Top

BMC Complementary Medicine and Therapies

Published in:

Open Access 01-12-2019 | Fertility | Research article

The effectiveness of traditional Japanese medicine Goshajinkigan in irradiation-induced aspermatogenesis in mice

Authors: Kumpei Takahashi, Kenta Nagahori, Ning Qu, Miyuki Kuramasu, Yoshie Hirayanagi, Shogo Hayashi, Yuki Ogawa, Naoyuki Hatayama, Hayato Terayama, Kaori Suyama, Shuichi Hirai, Kou Sakabe, Masahiro Itoh

Published in: BMC Complementary Medicine and Therapies | Issue 1/2019

Abstract

Background

Infertility and gonadal dysfunction are well known side-effects by cancer treatment in males. In particularly, chemotherapy and radiotherapy induced testicular damage, resulting in prolonged azoospermia. However, information regarding therapeutics to treat spermatogenesis disturbance after cancer treatment is scarce. Recently, we demonstrated that Goshajinkigan, a traditional Japanese medicine, can completely rescue severe busulfan-induced aspermatogenesis in mice. In this study, we aimed to detect the effects of Goshajinkigan on aspermatogenesis after irradiation.

Methods

This is animal research about the effects of traditional Japanese medicine on infertility after cancer treatment. C57BL/6 J male mice received total body irradiation (TBI: a single dose of 6Gy) at 4 weeks of age and after 60 days were reared a Goshajinkigan (TJ107)-containing or TJ107-free control diet from day 60 to day 120. Then, two untreated females were mated with a single male from each experimental group. On day 60, 120 and 150, respectively, the sets of testes and epididymis of the mice in each group after deep anesthetization were removed for histological and cytological examinations.

Results

Histological and histopathological data showed that 6Gy TBI treatment decreased the fertility rate (4/10) in the control diet group; in contrast, in the TJ107-diet group, the fertility rate was 10/10 (p < 0.05 vs. 6Gy group). Supplementation with TJ107 was found to rescue the disrupted inter-Sertoli tight junctions via the normalization of claudin11, occludin, and ZO-1 expression and reduce serum anti-germ cell autoantibodies.

Conclusions

These findings show the therapeutic effect on TBI-induced aspermatogenesis and the recovering disrupted gonadal functions by supplementation with TJ107.

Centola GM, Keller JW, Henzler M, Rubin P. Effect of low-dose testicular irradiation on sperm count and fertility in patients with esticularseminoma. J Androl. 1994;15:608–13. https://doi.org/10.1002/j.1939-4640.1994.tb00507.x.CrossRefPubMed

Sanders JE, Hawley J, Levy W, Gooley T, Buckner CD, Deeg HJ, Doney K, Storb R, Sullivan K, Witherspoon R, Appelbaum FR. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood. 1996;87:3045–52. https://doi.org/10.1182/blood.V87.7.3045.bloodjournal8773045.CrossRefPubMed

Vergouwen RP, Huiskamp R, Bas RJ, Roepers-Gajadien HL, de Jong FH, van Eerdenburg FJ, Davids JA, de Rooij DG. Radiosensitivity of testicular cells in the prepubertal mouse. Radiat Res. 1994;139:316–26. https://doi.org/10.2307/3578829.CrossRefPubMed

Khan S, Adhikari JS, Rizvi MA, Chaudhury NK. Radioprotective potential of melatonin against ⁶⁰Co γ-ray-induced testicular injury in male C57BL/6 mice. J Biomed Sci. 2015;22:61. https://doi.org/10.1186/s12929-015-0156-9.CrossRefPubMedPubMedCentral

Pino-Lataillade G, Velez de la Calle JF, Viguier-Martinez MC. Influence of germ cells upon Sertoli cells during continuous low-dose rate gamma-irradiation of adult rats. Mol Cell Endocrinol 1988;58: 51–63. dio:https://doi.org/10.1016/0303-7207(88)90053-6 CrossRef

Hasegawa M, Wilson G, Russell LD. Radiation-induced cell death in the mouse testis: relationship to apoptosis. Radiat Res. 1997;147:457–67. https://doi.org/10.2307/3579503.CrossRefPubMed

