283
Views
5
CrossRef citations to date
0
Altmetric
Original Research

An Integrated Analysis of Network Pharmacology, Molecular Docking, and Experiment Validation to Explore the New Candidate Active Component and Mechanism of Cuscutae Semen-Mori Fructus Coupled-Herbs in Treating Oligoasthenozoospermia

, , , , , , , , , , , , & show all
Pages 2059-2089 | Published online: 17 May 2021

References

  • Zegers-HochschildF, AdamsonGD, de MouzonJ, et al. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology, 2009. Hum Reprod. 2009;24(11):2683–2687. doi:10.1093/humrep/dep34319801627
  • DohleGR, ColpiGM, HargreaveTB, et al. EAU guidelines on male infertility. Eur Urol. 2005;48(5):703–711. doi:10.1016/j.eururo.2005.06.00216005562
  • AmoryJ, OstrowskiK, GannonJ, et al. Isotretinoin administration improves sperm production in men with infertility from oligoasthenozoospermia: a pilot study. Andrology. 2017;5(6):1115–1123. doi:10.1111/andr.1242028980413
  • CooperTG, NoonanE, von EckardsteinS, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16(3):231–245. doi:10.1093/humupd/dmp04819934213
  • MachenGL, SandlowJI. Causes of male infertility. Male Infertility Springer. 2020;3–14.
  • TournayeH, KrauszC, OatesRD. Concepts in diagnosis and therapy for male reproductive impairment. Lancet Diabetes Endocrinol. 2017;5(7):554–564. doi:10.1016/S2213-8587(16)30043-227395770
  • SinghB, ReschkeL, SegarsJ, BakerVL. Frozen-thawed embryo transfer: the potential importance of the corpus luteum in preventing obstetrical complications. Fertil Steril. 2020;113(2):252–257. doi:10.1016/j.fertnstert.2019.12.00732106972
  • IllianoE, TramaF, CostantiniE. Could COVID‐19 have an impact on male fertility? Andrologia. 2020;e13654. doi:10.1111/and.1365432436229
  • WangS, ZhouX, ZhangT, WangZ. The need for urogenital tract monitoring in COVID-19. Nat Rev Urol. 2020;1–2. doi:10.1038/s41585-020-0319-731676884
  • SegarsJ, KatlerQ, McQueenDB, et al. Prior and novel coronaviruses, COVID-19, and human reproduction: what is known? Fertil Steril. 2020. doi:10.1016/j.fertnstert.2020.04.025
  • XuJ, QiL, ChiX, et al. Orchitis: a complication of severe acute respiratory syndrome (SARS). Biol Reprod. 2006;74(2):410–416. doi:10.1095/biolreprod.105.04477616237152
  • YoussefK, AbdelhakK. Male genital damage in COVID-19 patients: are available data relevant? Asian J Urol. 2020. doi:10.1016/j.ajur.2020.06.005
  • AitkenRJ. COVID‐19 and human spermatozoa–potential risks for infertility and sexual transmission. Andrology. 2020;1–5. doi:10.1111/andr.1285933167073
  • StarcA, TrampušM, Pavan JukićD, Grgas-BileC, JukićT, Polona MivšekA. Infertility and sexual dysfunctions: a systematic literature review. Acta Clinica Croatica. 2019;58(3):508–515. doi:10.20471/acc.2019.58.03.1531969764
  • ForestaC, BettellaA, MericoM, GarollaA, FerlinA, RossatoM. Use of recombinant human follicle-stimulating hormone in the treatment of male factor infertility. Fertil Steril. 2002;77(2):238–244. doi:10.1016/s0015-0282(01)02966-111821078
  • HenkelR, SandhuIS, AgarwalA. The excessive use of antioxidant therapy: a possible cause of male infertility? Andrologia. 2019;51(1):e13162. doi:10.1111/and.1316230259539
  • HeloS, EllenJ, MechlinC, et al. A randomized prospective double‐blind comparison trial of clomiphene citrate and anastrozole in raising testosterone in hypogonadal infertile men. J Sex Med. 2015;12(8):1761–1769. doi:10.1111/jsm.1294426176805
  • JungJH, SeoJT. Empirical medical therapy in idiopathic male infertility: promise or panacea? Clin Exp Reprod Med. 2014;41(3):108. doi:10.5653/cerm.2014.41.3.10825309854
  • WangM, WangQ, DuY, JiangH, ZhangX. Vitamins combined with traditional Chinese medicine for male infertility: a systematic review and meta‐analysis. Andrology. 2020;8(5):1038–1050. doi:10.1111/andr.1278732170803
  • NagataM, SuzukiT. L-carnitine partially improves metabolic syndrome symptoms but does not re-verse perturbed sperm function or infertility in high fat diet-induced obese mice. MJ Nutr. 2017;2(1):013.
