{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:57:59Z","timestamp":1790391479691,"version":"4.1.0"},"reference-count":75,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T00:00:00Z","timestamp":1716940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Grant Award 2021 from the Japanese Society of Anti-Aging Medicine","award":["22K15031"],"award-info":[{"award-number":["22K15031"]}]},{"name":"Research Grant Award 2021 from the Japanese Society of Anti-Aging Medicine","award":["24K12518"],"award-info":[{"award-number":["24K12518"]}]},{"name":"Japan Association for Diabetes Education and Care","award":["22K15031"],"award-info":[{"award-number":["22K15031"]}]},{"name":"Japan Association for Diabetes Education and Care","award":["24K12518"],"award-info":[{"award-number":["24K12518"]}]},{"name":"Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan","award":["22K15031"],"award-info":[{"award-number":["22K15031"]}]},{"name":"Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan","award":["24K12518"],"award-info":[{"award-number":["24K12518"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Type 2 diabetes mellitus (T2DM) is a risk factor for male infertility, but the underlying molecular mechanisms remain unclear. Advanced glycation end products (AGEs) are pathogenic molecules for diabetic vascular complications. Here, we investigated the effects of the DNA aptamer raised against AGEs (AGE-Apt) on testicular and sperm abnormalities in a T2DM mouse model. KK-Ay (DM) and wild-type (non-DM) 4- and 7-week-old male mice were sacrificed to collect the testes and spermatozoa for immunofluorescence, RT-PCR, and histological analyses. DM and non-DM 7-week-old mice were subcutaneously infused with the AGE-Apt or control-aptamer for 6 weeks and were then sacrificed. Plasma glucose, testicular AGEs, and Rage gene expression in 4-week-old DM mice and plasma glucose, testicular AGEs, oxidative stress, and pro-inflammatory gene expressions in 7-week-old DM mice were higher than those in age-matched non-DM mice, the latter of which was associated with seminiferous tubular dilation. AGE-Apt did not affect glycemic parameters, but it inhibited seminiferous tubular dilation, reduced the number of testicular macrophages and apoptotic cells, and restored the decrease in sperm concentration, motility, and viability of 13-week-old DM mice. Our findings suggest that AGEs-Apt may improve sperm abnormality by suppressing AGE\u2013RAGE-induced oxidative stress and inflammation in the testes of DM mice.<\/jats:p>","DOI":"10.3390\/ijms25115947","type":"journal-article","created":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T10:42:34Z","timestamp":1717065754000},"page":"5947","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["DNA Aptamer Raised against Advanced Glycation End Products Improves Sperm Concentration, Motility, and Viability by Suppressing Receptors for Advanced Glycation End Product-Induced Oxidative Stress and Inflammation in the Testes of Diabetic Mice"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1734-0605","authenticated-orcid":false,"given":"Yusaku","family":"Mori","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Anti-Glycation Research Section, Showa University Graduate School of Medicine, Shinagawa 142-8555, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7405-7419","authenticated-orcid":false,"given":"Michishige","family":"Terasaki","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University Graduate School of Medicine, Shinagawa 142-8555, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoya","family":"Osaka","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University Graduate School of Medicine, Shinagawa 142-8555, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Fujikawa","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University Graduate School of Medicine, Shinagawa 142-8555, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Yashima","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University Graduate School of Medicine, Shinagawa 142-8555, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomi","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University Graduate School of Medicine, Shinagawa 142-8555, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurie","family":"Kataoka","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University Graduate School of Medicine, Shinagawa 142-8555, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Ohara","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University Graduate School of Medicine, Shinagawa 142-8555, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-8598","authenticated-orcid":false,"given":"Yuichiro","family":"Higashimoto","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Kurume University School of Medicine, Kurume 830-0011, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9506-7571","authenticated-orcid":false,"given":"Takanori","family":"Matsui","sequence":"additional","affiliation":[{"name":"Department of Bioscience and Biotechnology, Fukui Prefectural University, Eiheiji 910-1195, Fukui, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0102-0823","authenticated-orcid":false,"given":"Sho-ichi","family":"Yamagishi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University Graduate School of Medicine, Shinagawa 142-8555, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.4103\/0974-1208.170370","article-title":"Trends of male factor infertility, an important cause of infertility: A review of literature","volume":"8","author":"Kumar","year":"2015","journal-title":"J. Hum. Reprod. Sci."