{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:43:07Z","timestamp":1790728987242,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T00:00:00Z","timestamp":1666915200000},"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":"Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI)","award":["2022R1A4A10189001"],"award-info":[{"award-number":["2022R1A4A10189001"]}]},{"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":"Ministry of Health &amp; Welfare, Republic of Korea","award":["2022R1A4A10189001"],"award-info":[{"award-number":["2022R1A4A10189001"]}]},{"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":"National Research Foundation of Korea (NRF)","award":["2022R1A4A10189001"],"award-info":[{"award-number":["2022R1A4A10189001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Xuebijing injection (XBJI) (comprising of five herbs) is a widely used traditional Chinese medicine for sepsis treatment. However, the bioactive components of XBJI and the mechanisms responsible for its sepsis-mitigating action have not been experimentally determined. One of the main bioactive compounds in XBJI\u2014benzoylpaeoniflorin (BPF)\u2014inhibits the expressions of key mediators of inflammation such as nuclear factor kappa B (NF-\u03baB), cyclooxygenase-1 (COX-1), and COX-2. However, its effects on sepsis have not been determined yet. Therefore, here, we investigated the immunomodulatory effect of BPF on severely inflamed endothelial cells, THP-1 macrophages, peritoneal macrophages, and mice. Human umbilical vein endothelial cells (HUVECs) and THP-1-macrophages were activated using lipopolysaccharide (LPS) after pretreatment with BPF. Subsequently, changes in the expression profiles of pro-inflammatory molecules including inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-\u03b1, and interleukin (IL)-6 were determined using quantitative real-time polymerase chain reaction (qPCR) and Western blot analysis. Furthermore, we monitored the phosphorylation of NF-kB and mitogen-activated protein kinases (MAPKs) to determine their activation levels. Using the LPS-induced mouse model of sepsis, we studied the effects of BPF on inflammatory cytokine production, pulmonary histopathology, and survival rates. Finally, we evaluated whether BPF protects against cecal ligation and puncture (CLP)-induced sepsis, as it closely mimics human sepsis. BPF pretreatment inhibited LPS-induced increase in mRNA and protein levels of iNOS, TNF-\u03b1, and IL-6 in HUVECs and THP-1-macrophages. It also suppressed LPS-mediated phosphorylation of p65, p38, JNK, and ERK. Mice with LPS-induced-sepsis who were treated with BPF had lower serum levels of IL-6, TNF-\u03b1, IL-1\u03b2, CXCL1, and CXCL2 than the control mice treated with BPF. Histopathology revealed that BPF treatment alleviated LPS-induced lung damage. In addition, in mice given a lethal dose of LPS, BPF treatment showed a dose-dependent improvement in survival rates. BPF treatment dose-dependently inhibited the LPS-induced IL-6, TNF-\u03b1, and CXCL1 production in peritoneal macrophages. BPF treatment also dose-dependently improved the survival rates in mice with CLP-induced sepsis. These results show that BPF alleviates LPS-stimulated septic conditions and protects mice from CLP-induced sepsis. Our research marks BPF as a potential drug in the treatment of sepsis and various inflammatory diseases.<\/jats:p>","DOI":"10.3390\/ijms232113130","type":"journal-article","created":{"date-parts":[[2022,10,30]],"date-time":"2022-10-30T07:26:50Z","timestamp":1667114810000},"page":"13130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Benzoylpaeoniflorin Activates Anti-Inflammatory Mechanisms to Mitigate Sepsis in Cell-Culture and Mouse Sepsis Models"],"prefix":"10.3390","volume":"23","author":[{"given":"Chaeyeong","family":"Kim","sequence":"first","affiliation":[{"name":"College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunchae","family":"Sim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, 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, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Dickson, K., and Lehmann, C. (2019). Inflammatory Response to Different Toxins in Experimental Sepsis Models. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184341"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1089\/sur.2017.298","article-title":"Multiple Organ Dysfunction: The Defining Syndrome of Sepsis","volume":"19","author":"Ziesmann","year":"2018","journal-title":"Surg. Infect. Larchmt"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1007\/s12272-012-0901-5","article-title":"Role of high mobility group box 1 in inflammatory disease: Focus on sepsis","volume":"35","author":"Bae","year":"2012","journal-title":"Arch. Pharm. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/nature01320","article-title":"Points of control in inflammation","volume":"420","author":"Nathan","year":"2002","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.jpba.2017.09.010","article-title":"Simultaneous determination and pharmacokinetic study of twelve bioactive compounds in rat plasma after intravenous administration of Xuebijing injection by UHPLC-Q-Orbitrap HRMS","volume":"146","author":"Zuo","year":"2017","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.jpba.2017.01.024","article-title":"Rapid determination of 30 bioactive constituents in XueBiJing injection using ultra high performance liquid chromatography-high resolution hybrid quadrupole-orbitrap mass spectrometry coupled with principal component analysis","volume":"137","author":"Zuo","year":"2017","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"949254","DOI":"10.1155\/2014\/949254","article-title":"Treatment effects of xuebijing injection in severe septic patients with disseminated intravascular coagulation","volume":"2014","author":"Yin","year":"2014","journal-title":"Evid. Based Complement Alternat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s13063-016-1282-8","article-title":"Xuebijing injection in the treatment of severe pneumonia: Study protocol for a randomized controlled trial","volume":"17","author":"Wang","year":"2016","journal-title":"Trials"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.jep.2013.03.032","article-title":"Identification of NF-kappaB Inhibitors in Xuebijing injection for sepsis treatment based on bioactivity-integrated UPLC-Q\/TOF","volume":"147","author":"Jiang","year":"2013","journal-title":"J. Ethnopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2029134","DOI":"10.1155\/2020\/2029134","article-title":"Evaluation of Anti-Inflammatory Components of Guizhi Fuling Capsule, an Ancient Chinese Herbal Formula, in Human Umbilical Vein Endothelial Cells","volume":"2020","author":"Zheng","year":"2020","journal-title":"Evid Based Complement Alternat. Med."