Silva AM, Correia S, Casalta-Lopes JE, Mamede AC, Cavaco JE, Botelho MF, Socorro S, Maia CJ. The protective effect of regucalcin against radiation-induced damage in testicular cells. Life Sci. 2016;164:31–41. https://doi.org/10.1016/j.lfs.2016.09.003.CrossRefPubMed

Khan S, Adhikari JS, Rizvi MA, Chaudhury NK. Radioprotective potential of melatonin against Co γ-ray-induced testicular injury in male C57BL/6 mice. J Biomed Sci. 2015;22:61. https://doi.org/10.1186/s12929-015-0156-9.CrossRefPubMedPubMedCentral

Cordelli E, Fresegna AM, Leter G, Eleuteri P, Spano M, Villani P. Evaluation of DNA damage in different stages of mouse spermatogenesis after testicular X irradiation. Radiat Res. 2003;160:443–51. https://doi.org/10.1667/RR3053.CrossRefPubMed

10.

Ameli M, Hashemi MS, Moghimian M, Schokoohi M. Protective effect of tadalafil and verapamil on testicular function and oxidative stress after torsion/detorsion in adult male rat. Andrologia. 2018;50:e13068. https://doi.org/10.1111/and.13068.CrossRefPubMed

11.

Shokoohi M, Shoorei H, Soltani M, Abtahi-Eivari SH, Salimnejad R, Moghimian M. Protective effects of the hydroalcoholic extract of Fumaria parviflora on testicular injury induced by torsion/detorsion in adult rat. Andrologia. 2018;50(7):e13047. https://doi.org/10.1111/and.13047.CrossRefPubMed

12.

Shoorei H, Khaki A, Khaki AA, Hemmati AA, Moghimian M, Shokoohi M. The ameliorative effect of carvacrol on oxidative stress and germ cell apoptosis in testicular tissue of adult diabetic rats. Biomed Pharmacother. 2019;111:568–78. https://doi.org/10.1016/j.biopha.2018.12.054.CrossRefPubMed

13.

Levine J, Canada A, Stern CJ. Fertility preservation in adolescents and young adults with cancer. J Clin Oncol. 2010;28:4831–41.CrossRef

14.

Yokonishi T, Ogawa T. Cryopreservation of testis tissues and in vitro spermatogenesis. Reprod Med Biol. 2016;15:21–8. https://doi.org/10.1007/s12522-015-0218-4.CrossRefPubMed

15.

Onofre J, Baert Y, Faes K, Goossens E. Cryopreservation of testicular tissue or testicular cell suspensions: a pivotal step in fertility preservation. Hum Reprod Update. 2016;22:744–61. https://doi.org/10.1093/humupd/dmw029.CrossRefPubMedPubMedCentral

16.

Shetty G, Meistrich ML. Hormonal approaches to preservation and restoration of male fertility after cancer treatment. J Natl Cancer Inst Monogr. 2005;34:36–9. https://doi.org/10.1093/jncimonographs/lgi002.CrossRef

17.

Schally AV, Paz-Bouza JI, Schlosser JV, Karashima T, Debeljuk L, Gandle B, Sampson M. Protective effects of analogs of luteinizing hormone-releasing hormone against x-radiation-induced testicular damage in rats. Proc Natl Acad Sci. 1987;84:851–5. https://doi.org/10.1073/pnas.84.3.851.CrossRefPubMed

18.

van Alphen MM, van de Kant HJ, de Rooij DG. Protection from radiation-induced damage of spermatogenesis in the rhesus monkey (Macaca mulatta) by follicle-stimulating hormone. Cancer Res. 1989;49:533–6.PubMed

19.

Songthaveesin C, Saikhun J, Kitiyanant Y, Pavasuthipaisit K. Radio-protective effect of vitamin E on spermatogenesis in mice exposed to gamma-irradiation: a flow cytometric study. Asian J Androl. 2004;6:331–6.PubMed

20.

Mozdarani H, Nazari E. Cytogenetic damage in preimplantation mouse embryos generated after paternal and parental gamma-irradiation and the influence of vitamin C. Reproduction. 2009;137:35–43. https://doi.org/10.1530/REP-08-0073.CrossRefPubMed

21.