  • QinJ, ShengX, WangH, LiangD, TanH, XiaJ. Assisted reproductive technology and risk of congenital malformations: a meta-analysis based on cohort studies. Arch Gynecol Obstet. 2015;292(4):777–798. doi:10.1007/s00404-015-3707-025877221
  • JiangD, CoscioneA, LiL, ZengB-Y. Effect of Chinese herbal medicine on male infertility. Int Rev Neurobiol Elsevier. 2017;297–311.
  • JinX, ManC, GongD, FanY. Adjuvant treatment with Qilin pill for men with oligoasthenospermia: a meta‐analysis of randomized controlled trials. Phytother Res. 2017;31(9):1291–1297. doi:10.1002/ptr.585428635070
  • ZhouS, WengZ, LiangA, ZhangS. Experimental research on therapeutic efficacy of traditional chinese medicine Shengjing Capsule extracts in treating spermatogenesis impairment induced by oxidative stress. Med Sci Monitor. 2016;22:50. doi:10.12659/MSM.895336
  • LinM-K, LeeM-S, ChangW-T, YangM-C, ChuC-L. Study the immunomodulatory activity of semen cuscutae and identify the active components. J Biosci Bioeng. 2009;108:S19. doi:10.1016/j.jbiosc.2009.08.492
  • YangS, XuX, XuH, et al. Purification, characterization and biological effect of reversing the kidney-yang deficiency of polysaccharides from semen cuscutae. Carbohydr Polym. 2017;175:249–256. doi:10.1016/j.carbpol.2017.07.07728917863
  • Jian-HuiL, BoJ, Yong-MingB, Li-JiaA. Effect of Cuscuta chinensis glycoside on the neuronal differentiation of rat pheochromocytoma PC12 cells. Int J Develop Neurosci. 2003;21(5):277–281. doi:10.1016/S0736-5748(03)00040-6
  • NisaM, AkbarS, TariqM, HussainZ. Effect of Cuscuta chinensis water extract on 7, 12-dimethylbenz [a] anthracene-induced skin papillomas and carcinomas in mice. J Ethnopharmacol. 1986;18(1):21–31. doi:10.1016/0378-8741(86)90040-13102856
  • LeeJS, SynytsyaA, KimHB, et al. Purification, characterization and immunomodulating activity of a pectic polysaccharide isolated from Korean mulberry fruit Oddi (Morus alba L. Int Immunopharmacol. 2013;17(3):858–866. doi:10.1016/j.intimp.2013.09.01924120956
  • ChenC, YouL-J, HuangQ, et al. Modulation of gut microbiota by mulberry fruit polysaccharide treatment of obese diabetic db/db mice. Food Funct. 2018;9(7):3732–3742. doi:10.1039/C7FO01346A29995048
  • ChenY, YaoF, MingK, WangD, HuY, LiuJ. Polysaccharides from traditional Chinese medicines: extraction, purification, modification, and biological activity. Molecules. 2016;21(12):1705. doi:10.3390/molecules21121705
  • ZhaoS, IyengarR. Systems pharmacology: network analysis to identify multiscale mechanisms of drug action. Annu Rev Pharmacol Toxicol. 2012;52:505–521. doi:10.1146/annurev-pharmtox-010611-13452022235860
  • van HasseltJGC, IyengarR. Systems pharmacology: defining the interactions of drug combinations. Annu Rev Pharmacol Toxicol. 2019;59:21–40. doi:10.1146/annurev-pharmtox-010818-02151130260737
  • HopkinsAL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008;4(11):682. doi:10.1038/nchembio.11818936753
  • ShaoL, ZhangB. Traditional Chinese medicine network pharmacology: theory, methodology and application. Chin J Nat Med. 2013;11(2):110–120. doi:10.1016/S1875-5364(13)60037-023787177
  • LiJ, FuA, ZhangL. An overview of scoring functions used for protein–ligand interactions in molecular docking. Interdiscip Sci. 2019;1–9. doi:10.1007/s12539-019-00327-w
  • RuJ, LiP, WangJ, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform. 2014;6:13. doi:10.1186/1758-2946-6-1324735618
  • HuangL, XieD, YuY, et al. TCMID 2.0: a comprehensive resource for TCM. Nucleic Acids Res. 2018;46(D1):D1117–D1120. doi:10.1093/nar/gkx102829106634
  • FengW, AoH, YueS, PengC. Systems pharmacology reveals the unique mechanism features of Shenzhu Capsule for treatment of ulcerative colitis in comparison with synthetic drugs. Sci Rep. 2018;8(1):16160. doi:10.1038/s41598-018-34509-130385774
  • ZhangX, ShenY, WangX, YuanG, ZhangC, YangY. A novel homozygous CFAP65 mutation in humans causes male infertility with multiple morphological abnormalities of the sperm flagella. Clin Genet. 2019;96(6):541–548. doi:10.1111/cge.1364431571197
  • LiH, ZhaoL, ZhangB, et al. A network pharmacology approach to determine active compounds and action mechanisms of ge-gen-qin-lian decoction for treatment of type 2 diabetes. Evidence-Based Compl Alternative Med. 2014;2014:1–12.
