{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:49:54Z","timestamp":1791910194858,"version":"4.3.4"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T00:00:00Z","timestamp":1608249600000},"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>The crisis of male infertility is an issue of human reproductive health worldwide. The Wuzi Yanzong pill (WZYZP) is a traditional Chinese medicine prescription that shows efficacy in kidney reinforcement and essence benefit to ameliorate male reproductive dysfunctions. However, the pharmacological mechanisms of the WZYZP on male infertility have not been investigated and clarified clearly. This study was designed to investigate the effects of the WZYZP on spermatogenesis disorder and explore its underlying pharmacological mechanisms. First, based on a network pharmacology study, 39 bioactive compounds and 40 targets of the WZYZP associated with spermatogenesis disorder were obtained, forming a tight compound-target network. Molecular docking tests showed tight docking of these compounds with predicted targeted proteins. The protein\u2013protein interaction (PPI) network identified TP53, TNF, AKT1, Bcl-XL, Bcl-2, and I\u03baBA as hub targets. The Kyoto Encyclopedia of Genes and Genomes pathway network and pathway-target-compound network revealed that the apoptosis pathway was enriched by multiple signaling pathways and multiple targets, including the hub targets. Subsequently, the chemical characterization of WZYZP was analyzed using liquid chromatography to quadrupole\/time-of-flight mass spectrometry, and 40 compounds in positive ion mode and 41 compounds in negative ion mode in the WZYZP were identified. Furthermore, based on the prediction of a network pharmacology study, a rat model of spermatogenesis disorder was established to evaluate the curative role and underlying mechanisms of the WZYZP. The results showed that WZYZP treatment improved rat sperm quality and attenuated serum hormone levels, reversed histopathological damage of the testis, reduced cell apoptosis in testis tissues, and ameliorated the expression of the predicted hub targets (TP53, TNF-\u03b1, AKT1, NF\u03baB, and I\u03baBA) and the apoptosis related proteins (Bcl-XL, Bcl-2, Bax, Caspase 3, and Caspase 9). These results indicated that the WZYZP has a protective effect on spermatogenesis disorder, suggesting that it could be an alternative choice for male infertility therapy.<\/jats:p>","DOI":"10.3389\/fphar.2020.592827","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T08:25:53Z","timestamp":1608279953000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Wuzi Yanzong Pill\u2014Based on Network Pharmacology and In Vivo Evidence\u2014Protects Against Spermatogenesis Disorder via the Regulation of the Apoptosis Pathway"],"prefix":"10.3389","volume":"11","author":[{"given":"Wang-qiang","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai-fei","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-ye","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling-yi","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-min","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-xiong","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,12,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"117012","DOI":"10.1016\/j.lfs.2019.117012","article-title":"Ellagic acid attenuates testicular disruption in rheumatoid arthritis via targeting inflammatory signals, oxidative perturbations and apoptosis","volume":"15","author":"Arab","year":"2019","journal-title":"Life Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1093\/humupd\/dmx021","article-title":"The diagnosis of male infertility: an analysis of the evidence to support the development of global WHO guidance-challenges and future research opportunities","volume":"23","author":"Barratt","year":"2017","journal-title":"Hum. Reprod. Update"},{"key":"B3","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.fertnstert.2019.01.005","article-title":"Introduction: surgical treatment of male infertility: a state-of-the-art overview","volume":"111","author":"Brannigan","year":"2019","journal-title":"Fertil. Steril."},{"key":"B4","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/S0889-8529(03)00047-1","article-title":"Male factor infertility","volume":"32","author":"Brugh","year":"2003","journal-title":"Endocrinol Metab. Clin. N. Am."},{"key":"B5","doi-asserted-by":"publisher","first-page":"179","DOI":"10.3109\/19396368.2012.691943","article-title":"Spermatogenesis in mammals: proteomic insights","volume":"58","author":"Chocu","year":"2012","journal-title":"Syst. Biol. Reprod. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e35431","DOI":"10.1371\/journal.pone.0035431","article-title":"How contemporary human reproductive behaviors influence the role of fertility-related genes: the example of the p53 gene","volume":"7","author":"Corbo","year":"2012","journal-title":"PLoS One"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e13155","DOI":"10.1111\/aji.13155","article-title":"In vitro antioxidation effect of Quercetin on sperm function from the infertile patients with leukocytospermia","volume":"82","author":"Diao","year":"2019","journal-title":"Am. J. Reprod. Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"605","DOI":"10.2174\/1389200219666180302152752","article-title":"Pharmacokinetic and toxicological characteristics of tripterigium glycosides and their derivatives","volume":"19","author":"Du","year":"2018","journal-title":"Curr. Drug Metabol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"112525","DOI":"10.1016\/j.jep.2019.112525","article-title":"A combination of Semen Cuscutae and Fructus Lycii improves testicular cell proliferation and inhibits their apoptosis in rats with spermatogenic dysfunction by regulating the SCF\/c-kit--PI3K--Bcl-2 pathway","volume":"251","author":"Guan","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"B10","first-page":"36","article-title":"Reproductive systemic toxicity and mechanism of glucosides of tripterygium wilfordii Hook. F. (GTW)","volume":"49","author":"Guo","year":"2019","journal-title":"Ann. Clin. Lab. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1007\/s11655-017-2425-9","article-title":"Effect of modified Wuzi Yanzong Pill on Tip60-Mediated apoptosis in testis of male rats after microwave radiation","volume":"25","author":"Hu","year":"2019","journal-title":"Chin. J. Integr. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1038\/aja.2012.39","article-title":"Genetic variants in TP53 and MDM2 associated with male infertility in Chinese population","volume":"14","author":"Huang","year":"2012","journal-title":"Asian J. Androl."},{"key":"B13","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1093\/bib\/bbt035","article-title":"Systems pharmacology in drug discovery and therapeutic insight for herbal medicines","volume":"15","author":"Huang","year":"2014","journal-title":"Briefings Bioinf."},{"key":"B14","doi-asserted-by":"publisher","first-page":"113317","DOI":"10.1016\/j.envpol.2019.113317","article-title":"Aflatoxin B1 promotes autophagy associated with oxidative stress-related PI3K\/AKT\/mTOR signaling pathway in mice testis","volume":"255","author":"Huang","year":"2019","journal-title":"Environ. Pollut."},{"key":"B15","doi-asserted-by":"publisher","first-page":"215","DOI":"10.22074\/ijfs.2016.4912","article-title":"Human sperm quality and metal toxicants: protective effects of some flavonoids on male reproductive function","volume":"10","author":"Jamalan","year":"2016","journal-title":"Int. J. Fertil. Steril."},{"key":"B16","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1186\/s12906-016-1481-6","article-title":"Wuzi Yanzong pill, a Chinese polyherbal formula, alleviates testicular damage in mice induced by ionizing radiation","volume":"16","author":"Ji","year":"2016","journal-title":"BMC Compl. Alternative Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/bs.irn.2017.02.014","article-title":"Effect of Chinese herbal medicine on male infertility","volume":"135","author":"Jiang","year":"2017","journal-title":"Int. Rev. Neurobiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.1016\/j.biopha.2017.09.038","article-title":"Toxic effects of tripterygium wilfordii hook F on the reproductive system of adolescent male rats","volume":"95","author":"Jing","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"B19","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1111\/andr.12673","article-title":"The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap","volume":"7","author":"Jonge","year":"2019","journal-title":"Andrology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.fertnstert.2017.11.026","article-title":"p53 and reproduction","volume":"109","author":"Kang","year":"2018","journal-title":"Fertil. Steril."},{"key":"B21","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nrurol.2011.234","article-title":"Male factor infertility in 2011: semen quality, sperm selection and hematospermia","volume":"9","author":"Kilchevsky","year":"2012","journal-title":"Nat. Rev. Urol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1016\/S0094-0143(02)00093-9","article-title":"Apoptosis: its importance in spermatogenic dysfunction","volume":"29","author":"Kim","year":"2002","journal-title":"Urol. Clin."},{"key":"B23","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1177\/1933719111424449","article-title":"Decreased spermatogenesis, fertility, and altered Slc2A expression in Akt1-\/- and Akt2-\/- testes and sperm","volume":"19","author":"Kim","year":"2012","journal-title":"Reprod. Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1007\/s12011-015-0449-6","article-title":"The protective effects of melatonin against oxidative stress and inflammation induced by acute cadmium exposure in mice testis","volume":"170","author":"Li","year":"2016","journal-title":"Biol. Trace Elem. Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e15594","DOI":"10.1097\/MD.0000000000015594","article-title":"Effectiveness comparison of a Chinese dicitraditionalmene formula Wuzi Yanzong Pill and its analogous prescriptions for the treatment of oligoasthenozoospermia: a systematic review and meta-analysis protocol","volume":"98","author":"Li","year":"2019","journal-title":"Medicine"},{"key":"B26","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1007\/s11655-019-3064-0","article-title":"Network pharmacology in research of Chinese medicine formula: methodology, application and prospective","volume":"26","author":"Luo","year":"2020","journal-title":"Chin. J. Integr. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.biopha.2017.07.087","article-title":"Cadmium chloride-induced testicular toxicity in male wistar rats; prophylactic effect of quercetin, and assessment of testicular recovery following cadmium chloride withdrawal","volume":"94","author":"Nna","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"B28","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.ecl.2007.03.003","article-title":"Medical and surgical management male infertility","volume":"36","author":"Schiff","year":"2007","journal-title":"Endocrinol Metab. Clin. N. Am."},{"key":"B29","doi-asserted-by":"publisher","first-page":"746","DOI":"10.2741\/415","article-title":"Apoptosis, spermatogenesis and male infertility","volume":"4","author":"Shukla","year":"2012","journal-title":"Front. Biosci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"4984","DOI":"10.1096\/fj.201701096RR","article-title":"Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of PI3K\/Akt signaling","volume":"32","author":"Sinha","year":"2018","journal-title":"Faseb. J."},{"key":"B31","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1152\/physrev.00017.2015","article-title":"Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility","volume":"96","author":"Skakkebaek","year":"2016","journal-title":"Physiol. Rev."},{"key":"B32","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.intimp.2009.10.013","article-title":"Attenuation of cyclosporine A-induced testicular and spermatozoal damages associated with oxidative stress by ellagic acid","volume":"10","author":"T\u00fcrk","year":"2010","journal-title":"Int. Immunopharm."},{"key":"B33","doi-asserted-by":"publisher","first-page":"7517","DOI":"10.26355\/eurrev_201811_16293","article-title":"Melatonin protects methotrexate-induced testicular injury in rats","volume":"22","author":"Wang","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"240","DOI":"10.5114\/aoms.2018.81038","article-title":"In vivo administration of quercetin ameliorates sperm oxidative stress, inflammation, preserves sperm morphology and functions in streptozotocin-nicotinamide induced adult male diabetic rats","volume":"15","author":"Yelumalai","year":"2019","journal-title":"Arch. Med. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1080\/15384101.2017.1421874","article-title":"Interplay between p53 and Ink4c in spermatogenesis and fertility","volume":"17","author":"Zalzali","year":"2018","journal-title":"Cell Cycle"},{"key":"B36","doi-asserted-by":"publisher","first-page":"21770","DOI":"10.18632\/oncotarget.24985","article-title":"Qilin pills alleviate oligoasthenospermia by inhibiting Bax-caspase-9 apoptosis pathway in the testes of model rats","volume":"9","author":"Zhang","year":"2018","journal-title":"Oncotarget"},{"key":"B37","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1111\/jphp.12668","article-title":"Oleanolic acid rejuvenates testicular function through attenuating germ cell DNA damage and apoptosis via deactivation of NF-\u03baB, p53 and p38 signalling pathways","volume":"69","author":"Zhao","year":"2017","journal-title":"J. Pharm. Pharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e13181","DOI":"10.1111\/and.13181","article-title":"Protective effect of Wuzi Yanzong recipe on testicular dysfunction through inhibition of germ cell apoptosis in ageing rats via endoplasmic reticulum stress","volume":"51","author":"Zhao","year":"2019","journal-title":"Andrologia"},{"key":"B39","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1186\/s13063-019-3647-2","article-title":"A double-blinded, randomized placebo-controlled trial on the effect of traditional Chinese medicine formula Wuzi Yanzong pill on improving semen qualities in men with suboptimal parameters","volume":"20","author":"Zhao","year":"2019","journal-title":"Trials"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2968025","DOI":"10.1155\/2018\/2968025","article-title":"The therapeutic effects of a traditional Chinese medicine formula Wuzi Yanzong pill for the treatment of Oligoasthenozoospermia: a meta-analysis of randomized controlled trials","volume":"2018","author":"Zhao","year":"2018","journal-title":"Evid. Based. Complement. Alternat. Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1007\/s12011-018-1338-6","article-title":"Positive PCNA and Ki-67 expression in the testis correlates with spermatogenesis dysfunction in fluoride-treated rats","volume":"186","author":"Zhao","year":"2018","journal-title":"Biol. Trace Elem. Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"175","DOI":"10.5534\/wjmh.180069","article-title":"Traditional Chinese medicine as a remedy for male infertility: a review","volume":"37","author":"Zhou","year":"2019","journal-title":"World J. Mens Health."}],"updated-by":[{"DOI":"10.3389\/fphar.2022.1129448","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T00:00:00Z","timestamp":1673481600000}}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2020.592827\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T15:31:38Z","timestamp":1673883098000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2020.592827\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,18]]},"references-count":42,"alternative-id":["10.3389\/fphar.2020.592827"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2020.592827","relation":{"corrigendum":[{"id-type":"doi","id":"10.3389\/fphar.2022.1129448","asserted-by":"object"}]},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,18]]},"article-number":"592827"}}