Bahmanpour S, Vojdan Z, Panjehshahin MR, Hoballah H, Kassas H. Effects of Carthamus tinctorius on semen quality and gonadal hormone levels in partially sterile male rats. Korean J Urol. 2012;53:705. https://doi.org/10.4111/kju.2012.53.10.705.CrossRefPubMedPubMedCentral

22.

Fedail JS, Ahmed AA, Musa HH, Ismail E, Sifaldin AZ, Musa TH. Gum Arabic improves semen quality and oxidative stress capacity in alloxan induced diabetes rats. Asian Pac J Reprod. 2016;5:434–41. https://doi.org/10.1016/j.apjr.2016.07.014.CrossRef

23.

Zang ZJ, Ji SY, Dong W, Zhang YN, Zhang EH, Bin Z. A herbal medicine, saikokaryukotsuboreito, improves serum testosterone levels and affects sexual behavior in old male mice. Aging Male. 2015;18:106–11. https://doi.org/10.3109/13685538.2014.963042.CrossRefPubMed

24.

Zhu W, Du Y, Meng H, Dong Y, Li L. A review of traditional pharmacological uses, phytochemistry, and pharmacological activities of Tribulus terrestris. Chem Cent J 2017;11. https://doi.org/10.1186/s13065-017-0289-x.

25.

Mohammadi F, Nikzad H, Taherian A, Amini Mahabadi J, Salehi M. Effects of herbal medicine on male infertility. Anatom Sci J. 2013;10(4):3–16.

26.

Jo J, Lee SH, Yoon SR, Kim K-II. The effectiveness of Korean herbal medicine in infertile men with poor semen quality: a prospective observational pilot study. Andrologia. 2019;51:e13226. https://doi.org/10.1111/and.13226.CrossRefPubMed

27.

Mizuno K, Kono T, Suzuki Y, Miyagi C, Omiya Y, Miyano K, Kase Y, Uezono Y. Goshajinkigan, a traditional Japanese medicine, prevents oxaliplatin-induced acute peripheral neuropathy by suppressing functional alteration of TRP channels in rat. J Pharmacol Sci. 2014;125:91–8. https://doi.org/10.1254/jphs.13244FP.CrossRefPubMed

28.

Matsumura Y, Yokoyama Y, Hirakawa H, Shigeto T, Futagami M, Mizunuma H. The prophylactic effects of a traditional Japanese medicine, goshajinkigan, on paclitaxel-induced peripheral neuropathy and its mechanism of action. Mol Pain. 2014;10:61. https://doi.org/10.1186/1744-8069-10-61.CrossRefPubMedPubMedCentral

29.

Yagi H, Sato R, Nishio K, Arai G, Soh S, Okada H. Clinical efficacy and tolerability of two Japanese traditional herbal medicines, Hachimi-jio-gan and Gosha-jinki-gan, for lower urinary tract symptoms with cold sensitivity. J Tradit Complement Med. 2015;5:258–61. https://doi.org/10.1016/j.jtcme.2015.03.010.CrossRefPubMedPubMedCentral

30.

Kono T, Suzuki Y, Mizuno K, Miyagi C, Omiya Y, Sekine H, Mizuhara Y, Miyano K, Kase Y, Uezono Y. Preventive effect of oral goshajinkigan on chronic oxaliplatin-induced hypoesthesia in rats. Sci Rep. 2015;5:16078. https://doi.org/10.1038/srep16078.CrossRefPubMedPubMedCentral

31.

Kishida Y, Kagawa S, Arimitsu J, Nakanishi M, Otsuka S, Yoshikawa H, Hagihara K. Go-sha-jinki-Gan (GJG), a traditional Japanese herbal medicine, protects against sarcopenia in senescence-accelerated mice. Phytomedicine. 2015;22:16–22. https://doi.org/10.1016/j.phymed.2014.11.005.CrossRefPubMed

32.

