{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T10:11:30Z","timestamp":1769249490122,"version":"3.49.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T00:00:00Z","timestamp":1646870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Septicemia is a severe inflammatory response caused by the invasion of foreign pathogens. Severe sepsis-induced shock and multiple organ failure are the two main causes of patient death. The overexpression of many proinflammatory cytokines, such as TNF-\u03b1, IL-1\u03b2, and IL-6, is closely related to severe sepsis. Although the treatment of sepsis has been subject to many major breakthroughs of late, the treatment of patients with septic shock is still accompanied by a high mortality rate. In our previous research, we used computer simulations to design the multifunctional peptide KCF18 that can bind to TNF-\u03b1, IL-1\u03b2, and IL-6 based on the binding regions of receptors and proinflammatory cytokines. In this study, proinflammatory cytokines were used to stimulate human monocytes to trigger an inflammatory response, and the anti-inflammatory ability of the multifunctional KCF18 peptide was further investigated. Cell experiments demonstrated that KCF18 significantly reduced the binding of proinflammatory cytokines to their cognate receptors and inhibited the mRNA and protein expressions of TNF-\u03b1, IL-1\u03b2, and IL-6. It could also reduce the expression of reactive oxygen species induced by cytokines in human monocytes. KCF18 could effectively decrease the p65 nucleus translocation induced by cytokines, and a mice endotoxemia experiment demonstrated that KCF18 could reduce the expression of IL-6 and the increase of white blood cells in the blood stimulated by lipopolysaccharides. According to our study of tissue sections, KCF18 alleviated liver inflammation. By reducing the release of cytokines in plasma and directly affecting vascular cells, KCF18 is believed to significantly reduce the risk of vascular inflammation.<\/jats:p>","DOI":"10.3389\/fphar.2022.853818","type":"journal-article","created":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T12:57:04Z","timestamp":1646917024000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["A Multitarget Therapeutic Peptide Derived From Cytokine Receptors Based on in Silico Analysis Alleviates Cytokine-Stimulated Inflammation"],"prefix":"10.3389","volume":"13","author":[{"given":"Chun-Chun","family":"Chang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shih-Yi","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao-Hsiang","family":"Tsao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsin-Ting","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing-Yan","family":"Lai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao-Jen","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinn-Jong","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1942","DOI":"10.1128\/iai.68.4.1942-1945.2000","article-title":"Predictive Value of Nuclear Factor kappaB Activity and Plasma Cytokine Levels in Patients with Sepsis","volume":"68","author":"Arnalich","year":"2000","journal-title":"Infect. Immun."},{"key":"B2","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1111\/j.1398-9995.1999.tb04413.x","article-title":"Effect of Intranasal Corticosteroids on Release of Cytokines and Inflammatory Mediators","author":"Bachert","year":"1999","journal-title":"Allergy"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1056\/NEJM199606273342607","article-title":"The Tumor Necrosis Factor Ligand and Receptor Families","volume":"334","author":"Bazzoni","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"9582430","DOI":"10.1155\/2016\/9582430","article-title":"Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis","volume":"2016","author":"Bobryshev","year":"2016","journal-title":"Biomed. Res. Int."},{"key":"B5","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1172\/JCI119648","article-title":"Role of NFkappaB in the Mortality of Sepsis","volume":"100","author":"B\u00f6hrer","year":"1997","journal-title":"J. Clin. Invest."},{"key":"B6","doi-asserted-by":"publisher","first-page":"R49","DOI":"10.1186\/cc5783","article-title":"Cytokine Profiles as Markers of Disease Severity in Sepsis: a Multiplex Analysis","volume":"11","author":"Bozza","year":"2007","journal-title":"Crit. Care"},{"key":"B7","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1152\/physiologyonline.2000.15.6.298","article-title":"Inflammatory Cytokines in Nonpathological States","volume":"15","author":"Cannon","year":"2000","journal-title":"News Physiol. