Role of KU70, SIRT1, and SIRT6 Proteins in Diabetic Rat Testis Tissue
Year 2024,
Volume: 13 Issue: 3, 82 - 91, 26.09.2024
Selim Demirtaş
,
Onur Ersoy
,
Gülnur Kızılay
Abstract
Diabetic male infertility/subfertility is an important complication of diabetes. The molecular mechanisms responsible for this complication have not been thoroughly investigated. We aimed to elucidate the role of KU70, SIRT1, and SIRT6 proteins in diabetic testis. Sprague–Dawley male rats were maintained under stable laboratory conditions. The rats were divided into a control group (n=8) and a diabetes group (n=8 treated with a single dose of 50 mg/kg streptozotocin). At the end of the 1-month experimental period, animals were sacrificed under anesthesia. Both testicles were removed, processed lightly, and studied through electron transmission microscopy and western blotting. Blood samples were collected for biochemical analysis. Histopathological analysis revealed that, in the diabetes group, the diaphragmatic tubule diameters and serum testosterone levels were decreased. KU70 immunoreactivity was statistically significantly increased, whereas SIRT1 and SIRT6 expression was significantly decreased compared with that observed in the control group. This is the first study to examine the expression of KU70, SIRT1, and SIRT6 in diabetic testicular tissue for the first time. According to the results, KU70, SIRT1, and SIRT6 may play an important role in cell apoptosis in diabetic testicular tissue. Importance of these proteins should be investigated further in additional quantitative studies.
Ethical Statement
The authors report no conflicts of interest.
Supporting Institution
This study was supported by a grant from the Trakya University Scientific Research Committee, Edirne, Turkey (Project number: 2017/184).
Thanks
The authors also thank Istanbul Bilgi University for contributing to the proofreading service.
References
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- Raffaele M, Li Volti G, Barbagallo IA, Vanella L. Therapeutic efficacy of stem cells transplantation in diabetes: role of heme oxygenase. Front Cell Dev Biol. 2016;4:80.
- Zha W, Bai Y, Xu L, et al. Curcumin attenuates testicular injury in rats with streptozotocin-induced diabetes. BioMed Res Int. 2018;2018:7468019.
- Alves MG, Martins AD, Rato L, Moreira PI, Socorro S, Oliveira PF. Molecular mechanisms beyond glucose transport in diabetes-related male infertility. Biochim Biophys Acta. 2013;1832(5):626-635.
- Amaral S, Oliveira PJ, Ramalho-Santos J. Diabetes and the impairment of reproductive function: possible role of mitochondria and reactive oxygen species. Curr Diabetes Rev. 2008;4(1):46-54.
- Ersoy O, Kizilay G. Effects of fucoidan on diabetic rat testicular tissue. Biotech Histochem. 2018;93(4):277-285.
- Trindade AA, Simoes AC, Silva RJ, Macedo CS, Spadella CT. Long term evaluation of morphometric and ultrastructural changes of testes of alloxan-induced diabetic rats. Acta Cir Bras. 2013;28(4):256-265.
- Fell, VL, Schild-Poulter C. The Ku heterodimer: function in DNA repair and beyond. Mutat Res Rev Mutat Res. 2015;763:15-29.
- Hada M, Kwok RP. Regulation of Ku70-Bax complex in cells. J Cell Death. 2014;7:11-13.
- Bayram A, İğci M. Sirtuin genes and functions. Fırat Med J. 2013;18(3):136-140.
- Chalkiadaki A, Guarente L. The multifaceted functions of sirtuins in cancer. Nat Rev Cancer. 2015;15(10):608-624.
- Gomez JA, Gama V, Yoshida T, Sun W, Hayes P, Leskov K, et al. Bax-inhibiting peptides derived from Ku70 and cell-penetrating pentapeptides. Biochem Soc Trans. 2007;35(Pt 4):797-801.
- Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J. 2007;404(1):1-13.
