Register      Login
Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Iloprost supports early development of in vitro-produced porcine embryos through activation of the phosphatidylinositol 3-kinase/AKT signalling pathway

Pil-Soo Jeong A B , Seung-Bin Yoon A C , Seon-A Choi A , Bong-Seok Song A , Ji-Su Kim A C , Bo-Woong Sim A , Young-Ho Park A , Hae-Jun Yang A , Seong-Eun Mun A , Young-Hyun Kim A C , Philyong Kang A , Kang-Jin Jeong A , Youngjeon Lee A , Yeung Bae Jin A , Jae-Won Huh A C , Sang-Rae Lee A C , Deog-Bon Koo B , Young Il Park D , Sun-Uk Kim A C E and Kyu-Tae Chang A C E
+ Author Affiliations
- Author Affiliations

A National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, 30, Yeongudanjiro, Ochangeup, Cheongwon-gu, Cheongju-si, Chungcheongbuk-do 28116, Republic of Korea.

B Department of Biotechnology, College of Engineering, Daegu University, Jillyang-eup, Gyeongsan-si, Gyeongsangbuk-do 38453, Republic of Korea.

C Department of Functional Genomics, University of Science and Technology, 217 Gajeong-gu, Daejeon 34113, Republic of Korea.

D Graduate School Department of Digital Media, Ewha Womans University, Daehyeon-dong, Seodaemun-gu, Seoul 03760, Korea.

E Corresponding authors: Emails: sunuk@kribb.re.kr; changkt@kribb.re.kr

Reproduction, Fertility and Development 29(7) 1306-1318 https://doi.org/10.1071/RD15391
Submitted: 2 October 2015  Accepted: 20 April 2016   Published: 9 June 2016

Abstract

Despite evidence of the presence of prostaglandin (PG) I2 in mammalian oviducts, its role in early development of in vitro-produced (IVP) embryos is largely unknown. Thus, in the present study we examined the effects of iloprost, a PGI2 analogue, on the in vitro developmental competence of early porcine embryos and the underlying mechanism(s). To examine the effects of iloprost on the development rate of IVF embryos, iloprost was added to the in vitro culture (IVC) medium and cultured for 6 days. Supplementation of the IVC medium with iloprost significantly improved developmental parameters, such as blastocyst formation rate, the trophectoderm : inner cell mass ratio and cell survival in IVF and parthenogenetically activated (PA) embryos. In addition, post-blastulation development into the expanded blastocyst stage was improved in iloprost-treated groups compared with controls. Interestingly, the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway was significantly activated by iloprost supplementation in a concentration-dependent manner (10–1000 nM), and the beneficial effects of iloprost on the early development of porcine IVF and PA embryos was completely ablated by treatment with 2.5 μM wortmannin, a PI3K/AKT signalling inhibitor. Importantly, expression of the PI3K/AKT signalling pathway was significantly reduced in somatic cell nuclear transfer (SCNT) compared with IVF embryos, and iloprost supported the early development of SCNT embryos, as was the case for IVF and PA embryos, suggesting a consistent effect of iloprost on the IVC of IVP porcine embryos. Together, these results indicate that iloprost can be a useful IVC supplement for production of IVP early porcine embryos with high developmental competence.

Additional keywords: culture medium, signal transduction.


References

Ahlström, A., Westin, C., Reismer, E., Wikland, M., and Hardarson, T. (2011). Trophectoderm morphology: an important parameter for predicting live birth after single blastocyst transfer. Hum. Reprod. 26, 3289–3296.
Trophectoderm morphology: an important parameter for predicting live birth after single blastocyst transfer.Crossref | GoogleScholarGoogle Scholar | 21972253PubMed |

Beebe, L. F., McIlfatrick, S. J., and Nottle, M. B. (2009). Cytochalasin B and trichostatin a treatment postactivation improves in vitro development of porcine somatic cell nuclear transfer embryos. Cloning Stem Cells 11, 477–482.
Cytochalasin B and trichostatin a treatment postactivation improves in vitro development of porcine somatic cell nuclear transfer embryos.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXjvVCisQ%3D%3D&md5=b8b11771f0bedcab5155e6c160572ae8CAS | 19780698PubMed |

