{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T18:26:59Z","timestamp":1773167219103,"version":"3.50.1"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,7,17]],"date-time":"2021-07-17T00:00:00Z","timestamp":1626480000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,17]],"date-time":"2021-07-17T00:00:00Z","timestamp":1626480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Pharmacol Toxicol"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Abnormally elevated xanthine oxidase (XO) activity has been verified to cause various pathological processes, such as gout, oxidative stress injury and metabolic syndrome. Thus, XO activators may exhibit above potential toxicological properties. Plumbagin (PLB) is an important active compound in traditional Chinese medicine (TCM), while its obvious toxic effects have been reported, including diarrhea, skin rashes and hepatic toxicity. However, the potential toxicity associated with enhancement of XO activity has not been fully illuminated so far.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The present study investigated the effect of PLB on XO activity by culturing mouse liver S9 (MLS9), human liver S9 (HLS9), XO monoenzyme system with PLB and xanthine. Then, the molecular docking and biolayer interferometry analysis were adopted to study the binding properties between PLB and XO. Finally, the in vivo acceleration effect also investigated by injected intraperitoneally PLB to KM mice for 3 days.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>PLB could obviously accelerate xanthine oxidation in the above three incubation systems. Both the V<jats:sub>max<\/jats:sub> values and intrinsic clearance values (CL<jats:sub>int<\/jats:sub>, V<jats:sub>max<\/jats:sub>\/K<jats:sub>m<\/jats:sub>) of XO in the three incubation systems increased along with elevated PLB concentration. In addition, the molecular docking study and label-free biolayer interferometry assay displayed that PLB was well bound to XO. In addition, the in vivo results showed that PLB (2 and 10\u2009mg\/kg) significantly increased serum uric acid levels and enhanced serum XO activity in mice.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>In summary, this study outlines a potential source of toxicity for PLB due to the powerful enhancement of XO activity, which may provide the crucial reminding for the PLB-containing preparation development and clinical application.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40360-021-00511-z","type":"journal-article","created":{"date-parts":[[2021,7,17]],"date-time":"2021-07-17T17:02:46Z","timestamp":1626541366000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Plumbagin can potently enhance the activity of xanthine oxidase: in vitro, in vivo and in silico studies"],"prefix":"10.1186","volume":"22","author":[{"given":"Liang","family":"Yue","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anguo","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenqiao","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dalian","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sicheng","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianming","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,7,17]]},"reference":[{"issue":"10","key":"511_CR1","doi-asserted-by":"publisher","first-page":"e1800165","DOI":"10.1002\/ardp.201800165","volume":"351","author":"\u0130E K\u0131br\u0131z","year":"2018","unstructured":"K\u0131br\u0131z \u0130E, Sa\u00e7mac\u0131 M, Y\u0131ld\u0131r\u0131m \u0130, Abbas Ali Noma S, Ta\u015fk\u0131n Tok T, Ate\u015f B. Xanthine oxidase inhibitory activity of new pyrrole carboxamide derivatives: in vitro and in silico studies. Arch Pharm (Weinheim). 2018;351(10):e1800165. https:\/\/doi.org\/10.1002\/ardp.201800165.","journal-title":"Arch Pharm (Weinheim)"},{"key":"511_CR2","doi-asserted-by":"publisher","first-page":"101072","DOI":"10.1016\/j.redox.2018.101072","volume":"21","author":"HM Schmidt","year":"2019","unstructured":"Schmidt HM, Kelley EE, Straub AC. The impact of xanthine oxidase (XO) on hemolytic diseases. Redox Biol. 2019;21:101072. https:\/\/doi.org\/10.1016\/j.redox.2018.101072.","journal-title":"Redox Biol"},{"issue":"4","key":"511_CR3","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1002\/med.21457","volume":"38","author":"R Kumar","year":"2018","unstructured":"Kumar R, Joshi G, Kler H, Kalra S, Kaur M, Arya R. Toward an understanding of structural insights of xanthine and aldehyde oxidases: an overview of their inhibitors and role in various diseases. Med Res Rev. 