- Sharma A, Diecke S, Zhang WY, Lan F, He C, Mordwinkin NM, et al. The role of SIRT6 protein in aging and reprogramming of human induced pluripotent stem cells. J Biol Chem. 2013;288(25):18439-18447.
- Wang W, Sun W, Cheng Y, Xu Z, Cai L. Role of sirtuin-1 in diabetic nephropathy. J Mol Med (Berl). 2019;97(3):291-309.
- Tao NN, Ren JH, Tang H, Ran LK, Zhou HZ, Liu B, et al. Deacetylation of Ku70 by SIRT6 attenuates Bax-mediated apoptosis in hepatocellular carcinoma. Biochem Biophys Res Commun. 2017;485(4):713-719.
- Nasirian F, Sarir H, Moradi-kor N. Antihyperglycemic and antihyperlipidemic activities of Nannochloropsis oculata microalgae in streptozotocin-induced diabetic rats. Biomol Concepts. 2019;10(1):37-43.
- Franca L, Suescun M, Miranda J, Giovambatista A, Perello M, Spinedi E, et al. Testis structure and function in a nongenetic hyperadipose rat model at prepubertal and adult ages. Endocrinology. 2006;147(3):1556-1563.
- Sadik NA, El-Seweidy MM, Shaker OG. The antiapoptotic effects of sulphurous mineral water and sodium hydrosulphide on diabetic rat testes. Cell Physiol Biochem. 2011;28(5):887-898.
- Bayram S, Kizilay G, Topcu-Tarladacalisir Y. Evaluation of the Fas/FasL signaling pathway in diabetic rat testis. Biotech Histochem. 2016;91(3):204-211.
- Li C, Wang L, Zheng L, et al. SIRT1 expression is associated with poor prognosis of lung adenocarcinoma. OncoTargets Ther. 2015;8:977.
- Choi EK, Lee YH, Choi YS, Kwon HM, Choi MS, Ro JY, et al. Heterogeneous expression of Ku70 in human tissues is associated with morphological and functional alterations of the nucleus. J Pathol. 2002;198(1):121-130.
- Jangir RN, Jain GC. Diabetes mellitus induced impairment of male reproductive functions: a review. Curr Diabetes Rev. 2014;10(3):147-157.
- Ghosh S, Chowdhury S, Das AK, Sil PC. Taurine ameliorates oxidative stress induced inflammation and ER stress mediated testicular damage in stz-induced diabetic Wistar rats. Food Chem Toxicol. 2019;124:64-80.
- Cameron DF, Murray FT, Drylie DD. Interstitial compartment pathology and spermatogenic disruption in testes from impotent diabetic men. Anat Rec. 1985;213(1):53-62.
- Öztürk F, Gül M, Ağkadir M, Yağmurca M. Histological alterations of rat testes in experimental diabetes. Turkiye Klinikleri J Med Sci. 2002;22(2):173-178.
- Koroglu P, Senturk GE, Yucel D, Ozakpinar OB, Uras F, Arbak S. The effect of exogenous oxytocin on streptozotocin (STZ)-induced diabetic adult rat testes. Peptides. 2015;63:47-54.
- Kianifard D, Sadrkhanlou RA, Hasanzadeh S. The ultrastructural changes of the Sertoli and leydig cells following streptozotocin induced diabetes. Iran J Basic Med Sci. 2012;15(1):623-635.
- Cambay Z, Baydas G, Tuzcu M, Bal R. Pomegranate (Punica granatum L.) flower improves learning and memory performances impaired by diabetes mellitus in rats. Acta Physiol Hung. 2011;98(4):409-420.
- Ding C, Wang Q, Hao Y, Ma X, Wu L, du M, et al. Vitamin D supplement improved testicular function in diabetic rats. Biochem Biophys Res Commun. 2016;473(1):161-167.
- Öztaş E, Yılmaz TE, Güzel E, Sezer Z, Okyar A, Özhan G. Gliclazide alone or in combination with atorvastatin ameliorated reproductive damage in streptozotocin-induced type 2 diabetic male rats. Saudi Pharm J. 2019;27(3):422-431.
