{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T00:29:35Z","timestamp":1794097775551,"version":"4.8.0"},"reference-count":66,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec>\n<jats:title>Purpose<\/jats:title>\n<jats:p>Cisplatin is a commonly used chemotherapy agent effective against various cancers, however it induces significant gonadotoxicity and infertility due to its adverse effects on testicular function. The underlying mechanisms of cisplatin-induced testicular damage include oxidative stress and dysregulated autophagy. This study investigates the potential of extracellular vesicles (EVs) to mitigate cisplatin-induced testicular damage through their regenerative, antioxidant, and autophagy-modulating properties.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>In the testicular toxicity model, thirty-two male rats were randomly divided into four groups (n\u2009=\u20098): control, EVs-only, Cis-only, and Cis\u2009+\u2009EVs. A single intraperitoneal dose of 7.5mg\/kg cisplatin was administered on the first day. On the six day, the EVs treatment group received a single dose of EVs (8x10<jats:sup>7<\/jats:sup>\/100\u03bcl) intravenously. Animals were sacrificed on day eight. Testicular histoarchitecture was assessed via hematoxylin and eosin staining. Sperm parameters, including motility and count, were measured using light microscopy. Hormone levels (testosterone and inhibin) were determined via enzyme-linked immunosorbent assay (ELISA). Oxidative stress markers, such as glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), catalase (CAT), and is a metabolite malondialdehyde (MDA), were quantified using colorimetric assays. Autophagy and steroidogenesis were evaluated through immunohistochemical analysis of Beclin-1, p62, LC3\u20132, SF-1, and StAR.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Cisplatin exposure caused significant testicular damage, characterized by reduced germinal epithelium and degeneration of seminiferous tubules (p\u2009&lt;\u20090.001). These structural changes led to hormonal imbalances, as evidenced by declines in testosterone (p\u2009&lt;\u20090.005) and inhibin (p\u2009&lt;\u20090.001). Additionally, sperm motility (p\u2009&lt;\u20090.05) and count (p\u2009&lt;\u20090.001) were adversely affected.<\/jats:p>\n<jats:p>Immunohistochemical analysis revealed upregulation of autophagy markers (p\u2009&lt;\u20090.001), indicating heightened autophagic activity, alongside downregulation of steroidogenic factors (p\u2009&lt;\u20090.001), which contributed to impaired steroidogenesis. Elevated levels of malondialdehyde (MDA) (p\u2009&lt;\u20090.01) and decreased activities of antioxidant enzymes\u2014GSH-PX, SOD, and CAT (p\u2009&lt;\u20090.001) pointed to increased oxidative stress as a contributing mechanism.<\/jats:p>\n<jats:p>In contrast, treatment with extracellular vesicles (EVs) significantly improved testicular histoarchitecture (p\u2009&lt;\u20090.001) and restored hormonal levels toward normal (testosterone p\u2009&lt;\u20090.005, inhibin p\u2009&lt;\u20090.001). Furthermore, EVs reduced the expression of autophagy markers (p\u2009&lt;\u20090.001) and enhanced the levels of steroidogenic factors (p\u2009&lt;\u20090.05). Notably, MDA levels decreased (p\u2009&lt;\u20090.001), while antioxidant activities increased (p\u2009&lt;\u20090.001), suggesting a protective effect of EVs against oxidative stress.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>EVs protect against cisplatin-induced reproductive toxicity by modulating oxidative stress and autophagy pathways, preserving testicular function and fertility. These findings suggest that EVs may be a promising therapeutic strategy for mitigating cisplatin\u2019s negative effects on reproductive health. Further exploration of dosing regimens and localized applications is recommended for improved efficacy.