{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:21:18Z","timestamp":1791390078720,"version":"4.3.3"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T00:00:00Z","timestamp":1662681600000},"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>\n                    <jats:bold>Background:<\/jats:bold>\n                    Varicocele (VC) is a relatively common and treatable cause of male infertility. Mailuoshutong pill (MLST), a traditional Chinese patent medicine, is widely used for treating varicose vein disease, but the underlying mechanism of MLST on varicocele-associated male infertility is unclear.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Objective:<\/jats:bold>\n                    To reveal the phytochemical characterisation and multitarget mechanism of MLST on varicocele-associated male infertility.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    The components in MLST were determined using UHPLC-MS\/MS. Through network analysis, we constructed the \u201cDrug-Components-Targets-Disease\u201d network and predicted the potential biological functions and signaling pathways of MLST. Finally, the therapeutic effects and potential mechanisms of MLST were discovered by pharmacological experiments.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    By network analysis, the \u201cDrug-Components-Targets-Disease\u201d network was constructed, 62 components such as apigenin, limonin, kaempferol, and obacunoic acid may be the main active components of MLST for varicocele-associated male infertility, 28 targets such as VEGFA, PIK3CA, AKT1, and MTOR are considered as hub targets, signaling pathways such as HIF-1, Estrogen, PI3K\/Akt, and mTOR may be key pathways for MLST against varicocele-associated male infertility. Through pharmacological experiments, we found that MLST ameliorated VC-induced testicular atrophy. Further histomorphology showed that MLST reduced VC-induced damage to testicular spermatogonia and seminiferous tubule, while MLST reduced ROS and MDA levels and increased antioxidant enzymes (GSH, GSH-Px, SOD, and CAT) levels. TUNEL staining and immunofluorescence showed that MLST reduced VC-induced apoptosis in testicular tissue, decreased BAX, and increased BCL2. Western blot results showed that MLST decreased the phosphorylation of PI3K, AKT, and mTOR proteins, and decreased the expression of HIF1\u03b1.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusion:<\/jats:bold>\n                    The phytochemical characterisation and multitarget mechanism of MLST on varicocele-associated male infertility were discovered using network analysis and pharmacological experiments. We verified that MLST can inhibit the activation of the PI3K\/Akt\/mTOR signaling pathway, reduce the expression of HIF1\u03b1, and further attenuate VC-induced oxidative stress and apoptosis in the testis. These findings provide evidence for the therapeutic role of MLST in varicocele-associated male infertility.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2022.961011","type":"journal-article","created":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T01:27:22Z","timestamp":1662686842000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Mailuoshutong pill for varicocele-associated male infertility\u2014Phytochemical characterisation and multitarget mechanism"],"prefix":"10.3389","volume":"13","author":[{"given":"Dongfang","family":"Lv","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuozhuo","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengfei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taotao","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaowang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongfu","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"308","DOI":"10.5534\/wjmh.190068","article-title":"A schematic overview of the current status of male infertility practice","volume":"38","author":"Agarwal","year":"2020","journal-title":"World J. Mens. Health"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e13879","DOI":"10.1111\/and.13879","article-title":"Dietary supplements in the management of varicocele-induced infertility: A review of potential mechanisms","volume":"53","author":"Arab","year":"2021","journal-title":"Andrologia"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s43032-021-00696-y","article-title":"Expression of hypoxia-inducible factor1-alpha in varicocele disease: A comprehensive systematic review","author":"Babaei","year":"2021","journal-title":"Reprod. Sci"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e1417","DOI":"10.1002\/wsbm.1417","article-title":"PharmGKB: A worldwide resource for pharmacogenomic information","volume":"10","author":"Barbarino","year":"2018","journal-title":"Wiley Interdiscip. Rev. Syst. Biol. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.1096\/fj.14-269043","article-title":"Translating dosages from animal models to human clinical trials--revisiting body surface area scaling","volume":"29","author":"Blanchard","year":"2015","journal-title":"FASEB J."