},{"key":"ref_2","first-page":"18","article-title":"Causes of male infertility: A 9-year prospective monocentre study on 1737 patients with reduced total sperm counts","volume":"32","author":"Punab","year":"2017","journal-title":"Hum. Reprod."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1111\/andr.12947","article-title":"Male factor infertility trends throughout the last 10 years: Report from a tertiary-referral academic andrology centre","volume":"9","author":"Fallara","year":"2021","journal-title":"Andrology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.2337\/dc23-S002","article-title":"Classification and Diagnosis of Diabetes: Standards of Care in Diabetes-2023","volume":"46","author":"ElSayed","year":"2023","journal-title":"Diabetes Care"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"205","DOI":"10.3389\/fendo.2014.00205","article-title":"Autonomic neuropathy in diabetes mellitus","volume":"5","author":"Verrotti","year":"2014","journal-title":"Front. Endocrinol."},{"key":"ref_6","first-page":"95","article-title":"Diabetes and sexual dysfunction: Current perspectives","volume":"7","author":"Maiorino","year":"2014","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1007\/s11255-009-9565-6","article-title":"Is male fertility associated with type 2 diabetes mellitus?","volume":"41","author":"Bener","year":"2009","journal-title":"Int. Urol. Nephrol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"M110.007187","DOI":"10.1074\/mcp.M110.007187","article-title":"Identification of increased amounts of eppin protein complex components in sperm cells of diabetic and obese individuals by difference gel electrophoresis","volume":"10","author":"Paasch","year":"2011","journal-title":"Mol. Cell. Proteom."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1111\/j.1439-0272.2011.01213.x","article-title":"Noninsulin-dependent diabetes mellitus: Effects on sperm morphological and functional characteristics, nuclear DNA integrity and outcome of assisted reproductive technique","volume":"44","author":"Rama","year":"2012","journal-title":"Andrologia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"268","DOI":"10.3389\/fendo.2018.00268","article-title":"Diabetes Mellitus and Infertility: Different Pathophysiological Effects in Type 1 and Type 2 on Sperm Function","volume":"9","author":"Condorelli","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"R13","DOI":"10.1530\/REP-17-0390","article-title":"Antidiabetic therapies and male reproductive function: Where do we stand?","volume":"155","author":"Tavares","year":"2018","journal-title":"Reproduction"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.biocel.2016.06.016","article-title":"Advanced glycation end products and their receptor in age-related, non-communicable chronic inflammatory diseases; Overview of clinical evidence and potential contributions to disease","volume":"81","author":"Reynaert","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.cmet.2018.08.014","article-title":"The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality","volume":"28","author":"Chaudhuri","year":"2018","journal-title":"Cell Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1253\/circj.CJ-19-0618","article-title":"Role of Advanced Glycation Endproduct (AGE)-Receptor for Advanced Glycation Endproduct (RAGE) Axis in Cardiovascular Disease and Its Therapeutic Intervention","volume":"83","author":"Yamagishi","year":"2019","journal-title":"Circ. J."},{"key":"ref_15","first-page":"106","article-title":"Skin autofluorescence\u2014A non-invasive measurement for assessing cardiovascular risk and risk of diabetes","volume":"10","author":"Stirban","year":"2014","journal-title":"Eur. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1080\/2090598X.2019.1599624","article-title":"Oxidative stress and sperm function: A systematic review on evaluation and management","volume":"17","author":"Dutta","year":"2019","journal-title":"Arab. J. Urol."},{"key":"ref_17","first-page":"123","article-title":"Impact of Inflammation on Male Reproductive Tract","volume":"16","author":"Azenabor","year":"2015","journal-title":"J. Reprod. Infertil."