Belkhiri, A., Dar, A. A., Zaika, A., Kelley, M., and El-Rifai, W. (2008). t-Darpp promotes cancer cell survival by up-regulation of Bcl2 through Akt-dependent mechanism. Cancer Res. 68, 395–403.
t-Darpp promotes cancer cell survival by up-regulation of Bcl2 through Akt-dependent mechanism.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXmt1Onsw%3D%3D&md5=e5489ce0fc4b63e0fcfccc7d14a62fa6CAS | 18199533PubMed |

Brazil, D. P., and Hemmings, B. A. (2001). Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem. Sci. 26, 657–664.
Ten years of protein kinase B signalling: a hard Akt to follow.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXotFSmsrg%3D&md5=5e46bcbd4f4fe3420b66ea9fb88bc140CAS | 11701324PubMed |

Castillo-Martín, M., Bonet, S., Morató, R., and Yeste, M. (2014). Comparative effects of adding beta-mercaptoethanol or l-ascorbic acid to culture or vitrification–warming media on IVF porcine embryos. Reprod. Fertil. Dev. 26, 875–882.
Comparative effects of adding beta-mercaptoethanol or l-ascorbic acid to culture or vitrification–warming media on IVF porcine embryos.Crossref | GoogleScholarGoogle Scholar | 23815877PubMed |

Chan, W. H. (2010). Cytotoxic effects of 2-bromopropane on embryonic development in mouse blastocysts. Int. J. Mol. Sci. 11, 731–744.
Cytotoxic effects of 2-bromopropane on embryonic development in mouse blastocysts.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXit1ygurg%3D&md5=49c9cbfd0d00ab0c0607f7810daa0aebCAS | 20386664PubMed |

Franke, T. F., Kaplan, D. R., and Cantley, L. C. (1997). PI3K: downstream AKTion blocks apoptosis. Cell 88, 435–437.
PI3K: downstream AKTion blocks apoptosis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXhtlKqs70%3D&md5=92d3c5b58a9a8a20e2d61b09f644b584CAS | 9038334PubMed |

Funahashi, H., Cantley, T. C., Stumpf, T. T., Terlouw, S. L., and Day, B. N. (1994). In vitro development of in vitro-matured porcine oocytes following chemical activation or in vitro fertilization. Biol. Reprod. 50, 1072–1077.
In vitro development of in vitro-matured porcine oocytes following chemical activation or in vitro fertilization.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK2c3pslSktQ%3D%3D&md5=5b40270b637a3ef74f7fde2a3359e917CAS | 8025163PubMed |

García, Z., Silio, V., Marqués, M., Cortés, I., Kumar, A., Hernandez, C., Checa, A. I., Serrano, A., and Carrera, A. C. (2006). A PI3K activity-independent function of p85 regulatory subunit in control of mammalian cytokinesis. EMBO J. 25, 4740–4751.
A PI3K activity-independent function of p85 regulatory subunit in control of mammalian cytokinesis.Crossref | GoogleScholarGoogle Scholar | 17024187PubMed |

Gross, V. S., Hess, M., and Cooper, G. M. (2005). Mouse embryonic stem cells and preimplantation embryos require signaling through the phosphatidylinositol 3-kinase pathway to suppress apoptosis. Mol. Reprod. Dev. 70, 324–332.
Mouse embryonic stem cells and preimplantation embryos require signaling through the phosphatidylinositol 3-kinase pathway to suppress apoptosis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXhtVShu7s%3D&md5=6b44c50b58f80024a2d47f533574b982CAS | 15625701PubMed |

Hamm, J., Tessanne, K., Murphy, C. N., and Prather, R. S. (2014). Transcriptional regulators TRIM28, SETDB1, and TP53 are aberrantly expressed in porcine embryos produced by in vitro fertilization in comparison to in vivo- and somatic-cell nuclear transfer-derived embryos. Mol. Reprod. Dev. 81, 552–566.
Transcriptional regulators TRIM28, SETDB1, and TP53 are aberrantly expressed in porcine embryos produced by in vitro fertilization in comparison to in vivo- and somatic-cell nuclear transfer-derived embryos.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXmt1agsLk%3D&md5=c6d533bd5d20fdd1e21cb890607e7f30CAS | 24659575PubMed |

