidative Stress: Con(\u03b2) Catenating NRF2 and FOXO","volume":"2012","author":"Polvani","year":"2012","journal-title":"PPAR Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u039aB Signaling in Inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/j.1552-4604.1996.tb05040.x","article-title":"Stereoselective Inhibition of Inducible Cyclooxygenase by Chiral Nonsteroidal Antiinflammatory Drugs","volume":"36","author":"Carabaza","year":"1996","journal-title":"J. Clin. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"19S","DOI":"10.1002\/j.1552-4604.1998.tb04413.x","article-title":"Clinical Endoscopic Evaluation of the Gastroduodenal Tolerance to (R)-Ketoprofen, (R)-Flurbiprofen, Racemic Ketoprofen, and Paracetamol: A Randomized, Single-Blind, Placebo-Controlled Trial","volume":"38","author":"Jerussi","year":"1998","journal-title":"J. Clin. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1126\/science.8052854","article-title":"Inhibition of NF-\u039aB by Sodium Salicylate and Aspirin","volume":"265","author":"Kopp","year":"1994","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/jcb.240570214","article-title":"Suppression of NF\u03baB Activation and NF\u03baB-Dependent Gene Expression by Tepoxalin, a Dual Inhibitor of Cyclooxygenase and 5-Lipoxygenase","volume":"57","author":"Kazmi","year":"1995","journal-title":"J. Cell. Biochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/sj.bjp.0701652","article-title":"Modulation of Transcription Factor NF-\u039aB by Enantiomers of the Nonsteroidal Drug Ibuprofen: Inhibition of NF-\u039aB by R-Ibuprofen","volume":"123","author":"Scheuren","year":"1998","journal-title":"Br. J. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1002\/jez.10165","article-title":"Effects of Prenyl Pyrophosphates on the Binding of S-Ras Proteins with KSR","volume":"293","author":"Chen","year":"2002","journal-title":"J. Exp. Zool."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"9247","DOI":"10.1038\/sj.onc.1208169","article-title":"Nonsteroidal Anti-Inflammatory Agents Differ in Their Ability to Suppress NF-\u039aB Activation, Inhibition of Expression of Cyclooxygenase-2 and Cyclin D1, and Abrogation of Tumor Cell Proliferation","volume":"23","author":"Takada","year":"2004","journal-title":"Oncogene"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1002\/art.38328","article-title":"Activation of Spinal NF-\u039aB\/P65 Contributes to Peripheral Inflammation and Hyperalgesia in Rat Adjuvant-Induced Arthritis: Spinal NF-\u039aB\/P65 in Rat Arthritis","volume":"66","author":"Luo","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"174480692090569","DOI":"10.1177\/1744806920905691","article-title":"Spinal NF-KB Upregulation Contributes to Hyperalgesia in a Rat Model of Advanced Osteoarthritis","volume":"16","author":"Li","year":"2020","journal-title":"Mol. Pain"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1002\/glia.24181","article-title":"NF\u03baB-signaling Promotes Glial Reactivity and Suppresses M\u00fcller Glia-mediated Neuron Regeneration in the Mammalian Retina","volume":"70","author":"Palazzo","year":"2022","journal-title":"Glia"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/5\/728\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:41:42Z","timestamp":1760121702000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/5\/728"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,24]]},"references-count":61,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["cells12050728"],"URL":"https:\/\/doi.org\/10.3390\/cells12050728","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,24]]}}}