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0314093","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T17:30:28Z","timestamp":1746207028000},"page":"e0314093","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Extracellular vesicles therapy alleviates cisplatin-\u0131nduced testicular tissue toxicity in a rat model"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4310-6238","authenticated-orcid":true,"given":"Halime","family":"Tozak Y\u0131ld\u0131z","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K\u00fcbra Tu\u011f\u00e7e","family":"Kalkan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Numan","family":"Baydilli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeynep Bur\u00e7in","family":"G\u00f6nen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6zge","family":"Cengiz Mat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eda","family":"K\u00f6seo\u011flu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6zde \u00d6zge","family":"\u00d6nder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arzu","family":"Yay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"issue":"7","key":"pone.0314093.ref001","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.3390\/cancers13071572","article-title":"Mechanisms of cisplatin-induced acute kidney injury: Pathological mechanisms, pharmacological interventions, and genetic mitigations","volume":"13","author":"KR McSweeney","year":"2021","journal-title":"Cancers (Basel)"},{"key":"pone.0314093.ref002","doi-asserted-by":"crossref","first-page":"111481","DOI":"10.1016\/j.biopha.2021.111481","article-title":"Melatonin protects rats testes against bleomycin etoposide and cisplatin-induced toxicity via mitigating nitro-oxidative stress and apoptosis","volume":"138","author":"M Moradi","year":"2021","journal-title":"Biomed Pharmacother"},{"issue":"1","key":"pone.0314093.ref003","doi-asserted-by":"crossref","first-page":"147","DOI":"10.29261\/pakvetj\/2020.082","article-title":"The ameliorative effects of l-carnitine against cisplatin-induced gonadal toxicity in rats","volume":"41","author":"AO Sallam","year":"2021","journal-title":"Pak Vet J"},{"issue":"2","key":"pone.0314093.ref004","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/(SICI)1096-911X(199608)27:2<74::AID-MPO2>3.0.CO;2-Q","article-title":"Gonadal function following chemotherapy for childhood Hodgkin\u2019s disease","volume":"27","author":"EJ Mackie","year":"1996","journal-title":"Med Pediatr Oncol"},{"issue":"3","key":"pone.0314093.ref005","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.3390\/ijms23031532","article-title":"Pharmacological effects of cisplatin combination with natural products in cancer chemotherapy","volume":"23","author":"S Dasari","year":"2022","journal-title":"Int J Mol Sci"},{"key":"pone.0314093.ref006","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1477-7827-11-16","article-title":"Combination of a GnRH agonist with an antagonist prevents flare-up effects and protects primordial ovarian follicles in the rat ovary from cisplatin-induced toxicity: a controlled experimental animal study","volume":"11","author":"X Li","year":"2013","journal-title":"Reprod Biol Endocrinol"},{"issue":"34","key":"pone.0314093.ref007","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1093\/jncimonographs\/lgi006","article-title":"Mechanisms of toxic damage to spermatogenesis","author":"K Boekelheide","year":"2005","journal-title":"J Natl Cancer Inst Monogr"},{"issue":"5","key":"pone.0314093.ref008","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1111\/j.1745-7262.2006.00179.x","article-title":"Effects of ginger and roselle on cisplatin induced reproductive toxicity in rats","volume":"8","author":"A Amin","year":"2006","journal-title":"Asian J Androl"},{"issue":"2","key":"pone.0314093.ref009","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/j.1745-7262.2008.00379.x","article-title":"Herbal extracts counteract cisplatin-mediated cell death in rat testis","volume":"10","author":"A Amin","year":"2008","journal-title":"Asian J Androl"},{"key":"pone.0314093.ref010","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s12894-021-00889-2","article-title":"The protective effect of crocin on cisplatin-induced testicular impairment in rats","volume":"21","author":"B Mesbahzadeh","year":"2021","journal-title":"BMC Urol"},{"key":"pone.0314093.ref011","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0014-2999(02)02251-3","article-title":"Protection by a radical scavenger edaravone against cisplatin-induced nephrotoxicity in rats","volume":"451","author":"K Sueishi","year":"2002","journal-title":"Eur J Pharmacol"},{"issue":"3","key":"pone.0314093.ref012","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1095\/biolreprod.114.123570","article-title":"Ghrelin