2018;38(4):1073\u2013125. https:\/\/doi.org\/10.1002\/med.21457.","journal-title":"Med Res Rev"},{"issue":"35","key":"511_CR4","doi-asserted-by":"publisher","first-page":"4027","DOI":"10.2174\/0929867323666160725091915","volume":"23","author":"MG Battelli","year":"2016","unstructured":"Battelli MG, Polito L, Bortolotti M, et al. Xanthine oxidoreductase in drug metabolism: beyond a role as a detoxifying enzyme. Curr Med Chem. 2016;23(35):4027\u201336. https:\/\/doi.org\/10.2174\/0929867323666160725091915.","journal-title":"Curr Med Chem"},{"issue":"10","key":"511_CR5","doi-asserted-by":"publisher","first-page":"4239","DOI":"10.1039\/C6FO00822D","volume":"7","author":"JJ Jhang","year":"2016","unstructured":"Jhang JJ, Ong JW, Lu CC, Hsu CL, Lin JH, Liao JW, et al. Hypouricemic effects of Mesona procumbens Hemsl. Through modulating xanthine oxidase activity in vitro and in vivo. Food Funct. 2016;7(10):4239\u201346. https:\/\/doi.org\/10.1039\/C6FO00822D.","journal-title":"Food Funct"},{"issue":"10055","key":"511_CR6","doi-asserted-by":"publisher","first-page":"2039","DOI":"10.1016\/S0140-6736(16)00346-9","volume":"388","author":"N Dalbeth","year":"2016","unstructured":"Dalbeth N, Merriman TR, Stamp LK. Gout. Gout Lancet. 2016;388(10055):2039\u201352. https:\/\/doi.org\/10.1016\/S0140-6736(16)00346-9.","journal-title":"Gout Lancet"},{"key":"511_CR7","doi-asserted-by":"publisher","first-page":"3527579","DOI":"10.1155\/2016\/3527579","volume":"2016","author":"MG Battelli","year":"2016","unstructured":"Battelli MG, Polito L, Bortolotti M, et al. Xanthine oxidoreductase-derived reactive species: physiological and pathological effects. Oxidative Med Cell Longev. 2016;2016:3527579.","journal-title":"Oxidative Med Cell Longev"},{"issue":"25","key":"511_CR8","doi-asserted-by":"publisher","first-page":"2154","DOI":"10.2174\/1568026619666181120143050","volume":"18","author":"N Malik","year":"2018","unstructured":"Malik N, Dhiman P, Sobarzo-Sanchez E, Khatkar A. Flavonoids and anthranquinones as xanthine oxidase and monoamine oxidase inhibitors: a new approach towards inflammation and oxidative stress. Curr Top Med Chem. 2018;18(25):2154\u201364. https:\/\/doi.org\/10.2174\/1568026619666181120143050.","journal-title":"Curr Top Med Chem"},{"key":"511_CR9","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.metabol.2017.01.031","volume":"70","author":"KW Washio","year":"2017","unstructured":"Washio KW, Kusunoki Y, Murase T, et al. Xanthine oxidoreductase activity is correlated with insulin resistance and subclinical inflammation in young humans. Metabolism. 2017;70:51\u20136. https:\/\/doi.org\/10.1016\/j.metabol.2017.01.031.","journal-title":"Metabolism."},{"key":"511_CR10","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.fct.2019.01.018","volume":"125","author":"SK Tripathi","year":"2019","unstructured":"Tripathi SK, Panda M, Biswal BK. Emerging role of plumbagin: cytotoxic potential and pharmaceutical relevance towards cancer therapy. Food Chem Toxicol. 2019;125:566\u201382. https:\/\/doi.org\/10.1016\/j.fct.2019.01.018.","journal-title":"Food Chem Toxicol"},{"issue":"2","key":"511_CR11","doi-asserted-by":"publisher","first-page":"e0228657","DOI":"10.1371\/journal.pone.0228657","volume":"15","author":"A Sarkar","year":"2020","unstructured":"Sarkar A, Ghosh S, Shaw R, Patra MM, Calcuttawala F, Mukherjee N, et al. Mycobacterium tuberculosis thymidylate synthase (ThyX) is a target for plumbagin, a natural product with antimycobacterial activity. PLoS One. 2020;15(2):e0228657. https:\/\/doi.org\/10.1371\/journal.pone.0228657.","journal-title":"PLoS One"},{"issue":"4","key":"511_CR12","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.ijmm.2016.05.004","volume":"306","author":"SV Nair","year":"2016","unstructured":"Nair SV, Baranwal G, Chatterjee M, Sachu A, Vasudevan AK, Bose C, et al. Antimicrobial activity of plumbagin, a naturally occurring naphthoquinone from Plumbago rosea, against Staphylococcus aureus and Candida albicans. Int J Med Microbiol. 2016;306(4):237\u201348. https:\/\/doi.org\/10.1016\/j.ijmm.2016.05.004.","journal-title":"Int J Med Microbiol"},{"issue":"12","key":"511_CR13","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1002\/tox.23002","volume":"35","author":"Z Li","year":"2020","unstructured":"Li Z, Chinnathambi A, Ali Alharbi S, Yin F. Plumbagin protects the myocardial damage by modulating the cardiac biomarkers, antioxidants, and apoptosis signaling in the doxorubicin-induced cardiotoxicity in rats. Environ Toxicol. 