- Wankeu-Nya M, Florea A, Bâlici S, Watcho P, Matei H, Kamanyi A. Dracaena arborea alleviates ultra-structural spermatogenic alterations in streptozotocin-induced diabetic rats. BMC Compl Alternative Med. 2013;13(1):71.
- Yin Y, DeWolf WC, Morgentaler A. Experimental cryptorchidism induces testicular germ cell apoptosis by p53-dependent and-independent pathways in mice. Biol Reprod. 1998;58(2):492-496.
- Li Y-J, Song T-B, Cai Y-Y, et al. Bisphenol A exposure induces apoptosis and upregulation of Fas/FasL and caspase-3 expression in the testes of mice. Toxicol Sci. 2009;108(2):427-436.
- Liu Y, Yang Z, Kong D, Zhang Y, Yu W, Zha W. Metformin ameliorates testicular damage in male mice with streptozotocin-induced type 1 diabetes through the PK2/PKR pathway. Oxid Med Cell Longev. 2019;2019:5681701.
- Koh PO. Streptozotocin-induced diabetes increases apoptosis through JNK phosphorylation and Bax activation in rat testes. J Vet Med Sci. 2007;69(9):969-971.
- Koh PO. Streptozotocin-induced diabetes increases the interaction of Bad/Bcl-XL and decreases the binding of pBad/14-3-3 in rat testis. Life Sci. 2007;81(13):1079-1084.
- İrtegün S, Deveci E. Examining the expression level of VEGF and Bcl-2 by immunohistochemistry and western blot in testis tissue of diabetic rats. Dicle Med J. 2016;43(4):527-533.
- Khamis T, Abdelalim AF, Abdallah SH, Saeed AA, Edress NM, Arisha AH. Early intervention with breast milk mesenchymal stem cells attenuates the development of diabetic-induced testicular dysfunction via hypothalamic Kisspeptin/Kiss1r-GnRH/GnIH system in male rats. Biochim Biophys Acta Mol Basis Dis. 2020;1866(1):165577.
- Ahmed EA, Sfeir, A, Takai H, Scherthan H. Ku70 and non-homologous end joining protect testicular cells from DNA damage. J Cell Sci. 2013;126(14):3095-104.
- Tuncdemir M, Ozturk M. Regulation of the Ku70 and apoptosis-related proteins in experimental diabetic nephropathy. Metabolism. 2016;65(10):1466-1477.
- Wang Y, Lai L, Guo W, Peng S, Liu R, Hong P, et al. Inhibition of Ku70 in a high-glucose environment aggravates bupivacaine-induced dorsal root ganglion neurotoxicity. Toxicol Lett. 2020;318:104-113.
- Xu T, Liu Y, Li P, Xu X, Zeng J. Insulin in combination with selenium inhibits HG/Pal-induced cardiomyocyte apoptosis by Cbl-b regulating p38MAPK/CBP/Ku70 pathway. Eur Rev Med Pharmacol Sci. 2016;20(15):3297-3303.
- Kerr E, Holohan C, McLaughlin KM, et al. Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. Cell Death Differ. 2012;19(8):1317-1327.
- Matsuyama S, Palmer J, Bates A, Poventud-Fuentes I, Wong K, Ngo J, et al. Bax-induced apoptosis shortens the life span of DNA repair defect Ku70-knockout mice by inducing emphysema. Exp Biol Med. 2016;241(12):1265-1271.
- McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR, et al. The mammalian SIR2 protein has a role in embryogenesis and gametogenesis. Mol Cell Biol. 2003;23(1):38-54.
- Ogawa T, Wakai C, Saito T, et al. Distribution of the longevity gene product, SIRT1, in developing mouse organs. Congenit Anom. 2011;51(2):70-79.