  • ZuoH, ZhangQ, SuS, ChenQ, YangF, HuY. A network pharmacology-based approach to analyse potential targets of traditional herbal formulas: an example of Yu Ping Feng decoction. Sci Rep. 2018;8(1):1–15. doi:10.1038/s41598-018-29764-129311619
  • XuX, ZhangW, HuangC, et al. A novel chemometric method for the prediction of human oral bioavailability. Int J Mol Sci. 2012;13(6):6964–6982. doi:10.3390/ijms1306696422837674
  • WaltersWP, MurckoMA. Prediction of ‘drug-likeness’. Adv Drug Deliv Rev. 2002;54(3):255–271. doi:10.1016/s0169-409x(02)00003-011922947
  • BardouP, MarietteJ, EscudiéF, DjemielC, KloppC. jvenn: an interactive Venn diagram viewer. BMC Bioinform. 2014;15(1):1–7. doi:10.1186/1471-2105-15-293
  • KimS, ChenJ, ChengT, et al. PubChem 2019 update: improved access to chemical data. Nucleic Acids Res. 2019;47(D1):D1102–D1109. doi:10.1093/nar/gky103330371825
  • TetkoIV, PodaGI. Application of ALOGPS 2.1 to predict log D distribution coefficient for Pfizer proprietary compounds. J Med Chem. 2004;47(23):5601–5604. doi:10.1021/jm049509l15509156
  • GfellerD, GrosdidierA, WirthM, DainaA, MichielinO, ZoeteV. SwissTargetPrediction: a web server for target prediction of bioactive small molecules. Nucleic Acids Res. 2014;42(Web Server issue):W32–8. doi:10.1093/nar/gku29324792161
  • UniProtC. UniProt: a hub for protein information. Nucleic Acids Res. 2015;43(Database issue):D204–12. doi:10.1093/nar/gku98925348405
  • ShannonP, MarkielA, OzierO, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–2504. doi:10.1101/gr.123930314597658
  • AssenovY, RamirezF, SchelhornSE, LengauerT, AlbrechtM. Computing topological parameters of biological networks. Bioinformatics. 2008;24(2):282–284. doi:10.1093/bioinformatics/btm55418006545
  • PineroJ, BravoA, Queralt-RosinachN, et al. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res. 2017;45(D1):D833–D839. doi:10.1093/nar/gkw94327924018
  • DavisAP, GrondinCJ, JohnsonRJ, et al. The Comparative Toxicogenomics Database: update 2019. Nucleic Acids Res. 2019;47(D1):D948–D954. doi:10.1093/nar/gky86830247620
  • AmbergerJS, HamoshA. Searching Online Mendelian Inheritance in Man (OMIM): a knowledgebase of human genes and genetic phenotypes. Curr Protoc Bioinformatics. 2017;58:1 2 1–1 2 12. doi:10.1002/cpbi.2728654725
  • StelzerG, RosenN, PlaschkesI, et al. The genecards suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinformatics. 2016;54:1 30 1–1 30 33. doi:10.1002/cpbi.527322403
  • BrownGR, HemV, KatzKS, et al. Gene: a gene-centered information resource at NCBI. Nucleic Acids Res. 2015;43(Database issue):D36–42. doi:10.1093/nar/gku105525355515
  • YangZ, ZhangX, ChenZ, HuC. Effect of Wuzi Yanzong on Reproductive Hormones and TGF-beta1/Smads signal pathway in rats with oligoasthenozoospermia. Evid Based Complement Alternat Med. 2019;2019:7628125. doi:10.1155/2019/762812531118967
  • SzklarczykD, FranceschiniA, WyderS, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43(Database issue):D447–52. doi:10.1093/nar/gku100325352553
  • BaderGD, HogueCW. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform. 2003;4:2. doi:10.1186/1471-2105-4-2
