{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T17:55:36Z","timestamp":1769277336564,"version":"3.49.0"},"reference-count":67,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T00:00:00Z","timestamp":1560729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"IPET, MAFRA and BK 21 Plus","award":["117029-3"],"award-info":[{"award-number":["117029-3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Melatonin, a nighttime-secreted antioxidant hormone produced by the pineal gland, and AKT, a serine\/threonine-specific protein kinase, have been identified as regulators for several cellular processes essential for reproduction. The current study aimed to investigate the potential interplay between melatonin and AKT in bovine oocytes in the context of embryo development. Results showed that the inclusion of SH6, a specific AKT inhibitor, during in vitro maturation (IVM) significantly reduced oocyte maturation, cumulus cell expansion, cleavage, and blastocyst development that were rescued upon addition of melatonin. Oocytes treated with SH6 in the presence of melatonin showed lower levels of reactive oxygen species (ROS) and blastocysts developed exhibited low apoptosis while the mitochondrial profile was significantly improved compared to the SH6-treated group. The RT-qPCR results showed up-regulation of the mRNA of maturation-, mitochondrial-, and cumulus expansion-related genes including GDF-9, BMP-15, MARF1, ATPase, ATP5F1E, POLG2, HAS2, TNFAIP6, and PTGS2 and down-regulation of Bcl-2 associated X apoptosis regulator (BAX), caspase 3, and p21 involved in apoptosis and cell cycle arrest in melatonin-SH6 co-treated group compared to SH6 sole treatment. The immunofluorescence showed high levels of caspase 3 and caspase 9, and low AKT phosphorylation in the SH6-treated group compared to the control and melatonin-SH6 co-treatment. Taken together, our results showed the importance of both melatonin and AKT for overall embryonic developmental processes and, for the first time, we report that melatonin could neutralize the deleterious consequences of AKT inhibition, suggesting a potential role in regulation of AKT signaling in bovine oocytes.<\/jats:p>","DOI":"10.3390\/ijms20122956","type":"journal-article","created":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T11:24:45Z","timestamp":1560770685000},"page":"2956","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Melatonin Abrogates the Anti-Developmental Effect of the AKT Inhibitor SH6 in Bovine Oocytes and Embryos"],"prefix":"10.3390","volume":"20","author":[{"given":"Marwa","family":"El Sheikh","sequence":"first","affiliation":[{"name":"Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea"},{"name":"Department of Microbial Biotechnology, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Cairo 12622, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6448-1160","authenticated-orcid":false,"given":"Ayman","family":"Mesalam","sequence":"additional","affiliation":[{"name":"Department of Theriogenology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4605-2976","authenticated-orcid":false,"given":"Ahmed Atef","family":"Mesalam","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9715-0691","authenticated-orcid":false,"given":"Muhammad","family":"Idrees","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyeong-Lim","family":"Lee","sequence":"additional","affiliation":[{"name":"The King Kong Corp Ltd., Jinju 52828, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5567-1088","authenticated-orcid":false,"given":"Il-Keun","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea"},{"name":"The King Kong Corp Ltd., Jinju 52828, Korea"},{"name":"Institute of Agriculture and Life Science, Gyeongsang National University, Jinju 52828, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/mrd.1080370107","article-title":"Effect of follicle size on bovine oocyte quality and developmental competence following maturation, fertilization, and culture in vitro","volume":"37","author":"Lonergan","year":"1994","journal-title":"Mol. Reprod. Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.2527\/1999.7782219x","article-title":"Effect of duration of dominance of the ovulatory follicle on onset of estrus and fertility in heifers","volume":"77","author":"Austin","year":"1999","journal-title":"J. Anim. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1017\/S0967199403002156","article-title":"Reversible changes in protein phosphorylation during germinal vesicle breakdown and pronuclear formation in bovine oocytes in vitro","volume":"11","author":"Chian","year":"2003","journal-title":"Zygote"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.ceb.2003.10.010","article-title":"Cell-cycle control during meiotic maturation","volume":"15","author":"Kishimoto","year":"2003","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_5","first-page":"274","article-title":"A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region","volume":"254","author":"Bellacosa","year":"1991","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1126\/science.1106148","article-title":"Phosphorylation and regulation of Akt\/PKB by the rictor-mTOR complex","volume":"307","author":"Sarbassov","year":"2005","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6473","DOI":"10.1038\/onc.2008.313","article-title":"PI3K\/Akt: Getting it right matters","volume":"27","author":"Franke","year":"2008","journal-title":"Oncogene"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.cell.2017.04.001","article-title":"AKT\/PKB Signaling: Navigating the Network","volume":"169","author":"Manning","year":"2017","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Wang, J., Zhao, W., Guo, H., Fang, Y., Stockman, S.E., Bai, S., Ng, P.K., Li, Y., Yu, Q., and Lu, Y. (2018). AKT isoform-specific expression and activation across cancer lineages. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4654-5"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1042\/BST0350231","article-title":"Physiological roles of PKB\/Akt isoforms in development and disease","volume":"35","author":"Dummler","year":"2007","journal-title":"Biochem. Soc. Trans."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1042\/BC20050020","article-title":"PKB\/AKT is involved in resumption of meiosis in mouse oocytes","volume":"98","author":"Kalous","year":"2006","journal-title":"Biol. Cell."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.ydbio.2007.12.005","article-title":"Protein kinase B (PKB\/Akt) is required for the completion of meiosis in mouse oocytes","volume":"314","author":"Hoshino","year":"2008","journal-title":"Dev. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1530\/rep.1.00754","article-title":"Activation of Akt (protein kinase B) stimulates metaphase I to metaphase II transition in bovine oocytes","volume":"130","author":"Tomek","year":"2005","journal-title":"Reproduction"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1530\/REP-08-0461","article-title":"AKT (protein kinase B) is implicated in meiotic maturation of porcine oocytes","volume":"138","author":"Kalous","year":"2009","journal-title":"Reproduction"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1095\/biolreprod.107.060129","article-title":"Direct evidence for the action of phosphatidylinositol (3,4,5)-trisphosphate-mediated signal transduction in the 2-cell mouse embryo","volume":"77","author":"Li","year":"2007","journal-title":"Biol. Reprod."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.ydbio.2005.05.033","article-title":"The PI3K\/Akt pathway is present and functional in the preimplantation mouse embryo","volume":"284","author":"Riley","year":"2005","journal-title":"Dev. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12958-017-0318-6","article-title":"Functional role of AKT signaling in bovine early embryonic development: Potential link to embryotrophic actions of follistatin","volume":"16","author":"Ashry","year":"2018","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0092-8674(00)80405-5","article-title":"Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery","volume":"91","author":"Datta","year":"1997","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1126\/science.282.5392.1318","article-title":"Regulation of cell death protease caspase-9 by phosphorylation","volume":"282","author":"Cardone","year":"1998","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1126\/science.278.5338.687","article-title":"Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt","volume":"278","author":"Page","year":"1997","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Song, B.S., Jeong, P.S., Lee, J.H., Lee, M.H., Yang, H.J., Choi, S.A., Lee, H.Y., Yoon, S.B., Park, Y.H., and Jeong, K.J. (2018). The effects of kinase modulation on in vitro maturation according to different cumulus-oocyte complex morphologies. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0205495"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1210\/en.2004-1152","article-title":"Dexamethasone induces apoptosis in proliferative chondrocytes through activation of caspases and suppression of the Akt-phosphatidylinositol 3\u2032-kinase signaling pathway","volume":"146","author":"Chrysis","year":"2005","journal-title":"Endocrinology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.virol.2007.09.003","article-title":"PI3K\/AKT inhibition induces caspase-dependent apoptosis in HTLV-1-transformed cells","volume":"370","author":"Jeong","year":"2008","journal-title":"Virology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.smrv.2004.08.001","article-title":"The basic physiology and pathophysiology of melatonin","volume":"9","author":"Claustrat","year":"2005","journal-title":"Sleep Med. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1111\/j.1742-4658.2006.05322.x","article-title":"Melatonin: Nature\u2019s most versatile biological signal?","volume":"273","author":"Srinivasan","year":"2006","journal-title":"FEBS J"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/j.theriogenology.2014.07.011","article-title":"Essential actions of melatonin in protecting the ovary from oxidative damage","volume":"82","author":"Cruz","year":"2014","journal-title":"Theriogenology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1111\/jphp.12682","article-title":"A review of the protective role of melatonin during phosphine-induced cardiotoxicity: Focus on mitochondrial dysfunction, oxidative stress and apoptosis","volume":"69","author":"Asghari","year":"2017","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1111\/jpi.12267","article-title":"Melatonin: An ancient molecule that makes oxygen metabolically tolerable","volume":"59","author":"Manchester","year":"2015","journal-title":"J. Pineal Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.anireprosci.2014.01.011","article-title":"Role of melatonin on production and preservation of gametes and embryos: A brief review","volume":"145","author":"Cruz","year":"2014","journal-title":"Anim. Reprod. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.theriogenology.2017.05.012","article-title":"2-Methoxystypandrone improves in vitro-produced bovine embryo quality through inhibition of IKBKB","volume":"99","author":"Mesalam","year":"2017","journal-title":"Theriogenology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1530\/jrf.0.0990673","article-title":"Oxygen tension in the oviduct and uterus of rhesus monkeys, hamsters and rabbits","volume":"99","author":"Fischer","year":"1993","journal-title":"J. Reprod. Fertil."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yang, M., Tao, J., Chai, M., Wu, H., Wang, J., Li, G., He, C., Xie, L., Ji, P., and Dai, Y. (2017). Melatonin Improves the Quality of Inferior Bovine Oocytes and Promoted Their Subsequent IVF Embryo Development: Mechanisms and Results. Molecules, 22.","DOI":"10.3390\/molecules22122059"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4175","DOI":"10.18632\/aging.101715","article-title":"Melatonin alleviates meiotic defects in fetal mouse oocytes induced by Di (2-ethylhexyl) phthalate in vitro","volume":"10","author":"Sun","year":"2018","journal-title":"Aging (Albany NY)"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e12532","DOI":"10.1111\/jpi.12532","article-title":"Melatonin protects against paraquat-induced damage during in vitro maturation of bovine oocytes","volume":"66","author":"Pang","year":"2019","journal-title":"J. Pineal Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Park, H.J., Park, S.Y., Kim, J.W., Yang, S.G., Kim, M.J., Jegal, H.G., Kim, I.S., Choo, Y.K., and Koo, D.B. (2018). Melatonin Improves Oocyte Maturation and Mitochondrial Functions by Reducing Bisphenol A-Derived Superoxide in Porcine Oocytes In Vitro. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113422"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e12543","DOI":"10.1111\/jpi.12543","article-title":"Melatonin protects in vitro matured porcine oocytes from toxicity of Aflatoxin B1","volume":"66","author":"Cheng","year":"2019","journal-title":"J. Pineal Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.etap.2019.03.005","article-title":"Melatonin alleviates beta-zearalenol and HT-2 toxin-induced apoptosis and oxidative stress in bovine ovarian granulosa cells","volume":"68","author":"Yang","year":"2019","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Andrade, G.M., da Silveira, J.C., Perrini, C., Del Collado, M., Gebremedhn, S., Tesfaye, D., Meirelles, F.V., and Perecin, F. (2017). The role of the PI3K-Akt signaling pathway in the developmental competence of bovine oocytes. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185045"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3372","DOI":"10.1096\/fj.201601382RR","article-title":"CB1 cannabinoid receptor drives oocyte maturation and embryo development via PI3K\/Akt and MAPK pathways","volume":"31","author":"Pericuesta","year":"2017","journal-title":"FASEB J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1002\/mrd.22848","article-title":"Ganglioside GM3 induces cumulus cell apoptosis through inhibition of epidermal growth factor receptor-mediated PI3K\/AKT signaling pathways during in vitro maturation of pig oocytes","volume":"84","author":"Park","year":"2017","journal-title":"Mol. Reprod. Dev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/j.1600-079X.2005.00283.x","article-title":"Sustained activation of Akt by melatonin contributes to the protection against kainic acid-induced neuronal death in hippocampus","volume":"40","author":"Lee","year":"2006","journal-title":"J. Pineal Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"404","DOI":"10.7150\/ijbs.27912","article-title":"Melatonin Stimulates STAR Expression and Progesterone Production via Activation of the PI3K\/AKT Pathway in Bovine Theca Cells","volume":"15","author":"Wang","year":"2019","journal-title":"Int. J. Biol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1111\/j.1447-0578.2003.00035.x","article-title":"Melatonin as a new drug for improving oocyte quality","volume":"2","author":"Takasaki","year":"2003","journal-title":"Reprod. Med. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1071\/RD12091","article-title":"The rat oocyte synthesises melatonin","volume":"25","author":"Sakaguchi","year":"2013","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/mrd.21295","article-title":"Evidence of melatonin synthesis in the cumulus oocyte complexes and its role in enhancing oocyte maturation in vitro in cattle","volume":"78","author":"Geshi","year":"2011","journal-title":"Mol. Reprod. Dev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/j.theriogenology.2016.05.026","article-title":"Effects of melatonin during IVM in defined medium on oocyte meiosis, oxidative stress, and subsequent embryo development","volume":"86","author":"Mesquita","year":"2016","journal-title":"Theriogenology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1017\/S0967199414000161","article-title":"Melatonin enhances the in vitro maturation and developmental potential of bovine oocytes denuded of the cumulus oophorus","volume":"23","author":"Zhao","year":"2015","journal-title":"Zygote"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.rbmo.2009.10.011","article-title":"Akt expression in mouse oocytes matured in vivo