{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T17:27:57Z","timestamp":1781630877642,"version":"3.54.5"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T00:00:00Z","timestamp":1682553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI)","award":["HI15C0001"],"award-info":[{"award-number":["HI15C0001"]}]},{"name":"Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI)","award":["2020R1A2C1004131"],"award-info":[{"award-number":["2020R1A2C1004131"]}]},{"name":"Ministry of Health &amp; Welfare, Republic of Korea","award":["HI15C0001"],"award-info":[{"award-number":["HI15C0001"]}]},{"name":"Ministry of Health &amp; Welfare, Republic of Korea","award":["2020R1A2C1004131"],"award-info":[{"award-number":["2020R1A2C1004131"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["HI15C0001"],"award-info":[{"award-number":["HI15C0001"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["2020R1A2C1004131"],"award-info":[{"award-number":["2020R1A2C1004131"]}]},{"name":"Korean government (MSIT)","award":["HI15C0001"],"award-info":[{"award-number":["HI15C0001"]}]},{"name":"Korean government (MSIT)","award":["2020R1A2C1004131"],"award-info":[{"award-number":["2020R1A2C1004131"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute lung injury (ALI) is a frequent and challenging aspect of sepsis that currently lacks effective treatments. Procyanidin B2 (PB2) has anti-inflammatory and antioxidant properties. The aim of this study was to determine the effectiveness and mechanism of action of PB2 in treating sepsis-induced ALI using animal experiments. A sepsis-induced ALI mouse model was used by administering lipopolysaccharide (LPS) and then evaluating the levels of inflammatory cytokines and lung injury through measurements of cytokine levels using enzyme-linked immunosorbent assay (ELISA), Western blot and real-time PCR, as well as by the examination of relevant signaling pathways. The animal experiments showed that PB2 protected the lungs from injury caused by LPS and reduced the levels of various inflammatory cytokines in both the serum and lung tissue. Western blot analysis showed that PB2 reduced the expression of TLR4\/NF-\u03baB and increased the expression of PI3K\/Akt, and also inhibited the Hippo and Rho signaling pathways. The results of the study showed that PB2 helps to treat sepsis-induced ALI by controlling cytokine storms and reducing inflammation by altering the expressions of the TLR4\/NF-\u03baB, PI3K\/Akt, Hippo and Rho signaling pathways. This research provides a foundation for the further investigation of PB2\u2019s mechanism and its potential use in treating sepsis.<\/jats:p>","DOI":"10.3390\/ijms24097930","type":"journal-article","created":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T04:30:47Z","timestamp":1682569847000},"page":"7930","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Procyanidin B2 Attenuates Sepsis-Induced Acute Lung Injury via Regulating Hippo\/Rho\/PI3K\/NF-\u03baB Signaling Pathway"],"prefix":"10.3390","volume":"24","author":[{"given":"Go Oun","family":"Kim","sequence":"first","affiliation":[{"name":"College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Ho","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5756-9367","authenticated-orcid":false,"given":"Jong-Sup","family":"Bae","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1093\/cvr\/cvaa070","article-title":"The effects of sepsis on endothelium and clinical implications","volume":"117","author":"Dolmatova","year":"2021","journal-title":"Cardiovasc. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"32","DOI":"10.21037\/atm.2017.12.18","article-title":"New insights into the mechanisms of pulmonary edema in acute lung injury","volume":"6","author":"Herrero","year":"2018","journal-title":"Ann. Trans. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3501373","DOI":"10.1155\/2016\/3501373","article-title":"A Pathophysiologic Approach to Biomarkers in Acute Respiratory Distress Syndrome","volume":"2016","author":"Blondonnet","year":"2016","journal-title":"Dis. Markers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1089\/jir.2019.0085","article-title":"Constitutive Inflammatory Cytokine Storm: A Major Threat to Human Health","volume":"40","author":"Gupta","year":"2020","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"53","DOI":"10.4046\/trd.2016.79.2.53","article-title":"Sepsis and Acute Respiratory Distress Syndrome: Recent Update","volume":"79","author":"Kim","year":"2016","journal-title":"Tuberc. Respir. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3391","DOI":"10.2147\/DDDT.S222296","article-title":"Paclitaxel alleviated sepsis-induced acute lung injury by activating MUC1 and suppressing TLR-4\/NF-kappaB pathway","volume":"13","author":"Wang","year":"2019","journal-title":"Drug. Des. Devel. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1056\/NEJM200103083441001","article-title":"Efficacy and safety of recombinant human activated protein C for severe sepsis","volume":"344","author":"Bernard","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/j.1365-2141.2011.09019.x","article-title":"The withdrawal of Activated Protein C from the use in patients with severe sepsis and DIC [Amendment to the BCSH guideline on disseminated intravascular coagulation]","volume":"157","author":"Thachil","year":"2012","journal-title":"Br. J. Haematol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1056\/NEJMoa1202290","article-title":"Drotrecogin alfa (activated) in adults with septic shock","volume":"366","author":"Ranieri","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1002\/mnfr.201400370","article-title":"Procyanidin B2 inhibits inflammasome-mediated IL-1beta production in lipopolysaccharide-stimulated macrophages","volume":"59","author":"Pinent","year":"2015","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"232836","DOI":"10.1155\/2015\/232836","article-title":"Direct effects of (-)-epicatechin and procyanidin B2 on the respiration of rat heart mitochondria","volume":"2015","author":"Kopustinskiene","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6147345","DOI":"10.1155\/2016\/6147345","article-title":"Critical Role of FoxO1 in Granulosa Cell Apoptosis Caused by Oxidative Stress and Protective Effects of Grape Seed Procyanidin B2","volume":"2016","author":"Zhang","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1039\/C5FO01062D","article-title":"Grape seed procyanidin B2 protects podocytes from high glucose-induced mitochondrial dysfunction and apoptosis via the AMPK-SIRT1-PGC-1alpha axis in vitro","volume":"7","author":"Cai","year":"2016","journal-title":"Food Funct."