2020;35(12):1374\u201385. https:\/\/doi.org\/10.1002\/tox.23002.","journal-title":"Environ Toxicol"},{"issue":"2","key":"511_CR14","doi-asserted-by":"publisher","first-page":"137","DOI":"10.5455\/jice.20160301094913","volume":"5","author":"N Sukkasem","year":"2016","unstructured":"Sukkasem N, Chatuphonprasert W, Tatiya-Aphiradee N, et al. Imbalance of the antioxidative system by plumbagin and Plumbago indica L. extract induces hepatotoxicity in mice. J Intercult Ethnopharmacol. 2016;5(2):137\u201345. https:\/\/doi.org\/10.5455\/jice.20160301094913.","journal-title":"J Intercult Ethnopharmacol"},{"issue":"2","key":"511_CR15","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.tiv.2011.12.007","volume":"26","author":"H Shimada","year":"2012","unstructured":"Shimada H, Yamaoka Y, Morita R, Mizuno T, Gotoh K, Higuchi T, et al. Possible mechanism of superoxide formation through redox cycling of plumbagin in pig heart. Toxicol in Vitro. 2012;26(2):252\u20137. https:\/\/doi.org\/10.1016\/j.tiv.2011.12.007.","journal-title":"Toxicol in Vitro"},{"key":"511_CR16","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.phrs.2018.04.011","volume":"133","author":"T Wu","year":"2018","unstructured":"Wu T, Yu GY, Xiao J, Yan C, Kurihara H, Li YF, et al. Fostering efficacy and toxicity evaluation of traditional Chinese medicine and natural products: Chick embryo as a high throughput model bridging in vitro and in vivo studies. Pharmacol Res. 2018;133:21\u201334. https:\/\/doi.org\/10.1016\/j.phrs.2018.04.011.","journal-title":"Pharmacol Res"},{"issue":"6","key":"511_CR17","doi-asserted-by":"publisher","first-page":"343","DOI":"10.3390\/md17060343","volume":"17","author":"YT Chau","year":"2019","unstructured":"Chau YT, Chen HY, Lin PH, Hsia SM. Preventive effects of fucoidan and fucoxanthin on hyperuricemic rats induced by potassium oxonate. Mar Drugs. 2019;17(6):343. https:\/\/doi.org\/10.3390\/md17060343.","journal-title":"Mar Drugs"},{"issue":"7","key":"511_CR18","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1007\/s11655-016-2649-0","volume":"23","author":"B Han","year":"2017","unstructured":"Han B, Zhu CX, Shi W, Huang HZ, Hu XG, Zhou XM, et al. Effect of rhizoma polygoni cuspidati and ramulus cinnamomi compatibility on uric acid metabolism and urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in rats with hyperuricemia. Chin J Integr Med. 2017;23(7):535\u201342. https:\/\/doi.org\/10.1007\/s11655-016-2649-0.","journal-title":"Chin J Integr Med"},{"issue":"2","key":"511_CR19","doi-asserted-by":"publisher","first-page":"51","DOI":"10.3390\/ph11020051","volume":"11","author":"A Jordan","year":"2018","unstructured":"Jordan A, Gresser U. Side effects and interactions of the xanthine oxidase inhibitor Febuxostat. Pharmaceuticals (Basel). 2018;11(2):51. https:\/\/doi.org\/10.3390\/ph11020051.","journal-title":"Pharmaceuticals (Basel)"},{"key":"511_CR20","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1007\/978-3-319-41342-6_10","volume":"929","author":"P Panichayupakaranant","year":"2016","unstructured":"Panichayupakaranant P, Ahmad MI. Plumbagin and its role in chronic diseases. Adv Exp Med Biol. 2016;929:229\u201346. https:\/\/doi.org\/10.1007\/978-3-319-41342-6_10.","journal-title":"Adv Exp Med Biol"}],"container-title":["BMC Pharmacology and Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40360-021-00511-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40360-021-00511-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40360-021-00511-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,17]],"date-time":"2021-07-17T17:02:51Z","timestamp":1626541371000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcpharmacoltoxicol.biomedcentral.com\/articles\/10.1186\/s40360-021-00511-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,17]]},"references-count":20,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["511"],"URL":"https:\/\/doi.org\/10.1186\/s40360-021-00511-z","relation":{},"ISSN":["2050-6511"],"issn-type":[{"value":"2050-6511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,17]]},"assertion":[{"value":"6 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The in vivo study was in accordance with the ARRIVE guidelines and approved by the Institutional Animal Ethics Committee of Southwest Medical University (Approval no 20190999). The use of human liver S9 was done in accordance with the guidelines of Southwest Medical University and approved by the Institutional Ethics Committee of Southwest Medical University (Approval no 20190013H).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declared that have no competing interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"45"}}