partially protects against cisplatin-induced male murine gonadal toxicity in a GHSR-1a-dependent manner","volume":"92","author":"SD Whirledge","year":"2015","journal-title":"Biol Reprod"},{"issue":"9","key":"pone.0314093.ref013","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1002\/sctm.16-0477","article-title":"Stem cell-derived extracellular vesicles as a novel potential therapeutic tool for tissue repair","volume":"6","author":"B Chen","year":"2017","journal-title":"Stem Cells Transl Med"},{"key":"pone.0314093.ref014","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3389\/fcell.2018.00018","article-title":"Exosome-based cell-cell communication in the tumor microenvironment","volume":"6","author":"J Maia","year":"2018","journal-title":"Front Cell Dev Biol"},{"key":"pone.0314093.ref015","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12964-023-01408-6","article-title":"Protein cargo in extracellular vesicles as the key mediator in the progression of cancer","volume":"22","author":"K H\u00e1n\u011blov\u00e1","year":"2024","journal-title":"Cell Commun Signal"},{"key":"pone.0314093.ref016","doi-asserted-by":"crossref","first-page":"115801","DOI":"10.1016\/j.biopha.2023.115801","article-title":"Exosomal Cargo: pro-angiogeneic, anti-inflammatory, and regenerative effects in ischemic and non-ischemic heart diseases - a comprehensive review","volume":"168","author":"K Gougheri","year":"2023","journal-title":"Biomed Pharmacother"},{"key":"pone.0314093.ref017","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1038\/mt.2015.44","article-title":"Mesenchymal stem cell derived extracellular vesicles: toward cell-free therapeutic applications","volume":"23","author":"S Rani","year":"2015","journal-title":"Mol Ther"},{"key":"pone.0314093.ref018","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/bs.ctdb.2015.07.012","article-title":"Autophagy in cell life and cell death","volume":"114","author":"AL Anding","year":"2015","journal-title":"Curr Top Dev Biol"},{"issue":"1","key":"pone.0314093.ref019","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/cdd.2011.96","article-title":"Molecular definitions of cell death subroutines: recommendations of the nomenclature committee on cell death","volume":"19","author":"L Galluzzi","year":"2012","journal-title":"Cell Death Differ"},{"issue":"3-4","key":"pone.0314093.ref020","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.cytogfr.2007.04.006","article-title":"Autophagy and Nf-Kb: fight for fate","volume":"18","author":"G Xiao","year":"2007","journal-title":"Cytokine Growth Factor Rev"},{"issue":"1-2","key":"pone.0314093.ref021","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s00109-022-02276-2","article-title":"EVs vs. EVs: MSCs and Tregs as a source of invisible possibilities","volume":"101","author":"Z Heydari","year":"2023","journal-title":"J Mol Med (Berl)"},{"issue":"12","key":"pone.0314093.ref022","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1016\/j.jcyt.2018.09.008","article-title":"Immune regulatory targets of mesenchymal stromal cell exosomes\/small extracellular vesicles in tissue regeneration","volume":"20","author":"WS Toh","year":"2018","journal-title":"Cytotherapy"},{"issue":"1","key":"pone.0314093.ref023","doi-asserted-by":"crossref","first-page":"e0170628","DOI":"10.1371\/journal.pone.0170628","article-title":"A comparative study of serum exosome isolation using differential ultracentrifugation and three commercial reagents","volume":"12","author":"I Helwa","year":"2017","journal-title":"PLoS One"},{"issue":"5","key":"pone.0314093.ref024","doi-asserted-by":"crossref","first-page":"863","DOI":"10.3390\/antiox11050863","article-title":"Cisplatin-induced reproductive toxicity and oxidative stress: ameliorative effect of kinetin","volume":"11","author":"R Abdel-Latif","year":"2022","journal-title":"Antioxidants"},{"issue":"1","key":"pone.0314093.ref025","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1186\/s12885-017-3898-9","article-title":"Acacia hydaspica ethyl acetate extract protects against cisplatin-induced DNA damage, oxidative stress and testicular injuries in adult male rats","volume":"17","author":"T Afsar","year":"2017","journal-title":"BMC Cancer"},{"key":"pone.0314093.ref026","volume-title":"Methods for