{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T17:13:02Z","timestamp":1782234782290,"version":"3.54.5"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T00:00:00Z","timestamp":1612137600000},"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. Physiol."],"abstract":"<jats:p>Ophiopogonin, including Ophiopogonin A, B, C, D, is an effective active component of traditional Chinese medicine <jats:italic>Ophiopogon japonicus<\/jats:italic> which has a wide range of pharmacological effects such as protecting myocardial ischemia, resisting myocardial infarction, immune regulation, lowering blood glucose, and anti-tumor. However, the functions of ophiopogonin A on hemorrhagic shock (HS)-induced renal injury remain unclear. First, this study constructed an HS rat model and hypoxia HK-2 cell model to assess the effects of ophiopogonin A <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. <jats:italic>In vivo<\/jats:italic>, HE and TUNEL staining show that ophiopogonin A dose-dependently inhibits HS-induced tissue damage and apoptosis. Moreover, ophiopogonin A dose-dependently downregulates the levels of blood urea nitrogen (BUN), creatinine (Cr), KIM-1, NGAL, iNOS, TNF-\u03b1, IL-1\u03b2, and IL-6 in HS rats kidney tissues, and decreases the number of MPO-positive cells. <jats:italic>In vitro<\/jats:italic>, we get similar results that ophiopogonin A dose-dependently improves hypoxia-induced HK-2 cell apoptosis and damage. In addition, ophiopogonin A dose-dependently increases the expression of NF E2-related factor 2 (Nrf2), while knockdown of Nrf2 reverses the functions of ophiopogonin A <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. Furthermore, ophiopogonin A dose-dependently promotes the phosphorylation of ERK in HS kidney tissues and hypoxia-treated HK-2 cells, suggesting that ophiopogonin A functions via the p-ERK\/ERK signaling pathway.<\/jats:p>","DOI":"10.3389\/fphys.2020.619740","type":"journal-article","created":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T05:23:36Z","timestamp":1612157016000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Ophiopogonin A Alleviates Hemorrhagic Shock-Induced Renal Injury via Induction of Nrf2 Expression"],"prefix":"10.3389","volume":"11","author":[{"given":"Xiaoming","family":"Sheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JiaJia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junbo","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingsong","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,1]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","DOI":"10.1186\/1749-8090-6-81","article-title":"Leukotriene biosynthesis inhibition ameliorates acute lung injury following hemorrhagic shock in rats.","volume":"6","author":"Al-Amran","year":"2011","journal-title":"J. Cardiothorac. Surg."},{"key":"B2","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1007\/s00726-016-2367-0","article-title":"C-type natriuretic peptide prevents kidney injury and attenuates oxidative and inflammatory responses in hemorrhagic shock.","volume":"49","author":"Chen","year":"2017","journal-title":"Amino Acids"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2008.12.014","article-title":"Effects of synthetic colloids on oxidative stress and inflammatory response in hemorrhagic shock: comparison of hydroxyethyl starch 130\/0.4, hydroxyethyl starch 200\/0.5, and succinylated gelatin.","volume":"17","author":"Chen","year":"2013","journal-title":"Crit. Care"},{"key":"B4","doi-asserted-by":"publisher","first-page":"237","DOI":"10.3892\/etm.2015.2446","article-title":"Cystatin C is a moderate predictor of acute kidney injury in the early stage of traumatic hemorrhagic shock.","volume":"10","author":"Chen","year":"2015","journal-title":"Exp. Ther. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1007\/s00268-007-9087-2","article-title":"Epidemiology of urban trauma deaths: a comprehensive reassessment 10 years later.","volume":"31","author":"Cothren","year":"2007","journal-title":"World J. Surg."},{"key":"B6","doi-asserted-by":"publisher","first-page":"295","DOI":"10.3109\/08941939.2010.497239","article-title":"Pyrrolidine dithiocarbamate modulates HSP70, iNOS, and apoptosis during hemorrhagic shock resuscitation in rats.","volume":"23","author":"Cotogni","year":"2010","journal-title":"J. Invest. Surg."},{"key":"B7","doi-asserted-by":"publisher","first-page":"5988","DOI":"10.3748\/wjg.v19.i36.5988","article-title":"Electroacupuncture improves gut barrier dysfunction in prolonged hemorrhagic shock rats through vagus anti-inflammatory mechanism.","volume":"19","author":"Du","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2044","DOI":"10.1200\/jco.2017.76.5966","article-title":"Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2\/neu.","volume":"36","author":"Fader","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1124\/jpet.107.119792","article-title":"Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney.","volume":"322","author":"Faubel","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B10","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/S0140-6736(17)32152-9","article-title":"Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016.","volume":"390","year":"2017","journal-title":"Lancet"},{"key":"B11","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1042\/cs20090452","article-title":"Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition.","volume":"118","author":"Glaros","year":"2010","journal-title":"Clin. Sci. (Lond)"},{"key":"B12","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/j.ejphar.2013.07.036","article-title":"Ruscogenin