- Al-Bader M, Kilarkaje N. Effects of Trans-Resveratrol on hyperglycemia-induced abnormal spermatogenesis, DNA damage and alterations in poly (ADP-ribose) polymerase signaling in rat testis. Toxicol Appl Pharmacol. 2016;311:61-73.
- Al-Bader M, Kilarkaje N. Dataset of Trans-Resveratrol on diabetes-induced abnormal spermatogenesis, poly (ADP-ribose) polymerase-1 (PARP1) expression in intra-testicular blood vessels, and stage-dependent expression of PARP1 and Sirtuin 1 in the rat testis. Data Brief. 2017;10:230-237.
- He W, Liu H, Hu L, Wang Y, Huang L, Liang A, et al. Icariin improves testicular dysfunction via enhancing proliferation and inhibiting mitochondria-dependent apoptosis pathway in high-fat diet and streptozotocin-induced diabetic rats. Reprod Biol Endocrinol. 2021;19(1):168.
- Huang T, Zhou Y, Lu X, Tang C, Ren C, Bao X, et al. Cordycepin, a major bioactive component of Cordyceps militaris, ameliorates diabetes-induced testicular damage through the Sirt1/Foxo3a pathway. Andrologia. 2022;54(1):e14294.
- Lei X, Huo P, Xie YJ, Wang Y, Liu G, Tu H, et al. Dendrobium nobile Lindl polysaccharides improve testicular spermatogenic function in streptozotocin-induced diabetic rats. Mol Reprod Dev. 2022;89(4):202-213.
- Wang P, Zhang S, Lin S, Lv Z. Melatonin ameliorates diabetic hyperglycaemia-induced impairment of Leydig cell steroidogenic function through activation of SIRT1 pathway. Reprod Biol Endocrinol. 2022;20(1):117.
- Zhang S, Zhang M, Sun S, Wei X, Chen Y, Zhou P, et al. Moderate calorie restriction ameliorates reproduction via attenuating oxidative stress-induced apoptosis through SIRT1 signaling in obese mice. Ann Transl Med. 2021;9(11):933.
- Gaderpour S, Ghiasi R, Hamidian G, Heydari H, Keyhanmanesh R. Voluntary exercise improves spermatogenesis and testicular apoptosis in type 2 diabetic rats through alteration in oxidative stress and mir-34a/SIRT1/p53 pathway. Iran J Basic Med Sci. 2021;24(1):58-65.
- Jiao D, Zhang H, Jiang Z, Huang W, Liu Z, Wang Z, et al. MicroRNA-34a targets sirtuin 1 and leads to diabetes-induced testicular apoptotic cell death. J Mol Med. 2018;96(9):939-949.
- Zhao Y, Tan Y, Dai J, Wang B, Li B, Guo L, et al. Zinc deficiency exacerbates diabetic down-regulation of Akt expression and function in the testis: essential roles of PTEN, PTP1B and TRB3. J Nutr Biochem. 2012;23(8):1018-1026.
- Tatone C, Di Emidio G, Barbonetti A, Carta G, Luciano AM, Falone S, et al. Sirtuins in gamete biology and reproductive physiology: emerging roles and therapeutic potential in female and male infertility. Hum Reprod Update. 2018;24(3):267-289.
- Ki BS, Park M, Woo Y, Lee WS, Ko JJ, Choi Y. Expression of Sirt1, Sirt2, Sirt5, and Sirt6 in the mouse testis. Reprod Dev Biol. 2015;39(2):73-47.
- Palmer NO, Fullston T, Mitchell M, Setchell BP, Lane M. SIRT6 in mouse spermatogenesis is modulated by diet-induced obesity. Reprod Fertil Dev. 2011;23(7):929-939.
- Fan Y, Yang Q, Yang Y, Gao Z, Ma Y, Zhang L, et al. Sirt6 suppresses high glucose-induced mitochondrial dysfunction and apoptosis in podocytes through AMPK activation. Int J Biol Sci. 2019;15(3):701-713.