  • AhmedHA, BhattacharyyaDK, KalitaJK. Core and peripheral connectivity based cluster analysis over PPI network. Comput Biol Chem. 2015;59(Pt):B:32–41. doi:10.1016/j.compbiolchem.2015.08.008
  • The Gene Ontology C. Expansion of the Gene Ontology knowledgebase and resources. Nucleic Acids Res. 2017;45(D1):D331–D338. doi:10.1093/nar/gkw1108.27899567
  • DuJ, YuanZ, MaZ, SongJ, XieX. KEGG-PATH: kyoto encyclopedia of genes and genomes-based pathway analysis using a path analysis model. Mol Biosyst. 2014;10(9):2441–2447. doi:10.1039/c4mb00287c24994036
  • ZhouY, ZhouB, PacheL, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1–10. doi:10.1073/pnas.182216411630602773
  • WilsonCL, MillerCJ. Simpleaffy: a bioconductor package for affymetrix quality control and data analysis. Bioinformatics. 2005;21(18):3683–3685. doi:10.1093/bioinformatics/bti60516076888
  • BindeaG, MlecnikB, HacklH, et al. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009;25(8):1091–1093. doi:10.1093/bioinformatics/btp10119237447
  • BermanHM, WestbrookJ, FengZ, et al. The protein data bank. Nucleic Acids Res. 2000;28(1):235–242. doi:10.1093/nar/28.1.23510592235
  • YuanS, ChanHCS, FilipekS, VogelH. PyMOL and inkscape bridge the data and the data visualization. Structure. 2016;24(12):2041–2042. doi:10.1016/j.str.2016.11.01227926832
  • TrottO, OlsonAJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31(2):455–461. doi:10.1002/jcc.2133419499576
  • LanR, XiangJ, WangG-H, et al. Xiao-Xu-Ming decoction protects against blood-brain barrier disruption and neurological injury induced by cerebral ischemia and reperfusion in rats. Evidence-Based Compl Alternative Med. 2013;2013.
  • ZhangQ, ZhaoH, WangL, ZhangQ, WangH. Effects of wind-dispelling drugs and deficiency-nourishing drugs of Houshiheisan compound prescription on astrocyte activation and inflammatory factor expression in the corpus striatum of cerebral ischemia rats. Neural Regeneration Res. 2012;7(24):1851.
  • WangY, XiaoJ, SuzekTO, ZhangJ, WangJ, BryantSH. PubChem: a public information system for analyzing bioactivities of small molecules. Nucleic Acids Res. 2009;37(suppl_2):W623–W633. doi:10.1093/nar/gkp45619498078
  • AkramH, PakdelFG, AhmadiA, ZareS. Beneficial effects of american ginseng on epididymal sperm analyses in cyclophosphamide treated rats. Cell Journal (Yakhteh). 2012;14(2):116.
  • BakhtiaryZ, ShahroozR, AhmadiA, ZareiL. Evaluation of antioxidant effects of crocin on sperm quality in cyclophosphamide treated adult mice. Faculty of Veterinary Medicine, Urmia University, Urmia, Iran. Veterinary Res Forum Int Quart J. 2014;(3):213.
  • ZhaoH, JinB, ZhangX, et al. Yangjing capsule ameliorates spermatogenesis in male mice exposed to cyclophosphamide. Evidence-Based Compl Alternative Med. 2015;2015:1–8. doi:10.1155/2015/980583
  • YanG, TianF, LiuP, et al. Sheng Jing Decoction, as a Traditional Chinese Medicine Prescription, Can Promote Spermatogenesis and Increase Sperm Motility. Research Square. 2021:1–16. doi:10.21203/rs.3.rs-167175/v1.