Nakanishi M, Nakae A, Kishida Y, Baba K, Sakashita N, Shibat M, Yoshikawa H, Hagihara K. Go-sha-jinki-Gan (GJG) ameliorates allodynia in chronic constriction injury-model mice via suppression of TNF-α expression in the spinal cord. Mol Pain 2016;12. https://doi.org/10.1177/1744806916656382.CrossRef

33.

Liu CL, Cheng L, Ko CH, Wong CW, Cheng WH, Cheung DW, Leung PC, Fung KP, Bik-San LC. Bioassay-guided isolation of anti-inflammatory components from the root of Rehmannia glutinosa and its underlying mechanism via inhibition of iNOS pathway. J Ethnopharmacol. 2012;143(3):867–75. https://doi.org/10.1016/j.jep.2012.08.012.CrossRefPubMed

34.

Park CH, Noh JS, Kim JH, Tanaka T, Zhao Q, Matsumoto K, Shibahara N, Yokozawa T. Evaluation of morroniside, iridoid glycoside from Corni Fructus, on diabetes-induced alterations such as oxidative stress, inflammation, and apoptosis in the liver of type 2 diabetic db/db mice. Biol Pharm Bull. 2011;34:1559–65. https://doi.org/10.1248/bpb.34.1559.CrossRefPubMed

35.

Chiu CS, Deng JS, Chang HY, Chen YC, Lee MM, Hou WC, Lee CY, Huang SS, Huang GJ. Antioxidant and anti-inflammatory properties of Taiwanese yam (Dioscorea japonica Thunb. var. pseudojaponica (Hayata) Yamam.) and its reference compounds. Food Chem. 2013;141:1087–96. https://doi.org/10.1016/j.foodchem.2013.04.031.CrossRefPubMed

36.

Fu PK, Yang CY, Tsai TH, Hsieh CL. Moutan cortex radicis improves lipopolysaccharide-induced acute lung injury in rats through anti-inflammation. Phytomedicine. 2012;19:1206–15. https://doi.org/10.1016/j.phymed.2012.07.013.CrossRefPubMed

37.

Kubo M, Ma S, Wu J, Matsuda H. Anti-inflammatory activities of 70% methanolic extract from Cinnamomi Cortex. Biol Pharm Bull. 1996;19:1041–5. https://doi.org/10.1248/bpb.19.1041.CrossRefPubMed

38.

Liao JC, Deng JS, Chiu CS, Hou WC, Huang SS, Shie PH, Huang GJ. Anti-inflammatory activities of Cinnamomum cassia constituents in vitro and in vivo. Evid Based Complement Alternat Med. 2012;2012:429320. https://doi.org/10.1155/2012/429320.CrossRefPubMedPubMedCentral

39.

Qu N, Kuramasu M, Hirayanagi Y, Nagahori K, Hayashi S, Ogawa Y, Terayama H, Suyama K, Naito M, Sakabe K, Itoh M. Gosha-Jinki-Gan recovers spermatogenesis in mice with busulfan-induced aspermatogenesis. Int J Mol Sci. 2018;19(pii):E2606. https://doi.org/10.3390/ijms19092606.CrossRefPubMed

40.

Hirai S, Hatayama N, Naito M, Nagahori K, Kawata S, Hayashi S, Qu N, Terayama H, Shoji S, Itoh M. Pathological effect of arterial ischaemia and venous congestion on rat testes. Sci Rep. 2017;7(1):5422. https://doi.org/10.1038/s41598-017-05880-2.CrossRefPubMedPubMedCentral

41.

Qu N, Terayama H, Hirayanagi Y, Kuramasu M, Ogawa Y, Hayashi S, Hirai S, Naito M, Itoh M. Induction of experimental autoimmune orchitis by immunization with xenogenic testicular germ cells in mice. J Reprod Immunol. 2017;121:11–6. https://doi.org/10.1016/j.jri.2017.04.006.CrossRefPubMed

42.

Hirai S, Naito M, Kuramasu M, Ogawa Y, Terayama H, Qu N, Hatayama N, Hayashi S, Itoh M. Low-dose exposure to di-(2-ethylhexyl) phthalate (DEHP) increases susceptibility to testicular autoimmunity in mice. Reprod Biol. 2015;15(3):163–71. https://doi.org/10.1016/j.repbio.2015.06.004.CrossRefPubMed

43.