reduces cerebral ischemic injury via NF-kappaB-mediated inflammatory pathway in the mouse model of experimental stroke.","volume":"714","author":"Guan","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1097\/ta.0000000000002624","article-title":"Effect of fibrinogen concentrate administration on early mortality in traumatic hemorrhagic shock: a propensity score analysis.","volume":"88","author":"Hamada","year":"2020","journal-title":"J. Trauma Acute Care Surg."},{"key":"B14","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1016\/j.jacc.2017.04.041","article-title":"Traditional Chinese medicine for cardiovascular disease: evidence and potential mechanisms.","volume":"69","author":"Hao","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"B15","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1097\/MCC.0000000000000463","article-title":"Acute kidney injury in trauma patients.","volume":"23","author":"Harrois","year":"2017","journal-title":"Curr. Opin. Crit. Care"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1016\/j.jhep.2020.01.023","article-title":"NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly.","volume":"72","author":"He","year":"2020","journal-title":"J. Hepatol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.ccell.2015.07.001","article-title":"Small molecule inhibition of ERK dimerization prevents tumorigenesis by RAS-ERK pathway oncogenes.","volume":"28","author":"Herrero","year":"2015","journal-title":"Cancer Cell"},{"key":"B18","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1007\/s00134-019-05919-0","article-title":"Identification and validation of biomarkers of persistent acute kidney injury: the RUBY study.","volume":"46","author":"Hoste","year":"2020","journal-title":"Intensive Care Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1016\/j.jss.2013.03.007","article-title":"BML-111 attenuates hemorrhagic shock-induced acute lung injury through inhibiting activation of mitogen-activated protein kinase pathway in rats.","volume":"183","author":"Li","year":"2013","journal-title":"J. Surg. Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1016\/S1474-4422(19)30224-8","article-title":"Parkinson\u2019s disease in traditional Chinese medicine.","volume":"18","author":"Li","year":"2019","journal-title":"Lancet Neurol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"258","DOI":"10.2119\/molmed.2017.00013","article-title":"miR-210 protects renal cell against hypoxia-induced apoptosis by targeting HIF-1 alpha.","volume":"23","author":"Liu","year":"2017","journal-title":"Mol. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/ki.2009.157","article-title":"Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice.","volume":"76","author":"Liu","year":"2009","journal-title":"Kidney Int."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aba3613","article-title":"Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease.","volume":"12","author":"Lu","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"B24","first-page":"439","article-title":"Ophiopogonin D\u2019 induces RIPK1dependent necroptosis in androgendependent LNCaP prostate cancer cells.","volume":"56","author":"Lu","year":"2020","journal-title":"Int. J. Oncol."},{"key":"B25","doi-asserted-by":"crossref","first-page":"e874","DOI":"10.1016\/j.jogc.2018.10.004","article-title":"No. 115-hemorrhagic shock.","volume":"40","author":"Martel","year":"2018","journal-title":"J. Obstet. Gynaecol. Can."},{"key":"B26","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1097\/ta.0000000000001198","article-title":"Effect of time to operation on mortality for hypotensive patients with gunshot wounds to the torso: the golden 10 minutes.","volume":"81","author":"Meizoso","year":"2016","journal-title":"J. Trauma Acute Care Surg."},{"key":"B27","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1097\/shk.0000000000000219","article-title":"Long-term outcomes of patients receiving a massive transfusion after trauma.","volume":"42","author":"Mitra","year":"2014","journal-title":"Shock"},{"key":"B28","doi-asserted-by":"publisher","first-page":"9926","DOI":"10.1073\/pnas.91.21.9926","article-title":"Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2\/AP1 repeat of the beta-globin locus control region.","volume":"91","author":"Moi","year":"1994","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B29","doi-asserted-by":"crossref","DOI":"10.1186\/s13054-016-1288-3","article-title":"Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE.","volume":"20","author":"Nguyen","year":"2016","journal-title":"Crit. Care"},{"key":"B30","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1681\/asn.2015030261","article-title":"Acute dialysis quality initiative consensus XWG: inflammation in AKI: current understanding, key questions, and knowledge gaps.","volume":"27","author":"Rabb","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1172\/jci200421146","article-title":"Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice.","volume":"114","author":"Rangasamy","year":"2004","journal-title":"J. Clin. Invest."