},{"key":"B6","doi-asserted-by":"publisher","first-page":"6326","DOI":"10.1021\/jacs.1c13568","article-title":"Covalent proximity scanning of a distal cysteine to target PI3K\u03b1.","volume":"144","author":"Borsari","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"B7","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1002\/pro.4213","article-title":"RCSB Protein Data Bank: Celebrating 50 years of the PDB with new tools for understanding and visualizing biological macromolecules in 3D","volume":"31","author":"Burley","year":"2022","journal-title":"Protein Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/978-3-030-89340-8_3","article-title":"Pathological roles of reactive oxygen species in male reproduction","volume":"1358","author":"Chakraborty","year":"2022","journal-title":"Adv. Exp. Med. Biol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1055\/s-0030-1249774","article-title":"Chemical and biological differentiation of cortex phellodendri chinensis and cortex phellodendri amurensis","volume":"76","author":"Chen","year":"2010","journal-title":"Planta Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.canlet.2011.04.022","article-title":"Calycosin promotes proliferation of estrogen receptor-positive cells via estrogen receptors and ERK1\/2 activation in vitro and in vivo","volume":"308","author":"Chen","year":"2011","journal-title":"Cancer Lett."},{"key":"B11","doi-asserted-by":"publisher","first-page":"153643","DOI":"10.1016\/j.phymed.2021.153643","article-title":"Atractylodis rhizoma water extract attenuates fructose-induced glomerular injury in rats through anti-oxidation to inhibit TRPC6\/p-CaMK4 signaling","volume":"91","author":"Chen","year":"2021","journal-title":"Phytomedicine."},{"key":"B12","doi-asserted-by":"publisher","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"B13","doi-asserted-by":"publisher","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.fct.2017.09.025","article-title":"Protective effects of apigenin against acrylonitrile-induced subchronic sperm injury in rats","volume":"109","author":"Dang","year":"2017","journal-title":"Food Chem. Toxicol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1111\/and.12091","article-title":"Impact of micronised purified flavonoid fraction on increased malondialdehyde and decreased metalloproteinase-2 and metalloproteinase-9 levels in varicocele: Outcome of an experimentally induced varicocele","volume":"46","author":"Dogan","year":"2014","journal-title":"Andrologia"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e13826","DOI":"10.1111\/and.13826","article-title":"Fumaria parviflora regulates oxidative stress and apoptosis gene expression in the rat model of varicocele induction","volume":"52","author":"Dolatkhah","year":"2020","journal-title":"Andrologia"},{"key":"B17","doi-asserted-by":"publisher","first-page":"689056","DOI":"10.1155\/2015\/689056","article-title":"Traditional Chinese herb combined with surgery versus surgery for varicocele infertility: A systematic review and meta-analysis","volume":"2015","author":"Dun","year":"2015","journal-title":"Evid. Based. Complement. Altern. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"E3679","DOI":"10.3390\/molecules24203679","article-title":"Limonin: A review of its Pharmacology, toxicity, and pharmacokinetics","volume":"24","author":"Fan","year":"2019","journal-title":"Molecules"},{"key":"B19","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1093\/humupd\/dmh034","article-title":"Regulation of sperm function by reactive oxygen species","volume":"10","author":"Ford","year":"2004","journal-title":"Hum. Reprod. Update"},{"key":"B20","doi-asserted-by":"publisher","first-page":"222","DOI":"10.4103\/1008-682X.171657","article-title":"An update on the role of medical treatment including antioxidant therapy in varicocele","volume":"18","author":"Garg","year":"2016","journal-title":"Asian J. Androl."},{"key":"B21","doi-asserted-by":"publisher","first-page":"5977","DOI":"10.3390\/ijerph18115977","article-title":"The negative impact of varicocele on basic semen parameters, sperm nuclear DNA dispersion and oxidation-reduction potential in semen","volume":"18","author":"Gill","year":"2021","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"B22","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1002\/ptr.6227","article-title":"Chemo-preventive and therapeutic effect of the dietary flavonoid kaempferol: A comprehensive review","volume":"33","author":"Imran","year":"2019","journal-title":"Phytother. Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1038\/nrurol.2017.98","article-title":"Varicocele and male infertility","volume":"14","author":"Jensen","year":"2017","journal-title":"Nat. Rev. Urol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1186\/s12906-019-2736-9","article-title":"The ameliorative effect of monotropein, astragalin, and spiraeoside on oxidative stress, endoplasmic reticulum stress, and mitochondrial signaling pathway in varicocelized rats","volume":"19","author":"Karna","year":"2019","journal-title":"BMC Complement. Altern. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.1097\/01.ju.0000135455.97627.15","article-title":"Experimental varicocele induces hypoxia inducible factor-1alpha, vascular endothelial growth factor expression and angiogenesis in the rat testis","volume":"172","author":"Kilinc","year":"2004","journal-title":"J. Urol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"D1202","DOI":"10.1093\/nar\/gkv951","article-title":"PubChem substance and compound databases","volume":"44","author":"Kim","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1777","DOI":"10.3390\/molecules27061777","article-title":"Apigenin isolated from carduus crispus protects against H2O2-induced oxidative damage and spermatogenic expression changes in GC-2spd sperm cells","volume":"27","author":"Kopalli","year":"2022","journal-title":"Molecules"},{"key":"B28","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/978-3-030-89340-8_10","article-title":"Oxidative stress and varicocele-associated male infertility","volume":"1358","author":"Lai","year":"2022","journal-title":"Adv. Exp. Med. Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1080\/15384101.2016.1158362","article-title":"Structure of the human dimeric ATM kinase","volume":"15","author":"Lau","year":"2016","journal-title":"Cell Cycle"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1016\/S0022-5347(05)00417-9","article-title":"Increased expression of hypoxia-inducible factor-1alpha in the internal spermatic vein of patients with varicocele","volume":"175","author":"Lee","year":"2006","journal-title":"J. Urol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/j.fertnstert.2021.04.003","article-title":"Effect of varicocelectomy on sperm deoxyribonucleic acid fragmentation rates in infertile men with clinical varicocele: A systematic review and meta-analysis","volume":"116","author":"Lira Neto","year":"2021","journal-title":"Fertil. Steril."},{"key":"B32","doi-asserted-by":"publisher","first-page":"115386","DOI":"10.1016\/j.jep.2022.115386","article-title":"Investigating the multi-target therapeutic mechanism of Guihuang formula on Chronic Prostatitis","volume":"294","author":"Liu","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"252","DOI":"10.3969\/j.issn.1673-7202.2020.02.024","article-title":"Clinical efficacy and safety analysis on mailuo shutong pills in the treatment of varicocele","volume":"15","author":"Liu","year":"2020","journal-title":"World Chin. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"e13658","DOI":"10.1111\/and.13658","article-title":"Effects of liver-regulating herb compounds on testicular morphological and ultrastructural changes in varicocele rats through SCF\/C-KIT pathway","volume":"52","author":"Lu","year":"2020","journal-title":"Andrologia"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e13341","DOI":"10.1111\/and.13341","article-title":"The correlation between mammalian target of rapamycin (mTOR) gene expression and sperm DNA damage among infertile patients with and without varicocele","volume":"51","author":"Mahran","year":"2019","journal-title":"Andrologia"},{"key":"B36","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1111\/andr.12210","article-title":"A comprehensive investigation of sperm DNA damage and oxidative stress injury in infertile patients with subclinical, normozoospermic, and astheno\/oligozoospermic clinical varicocoele","volume":"4","author":"Ni","year":"2016","journal-title":"Andrology"},{"key":"B37","first-page":"266","article-title":"Phytochemical and pharmacological aspects of descurainia sophia webb ex prantl: Modern and traditional applications","volume":"6","author":"Nimrouzi","year":"2016","journal-title":"Avicenna J. Phytomed."},{"key":"B38","doi-asserted-by":"publisher","first-page":"D845","DOI":"10.1093\/nar\/gkz1021","article-title":"The DisGeNET knowledge platform for disease genomics: 2019 update","volume":"48","author":"Pinero","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B39","first-page":"412","article-title":"Comparative clinical study on treatment of varicocele caused infertility by tongling granule and surgical operation","volume":"21","author":"Qi","year":"2001","journal-title":"Zhongguo Zhong Xi Yi Jie He Za Zhi"},{"key":"B40","doi-asserted-by":"publisher","first-page":"879028","DOI":"10.3389\/fnut.2022.879028","article-title":"Limonin isolated from pomelo seed antagonizes a\u03b225-35-mediated neuron injury via PI3K\/AKT signaling pathway by regulating cell apoptosis","volume":"9","author":"Qiu","year":"2022","journal-title":"Front. Nutr."},{"key":"B41","doi-asserted-by":"publisher","first-page":"E1038","DOI":"10.3390\/molecules23051038","article-title":"Is it reliable to take the molecular docking top scoring position as the best solution without considering available structural data?","volume":"23","author":"Ramirez","year":"2018","journal-title":"Molecules"},{"key":"B42","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1111\/andr.12940","article-title":"Varicocoele and oxidative stress: New perspectives from animal and human studies","volume":"9","author":"Razi","year":"2021","journal-title":"Andrology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.urology.2007.08.019","article-title":"Relationship between testicular volume and varicocele in patients with infertility","volume":"71","author":"Sakamoto","year":"2008","journal-title":"Urology"},{"key":"B44","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1016\/j.fertnstert.2020.04.045","article-title":"Differential DNA methylation pattern and sperm quality in men with varicocele","volume":"114","author":"Santana","year":"2020","journal-title":"Fertil. Steril."