Lysiak JJ, Turner SD, Turner TT. Molecular pathway of germ cell apoptosis following ischemia/reperfusion of the rat testis. Biol Reprod. 2000;63:1465–72. https://doi.org/10.1095/biolreprod63.5.1465.CrossRefPubMed

44.

Meistrich ML, Shetty G. Inhibition of spermatogonial differentiation by testosterone. J Andro. 2003;24:135–48. https://doi.org/10.1002/j.1939-4640.2003.tb02652.x.CrossRef

45.

Zhang X, Wang T, Deng T, Xiong W, Lui P, Li N, Chen Y, Han D. Damaged spermatogenic cells induce inflammatory gene expression in mouse Sertoli cells through the activation of Toll-like receptors 2 and 4. Mol Cell Endocrinol. 2013;365:162–73. https://doi.org/10.1016/j.mce.2012.10.016.CrossRefPubMed

46.

Anand S, Bhartiya D, Sriraman K, Mallick A. Underlying mechanisms that restore spermatogenesis on transplanting healthy niche cells in busulphan treated mouse testis. Stem Cell Rev Rep. 2016;12:682–97. https://doi.org/10.1007/s12015-016-9685-1. Springer USCrossRefPubMed

47.

Wang CQ, Cheng CY. A seamless trespass: germ cell migration across the seminiferous epithelium during spermatogenesis. J Cell Biol. 2007;178:549–56. https://doi.org/10.1083/jcb.200704061.CrossRefPubMedPubMedCentral

48.

Meinhardt A, Hedger MP. Immunological, paracrine and endocrine aspects of testicular immune privilege. Mol Cell Endocrinol. 2011;335:60–8. https://doi.org/10.1016/j.mce.2010.03.022.CrossRefPubMed

49.

Cheng CY, Mruk DD. The blood-testis barrier and its implications for male contraception. Pharmacol Rev. 2012;64:16–64. https://doi.org/10.1124/pr.110.002790.CrossRefPubMedPubMedCentral

50.

Morita K, Furuse M, Fujimoto K, Tsukita S. Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc Natl Acad Sci. 1999;96:511–6. https://doi.org/10.1073/pnas.96.2.511.CrossRefPubMed

51.

Morita K, Sasaki H, Fujimoto K, Furuse M, Tsukita S. Claudin-11/OSP-based tight junction of myelin sheaths in brain and Sertoli cells in testis. J Cell Biol. 1999;145:579–88. https://doi.org/10.1083/jcb.145.3.579.CrossRefPubMedPubMedCentral

52.

Stevenson BR, Siliciano JD, Mooseker MS, Goodenough DA. Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol. 1986;103:755–66. https://doi.org/10.1083/jcb.103.3.755.CrossRefPubMed

53.

Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM. The tight junction protein ZO-1 establishes a link between the transmembrane protein occluding and the actin cytoskeleton. J Biol Chem. 1998;273:29745–53. https://doi.org/10.1074/jbc.273.45.29745.CrossRefPubMed

54.

Wang XW, Ding GR, Shi CH, Zeng LH, Liu JY, Li J, Zhao T, Chen YB, Guo GZ. Mechanisms involved in the blood-testis barrier increased permeability induced by EMP. Toxicology. 2010;276:58–63. https://doi.org/10.1016/j.tox.2010.07.003.CrossRefPubMed

55.

Son Y, Heo K, Bae MJ, Lee CG, Cho WS, Kim SD, Yang K, Shin IS, Lee MY, Kim JS. Injury to the blood-testis barrier after low-dose-rate chronic radiation exposure in mice. Radiat Prot Dosim. 2015;167:316–20. https://doi.org/10.1093/rpd/ncv270.CrossRef

56.

Jiang D, Coscione A, Li L, Zeng BY. Effect of Chinese herbal medicine on male infertility. Int Rev Neurobiol. 2017;135:297–311. https://doi.org/10.1016/bs.irn.2017.02.014.CrossRefPubMed

57.

Bhat R, Karim AA. Tongkat Ali (Eurycoma longifolia Jack): a review on its ethnobotany and pharmacological importance. Fitoterapia. 2010;81:669–79. https://doi.org/10.1016/j.fitote.2010.04.006.CrossRefPubMed

58.