Hardy, K., and Spanos, S. (2002). Growth factor expression and function in the human and mouse preimplantation embryo. J. Endocrinol. 172, 221–236.
Growth factor expression and function in the human and mouse preimplantation embryo.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XhvVejt78%3D&md5=6b284d3606a7151bcde9a620e27fff28CAS | 11834440PubMed |

Hennessy, B. T., Smith, D. L., Ram, P. T., Lu, Y., and Mills, G. B. (2005). Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discov. 4, 988–1004.
Exploiting the PI3K/AKT pathway for cancer drug discovery.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXht1yktbjI&md5=3edba64a145cbdd364d72e7140a8d818CAS | 16341064PubMed |

Hers, I., Vincent, E. E., and Tavare, J. M. (2011). Akt signalling in health and disease. Cell. Signal. 23, 1515–1527.
Akt signalling in health and disease.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXpslaisLo%3D&md5=c82b7af00d7b0dbcfbb4d9b700b92b41CAS | 21620960PubMed |

Hsu, Y. H., Chen, T. H., Chen, Y. C., Cheng, C. Y., Sue, Y. M., Chen, J. R., and Chen, C. H. (2013). Urotensin II exerts antiapoptotic effect on NRK-52E cells through prostacyclin-mediated peroxisome proliferator-activated receptor alpha and Akt activation. Mol. Cell. Endocrinol. 381, 168–174.
Urotensin II exerts antiapoptotic effect on NRK-52E cells through prostacyclin-mediated peroxisome proliferator-activated receptor alpha and Akt activation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhsFOnsr3F&md5=9f0e081682e2ec99685ecf84bac6e03eCAS | 23933501PubMed |

Hu, J., Cheng, D., Gao, X., Bao, J., Ma, X., and Wang, H. (2012). Vitamin C enhances the in vitro development of porcine pre-implantation embryos by reducing oxidative stress. Reprod. Domest. Anim. 47, 873–879.
Vitamin C enhances the in vitro development of porcine pre-implantation embryos by reducing oxidative stress.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhvFKgsbY%3D&md5=b2d48f0e0c04c9c9c3e31e7f42bc0a72CAS | 22239270PubMed |

Huang, J. C., Arbab, F., Tumbusch, K. J., Goldsby, J. S., Matijevic-Aleksic, N., and Wu, K. K. (2002). Human fallopian tubes express prostacyclin (PGI) synthase and cyclooxygenases and synthesize abundant PGI. J. Clin. Endocrinol. Metab. 87, 4361–4368.
Human fallopian tubes express prostacyclin (PGI) synthase and cyclooxygenases and synthesize abundant PGI.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XntFOltrw%3D&md5=c87d44c7294bfa4ed9193be5b5e04460CAS | 12213900PubMed |

Huang, J. C., Wun, W. S., Goldsby, J. S., Wun, I. C., Falconi, S. M., and Wu, K. K. (2003). Prostacyclin enhances embryo hatching but not sperm motility. Hum. Reprod. 18, 2582–2589.
Prostacyclin enhances embryo hatching but not sperm motility.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXpvVemu7w%3D&md5=32fe009d8654fd3c21a335ec7bbfb4a3CAS | 14645174PubMed |

Huang, J. C., Goldsby, J. S., and Wun, W. S. (2004). Prostacyclin enhances the implantation and live birth potentials of mouse embryos. Hum. Reprod. 19, 1856–1860.
Prostacyclin enhances the implantation and live birth potentials of mouse embryos.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXlvF2gtLw%3D&md5=217e0855f164d62ec3f48f52031dbd82CAS | 15205402PubMed |

Huang, J. C., Wun, W. S., Goldsby, J. S., Egan, K., FitzGerald, G. A., and Wu, K. K. (2007). Prostacyclin receptor signaling and early embryo development in the mouse. Hum. Reprod. 22, 2851–2856.
Prostacyclin receptor signaling and early embryo development in the mouse.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXht1Shu7nK&md5=9474f0c0ef331cd8456939cc21bf6e34CAS | 17905746PubMed |

Jeong, W., Kim, J., Bazer, F. W., and Song, G. (2014a). Proliferation-stimulating effect of colony stimulating factor 2 on porcine trophectoderm cells is mediated by activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase. PLoS One 9, e88731.
Proliferation-stimulating effect of colony stimulating factor 2 on porcine trophectoderm cells is mediated by activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase.Crossref | GoogleScholarGoogle Scholar | 24520418PubMed |