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"280","DOI":"10.3390\/ph13100280","article-title":"Peptide-Based TNF-Alpha-Binding Decoy Therapy Mitigates Lipopolysaccharide-Induced Liver Injury in Mice","volume":"13","author":"Chang","year":"2020","journal-title":"Pharmaceuticals (Basel)"},{"key":"B9","doi-asserted-by":"publisher","first-page":"35756","DOI":"10.1074\/jbc.M112.397703","article-title":"Inhibition of Neddylation Represses Lipopolysaccharide-Induced Proinflammatory Cytokine Production in Macrophage Cells","volume":"287","author":"Chang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B10","first-page":"669","article-title":"Role of Cytokines as a Double-Edged Sword in Sepsis","volume":"27","author":"Chaudhry","year":"2013","journal-title":"In Vivo"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1650","DOI":"10.1097\/00003246-199810000-00016","article-title":"Effect of a Chimeric Antibody to Tumor Necrosis Factor-Alpha on Cytokine and Physiologic Responses in Patients with Severe Sepsis-Aa Randomized, Clinical Trial","volume":"26","author":"Clark","year":"1998","journal-title":"Crit. Care Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1253\/circj.CJ-15-0464","article-title":"Reactive Oxygen Species in Endothelial Function - from Disease to Adaptation -","volume":"79","author":"Craige","year":"2015","journal-title":"Circ. J."},{"key":"B13","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1080\/10715760600669612","article-title":"Role of Oxidative Stress in Experimental Sepsis and Multisystem Organ Dysfunction","volume":"40","author":"Crimi","year":"2006","journal-title":"Free Radic. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1128\/CVI.00636-12","article-title":"Targeting the \"cytokine Storm\" for Therapeutic Benefit","volume":"20","author":"D'elia","year":"2013","journal-title":"Clin. Vaccin. Immunol"},{"key":"B15","first-page":"794","article-title":"Free Radicals and Antioxidants in Human Health: Current Status and Future Prospects","volume":"52","author":"Devasagayam","year":"2004","journal-title":"J. Assoc. Physicians India"},{"key":"B16","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1378\/chest.118.2.503","article-title":"Proinflammatory Cytokines","volume":"118","author":"Dinarello","year":"2000","journal-title":"Chest"},{"key":"B17","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.drudis.2014.10.003","article-title":"Peptide Therapeutics: Current Status and Future Directions","volume":"20","author":"Fosgerau","year":"2015","journal-title":"Drug Discov. Today"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1164\/arrd.1987.135.6.1345","article-title":"Sialic Acid Mediates the Initial Binding of Positively Charged Inorganic Particles to Alveolar Macrophage Membranes","volume":"135","author":"Gallagher","year":"1987","journal-title":"Am. Rev. Respir. Dis."},{"key":"B19","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1086\/315214","article-title":"Pro- versus Anti-inflammatory Cytokine Profile in Patients with Severe Sepsis: a Marker for Prognosis and Future Therapeutic Options","volume":"181","author":"Gogos","year":"2000","journal-title":"J. Infect. Dis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3817","DOI":"10.1128\/AAC.00534-10","article-title":"New Antiseptic Peptides to Protect against Endotoxin-Mediated Shock","volume":"54","author":"Gutsmann","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"B21","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.intimp.2015.10.027","article-title":"Protective Effects of Polydatin on Lipopolysaccharide-Induced Acute Lung Injury through TLR4-MyD88-NF-\u039ab Pathway","volume":"29","author":"Jiang","year":"2015","journal-title":"Int. Immunopharmacol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2317","DOI":"10.1038\/s41598-018-36492-z","article-title":"A Potential Peptide Derived from Cytokine Receptors Can Bind Proinflammatory Cytokines as a Therapeutic Strategy for Anti-inflammation","volume":"9","author":"Jiang","year":"2019","journal-title":"Sci. Rep."},{"key":"B23","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1002\/jcp.21068","article-title":"Cytokine Profile of Human Adipose-Derived Stem Cells: Expression of Angiogenic, Hematopoietic, and Pro-inflammatory Factors","volume":"212","author":"Kilroy","year":"2007","journal-title":"J. Cel Physiol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.addr.2016.06.002","article-title":"Peptide-based Strategies for Enhanced Cell Uptake, Transcellular Transport, and Circulation: Mechanisms and Challenges","author":"Komin","year":"2017","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B25","doi-asserted-by":"publisher","first-page":"74","DOI":"10.4103\/0972-5229.56052","article-title":"Cytokine Profile in Elderly Patients with Sepsis","volume":"13","author":"Kumar","year":"2009","journal-title":"Indian J. Crit. Care Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1016\/j.freeradbiomed.2011.11.002","article-title":"Role of Reactive Oxygen and Nitrogen Species in the Vascular Responses to Inflammation","volume":"52","author":"Kvietys","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"B27","doi-asserted-by":"crossref","first-page":"a001651","DOI":"10.1101\/cshperspect.a001651","article-title":"The Nuclear Factor NF-kappaB Pathway in Inflammation","volume":"1","author":"Lawrence","year":"2009","journal-title":"Cold Spring Harb Perspect. Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.cardiores.2005.09.009","article-title":"Oxidized LDL, a Critical Factor in Atherogenesis","volume":"68","author":"Li","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"L622","DOI":"10.1152\/ajplung.00477.2005","article-title":"NF-kappa B Activation as a Pathological Mechanism of Septic Shock and Inflammation","volume":"290","author":"Liu","year":"2006","journal-title":"Am. J. Physiol. Lung Cel Mol Physiol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1038\/nbt0303-255","article-title":"Proteomic Analysis of post-translational Modifications","volume":"21","author":"Mann","year":"2003","journal-title":"Nat. Biotechnol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.freeradbiomed.2007.03.034","article-title":"Trends in Oxidative Aging Theories","volume":"43","author":"Muller","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"62","DOI":"10.3389\/fchem.2014.00062","article-title":"Current Challenges in Peptide-Based Drug Discovery","volume":"2","author":"Otvos","year":"2014","journal-title":"Front. Chem."},{"key":"B33","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1152\/physrev.00029.2006","article-title":"Nitric Oxide and Peroxynitrite in Health and Disease","volume":"87","author":"Pacher","year":"2007","journal-title":"Physiol. Rev."},{"key":"B34","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1007\/978-1-60327-029-8_24","article-title":"Oxidized Low-Density Lipoprotein","volume":"610","author":"Parthasarathy","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1002\/biof.1150","article-title":"Peroxynitrite, a Potent Macrophage-Derived Oxidizing Cytotoxin to Combat Invading Pathogens","volume":"40","author":"Prolo","year":"2014","journal-title":"Biofactors"},{"key":"B36","doi-asserted-by":"publisher","first-page":"26464","DOI":"10.1074\/jbc.R113.472936","article-title":"Peroxynitrite, a Stealthy Biological Oxidant","volume":"288","author":"Radi","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/s0939-6411(98)00038-1","article-title":"Surface-modified Biodegradable Albumin Nano- and Microspheres. II: Effect of Surface Charges on In Vitro Phagocytosis and Biodistribution in Rats","volume":"46","author":"Roser","year":"1998","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"B38","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.intimp.2016.08.026","article-title":"Potential Therapeutic Targets for Inflammation in Toll-like Receptor 4 (TLR4)-Mediated Signaling Pathways","volume":"40","author":"Roy","year":"2016","journal-title":"Int. Immunopharmacol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"436","DOI":"10.3390\/jpm11050436","article-title":"Simultaneous Inhibition of Three Major Cytokines and its Therapeutic Effects: A Peptide-Based Novel Therapy against Endotoxemia in Mice","volume":"11","author":"Shih","year":"2021","journal-title":"J. Pers Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.neuroscience.2014.03.040","article-title":"Increased Macromolecular Damage Due to Oxidative Stress in the Neocortex and hippocampus of WNIN\/Ob, a Novel Rat Model of Premature Aging","volume":"269","author":"Sinha","year":"2014","journal-title":"Neuroscience"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1093\/infdis\/jis452","article-title":"Host Cytokine Storm Is Associated with Disease Severity of Severe Fever with Thrombocytopenia Syndrome","volume":"206","author":"Sun","year":"2012","journal-title":"J. Infect. Dis."},{"key":"B42","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/nrm3143","article-title":"Ubiquitylation in Apoptosis: a post-translational Modification at the Edge of Life and Death","volume":"12","author":"Vucic","year":"2011","journal-title":"Nat. Rev. Mol. Cel Biol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1038\/nature09973","article-title":"TLR Signalling Augments Macrophage Bactericidal Activity through Mitochondrial ROS","volume":"472","author":"West","year":"2011","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","first-page":"3435","DOI":"10.1016\/j.biomaterials.2011.01.021","article-title":"The Effect of Surface Charge on In Vivo Biodistribution of PEG-Oligocholic Acid Based Micellar Nanoparticles","volume":"32","author":"Xiao","year":"2011","journal-title":"Biomaterials"},{"key":"B45","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1172\/JCI11914","article-title":"Therapeutic Potential of Inhibition of the NF-kappaB Pathway in the Treatment of Inflammation and Cancer","volume":"107","author":"Yamamoto","year":"2001","journal-title":"J. Clin. Invest."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1111\/j.1462-5822.2005.00549.x","article-title":"Antimicrobial Peptides and Endotoxin Inhibit Cytokine and Nitric Oxide Release but Amplify Respiratory Burst Response in Human and Murine Macrophages","volume":"7","author":"Zughaier","year":"2005","journal-title":"Cell Microbiol"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.853818\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,10]],"date-time":"2022-03-10T12:57:08Z","timestamp":1646917028000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.853818\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,10]]},"references-count":46,"alternative-id":["10.3389\/fphar.2022.853818"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.853818","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,10]]},"article-number":"853818"}}