},{"key":"ref_12","first-page":"825","article-title":"Anti-anaphylactic potential of benzoylpaeoniflorin through inhibiting HDC and MAPKs from Paeonia lactiflora","volume":"19","author":"Zhong","year":"2021","journal-title":"Chin. J. Nat. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/1756-8722-6-61","article-title":"An evolving new paradigm: Endothelial cells\u2014Conditional innate immune cells","volume":"6","author":"Mai","year":"2013","journal-title":"J. Hematol. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"165974","DOI":"10.1155\/2013\/165974","article-title":"Cytokines in sepsis: Potent immunoregulators and potential therapeutic targets\u2014An updated view","volume":"2013","author":"Schulte","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nprot.2008.214","article-title":"Immunodesign of experimental sepsis by cecal ligation and puncture","volume":"4","author":"Rittirsch","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1055\/s-2004-815483","article-title":"Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules","volume":"70","author":"Calixto","year":"2004","journal-title":"Planta Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1854","DOI":"10.3748\/wjg.v10.i13.1854","article-title":"Theory of traditional Chinese medicine and therapeutic method of diseases","volume":"10","author":"Lu","year":"2004","journal-title":"World J. Gastroenterol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1111\/j.1582-4934.2009.00811.x","article-title":"Leukocyte-endothelial interactions in inflammation","volume":"13","author":"Langer","year":"2009","journal-title":"J. Cell Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1189\/jlb.0607373","article-title":"Inflammation, endothelium, and coagulation in sepsis","volume":"83","author":"Schouten","year":"2008","journal-title":"J. Leukoc. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4309","DOI":"10.1016\/S0040-4020(01)88953-5","article-title":"Chemical studies on the oriental plant drugs\u2014XXXIII: The absolute structures of paeoniflorin, albiflorin, oxypaeoniflorin and benzoylpaeoniflorin isolated from Chinese paeony root","volume":"28","author":"Kaneda","year":"1972","journal-title":"Tetrahedron"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"107452","DOI":"10.1016\/j.pharmthera.2019.107452","article-title":"Anti-inflammatory and immunoregulatory effects of paeoniflorin and total glucosides of paeony","volume":"207","author":"Zhang","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kany, S., Vollrath, J.T., and Relja, B. (2019). Cytokines in Inflammatory Disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20236008"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7204","DOI":"10.18632\/oncotarget.23208","article-title":"Inflammatory responses and inflammation-associated diseases in organs","volume":"9","author":"Chen","year":"2018","journal-title":"Oncotarget"},{"key":"ref_24","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":"ref_25","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1159\/000355888","article-title":"Sepsis-Induced Potentiation of Peritoneal Macrophage Migration Is Mitigated by Programmed Cell Death Receptor-1 Gene Deficiency","volume":"6","author":"Ayala","year":"2014","journal-title":"J. Innate Immun."},{"key":"ref_26","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_27","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_28","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1160\/TH08-02-0127","article-title":"Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand","volume":"100","author":"Bae","year":"2008","journal-title":"Thromb. Haemost."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.fct.2012.02.026","article-title":"Anti-inflammatory activities of oleanolic acid on HMGB1 activated HUVECs","volume":"50","author":"Yang","year":"2012","journal-title":"Food Chem. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"214","DOI":"10.5483\/BMBRep.2016.49.4.220","article-title":"Anti-septic effects of dabrafenib on HMGB1-mediated inflammatory responses","volume":"49","author":"Jung","year":"2016","journal-title":"BMB Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12257-019-0382-1","article-title":"Inhibitory Functions of Novel Compounds from Dioscorea batatas Decne Peel on HMGB1-mediated Septic Responses","volume":"25","author":"Jeong","year":"2020","journal-title":"Biotechnol. Bioprocess Eng."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1007\/s12257-020-0126-2","article-title":"Novel Herbal Medicine C-KOK Suppresses the Inflammatory Gene iNOS via the Inhibition of p-STAT-1 and NF-\u03baB","volume":"25","author":"Lee","year":"2020","journal-title":"Biotechnol. Bioprocess Eng."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1007\/s12257-020-0294-0","article-title":"Inhibitory Activities of Ononin on Particulate Matter-induced Oxidative Stress","volume":"26","author":"Lee","year":"2021","journal-title":"Biotechnol. Bioprocess Eng."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1007\/s12257-021-0050-0","article-title":"Suppressive Activities of Fisetin on Particulate Matter-induced Oxidative Stress","volume":"26","author":"Sim","year":"2021","journal-title":"Biotechnol. Bioprocess Eng."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13130\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:05:09Z","timestamp":1760144709000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13130"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,28]]},"references-count":34,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232113130"],"URL":"https:\/\/doi.org\/10.3390\/ijms232113130","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,28]]}}}