  • MehrabanZ, Ghaffari NovinM, GolmohammadiMG, SaghaM, PouriranK, NazarianH. Protective effect of gallic acid on apoptosis of sperm and in vitro fertilization in adult male mice treated with cyclophosphamide. J Cell Biochem. 2019;120(10):17250–17257. doi:10.1002/jcb.2898731135067
  • ChangZ, BaiX, TangY, et al. Pharmacological mechanisms of Yishen Xingyang capsule in the treatment of oligoasthenospermia in rats. J Traditional Chinese Med Sci. 2021;8(1):52–58. doi:10.1016/j.jtcms.2021.01.004
  • YangB, YangY-S, YangN, LiG, ZhuH-L. Design, biological evaluation and 3D QSAR studies of novel dioxin-containing pyrazoline derivatives with thiourea skeleton as selective HER-2 inhibitors. Sci Rep. 2016;6(1):1–12. doi:10.1038/srep2757128442746
  • AndersonD, SchmidTE, BaumgartnerA, Cemeli-CarratalaE, BrinkworthMH, WoodJM. Oestrogenic compounds and oxidative stress (in human sperm and lymphocytes in the Comet assay). Mutation Res Rev Mutation Res. 2003;544(2–3):173–178. doi:10.1016/j.mrrev.2003.06.016
  • JamalanM, GhaffariMA, HoseinzadehP, HashemitabarM, ZeinaliM. Human sperm quality and metal toxicants: protective effects of some flavonoids on male reproductive function. Int j Fertility Sterility. 2016;10(2):215.
  • GuidoC, PerrottaI, PanzaS, et al. Human sperm physiology: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) influence sperm metabolism and may be involved in the pathophysiology of varicocele‐associated male infertility. J Cell Physiol. 2011;226(12):3403–3412. doi:10.1002/jcp.2270321344398
  • AlvesMRC. Estrogens Regulate the Survival and Death Communication Between Sertoli and Germ Cells: A Clue for Male Infertility? Universidade da Beira Interior; 2013.
  • PoplinskiA, TüttelmannF, KanberD, HorsthemkeB, GromollJ. Idiopathic male infertility is strongly associated with aberrant methylation of MEST and IGF2/H19 ICR1. Int J Androl. 2010;33(4):642–649. doi:10.1111/j.1365-2605.2009.01000.x19878521
  • RasoulpourT, DiPalmaK, KolvekB, HixonM. Akt1 suppresses radiation-induced germ cell apoptosis in vivo. Endocrinology. 2006;147(9):4213–4221. doi:10.1210/en.2006-017416763066
  • Santos-AhmedJ, BrownC, SmithSD, et al. Akt1 protects against germ cell apoptosis in the postnatal mouse testis following lactational exposure to 6-N-propylthiouracil. Reprod Toxicol. 2011;31(1):17–25. doi:10.1016/j.reprotox.2010.09.01220951798
  • BreitbartH, EtkovitzN. Role and regulation of EGFR in actin remodeling in sperm capacitation and the acrosome reaction. Asian J Androl. 2011;13(1):106–110. doi:10.1038/aja.2010.7821200378
  • CocchiaN, PasoliniM, ManciniR, et al. Effect of sod (superoxide dismutase) protein supplementation in semen extenders on motility, viability, acrosome status and ERK (extracellular signal-regulated kinase) protein phosphorylation of chilled stallion spermatozoa. Theriogenology. 2011;75(7):1201–1210. doi:10.1016/j.theriogenology.2010.11.03121295831
  • LiMW, MrukDD, ChengCY. Mitogen-activated protein kinases in male reproductive function. Trends Mol Med. 2009;15(4):159–168. doi:10.1016/j.molmed.2009.02.00219303360
  • DumasiaK, KumarA, DeshpandeS, SonawaneS, BalasinorN. Differential roles of estrogen receptors, ESR1 and ESR2, in adult rat spermatogenesis. Mol Cell Endocrinol. 2016;428:89–100. doi:10.1016/j.mce.2016.03.02427004961
  • JosephA, HessRA, SchaefferDJ, et al. Absence of estrogen receptor alpha leads to physiological alterations in the mouse epididymis and consequent defects in sperm function. Biol Reprod. 2010;82(5):948–957. doi:10.1095/biolreprod.109.07988920130267
  • JosephA, ShurBD, KoC, ChambonP, HessRA. Epididymal hypo-osmolality induces abnormal sperm morphology and function in the estrogen receptor alpha knockout mouse. Biol Reprod. 2010;82(5):958–967. doi:10.1095/biolreprod.109.08036620130266
  • BrokkenLJS, Lundberg-GiwercmanY, De-meytsER, et al. Association of polymorphisms in genes encoding hormone receptors ESR1, ESR2 and LHCGR with the risk and clinical features of testicular germ cell cancer. Mol Cell Endocrinol. 2012;351(2):279–285. doi:10.1016/j.mce.2011.12.01822245602
  • LiX, LiH, JiaL, LiX, RahmanN. Oestrogen action and male fertility: experimental and clinical findings. Cell Mol Life Sci. 2015;72(20):3915–3930. doi:10.1007/s00018-015-1981-426160724
  • FerlinA, VinanziC, GarollaA, et al. Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations. Clin Endocrinol (Oxf). 2006;65(5):606–610. doi:10.1111/j.1365-2265.2006.02635.x17054461
  • DohleG, SmitM, WeberR. Androgens and male fertility. World J Urol. 2003;21(5):341–345. doi:10.1007/s00345-003-0365-914566423
  • O’HaraL, SmithLB. Androgen receptor roles in spermatogenesis and infertility. Best Pract Res Clin Endocrinol Metab. 2015;29(4):595–605. doi:10.1016/j.beem.2015.04.00626303086
  • YongE, LoyC, SimK. Androgen receptor gene and male infertility. Hum Reprod Update. 2003;9(1):1–7. doi:10.1093/humupd/dmg00312638777
  • MatfierJP. Establishment and characterization of two distinct mouse testicular epithelial cell line. Biol Reprod. 1980;23(1):243–252. doi:10.1095/biolreprod23.1.2436774781
  • HessRA, De FrancaLR. Spermatogenesis and cycle of the seminiferous epithelium. Mol Mechanisms Spermatogenesis. 2009;1–15.