- Liu M, Liang K, Zhen J, Zhou M, Wang X, Wang Z, et al. Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling. Nat Commun. 2017;8(1):1-15.
- Zhang L, Bai L, Ren Q, Sun G, Si Y. Protective effects of SIRT6 against lipopolysaccharide (LPS) are mediated by deacetylation of Ku70. Mol Immunol. 2018;101:312-318.
- Li L, Chen B, An T, Zhang H, Xia B, Li R, et al. BaZiBuShen alleviates altered testicular morphology and spermatogenesis and modulates Sirt6/P53 and Sirt6/NF-κB pathways in aging mice induced by D-galactose and NaNO2.J Ethnopharmacol. 2021;10;271:113810.
Year 2024,
Volume: 13 Issue: 3, 82 - 91, 26.09.2024
Selim Demirtaş
,
Onur Ersoy
,
Gülnur Kızılay
References
- Gökdemir GŞ, Baylan M. The effect of gliclazide use on BDNF and NGF levels in rats with diabetes mellitus. South Clin Ist Euras. 2023;34(4):306-311.
- Raffaele M, Li Volti G, Barbagallo IA, Vanella L. Therapeutic efficacy of stem cells transplantation in diabetes: role of heme oxygenase. Front Cell Dev Biol. 2016;4:80.
- Zha W, Bai Y, Xu L, et al. Curcumin attenuates testicular injury in rats with streptozotocin-induced diabetes. BioMed Res Int. 2018;2018:7468019.
- Alves MG, Martins AD, Rato L, Moreira PI, Socorro S, Oliveira PF. Molecular mechanisms beyond glucose transport in diabetes-related male infertility. Biochim Biophys Acta. 2013;1832(5):626-635.
- Amaral S, Oliveira PJ, Ramalho-Santos J. Diabetes and the impairment of reproductive function: possible role of mitochondria and reactive oxygen species. Curr Diabetes Rev. 2008;4(1):46-54.
- Ersoy O, Kizilay G. Effects of fucoidan on diabetic rat testicular tissue. Biotech Histochem. 2018;93(4):277-285.
- Trindade AA, Simoes AC, Silva RJ, Macedo CS, Spadella CT. Long term evaluation of morphometric and ultrastructural changes of testes of alloxan-induced diabetic rats. Acta Cir Bras. 2013;28(4):256-265.
- Fell, VL, Schild-Poulter C. The Ku heterodimer: function in DNA repair and beyond. Mutat Res Rev Mutat Res. 2015;763:15-29.
- Hada M, Kwok RP. Regulation of Ku70-Bax complex in cells. J Cell Death. 2014;7:11-13.
- Bayram A, İğci M. Sirtuin genes and functions. Fırat Med J. 2013;18(3):136-140.
- Chalkiadaki A, Guarente L. The multifaceted functions of sirtuins in cancer. Nat Rev Cancer. 2015;15(10):608-624.
- Gomez JA, Gama V, Yoshida T, Sun W, Hayes P, Leskov K, et al. Bax-inhibiting peptides derived from Ku70 and cell-penetrating pentapeptides. Biochem Soc Trans. 2007;35(Pt 4):797-801.
- Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function. Biochem J. 2007;404(1):1-13.
- Sharma A, Diecke S, Zhang WY, Lan F, He C, Mordwinkin NM, et al. The role of SIRT6 protein in aging and reprogramming of human induced pluripotent stem cells. J Biol Chem. 2013;288(25):18439-18447.
- Wang W, Sun W, Cheng Y, Xu Z, Cai L. Role of sirtuin-1 in diabetic nephropathy. J Mol Med (Berl). 2019;97(3):291-309.
- Tao NN, Ren JH, Tang H, Ran LK, Zhou HZ, Liu B, et al. Deacetylation of Ku70 by SIRT6 attenuates Bax-mediated apoptosis in hepatocellular carcinoma. Biochem Biophys Res Commun. 2017;485(4):713-719.
