Protective effect of Dioscorea zingiberensis ethanol extract on the disruption of blood–testes barrier in high‐fat diet/streptozotocin‐induced diabetic mice by upregulating ZO‐1 and Nrf2

Testicular injury is the primary pathogenesis of diabetes‐induced male infertility. Dioscorea zingiberensis (DZ), a traditional Chinese medicine (TCM) including saponins, flavonoids and cellulose, is used to treat diseases in the reproductive system. But the protective effects of DZ on diabetes‐induced testicular injury remain poorly understood. In this study, the therapeutic effects of chronic oral DZ treatment on testis impairment in a diabetic mouse model were explored by assessing sperm morphology, blood–testes barrier (BTB) integrity and testicular histological examination. Our results showed that DZ significantly reversed BTB disruption, testicular tissue injury and abnormal sperm morphology in diabetic mice. Interestingly, diabetes‐induced disruption of the BTB was associated with a decrease in the tight junction (TJ) protein zonula occludens‐1 (ZO‐1). Dioscorea zingiberensis effectively increased ZO‐1 expression in testis tissue to restore the integrity of the BTB. Moreover, DZ treatment significantly reduced hyperglycaemia‐induced increases in malondialdehyde (MDA) and 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) levels. Further mechanistic studies revealed that DZ substantially enhanced the expression of Nrf2, NOQ1 and HO‐1, which indicated that DZ exerts potential antioxidant effects against testicular tissue damage via the activation of Nrf2. In conclusion, the protective effects of DZ rely on repairing the integrity of the BTB and on reducing oxidative stress damage by mediating ZO‐1 and Nrf2. The study contributes to discovering the DZ possible mechanism of action.

[1]  B. Ma,et al.  Luteolin Ameliorates Testis Injury and Blood-Testis Barrier Disruption through the Nrf2 Signaling Pathway and by Upregulating Cx43. , 2019, Molecular nutrition & food research.

[2]  B. Ma,et al.  MitoQ ameliorates testis injury from oxidative attack by repairing mitochondria and promoting the Keap1‐Nrf2 pathway , 2019, Toxicology and applied pharmacology.

[3]  R. Sedaghat,et al.  Diosgenin ameliorates testicular damage in streptozotocin‐diabetic rats through attenuation of apoptosis, oxidative stress, and inflammation , 2019, International immunopharmacology.

[4]  Ming Yan,et al.  Regulation of blood-testis barrier dynamics by the mTORC1/rpS6 signaling complex: an in vitro study , 2019, Asian journal of andrology.

[5]  Sha Yan,et al.  Functional characterization of squalene epoxidase and NADPH-cytochrome P450 reductase in Dioscorea zingiberensis. , 2019, Biochemical and biophysical research communications.

[6]  Sicen Wang,et al.  Dioscorea zingiberensis C. H. Wright: An overview on its traditional use, phytochemistry, pharmacology, clinical applications, quality control, and toxicity. , 2018, Journal of Ethnopharmacology.

[7]  L. Cai,et al.  Resveratrol attenuates testicular apoptosis in type 1 diabetic mice: Role of Akt-mediated Nrf2 activation and p62-dependent Keap1 degradation , 2017, Redox biology.

[8]  B. Silvestrini,et al.  Cell polarity and cytoskeletons-Lesson from the testis. , 2017, Seminars in cell & developmental biology.

[9]  B. Ma,et al.  Triptolide induces Sertoli cell apoptosis in mice via ROS/JNK-dependent activation of the mitochondrial pathway and inhibition of Nrf2-mediated antioxidant response , 2017, Acta Pharmacologica Sinica.

[10]  Sicen Wang,et al.  Safety investigation on total steroid saponins extracts from Dioscorea zingiberensis C.H. Wright: Sub‐acute and chronic toxicity studies on dogs , 2017, Regulatory toxicology and pharmacology : RTP.

[11]  A. Giwercman,et al.  Risk of diabetes according to male factor infertility: a register-based cohort study , 2017, Human reproduction.

[12]  L. Cai,et al.  Sulforaphane Prevents Angiotensin II-Induced Testicular Cell Death via Activation of NRF2 , 2017, Oxidative medicine and cellular longevity.