},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2021.0117","article-title":"Redox regulation to modulate phosphorylation events in human spermatozoa","author":"Serafini","year":"2021","journal-title":"Antioxid. Redox Signal"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1016\/j.fertnstert.2007.08.030","article-title":"Involvement of vascular endothelial growth factor on spermatogenesis in testis with varicocele","volume":"90","author":"Shiraishi","year":"2008","journal-title":"Fertil. Steril."},{"key":"B47","doi-asserted-by":"publisher","first-page":"0","DOI":"10.4103\/aja2021125","article-title":"Predictors of microsurgical varicocelectomy efficacy in male infertility treatment: Critical assessment and systematization","author":"Shomarufov","year":"2022","journal-title":"Asian J. Androl."},{"key":"B48","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.eururo.2018.09.042","article-title":"Treatment of varicocele in children and adolescents: A systematic review and meta-analysis from the European association of urology\/European society for paediatric urology guidelines panel","volume":"75","author":"Silay","year":"2019","journal-title":"Eur. Urol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1080\/13880209.2017.1421672","article-title":"Protective effect of MOTILIPERM in varicocele-induced oxidative injury in rat testis by activating phosphorylated inositol requiring kinase 1\u03b1 (p-IRE1\u03b1) and phosphorylated c-Jun N-terminal kinase (p-JNK) pathways.","volume":"56","author":"Soni","year":"2018","journal-title":"Pharm. Biol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1 30 31","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards suite: From gene data mining to disease genome sequence analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr. Protoc. Bioinforma."},{"key":"B51","doi-asserted-by":"publisher","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B52","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.biosystems.2014.11.005","article-title":"CytoNCA: A cytoscape plugin for centrality analysis and evaluation of protein interaction networks","volume":"127","author":"Tang","year":"2015","journal-title":"Biosystems."},{"key":"B53","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1093\/humupd\/7.1.78","article-title":"The study of varicocele through the use of animal models","volume":"7","author":"Turner","year":"2001","journal-title":"Hum. Reprod. Update"},{"key":"B54","doi-asserted-by":"publisher","first-page":"2912","DOI":"10.1093\/bioinformatics\/btv300","article-title":"GOplot: an R package for visually combining expression data with functional analysis","volume":"31","author":"Walter","year":"2015","journal-title":"Bioinformatics"},{"key":"B55","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1177\/0268355515627717","article-title":"Increased expression of the sonic hedgehog and vascular endothelial growth factor with co-localization in varicocele veins","volume":"32","author":"Wang","year":"2017","journal-title":"Phlebology"},{"key":"B56","doi-asserted-by":"publisher","first-page":"109804","DOI":"10.1016\/j.biopha.2019.109804","article-title":"A Chinese herbal prescription Yiqi Jiedu decoction attenuates irradiation induced testis injury in mice","volume":"123","author":"Wang","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"B57","doi-asserted-by":"publisher","first-page":"850114","DOI":"10.3389\/fgene.2022.850114","article-title":"Role of oxidative stress in varicocele","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Genet."},{"key":"B58","doi-asserted-by":"publisher","first-page":"e12913","DOI":"10.1371\/journal.pone.0012913","article-title":"Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition","volume":"5","author":"Wu","year":"2010","journal-title":"PLoS One"},{"key":"B59","doi-asserted-by":"publisher","first-page":"100141","DOI":"10.1016\/j.xinn.2021.100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation."},{"key":"B60","doi-asserted-by":"publisher","first-page":"e29193","DOI":"10.1097\/MD.0000000000029193","article-title":"Effect of varicocelectomy on detailed sperm morphology parameters: An observational retrospective clinical cohort study","volume":"101","author":"Yaris","year":"2022","journal-title":"Med. Baltim."},{"key":"B61","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1021\/jf103610j","article-title":"New isoflavonoid glycosides and related constituents from astragali radix ( Astragalus membranaceus ) and their inhibitory activity on nitric oxide production","volume":"59","author":"Zhang","year":"2011","journal-title":"J. Agric. Food Chem."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.961011\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T01:27:29Z","timestamp":1662686849000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.961011\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,9]]},"references-count":61,"alternative-id":["10.3389\/fphar.2022.961011"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.961011","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,9]]},"article-number":"961011"}}