- Nasirian F, Sarir H, Moradi-kor N. Antihyperglycemic and antihyperlipidemic activities of Nannochloropsis oculata microalgae in streptozotocin-induced diabetic rats. Biomol Concepts. 2019;10(1):37-43.
- Franca L, Suescun M, Miranda J, Giovambatista A, Perello M, Spinedi E, et al. Testis structure and function in a nongenetic hyperadipose rat model at prepubertal and adult ages. Endocrinology. 2006;147(3):1556-1563.
- Sadik NA, El-Seweidy MM, Shaker OG. The antiapoptotic effects of sulphurous mineral water and sodium hydrosulphide on diabetic rat testes. Cell Physiol Biochem. 2011;28(5):887-898.
- Bayram S, Kizilay G, Topcu-Tarladacalisir Y. Evaluation of the Fas/FasL signaling pathway in diabetic rat testis. Biotech Histochem. 2016;91(3):204-211.
- Li C, Wang L, Zheng L, et al. SIRT1 expression is associated with poor prognosis of lung adenocarcinoma. OncoTargets Ther. 2015;8:977.
- Choi EK, Lee YH, Choi YS, Kwon HM, Choi MS, Ro JY, et al. Heterogeneous expression of Ku70 in human tissues is associated with morphological and functional alterations of the nucleus. J Pathol. 2002;198(1):121-130.
- Jangir RN, Jain GC. Diabetes mellitus induced impairment of male reproductive functions: a review. Curr Diabetes Rev. 2014;10(3):147-157.
- Ghosh S, Chowdhury S, Das AK, Sil PC. Taurine ameliorates oxidative stress induced inflammation and ER stress mediated testicular damage in stz-induced diabetic Wistar rats. Food Chem Toxicol. 2019;124:64-80.
- Cameron DF, Murray FT, Drylie DD. Interstitial compartment pathology and spermatogenic disruption in testes from impotent diabetic men. Anat Rec. 1985;213(1):53-62.
- Öztürk F, Gül M, Ağkadir M, Yağmurca M. Histological alterations of rat testes in experimental diabetes. Turkiye Klinikleri J Med Sci. 2002;22(2):173-178.
- Koroglu P, Senturk GE, Yucel D, Ozakpinar OB, Uras F, Arbak S. The effect of exogenous oxytocin on streptozotocin (STZ)-induced diabetic adult rat testes. Peptides. 2015;63:47-54.
- Kianifard D, Sadrkhanlou RA, Hasanzadeh S. The ultrastructural changes of the Sertoli and leydig cells following streptozotocin induced diabetes. Iran J Basic Med Sci. 2012;15(1):623-635.
- Cambay Z, Baydas G, Tuzcu M, Bal R. Pomegranate (Punica granatum L.) flower improves learning and memory performances impaired by diabetes mellitus in rats. Acta Physiol Hung. 2011;98(4):409-420.
- Ding C, Wang Q, Hao Y, Ma X, Wu L, du M, et al. Vitamin D supplement improved testicular function in diabetic rats. Biochem Biophys Res Commun. 2016;473(1):161-167.
- Öztaş E, Yılmaz TE, Güzel E, Sezer Z, Okyar A, Özhan G. Gliclazide alone or in combination with atorvastatin ameliorated reproductive damage in streptozotocin-induced type 2 diabetic male rats. Saudi Pharm J. 2019;27(3):422-431.
- Wankeu-Nya M, Florea A, Bâlici S, Watcho P, Matei H, Kamanyi A. Dracaena arborea alleviates ultra-structural spermatogenic alterations in streptozotocin-induced diabetic rats. BMC Compl Alternative Med. 2013;13(1):71.
- Yin Y, DeWolf WC, Morgentaler A. Experimental cryptorchidism induces testicular germ cell apoptosis by p53-dependent and-independent pathways in mice. Biol Reprod. 1998;58(2):492-496.