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1017\/S000711451400347X","article-title":"Grape seed procyanidin B2 ameliorates mitochondrial dysfunction and inhibits apoptosis via the AMP-activated protein kinase-silent mating type information regulation 2 homologue 1-PPARgamma co-activator-1alpha axis in rat mesangial cells under high-dose glucosamine","volume":"113","author":"Bao","year":"2015","journal-title":"Br. J. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.freeradbiomed.2018.08.024","article-title":"Procyanidin B2 ameliorates free fatty acids-induced hepatic steatosis through regulating TFEB-mediated lysosomal pathway and redox state","volume":"126","author":"Su","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s13613-019-0530-y","article-title":"Cytokine removal in human septic shock: Where are we and where are we going?","volume":"9","author":"Honore","year":"2019","journal-title":"Ann. Intensive Care"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1097\/SHK.0b013e318181af2a","article-title":"TLR signaling pathway in patients with sepsis","volume":"30","author":"Salomao","year":"2008","journal-title":"Shock"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Huang, M., Cai, S., and Su, J. (2019). The Pathogenesis of Sepsis and Potential Therapeutic Targets. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215376"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1159\/000315915","article-title":"Endotoxins and other sepsis triggers","volume":"167","author":"Opal","year":"2010","journal-title":"Contrib. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1586\/ers.10.71","article-title":"The value of the lipopolysaccharide-induced acute lung injury model in respiratory medicine","volume":"4","author":"Chen","year":"2010","journal-title":"Expert Rev. Respir. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1097\/01.shk.0000090843.66556.74","article-title":"Lipopolysaccharide dose response in baboons","volume":"20","author":"Haudek","year":"2003","journal-title":"Shock"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s40425-018-0343-9","article-title":"Cytokine release syndrome","volume":"6","author":"Godel","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","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-kappaB pathway","volume":"29","author":"Jiang","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S0006-291X(03)00837-4","article-title":"Gene expression of Toll-like receptors and associated molecules induced by inflammatory stimuli in the primary alveolar macrophage","volume":"305","author":"Oshikawa","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.cell.2010.01.022","article-title":"Pattern recognition receptors and inflammation","volume":"140","author":"Takeuchi","year":"2010","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1007\/s00018-020-03656-y","article-title":"TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling","volume":"78","author":"Ciesielska","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"449","DOI":"10.4049\/jimmunol.172.1.449","article-title":"Modulation of the phosphoinositide 3-kinase pathway alters innate resistance to polymicrobial sepsis","volume":"172","author":"Williams","year":"2004","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nrd2926","article-title":"Targeting the phosphoinositide 3-kinase pathway in cancer","volume":"8","author":"Liu","year":"2009","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.tibs.2005.02.008","article-title":"Signalling by PI3K isoforms: Insights from gene-targeted mice","volume":"30","author":"Vanhaesebroeck","year":"2005","journal-title":"Trends Biochem. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1038\/s41374-020-0404-9","article-title":"PI3K-Akt-mTOR\/PFKFB3 pathway mediated lung fibroblast aerobic glycolysis and collagen synthesis in lipopolysaccharide-induced pulmonary fibrosis","volume":"100","author":"Hu","year":"2020","journal-title":"Lab. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1073\/pnas.1118579109","article-title":"Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine\/threonine kinases PI3K\/Akt","volume":"109","author":"Troutman","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1248\/bpb.30.1617","article-title":"Role of phosphoinositide 3-kinase in innate immunity","volume":"30","author":"Hazeki","year":"2007","journal-title":"Biol. Pharm. Bull."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3559","DOI":"10.4161\/cc.21572","article-title":"Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K","volume":"11","author":"Troutman","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3389\/fonc.2013.00085","article-title":"Role of PI3K-AKT-mTOR and Wnt Signaling Pathways in Transition of G1-S Phase of Cell Cycle in Cancer Cells","volume":"3","author":"Vadlakonda","year":"2013","journal-title":"Front. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/gad.274027.115","article-title":"Mechanisms of Hippo pathway regulation","volume":"30","author":"Meng","year":"2016","journal-title":"Genes Dev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1161\/CIRCRESAHA.118.313143","article-title":"YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6","volume":"123","author":"Lv","year":"2018","journal-title":"Circ. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1146\/annurev.cellbio.21.020604.150721","article-title":"Rho GTPases: Biochemistry and biology","volume":"21","author":"Jaffe","year":"2005","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s12257-019-0096-4","article-title":"Pulmonary protective functions of rare ginsenoside Rg4 on particulate matter-induced inflammatory responses","volume":"24","author":"Lee","year":"2019","journal-title":"Biotechnol. Bioproc. Eng."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/7930\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:24:19Z","timestamp":1760124259000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/7930"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,27]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24097930"],"URL":"https:\/\/doi.org\/10.3390\/ijms24097930","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,27]]}}}