microvesicle isolation and selective removal","author":"T Antes"},{"issue":"5","key":"pone.0314093.ref027","doi-asserted-by":"crossref","first-page":"943","DOI":"10.11607\/jomi.9515","article-title":"Repair of rat calvarial bone defect by using exosomes of umbilical cord-derived mesenchymal stromal cells embedded in chitosan\/hydroxyapatite scaffolds","volume":"37","author":"D Bahar","year":"2022","journal-title":"Int J Oral Maxillofac Implants"},{"issue":"5","key":"pone.0314093.ref028","first-page":"355","article-title":"Effect of nano-zinc oxide on doxorubicin- induced oxidative stress and sperm disorders in adult male Wistar rats","volume":"11","author":"P Badkoobeh","year":"2013","journal-title":"Iran J Reprod Med"},{"issue":"1","key":"pone.0314093.ref029","first-page":"2","article-title":"Testicular biopsy score count--a method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males","volume":"1","author":"SG Johnsen","year":"1970","journal-title":"Hormones"},{"issue":"9","key":"pone.0314093.ref030","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1080\/09553002.2022.2033339","article-title":"Hepatotoxicity and renal toxicity induced by radiation and the protective efect of quercetin in male albino rats","volume":"98","author":"M Baran","year":"2022","journal-title":"Int J Radiat Biol"},{"issue":"38","key":"pone.0314093.ref031","first-page":"1918","article-title":"Linearization of the bradford protein assay","author":"O Ernst","year":"2010","journal-title":"J Vis Exp"},{"issue":"5","key":"pone.0314093.ref032","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1111\/and.12490","article-title":"In vitro toxicity assay of cisplatin on mouse acute lymphoblastic leukaemia and spermatogonial stem cells","volume":"48","author":"R Shabani","year":"2016","journal-title":"Andrologia"},{"issue":"11","key":"pone.0314093.ref033","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1093\/stmcls\/sxac057","article-title":"Immunomodulatory and regenerative effects of MSC-derived extracellular vesicles to treat acute GVHD","volume":"40","author":"S Fujii","year":"2022","journal-title":"Stem Cells"},{"issue":"1","key":"pone.0314093.ref034","first-page":"36","article-title":"Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges","volume":"10","author":"J-Y Ding","year":"2023","journal-title":"Mil Med Res"},{"issue":"4","key":"pone.0314093.ref035","doi-asserted-by":"crossref","first-page":"991","DOI":"10.3390\/cells9040991","article-title":"Mesenchymal stem cell derived extracellular vesicles for tissue engineering and regenerative medicine applications","volume":"9","author":"D Tsiapalis","year":"2020","journal-title":"Cells"},{"key":"pone.0314093.ref036","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.ejphar.2011.11.025","article-title":"Molecular effects of chemotherapeutic drugs and their modulation by antioxidants in the testis","volume":"674","author":"K Narayana","year":"2012","journal-title":"Eur J Pharmacol"},{"key":"pone.0314093.ref037","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.14202\/vetworld.2018.1349-1356","article-title":"Effects of secretome on cisplatin-induced testicular dysfunction in rats","volume":"11","author":"SA Prihatno","year":"2018","journal-title":"Vet World"},{"issue":"1","key":"pone.0314093.ref038","doi-asserted-by":"crossref","first-page":"e13850","DOI":"10.1111\/and.13850","article-title":"The ameliorative effects of methylene blue on testicular damage induced by cisplatin in rats","volume":"53","author":"F Gholami Jourabi","year":"2021","journal-title":"Andrologia"},{"issue":"1","key":"pone.0314093.ref039","doi-asserted-by":"crossref","first-page":"93","DOI":"10.34172\/PS.2019.60","article-title":"Comments on \u201cThe improvement effects of Gordonia bronchialis on male fertility of rats with diabetes mellitus induced by Streptozotocin\u201d","volume":"26","author":"M Hassanzadeh-Taheri","year":"2020","journal-title":"Pharm Sci"},{"key":"pone.0314093.ref040","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.mce.2009.07.003","article-title":"Molecular aspects of steroidogenic factor 1 (SF-1)","volume":"315","author":"EA Hoivik","year":"2010","journal-title":"Mol Cell Endocrinol"},{"key":"pone.0314093.ref041","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1080\/19396368.2018.1450460","article-title":"Grape