- Li Y-J, Song T-B, Cai Y-Y, et al. Bisphenol A exposure induces apoptosis and upregulation of Fas/FasL and caspase-3 expression in the testes of mice. Toxicol Sci. 2009;108(2):427-436.
- Liu Y, Yang Z, Kong D, Zhang Y, Yu W, Zha W. Metformin ameliorates testicular damage in male mice with streptozotocin-induced type 1 diabetes through the PK2/PKR pathway. Oxid Med Cell Longev. 2019;2019:5681701.
- Koh PO. Streptozotocin-induced diabetes increases apoptosis through JNK phosphorylation and Bax activation in rat testes. J Vet Med Sci. 2007;69(9):969-971.
- Koh PO. Streptozotocin-induced diabetes increases the interaction of Bad/Bcl-XL and decreases the binding of pBad/14-3-3 in rat testis. Life Sci. 2007;81(13):1079-1084.
- İrtegün S, Deveci E. Examining the expression level of VEGF and Bcl-2 by immunohistochemistry and western blot in testis tissue of diabetic rats. Dicle Med J. 2016;43(4):527-533.
- Khamis T, Abdelalim AF, Abdallah SH, Saeed AA, Edress NM, Arisha AH. Early intervention with breast milk mesenchymal stem cells attenuates the development of diabetic-induced testicular dysfunction via hypothalamic Kisspeptin/Kiss1r-GnRH/GnIH system in male rats. Biochim Biophys Acta Mol Basis Dis. 2020;1866(1):165577.
- Ahmed EA, Sfeir, A, Takai H, Scherthan H. Ku70 and non-homologous end joining protect testicular cells from DNA damage. J Cell Sci. 2013;126(14):3095-104.
- Tuncdemir M, Ozturk M. Regulation of the Ku70 and apoptosis-related proteins in experimental diabetic nephropathy. Metabolism. 2016;65(10):1466-1477.
- Wang Y, Lai L, Guo W, Peng S, Liu R, Hong P, et al. Inhibition of Ku70 in a high-glucose environment aggravates bupivacaine-induced dorsal root ganglion neurotoxicity. Toxicol Lett. 2020;318:104-113.
- Xu T, Liu Y, Li P, Xu X, Zeng J. Insulin in combination with selenium inhibits HG/Pal-induced cardiomyocyte apoptosis by Cbl-b regulating p38MAPK/CBP/Ku70 pathway. Eur Rev Med Pharmacol Sci. 2016;20(15):3297-3303.
- Kerr E, Holohan C, McLaughlin KM, et al. Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. Cell Death Differ. 2012;19(8):1317-1327.
- Matsuyama S, Palmer J, Bates A, Poventud-Fuentes I, Wong K, Ngo J, et al. Bax-induced apoptosis shortens the life span of DNA repair defect Ku70-knockout mice by inducing emphysema. Exp Biol Med. 2016;241(12):1265-1271.
- McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR, et al. The mammalian SIR2 protein has a role in embryogenesis and gametogenesis. Mol Cell Biol. 2003;23(1):38-54.
- Ogawa T, Wakai C, Saito T, et al. Distribution of the longevity gene product, SIRT1, in developing mouse organs. Congenit Anom. 2011;51(2):70-79.
- Al-Bader M, Kilarkaje N. Effects of Trans-Resveratrol on hyperglycemia-induced abnormal spermatogenesis, DNA damage and alterations in poly (ADP-ribose) polymerase signaling in rat testis. Toxicol Appl Pharmacol. 2016;311:61-73.
- Al-Bader M, Kilarkaje N. Dataset of Trans-Resveratrol on diabetes-induced abnormal spermatogenesis, poly (ADP-ribose) polymerase-1 (PARP1) expression in intra-testicular blood vessels, and stage-dependent expression of PARP1 and Sirtuin 1 in the rat testis. Data Brief. 2017;10:230-237.