Jeong, W., Kim, J., Bazer, F. W., and Song, G. (2014b). Stimulatory effect of vascular endothelial growth factor on proliferation and migration of porcine trophectoderm cells and their regulation by the phosphatidylinositol-3-kinase–AKT and mitogen-activated protein kinase cell signaling pathways. Biol. Reprod. 90, 50.
Stimulatory effect of vascular endothelial growth factor on proliferation and migration of porcine trophectoderm cells and their regulation by the phosphatidylinositol-3-kinase–AKT and mitogen-activated protein kinase cell signaling pathways.Crossref | GoogleScholarGoogle Scholar | 24451985PubMed |

Jeong, W., Song, G., Bazer, F. W., and Kim, J. (2014c). Insulin-like growth factor I induces proliferation and migration of porcine trophectoderm cells through multiple cell signaling pathways, including protooncogenic protein kinase 1 and mitogen-activated protein kinase. Mol. Cell. Endocrinol. 384, 175–184.
Insulin-like growth factor I induces proliferation and migration of porcine trophectoderm cells through multiple cell signaling pathways, including protooncogenic protein kinase 1 and mitogen-activated protein kinase.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXjslKisbY%3D&md5=de2dd073976ba8a71e8f0b577ea01141CAS | 24508636PubMed |

Jin, X. L., Chandrakanthan, V., Morgan, H. D., and O’Neill, C. (2009). Preimplantation embryo development in the mouse requires the latency of TRP53 expression, which is induced by a ligand-activated PI3 kinase/AKT/MDM2-mediated signaling pathway. Biol. Reprod. 80, 286–294.
Preimplantation embryo development in the mouse requires the latency of TRP53 expression, which is induced by a ligand-activated PI3 kinase/AKT/MDM2-mediated signaling pathway.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhtFOitLc%3D&md5=3d7e5a4222d7a4ca287c0049d0605315CAS | 18923161PubMed |

Jones, S. N., Roe, A. E., Donehower, L. A., and Bradley, A. (1995). Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378, 206–208.
Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXptlSmtb0%3D&md5=4f252342e9447646d4d67c885dbc5af4CAS | 7477327PubMed |

Kalous, J., Kubelka, M., Solc, P., Susor, A., and Motlík, J. (2009). AKT (protein kinase B) is implicated in meiotic maturation of porcine oocytes. Reproduction 138, 645–654.
AKT (protein kinase B) is implicated in meiotic maturation of porcine oocytes.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhtlShur3F&md5=3ff65056b7734f2e908703c7bcec43deCAS | 19633130PubMed |

Kang, H. J., Hwang, S. J., Yoon, J. A., Jun, J. H., Lim, H. J., Yoon, T. K., and Song, H. (2011). Activation of peroxisome proliferators-activated receptor δ (PPAR δ) promotes blastocyst hatching in mice. Mol. Hum. Reprod. 17, 653–660.
Activation of peroxisome proliferators-activated receptor δ (PPAR δ) promotes blastocyst hatching in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXht1SitbfM&md5=ee3de5cd9b094ce2aa6c3d1138569674CAS | 21511721PubMed |

Katome, T., Obata, T., Matsushima, R., Masuyama, N., Cantley, L. C., Gotoh, Y., Kishi, K., Shiota, H., and Ebina, Y. (2003). Use of RNA interference-mediated gene silencing and adenoviral overexpression to elucidate the roles of AKT/protein kinase B isoforms in insulin actions. J. Biol. Chem. 278, 28 312–28 323.
Use of RNA interference-mediated gene silencing and adenoviral overexpression to elucidate the roles of AKT/protein kinase B isoforms in insulin actions.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXlsFKrsbs%3D&md5=b2af7b4d36e11fb717a6429533b7bc20CAS |

Kawamura, K., Fukuda, J., Shimizu, Y., Kodama, H., and Tanaka, T. (2005). Survivin contributes to the anti-apoptotic activities of transforming growth factor alpha in mouse blastocysts through phosphatidylinositol 3′-kinase pathway. Biol. Reprod. 73, 1094–1101.
Survivin contributes to the anti-apoptotic activities of transforming growth factor alpha in mouse blastocysts through phosphatidylinositol 3′-kinase pathway.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXht1KqsL3I&md5=466ef3c186addae50bc0d8e4194d7b5aCAS | 16079309PubMed |