  • MathurPP, D’cruzSC. The effect of environmental contaminants on testicular function. Asian J Androl. 2011;13(4):585. doi:10.1038/aja.2011.4021706039
  • NeryS, VieiraM, Dela CruzC, et al. Seminal plasma concentrations of Anti-Müllerian hormone and inhibin B predict motile sperm recovery from cryopreserved semen in asthenozoospermic men: a prospective cohort study. Andrology. 2014;2(6):918–923. doi:10.1111/andr.27825269872
  • GarciaTX, FarmahaJK, KowS, HofmannM-C. RBPJ in mouse Sertoli cells is required for proper regulation of the testis stem cell niche. Development. 2014;141(23):4468–4478. doi:10.1242/dev.11396925406395
  • RebourcetD, DarbeyA, MonteiroA, et al. Sertoli cell number defines and predicts germ and Leydig cell population sizes in the adult mouse testis. Endocrinology. 2017;158(9):2955–2969. doi:10.1210/en.2017-0019628911170
  • HaqueR, Bin-HafeezB, AhmadI, ParvezS, PandeyS, RaisuddinS. Protective effects of Emblica officinalis Gaertn. in cyclophosphamide-treated mice. Hum Exp Toxicol. 2001;20(12):643–650. doi:10.1191/09603270171889056811936579
  • DasUB, MallickM, DebnathJM, GhoshD. Protective effect of ascorbic acid on cyclophosphamide-induced testicular gametogenic and androgenic disorders in male rats. Asian J Androl. 2002;4(3):201–208.12364977
  • GhoshD, DasU, GhoshS, MallickM, DebnathJ. Testicular gametogenic and steroidogenic activities in cyclophosphamide treated rat: a correlative study with testicular oxidative stress. Drug Chem Toxicol. 2002;25(3):281–292. doi:10.1081/DCT-12000589112173249
  • TraslerJM, HermoL, RobaireB. Morphological changes in the testis and epididymis of rats treated with cyclophosphamide: a quantitative approach. Biol Reprod. 1988;38(2):463–479. doi:10.1095/biolreprod38.2.4633358980
  • TraslerJM, HalesBF, RobaireB. Chronic low dose cyclophosphamide treatment of adult male rats: effect on fertility, pregnancy outcome and progeny. Biol Reprod. 1986;34(2):275–283. doi:10.1095/biolreprod34.2.2753082378
  • QureshiM, PenningtonJ, GoldsmithH, CoxP. Cyclophosphamide therapy and sterility. Lancet. 1972;300(7790):1290–1291. doi:10.1016/S0140-6736(72)92657-8
  • HowellSJ, ShaletSM. Spermatogenesis after cancer treatment: damage and recovery. JNCi Monographs. 2005;2005(34):12–17. doi:10.1093/jncimonographs/lgi003
  • GoldbergMA, AntinJH, GuinanEC, RappeportJM. Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood. 1986;68(5):1114–1118. doi:10.1182/blood.V68.5.1114.1114.
  • AitkenR, ClarksonJ. Cellular basis of defective sperm function and its association with the genesis of reactive oxygen species, lipid peroxidation and human sperm function. J Reprod Fertil. 1987;41:183–197.