},{"key":"B32","doi-asserted-by":"publisher","first-page":"7264","DOI":"10.4049\/jimmunol.0804248","article-title":"Disruption of Nrf2 impairs the resolution of hyperoxia-induced acute lung injury and inflammation in mice.","volume":"182","author":"Reddy","year":"2009","journal-title":"J. Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"392","DOI":"10.2174\/1570159x14666151230110058","article-title":"Molecular, cellular and clinical aspects of intracerebral hemorrhage: are the enemies within?","volume":"14","author":"Righy","year":"2016","journal-title":"Curr. Neuropharmacol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.ccc.2016.08.006","article-title":"Postinjury inflammation and organ dysfunction.","volume":"33","author":"Sauaia","year":"2017","journal-title":"Crit. Care Clin."},{"key":"B35","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1056\/NEJMoa1711584","article-title":"Balanced crystalloids versus saline in critically Ill adults.","volume":"378","author":"Semler","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/SLA.0000000000003407","article-title":"Resolvin D1 attenuates the organ injury associated with experimental hemorrhagic shock.","volume":"269","author":"Sordi","year":"2019","journal-title":"Ann. Surg."},{"key":"B37","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.intimp.2011.10.018","article-title":"Ruscogenin inhibits lipopolysaccharide-induced acute lung injury in mice: involvement of tissue factor, inducible NO synthase and nuclear factor (NF)-kappaB.","volume":"12","author":"Sun","year":"2012","journal-title":"Int. Immunopharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/s12192-015-0654-4","article-title":"Salidroside protects against bleomycin-induced pulmonary fibrosis: activation of Nrf2-antioxidant signaling, and inhibition of NF-kappaB and TGF-beta1\/Smad-2\/-3 pathways.","volume":"21","author":"Tang","year":"2016","journal-title":"Cell Stress Chaperones"},{"key":"B39","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1053\/j.gastro.2009.03.033","article-title":"Prohibitin is a novel regulator of antioxidant response that attenuates colonic inflammation in mice.","volume":"137","author":"Theiss","year":"2009","journal-title":"Gastroenterology"},{"key":"B40","doi-asserted-by":"publisher","first-page":"10210","DOI":"10.1002\/anie.201601967","article-title":"Artemisinin-a gift from traditional Chinese medicine to the world (Nobel Lecture).","volume":"55","author":"Tu","year":"2016","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"B41","doi-asserted-by":"crossref","DOI":"10.1186\/cc6111","article-title":"Multiple organ failure after trauma affects even long-term survival and functional status.","volume":"11","author":"Ulvik","year":"2007","journal-title":"Crit. Care"},{"key":"B42","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1038\/nbt.1623","article-title":"Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies.","volume":"28","author":"Vaidya","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1016\/j.bbrc.2018.06.110","article-title":"Ophiopogonin D alleviates cardiac hypertrophy in rat by upregulating CYP2J3 in vitro and suppressing inflammation in vivo.","volume":"503","author":"Wang","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1002\/med.21446","article-title":"Artemisinin as an anticancer drug: recent advances in target profiling and mechanisms of action.","volume":"37","author":"Wong","year":"2017","journal-title":"Med. Res. Rev."},{"key":"B45","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1080\/09537104.2019.1581921","article-title":"Platelet count as a new biomarker for acute kidney injury induced by hemorrhagic shock.","volume":"31","author":"Wu","year":"2020","journal-title":"Platelets"},{"key":"B46","doi-asserted-by":"crossref","DOI":"10.1111\/jpi.12586","article-title":"Epigenetic inhibition of the tumor suppressor ARHI by light at night-induced circadian melatonin disruption mediates STAT3-driven paclitaxel resistance in breast cancer.","volume":"67","author":"Xiang","year":"2019","journal-title":"J. Pineal Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.ejphar.2016.04.042","article-title":"Isorhamnetin attenuates liver fibrosis by inhibiting TGF-beta\/Smad signaling and relieving oxidative stress.","volume":"783","author":"Yang","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2020.104973","article-title":"Ophiopogonin D suppresses TGF-beta1-mediated metastatic behavior of MDA-MB-231 breast carcinoma cells via regulating ITGB1\/FAK\/Src\/AKT\/beta-catenin\/MMP-9 signaling axis.","volume":"69","author":"Zhu","year":"2020","journal-title":"Toxicol. In Vitro"}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2020.619740\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T05:23:42Z","timestamp":1612157022000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2020.619740\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,1]]},"references-count":48,"alternative-id":["10.3389\/fphys.2020.619740"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2020.619740","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,1]]},"article-number":"619740"}}