- He W, Liu H, Hu L, Wang Y, Huang L, Liang A, et al. Icariin improves testicular dysfunction via enhancing proliferation and inhibiting mitochondria-dependent apoptosis pathway in high-fat diet and streptozotocin-induced diabetic rats. Reprod Biol Endocrinol. 2021;19(1):168.
- Huang T, Zhou Y, Lu X, Tang C, Ren C, Bao X, et al. Cordycepin, a major bioactive component of Cordyceps militaris, ameliorates diabetes-induced testicular damage through the Sirt1/Foxo3a pathway. Andrologia. 2022;54(1):e14294.
- Lei X, Huo P, Xie YJ, Wang Y, Liu G, Tu H, et al. Dendrobium nobile Lindl polysaccharides improve testicular spermatogenic function in streptozotocin-induced diabetic rats. Mol Reprod Dev. 2022;89(4):202-213.
- Wang P, Zhang S, Lin S, Lv Z. Melatonin ameliorates diabetic hyperglycaemia-induced impairment of Leydig cell steroidogenic function through activation of SIRT1 pathway. Reprod Biol Endocrinol. 2022;20(1):117.
- Zhang S, Zhang M, Sun S, Wei X, Chen Y, Zhou P, et al. Moderate calorie restriction ameliorates reproduction via attenuating oxidative stress-induced apoptosis through SIRT1 signaling in obese mice. Ann Transl Med. 2021;9(11):933.
- Gaderpour S, Ghiasi R, Hamidian G, Heydari H, Keyhanmanesh R. Voluntary exercise improves spermatogenesis and testicular apoptosis in type 2 diabetic rats through alteration in oxidative stress and mir-34a/SIRT1/p53 pathway. Iran J Basic Med Sci. 2021;24(1):58-65.
- Jiao D, Zhang H, Jiang Z, Huang W, Liu Z, Wang Z, et al. MicroRNA-34a targets sirtuin 1 and leads to diabetes-induced testicular apoptotic cell death. J Mol Med. 2018;96(9):939-949.
- Zhao Y, Tan Y, Dai J, Wang B, Li B, Guo L, et al. Zinc deficiency exacerbates diabetic down-regulation of Akt expression and function in the testis: essential roles of PTEN, PTP1B and TRB3. J Nutr Biochem. 2012;23(8):1018-1026.
- Tatone C, Di Emidio G, Barbonetti A, Carta G, Luciano AM, Falone S, et al. Sirtuins in gamete biology and reproductive physiology: emerging roles and therapeutic potential in female and male infertility. Hum Reprod Update. 2018;24(3):267-289.
- Ki BS, Park M, Woo Y, Lee WS, Ko JJ, Choi Y. Expression of Sirt1, Sirt2, Sirt5, and Sirt6 in the mouse testis. Reprod Dev Biol. 2015;39(2):73-47.
- Palmer NO, Fullston T, Mitchell M, Setchell BP, Lane M. SIRT6 in mouse spermatogenesis is modulated by diet-induced obesity. Reprod Fertil Dev. 2011;23(7):929-939.
- Fan Y, Yang Q, Yang Y, Gao Z, Ma Y, Zhang L, et al. Sirt6 suppresses high glucose-induced mitochondrial dysfunction and apoptosis in podocytes through AMPK activation. Int J Biol Sci. 2019;15(3):701-713.
- Liu M, Liang K, Zhen J, Zhou M, Wang X, Wang Z, et al. Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling. Nat Commun. 2017;8(1):1-15.
- Zhang L, Bai L, Ren Q, Sun G, Si Y. Protective effects of SIRT6 against lipopolysaccharide (LPS) are mediated by deacetylation of Ku70. Mol Immunol. 2018;101:312-318.
- Li L, Chen B, An T, Zhang H, Xia B, Li R, et al. BaZiBuShen alleviates altered testicular morphology and spermatogenesis and modulates Sirt6/P53 and Sirt6/NF-κB pathways in aging mice induced by D-galactose and NaNO2.J Ethnopharmacol. 2021;10;271:113810.