Chen CK, Mohamad WMZW, Ooi FK, Ismail SB, Abdullah MR, George A. Supplementation of Eurycoma longifolia Jack extract for 6 weeks does not affect urinary testosterone: epitestosterone ratio, liver and renal functions in male recreational athletes. Int J Prev Med. 2014;5:728–33.PubMedPubMedCentral

59.

Neychev V, Mitev V. Pro-sexual and androgen enhancing effects of Tribulus terrestris L.: fact or fiction. J Ethnopharmacol. 2016;179:345–55. https://doi.org/10.1016/j.jep.2015.12.055.CrossRefPubMed

60.

Santos HO, Howell S, Teixeira FJ. Beyond Tribulus (Tribulus terrestris L.): The effects of phytotherapics on testosterone, sperm and prostate parameters. J Ethnopharmacol. 2019;235:392–405. https://doi.org/10.1016/j.jep.2019.02.033.CrossRefPubMed

61.

Khanijo T, Jiraungkoorskul W. Review ergogenic effect of long Jack, Eurycoma longifolia. Pharmacogn Rev. 2016;10:139–42. https://doi.org/10.4103/0973-7847.194041.CrossRefPubMedPubMedCentral

62.

Rehman SU, Choe K, Yoo HH. Review on a traditional herbal medicine, Eurycoma longifolia Jack (Tongkat Ali): its traditional uses, chemistry, evidence- based pharmacology and toxicology. Molecules. 2016;21:331. https://doi.org/10.3390/molecules21030331.CrossRefPubMedPubMedCentral

63.

Shokoohi M, Madarek EOS, Khaki A, Shoorei H, Khaki AA, Soltani M, Ainehchi N. Investigating the effects of onion juice on male fertility factors and pregnancy rate after testicular torsion/detorsion by intrauterine insemination method. Int J WHR Sci. 2018;4:499–505. https://doi.org/10.15296/ijwhr.2018.82.CrossRef

64.

Mahdavi R, Heshmati J, Namazi N. Effects of black seeds (Nigella sativa) on male infertility: a systematic review. J Herb Med. 2015;5:133–9. https://doi.org/10.1016/j.hermed.2015.03.002.CrossRef

65.

Talbott SM, Talbott JA, George A, Pugh M. Effect of Tongkat Ali on stress hormones and psychological mood state in moderately stressed subjects. J Int Soc Sports Nutr. 2013;10:28. https://doi.org/10.1186/1550-2783-10-28.CrossRefPubMedPubMedCentral

Title: The effectiveness of traditional Japanese medicine Goshajinkigan in irradiation-induced aspermatogenesis in mice
Authors: Kumpei Takahashi
Kenta Nagahori
Ning Qu
Miyuki Kuramasu
Yoshie Hirayanagi
Shogo Hayashi
Yuki Ogawa
Naoyuki Hatayama
Hayato Terayama
Kaori Suyama
Shuichi Hirai
Kou Sakabe
Masahiro Itoh
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Fertility
Infertility
Infertility
Published in: BMC Complementary Medicine and Therapies / Issue 1/2019
Electronic ISSN: 2662-7671
DOI: https://doi.org/10.1186/s12906-019-2786-z

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

The effectiveness of traditional Japanese medicine Goshajinkigan in irradiation-induced aspermatogenesis in mice

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2019

Investigation of anti-cancer and migrastatic properties of novel curcumin derivatives on breast and ovarian cancer cell lines

Critical pharmacokinetic and pharmacodynamic drug-herb interactions in rats between warfarin and pomegranate peel or guava leaves extracts

Microbial population dynamics under microdoses of the essential oil arborvitae

Ocimum gratissimum Linn. Leaves reduce the key enzymes activities relevant to erectile dysfunction in isolated penile and testicular tissues of rats

Qingkailing injection ameliorates cerebral ischemia-reperfusion injury and modulates the AMPK/NLRP3 Inflammasome Signalling pathway

Complementary medicine use among Australian patients in an acute hospital setting: an exploratory, cross sectional study