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.2119\/molmed.2015.00067","article-title":"Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes","volume":"21","author":"Yamagishi","year":"2015","journal-title":"Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1096\/fj.02-1102fje","article-title":"The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes","volume":"17","author":"Forbes","year":"2003","journal-title":"FASEB J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1093\/jnen\/59.12.1094","article-title":"Neurotoxicity of advanced glycation end-products for cultured cortical neurons","volume":"59","author":"Takeuchi","year":"2000","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S30","DOI":"10.1016\/j.diabres.2007.01.030","article-title":"Short-chain aldehyde-derived ligands for RAGE and their actions on endothelial cells","volume":"77","author":"Yamamoto","year":"2007","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/JVI.01749-19","article-title":"The High Content of Fructose in Human Semen Competitively Inhibits Broad and Potent Antivirals That Target High-Mannose Glycans","volume":"94","author":"Johnson","year":"2020","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s41387-020-0127-4","article-title":"Biochemical and nutritional overview of diet-induced metabolic syndrome models in rats: What is the best choice?","volume":"10","author":"Carvajal","year":"2020","journal-title":"Nutr. Diabetes"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1177\/1479164119866390","article-title":"Fructose causes endothelial cell damage via activation of advanced glycation end products-receptor system","volume":"16","author":"Sotokawauchi","year":"2019","journal-title":"Diab. Vasc. Dis. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Lai, B.S., and Juhas, M. (2019). Recent Advances in Aptamer Discovery and Applications. Molecules, 24.","DOI":"10.3390\/molecules24050941"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.mvr.2007.04.001","article-title":"In vitro selection of DNA aptamers that block toxic effects of AGE on cultured retinal pericytes","volume":"74","author":"Higashimoto","year":"2007","journal-title":"Microvasc. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.mvr.2013.08.010","article-title":"Blockade by phosphorothioate aptamers of advanced glycation end products-induced damage in cultured pericytes and endothelial cells","volume":"90","author":"Higashimoto","year":"2013","journal-title":"Microvasc. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.2337\/db12-1608","article-title":"DNA aptamer raised against AGEs blocks the progression of experimental diabetic nephropathy","volume":"62","author":"Kaida","year":"2013","journal-title":"Diabetes"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/labinvest.2014.5","article-title":"DNA aptamer raised against advanced glycation end products inhibits melanoma growth in nude mice","volume":"94","author":"Ojima","year":"2014","journal-title":"Lab. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1159\/000440768","article-title":"DNA Aptamer Raised against Advanced Glycation End Products Prevents Abnormalities in Electroretinograms of Experimental Diabetic Retinopathy","volume":"54","author":"Maeda","year":"2015","journal-title":"Ophthalmic Res."},{"key":"ref_31","first-page":"253","article-title":"DNA aptamer raised against advanced glycation end products (AGEs) improves glycemic control and decreases adipocyte size in fructose-fed rats by suppressing AGE-RAGE axis","volume":"47","author":"Ojima","year":"2015","journal-title":"Horm. Metab. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"George, B.T., Jhancy, M., Dube, R., Kar, S.S., and Annamma, L.M. (2023). The Molecular Basis of Male Infertility in Obesity: A Literature Review. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010179"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1210\/endo.138.3.5024","article-title":"Leptin treatment rescues the sterility of genetically obese ob\/ob males","volume":"138","author":"Mounzih","year":"1997","journal-title":"Endocrinology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1210\/endo.140.2.6470","article-title":"Effect of the genetic background on the reproduction of leptin-deficient obese mice","volume":"140","author":"Mounzih","year":"1999","journal-title":"Endocrinology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3484","DOI":"10.1172\/JCI24059","article-title":"Complete rescue of obesity, diabetes, and infertility in db\/db mice by neuron-specific LEPR-B transgenes","volume":"115","author":"Kowalski","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_36","first-page":"465","article-title":"Morphological characterization of systemic changes in KK-Ay mice as an animal model of type 2 diabetes","volume":"27","author":"Moroki","year":"2013","journal-title":"In Vivo"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1538\/expanim.51.191","article-title":"Diabetic nephropathy in KK and KK-Ay mice","volume":"51","author":"Okazaki","year":"2002","journal-title":"Exp. Anim."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1262\/jrd.2019-042","article-title":"Early production of offspring by in vitro fertilization using first-wave spermatozoa from prepubertal male mice","volume":"65","author":"Mochida","year":"2019","journal-title":"J. Reprod. Dev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/aja.1000990307","article-title":"Duration of spermatogenesis in the mouse and timing of stages of the cycle of the seminiferous epithelium","volume":"99","author":"Oakberg","year":"1956","journal-title":"Am. J. Anat."