[13]  A. Józkowicz,et al.  Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism , 2016, Cellular and Molecular Life Sciences.

[14]  D. Long,et al.  9,10-Dihydrophenanthrene derivatives and one 1,4-anthraquinone firstly isolated from Dioscorea zingiberensis C. H. Wright and their biological activities. , 2016, Fitoterapia.

[15]  L. Baker,et al.  Increased risk of incident chronic medical conditions in infertile men: analysis of United States claims data. , 2016, Fertility and sterility.

[16]  M. Słojewski,et al.  Nuclear factor E2-related factor-2 (Nrf2) expression and regulation in male reproductive tract , 2016, Pharmacological reports : PR.

[17]  Heba Al‐Hussaini,et al.  Resveratrol alleviates diabetes-induced testicular dysfunction by inhibiting oxidative stress and c-Jun N-terminal kinase signaling in rats. , 2015, Toxicology and applied pharmacology.

[18]  Weimin Fan,et al.  Diet-Induced Obesity in Male C57BL/6 Mice Decreases Fertility as a Consequence of Disrupted Blood-Testis Barrier , 2015, PloS one.

[19]  Yuzhen Wang,et al.  Diosgenin Stimulates Rat TM4 Cell Proliferation Through Activating Plasma Membrane Translocation and Transcriptional Activity of Estrogen Receptors1 , 2015, Biology of reproduction.

[20]  J. Geiger,et al.  Cholesterol-enriched diet disrupts the blood-testis barrier in rabbits. , 2014, American journal of physiology. Endocrinology and metabolism.

[21]  Y. Ko,et al.  Arecoline induces TNF-alpha production and Zonula Occludens-1 redistribution in mouse Sertoli TM4 cells , 2014, Journal of Biomedical Science.

[22]  蔡銘修,et al.  Arecoline induces TNF-alpha production and Zonula Occludens-1 redistribution in mouse Sertoli TM4 cells , 2014 .

[23]  L. Cai,et al.  Sulforaphane reduction of testicular apoptotic cell death in diabetic mice is associated with the upregulation of Nrf2 expression and function. , 2014, American journal of physiology. Endocrinology and metabolism.

[24]  J. Hervé,et al.  Influence of the scaffolding protein Zonula Occludens (ZOs) on membrane channels. , 2014, Biochimica et biophysica acta.

[25]  M. Alves,et al.  Diabetes, insulin-mediated glucose metabolism and Sertoli/blood-testis barrier function , 2013, Tissue barriers.

[26]  Y. Shoenfeld,et al.  The autoimmune bases of infertility and pregnancy loss. , 2012, Journal of autoimmunity.

[27]  Philippa T. K. Saunders,et al.  Edinburgh Research Explorer Selective ablation of the androgen receptor in mouse sertoli cells affects sertoli cell maturation, barrier formation and cytoskeletal development , 2022 .

[28]  J. Chan,et al.  Knockout of the transcription factor NRF2 disrupts spermatogenesis in an age-dependent manner. , 2010, Free radical biology & medicine.

[29]  James M. Anderson,et al.  Zonula Occludens‐1 and ‐2 Are Cytosolic Scaffolds That Regulate the Assembly of Cellular Junctions , 2009, Annals of the New York Academy of Sciences.

[30]  E. Vicari,et al.  Andrological characterization of the patient with diabetes mellitus. , 2009, Minerva endocrinologica.

[31]  P. di Sant'Agnese,et al.  Androgen receptor in sertoli cell is essential for germ cell nursery and junctional complex formation in mouse testes. , 2006, Endocrinology.

[32]  Hernan Rincon-Choles,et al.  ZO-1 expression and phosphorylation in diabetic nephropathy. , 2006, Diabetes.

[33]  A. Isidori,et al.  Medical treatment to improve sperm quality. , 2006, Reproductive biomedicine online.

[34]  D. Spray,et al.  Structural Changes in the Carboxyl Terminus of the Gap Junction Protein Connexin43 Indicates Signaling between Binding Domains for c-Src and Zonula Occludens-1* , 2004, Journal of Biological Chemistry.

[35]  M. Haas,et al.  Diabetes-Related Changes in Rat Cerebral Occludin and Zonula Occludens-1 (ZO-1) Expression , 2002, Neurochemical Research.