seed procyanidins extract attenuates Cisplatin-induced oxidative stress and testosterone synthase inhibition in rat testes","volume":"64","author":"M Tian","year":"2018","journal-title":"Syst Biol Reprod Med"},{"issue":"2","key":"pone.0314093.ref042","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1210\/edrv-9-2-267","article-title":"Inhibins, activins, and follistatins: gonadal proteins modulating the secretion of follicle-stimulating hormone","volume":"9","author":"SY Ying","year":"1988","journal-title":"Endocr Rev"},{"key":"pone.0314093.ref043","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.theriogenology.2023.02.016","article-title":"Role and regulatory mechanism of inhibin in animal reproductive system","volume":"202","author":"Y Han","year":"2023","journal-title":"Theriogenology"},{"key":"pone.0314093.ref044","doi-asserted-by":"crossref","first-page":"12735","DOI":"10.3390\/ijms222312735","article-title":"The roles of luteinizing hormone, follicle-stimulating hormone and testosterone in spermatogenesis and folliculogenesis revisited","volume":"22","author":"OO Oduwole","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"12","key":"pone.0314093.ref045","first-page":"3976","article-title":"Serum inhibin B in healthy pubertal and adolescent boys: relation to age, stage of puberty, and follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol levels","volume":"82","author":"AM Andersson","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"pone.0314093.ref046","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/bdrb.21046","article-title":"Inhibin B as a marker of sertoli cell damage and spermatogenic disturbance in the rat","volume":"98","author":"T Pfaff","year":"2013","journal-title":"Birth Defects Res B Dev Reprod Toxicol"},{"issue":"1\u20132","key":"pone.0314093.ref047","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.mce.2004.07.008","article-title":"The role of activin, follistatin and inhibin in testicular physiology","volume":"225","author":"DM de Kretser","year":"2004","journal-title":"Mol Cell Endocrinol"},{"issue":"2","key":"pone.0314093.ref048","doi-asserted-by":"crossref","first-page":"183","DOI":"10.3390\/antiox13020183","article-title":"Bone marrow mesenchymal stem cell-derived exosomes ameliorate aging-induced BTB impairment in porcine testes by activating autophagy and inhibiting ROS\/NLRP3 inflammasomes via the AMPK\/mTOR signaling pathway","volume":"13","author":"Y Zhou","year":"2024","journal-title":"Antioxidants (Basel)"},{"key":"pone.0314093.ref049","first-page":"8065771","article-title":"Adipose mesenchymal stromal cell-derived exosomes prevent testicular torsion injury via activating PI3K\/AKT and MAPK\/ERK1\/2 pathways","author":"H Liu","year":"2022","journal-title":"Oxid Med Cell Longev"},{"issue":"1","key":"pone.0314093.ref050","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1186\/s13287-019-1351-5","article-title":"Mesenchymal stem cells restore the sperm motility from testicular torsion-detorsion injury by regulation of glucose metabolism in sperm","volume":"10","author":"C-H Hsiao","year":"2019","journal-title":"Stem Cell Res Ther"},{"key":"pone.0314093.ref051","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.semcdb.2015.03.001","article-title":"Mesenchymal stem cell exosomes","volume":"40","author":"RC Lai","year":"2015","journal-title":"Semin Cell Dev Biol"},{"key":"pone.0314093.ref052","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13045-017-0436-9","article-title":"Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment","volume":"10","author":"GJ Yoshida","year":"2017","journal-title":"J Hematol Oncol"},{"issue":"7","key":"pone.0314093.ref053","doi-asserted-by":"crossref","first-page":"e41412","DOI":"10.1371\/journal.pone.0041412","article-title":"Autophagy and apoptosis act as partners to induce germ cell death after heat stress in mice","volume":"7","author":"M Zhang","year":"2012","journal-title":"PLoS One"},{"issue":"2","key":"pone.0314093.ref054","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3390\/cells5020024","article-title":"Advances in autophagy regulatory mechanisms","volume":"5","author":"LE