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.2337\/db16-1281","article-title":"RAGE- Aptamer Blocks the Development and Progression of Experimental Diabetic Nephropathy","volume":"66","author":"Matsui","year":"2017","journal-title":"Diabetes"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Mori, Y., Ohara, M., Terasaki, M., Osaka, N., Yashima, H., Saito, T., Otoyama-Kataoka, Y., Omachi, T., Higashimoto, Y., and Matsui, T. (2023). Subcutaneous Infusion of DNA-Aptamer Raised against Advanced Glycation End Products Prevents Loss of Skeletal Muscle Mass and Strength in Accelerated-Aging Mice. Biomedicines, 11.","DOI":"10.3390\/biomedicines11123112"},{"key":"ref_42","first-page":"dev162628","article-title":"Defects in efferent duct multiciliogenesis underlie male infertility in GEMC1-, MCIDAS- or CCNO-deficient mice","volume":"146","author":"Lewis","year":"2019","journal-title":"Development"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1080\/019262301301418865","article-title":"Pathogenesis of male reproductive toxicity","volume":"29","author":"Creasy","year":"2001","journal-title":"Toxicol. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1177\/0192623312463783","article-title":"Selective inhibition of PDE4 in Wistar rats can lead to dilatation in testis, efferent ducts, and epididymis and subsequent formation of sperm granulomas","volume":"41","author":"Heuser","year":"2013","journal-title":"Toxicol. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"107598","DOI":"10.1016\/j.intimp.2021.107598","article-title":"MCP-1: Function, regulation, and involvement in disease","volume":"101","author":"Singh","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"20309","DOI":"10.1074\/jbc.M202634200","article-title":"Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells","volume":"277","author":"Yamagishi","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1007\/s00125-002-1013-4","article-title":"Pigment epithelium- derived factor prevents advanced glycation end products-induced monocyte chemoattractant protein-1 production in microvascular endothelial cells by suppressing intracellular reactive oxygen species generation","volume":"46","author":"Inagaki","year":"2003","journal-title":"Diabetologia"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1615\/CritRevEukarGeneExpr.v20.i2.10","article-title":"Tumor necrosis factor-\u03b1 signaling in macrophages","volume":"20","author":"Parameswaran","year":"2010","journal-title":"Crit. Rev. Eukaryot. Gene Expr."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Jin, X., Yao, T., Zhou, Z., Zhu, J., Zhang, S., Hu, W., and Shen, C. (2015). Advanced Glycation End Products Enhance Macrophages Polarization into M1 Phenotype through Activating RAGE\/NF-\u03baB Pathway. Biomed. Res. Int., 2015.","DOI":"10.1155\/2015\/732450"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1007\/s10875-007-9071-5","article-title":"Effects of tumour necrosis factor-alpha on human sperm motility and apoptosis","volume":"27","author":"Perdichizzi","year":"2007","journal-title":"J. Clin. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1093\/biolre\/ioy235","article-title":"Lipopolysaccharide-induced testicular dysfunction and epididymitis in mice: A critical role of tumor necrosis factor alpha","volume":"100","author":"Wang","year":"2019","journal-title":"Biol. Reprod."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1016\/j.fertnstert.2004.11.068","article-title":"Infliximab may reverse the toxic effects induced by tumor necrosis factor alpha in human spermatozoa: An in vitro model","volume":"83","author":"Said","year":"2005","journal-title":"Fertil. Steril."},{"key":"ref_53","first-page":"60","article-title":"The role of oxidative stress and antioxidants in male fertility","volume":"66","author":"Wolski","year":"2013","journal-title":"Cent. Eur. J. Urol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/j.fertnstert.2007.05.029","article-title":"Increase of oxidative stress in human sperm with lower motility","volume":"89","author":"Kao","year":"2008","journal-title":"Fertil. Steril."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/S0015-0282(16)43999-3","article-title":"Peroxidative breakdown of phospholipids in human spermatozoa, spermicidal properties of fatty acid peroxides, and protective action of seminal plasma","volume":"31","author":"Jones","year":"1979","journal-title":"Fertil. Steril."