and in vitro","volume":"20","author":"Cecconi","year":"2010","journal-title":"Reprod Biomed Online"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/jpi.12163","article-title":"Beneficial effects of melatonin on bovine oocytes maturation: A mechanistic approach","volume":"57","author":"Tian","year":"2014","journal-title":"J. Pineal Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1530\/REP-10-0040","article-title":"Identification and regulation of glycogen synthase kinase-3 during bovine embryo development","volume":"140","author":"Aparicio","year":"2010","journal-title":"Reproduction"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Lee, S., Jin, J.X., Taweechaipaisankul, A., Kim, G.A., and Lee, B.C. (2018). Stimulatory Effects of Melatonin on Porcine In Vitro Maturation Are Mediated by MT2 Receptor. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061581"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1126\/science.1214680","article-title":"MARF1 regulates essential oogenic processes in mice","volume":"335","author":"Su","year":"2012","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"18653","DOI":"10.1073\/pnas.1216904109","article-title":"Meiosis arrest female 1 (MARF1) has nuage-like function in mammalian oocytes","volume":"109","author":"Su","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Fang, Y., Deng, S., Zhang, J., Liu, H., Li, Y., Zhang, X., and Liu, Y. (2018). Melatonin-Mediated Development of Ovine Cumulus Cells, Perhaps by Regulation of DNA Methylation. Molecules, 23.","DOI":"10.3390\/molecules23020494"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ydbio.2004.08.020","article-title":"Synergistic roles of BMP15 and GDF9 in the development and function of the oocyte-cumulus cell complex in mice: Genetic evidence for an oocyte-granulosa cell regulatory loop","volume":"276","author":"Su","year":"2004","journal-title":"Dev. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.18632\/aging.101252","article-title":"Melatonin prevents postovulatory oocyte aging and promotes subsequent embryonic development in the pig","volume":"9","author":"Wang","year":"2017","journal-title":"Aging (Albany NY)"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"He, C., Wang, J., Zhang, Z., Yang, M., Li, Y., Tian, X., Ma, T., Tao, J., Zhu, K., and Song, Y. (2016). Mitochondria Synthesize Melatonin to Ameliorate Its Function and Improve Mice Oocyte\u2019s Quality under in Vitro Conditions. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17060939"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.reprotox.2017.04.001","article-title":"Effect of lipopolysaccharide on developmental competence of oocytes","volume":"71","author":"Magata","year":"2017","journal-title":"Reprod. Toxicol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"9300","DOI":"10.1021\/bi050202d","article-title":"A novel metabolic pathway of melatonin: Oxidation by cytochrome C","volume":"44","author":"Semak","year":"2005","journal-title":"Biochemistry"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/j.1600-079X.2007.00490.x","article-title":"Melatonin protects against common deletion of mitochondrial DNA-augmented mitochondrial oxidative stress and apoptosis","volume":"43","author":"Jou","year":"2007","journal-title":"J. Pineal Res."},{"key":"ref_61","first-page":"2892","article-title":"Dynamic comparisons of high-resolution expression profiles highlighting mitochondria-related genes between in vivo and in vitro fertilized early mouse embryos","volume":"30","author":"Ren","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.cell.2007.06.009","article-title":"AKT\/PKB signaling: Navigating downstream","volume":"129","author":"Manning","year":"2007","journal-title":"Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"951724","DOI":"10.1155\/2012\/951724","article-title":"Akt: A double-edged sword in cell proliferation and genome stability","volume":"2012","author":"Xu","year":"2012","journal-title":"J. Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Ornelas, I.M., Silva, T.M., Fragel-Madeira, L., and Ventura, A.L. (2013). Inhibition of PI3K\/Akt pathway impairs G2\/M transition of cell cycle in late developing progenitors of the avian embryo retina. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053517"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.cell.2013.08.062","article-title":"The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit","volume":"155","author":"Spencer","year":"2013","journal-title":"Cell"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1101\/gad.1212704","article-title":"Upstream and downstream of mTOR","volume":"18","author":"Hay","year":"2004","journal-title":"Genes Dev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"E5326","DOI":"10.1073\/pnas.1800352115","article-title":"Oocyte stage-specific effects of MTOR determine granulosa cell fate and oocyte quality in mice","volume":"115","author":"Guo","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/12\/2956\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:59:04Z","timestamp":1760187544000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/12\/2956"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,17]]},"references-count":67,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,6]]}},"alternative-id":["ijms20122956"],"URL":"https:\/\/doi.org\/10.3390\/ijms20122956","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,17]]}}}