Gallagher","year":"2016","journal-title":"Cells"},{"issue":"1","key":"pone.0314093.ref055","doi-asserted-by":"crossref","first-page":"e12024","DOI":"10.1002\/jev2.12024","article-title":"Adipose-derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR-25","volume":"10","author":"Y Kuang","year":"2020","journal-title":"J Extracell Vesicles"},{"issue":"1","key":"pone.0314093.ref056","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1186\/s12885-017-3898-9","article-title":"Acacia hydaspica ethyl acetate extract protects against cisplatin-induced DNA damage oxidative stress and testicular injuries in adult male rats","volume":"17","author":"T Afsar","year":"2017","journal-title":"BMC Cancer"},{"key":"pone.0314093.ref057","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ejphar.2014.07.025","article-title":"Cisplatin in cancer therapy: molecular mechanisms of action","volume":"740","author":"S Dasari","year":"2014","journal-title":"Eur J Pharmacol"},{"issue":"14","key":"pone.0314093.ref058","doi-asserted-by":"crossref","first-page":"3384","DOI":"10.3390\/ijms20143384","article-title":"Mitochondrial involvement in cisplatin resistance","volume":"20","author":"V Cocetta","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"11","key":"pone.0314093.ref059","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1002\/stem.1208","article-title":"Injury-activated transforming growth factor \u03b2 controls mobilization of mesenchymal stem cells for tissue remodeling","volume":"30","author":"M Wan","year":"2012","journal-title":"Stem Cells"},{"issue":"9","key":"pone.0314093.ref060","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1507\/endocrj.EJ20-0149","article-title":"Cisplatin induced testicular damage through mitochondria mediated apoptosis, inflammation and oxidative stress in rats: impact of resveratrol","volume":"67","author":"H A A Aly","year":"2020","journal-title":"Endocr J"},{"issue":"11","key":"pone.0314093.ref061","doi-asserted-by":"crossref","first-page":"e2000671","DOI":"10.1002\/cbdv.202000671","article-title":"Protective effects of nucleosides-rich extract from cordyceps cicadae against cisplatin induced testicular damage","volume":"17","author":"L Wang","year":"2020","journal-title":"Chem Biodivers"},{"issue":"4","key":"pone.0314093.ref062","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.repbio.2019.11.001","article-title":"The inflammatory mediators TNF\u03b1 and nitric oxide arrest spermatogonia GC-1 cell cycle","volume":"19","author":"ME Ferreiro","year":"2019","journal-title":"Reprod Biol"},{"issue":"4","key":"pone.0314093.ref063","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s43188-024-00250-3","article-title":"Acetate attenuates lead-induced dysregulation of testicular steroidogenesis and spermatogenesis by targeting oxidative stress, inflammatory cytokines, and apoptosis","volume":"40","author":"EE Besong","year":"2024","journal-title":"Toxicol Res"},{"issue":"5","key":"pone.0314093.ref064","doi-asserted-by":"crossref","first-page":"547","DOI":"10.4103\/aja2022126","article-title":"The emerging role of exosomes in the development of testicular","volume":"25","author":"C-Y Li","year":"2023","journal-title":"Asian J Androl"},{"key":"pone.0314093.ref065","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1161\/CIRCRESAHA.122.320916","article-title":"Extracellular vesicles regulate sympatho-excitation by Nrf2 in heart failure","volume":"131","author":"C Tian","year":"2022","journal-title":"Circ Res"},{"issue":"4","key":"pone.0314093.ref066","doi-asserted-by":"crossref","first-page":"386","DOI":"10.4103\/aja.aja_98_20","article-title":"Protective effect of bone marrow mesenchymal stem cell-derived exosomes against the reproductive toxicity of cyclophosphamide is associated with the p38MAPK\/ERK and AKT signaling pathways","volume":"23","author":"X-B Guo","year":"2021","journal-title":"Asian J Androl"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0314093","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T17:30:46Z","timestamp":1746207046000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0314093"}},"subtitle":[],"editor":[{"given":"Roland Eghoghosoa","family":"Akhigbe,","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,5,2]]},"references-count":66,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5,2]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0314093","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,2]]}}}