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.freeradbiomed.2009.10.033","article-title":"Stimulation of mitochondrial reactive oxygen species production by unesterified, unsaturated fatty acids in defective human spermatozoa","volume":"48","author":"Koppers","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e12762","DOI":"10.1111\/and.12762","article-title":"Oxidative stress status and sperm DNA fragmentation in fertile and infertile men","volume":"49","author":"Dorostghoal","year":"2017","journal-title":"Andrologia"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1042\/BJ20110114","article-title":"Phosphoinositide 3-kinase signalling pathway involvement in a truncated apoptotic cascade associated with motility loss and oxidative DNA damage in human spermatozoa","volume":"436","author":"Koppers","year":"2011","journal-title":"Biochem. J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/S0015-0282(03)00756-8","article-title":"Oxidative stress is associated with increased apoptosis leading to spermatozoa DNA damage in patients with male factor infertility","volume":"80","author":"Wang","year":"2003","journal-title":"Fertil. Steril."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Aitken, R.J., Drevet, J.R., Moazamian, A., and Gharagozloo, P. (2022). Male Infertility and Oxidative Stress: A Focus on the Underlying Mechanisms. Antioxidants, 11.","DOI":"10.3390\/antiox11020306"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Sanocka, D., and Kurpisz, M. (2004). Reactive oxygen species and sperm cells. Reprod. Biol. Endocrinol., 2.","DOI":"10.1186\/1477-7827-2-12"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1248\/bpb.30.84","article-title":"Protection of testicular dysfunctions by MTEC, a formulated herbal drug, in streptozotocin induced diabetic rat","volume":"30","author":"Mallick","year":"2007","journal-title":"Biol. Pharm. Bull."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1093\/humrep\/dem077","article-title":"Insulin dependant diabetes mellitus: Implications for male reproductive function","volume":"22","author":"Agbaje","year":"2007","journal-title":"Hum. Reprod."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"572","DOI":"10.4103\/1008-682X.125401","article-title":"Blood-testis barrier and spermatogenesis: Lessons from genetically-modified mice","volume":"16","author":"Jiang","year":"2014","journal-title":"Asian J. Androl."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e23992","DOI":"10.4161\/tisb.23992","article-title":"Diabetes, insulin- mediated glucose metabolism and Sertoli\/blood-testis barrier function","volume":"1","author":"Alves","year":"2013","journal-title":"Tissue Barriers"},{"key":"ref_66","first-page":"e16288","article-title":"Comparison of Testosterone Levels in Patients with and without Type 2 Diabetes","volume":"13","author":"Kumari","year":"2021","journal-title":"Cureus"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5462","DOI":"10.1210\/jc.2004-0804","article-title":"Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes","volume":"89","author":"Dhindsa","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/aja.2013.46","article-title":"Mouse sperm acquire a new structure on the apical hook during epididymal maturation","volume":"15","author":"Lin","year":"2013","journal-title":"Asian J. Androl."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.1111\/bph.15193","article-title":"The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research","volume":"177","author":"Hurst","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_70","unstructured":"Committee for the Update of the Guide for the Care and Use of Laboratory Animals (2011). Guide for the Care and Use of Laboratory Animals, National Academies Press (US). [8th ed.]."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/s12933-019-0947-5","article-title":"Luseogliflozin attenuates neointimal hyperplasia after wire injury in high-fat diet-fed mice via inhibition of perivascular adipose tissue remodeling","volume":"18","author":"Mori","year":"2019","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1530\/REP-11-0245","article-title":"Postnatal testicular development in mouse species with different levels of sperm competition","volume":"143","author":"Montoto","year":"2012","journal-title":"Reproduction"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/978-1-62703-038-0_27","article-title":"Assessment of spermatogenesis through staging of seminiferous tubules","volume":"927","author":"Meistrich","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1111\/aji.12420","article-title":"GLP-1 Receptor Agonist Exenatide Attenuates the Detrimental Effects of Obesity on Inflammatory Profile in Testis and Sperm Quality in Mice","volume":"74","author":"Zhang","year":"2015","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_75","unstructured":"World Health Organization (2016). WHO Laboratory Manual for the Examination and Processing of Human Semen, WHO Press. [6th ed.]."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/5947\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:50:17Z","timestamp":1760107817000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/5947"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,29]]},"references-count":75,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ijms25115947"],"URL":"https:\/\/doi.org\/10.3390\/ijms25115947","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,29]]}}}