Kawamura, K., Kawamura, N., Sato, W., Fukuda, J., Kumagai, J., and Tanaka, T. (2009). Brain-derived neurotrophic factor promotes implantation and subsequent placental development by stimulating trophoblast cell growth and survival. Endocrinology 150, 3774–3782.
Brain-derived neurotrophic factor promotes implantation and subsequent placental development by stimulating trophoblast cell growth and survival.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXpsV2ru74%3D&md5=75b8f14ba2dcae1d8facf58f39cf7598CAS | 19372195PubMed |

Kim, J. S., Chae, J. I., Song, B. S., Lee, K. S., Choo, Y. K., Chang, K. T., Park, H., and Koo, D. B. (2010). Iloprost, a prostacyclin analogue, stimulates meiotic maturation and early embryonic development in pigs. Reprod. Fertil. Dev. 22, 437–447.
Iloprost, a prostacyclin analogue, stimulates meiotic maturation and early embryonic development in pigs.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXjtlej&md5=b61af7967a991ede60841ae0581b33d5CAS | 20047729PubMed |

Koo, D. B., Kang, Y. K., Park, J. S., Park, J. K., Chang, W. K., Lee, K. K., and Han, Y. M. (2004). A paucity of structural integrity in cloned porcine blastocysts produced in vitro. Theriogenology 62, 779–789.
A paucity of structural integrity in cloned porcine blastocysts produced in vitro.Crossref | GoogleScholarGoogle Scholar | 15251229PubMed |

Krisher, R. L., and Prather, R. S. (2012). A role for the Warburg effect in preimplantation embryo development: metabolic modification to support rapid cell proliferation. Mol. Reprod. Dev. 79, 311–320.
A role for the Warburg effect in preimplantation embryo development: metabolic modification to support rapid cell proliferation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XlsFygs7Y%3D&md5=3c95d75be47446abba563fdee9976afaCAS | 22431437PubMed |

Kumar, P., and Mahajan, S. (2013). Preimplantation and postimplantation therapy for the treatment of reproductive failure. J. Hum. Reprod. Sci. 6, 88–92.
Preimplantation and postimplantation therapy for the treatment of reproductive failure.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXht1yksbvM&md5=028b9999a77dda79a675e7ff676367a0CAS | 24082648PubMed |

Lee, K., Redel, B. K., Spate, L., Teson, J., Brown, A. N., Park, K. W., Walters, E., Samuel, M., Murphy, C. N., and Prather, R. S. (2013). Piglets produced from cloned blastocysts cultured in vitro with GM-CSF. Mol. Reprod. Dev. 80, 145–154.
Piglets produced from cloned blastocysts cultured in vitro with GM-CSF.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhtFOis7w%3D&md5=f2b7d58d63d56fbe3e15e9f589e541d2CAS | 23239239PubMed |

Li, Y., Chandrakanthan, V., Day, M. L., and O’Neill, C. (2007). Direct evidence for the action of phosphatidylinositol (3,4,5)-trisphosphate-mediated signal transduction in the 2-cell mouse embryo. Biol. Reprod. 77, 813–821.
Direct evidence for the action of phosphatidylinositol (3,4,5)-trisphosphate-mediated signal transduction in the 2-cell mouse embryo.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXht1CnurfL&md5=83adcb75bc887b6f261155812aea7bb8CAS | 17634444PubMed |

Li, X. X., Lee, K. B., Lee, J. H., Kim, K. J., Kim, E. Y., Han, K. W., Park, K. S., Yu, J., and Kim, M. K. (2014). Glutathione and cysteine enhance porcine preimplantation embryo development in vitro after intracytoplasmic sperm injection. Theriogenology 81, 309–314.
Glutathione and cysteine enhance porcine preimplantation embryo development in vitro after intracytoplasmic sperm injection.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhs1Grtr%2FP&md5=3165b526b3c0142013d631918e71b1b8CAS | 24139601PubMed |

Lu, D. P., Chandrakanthan, V., Cahana, A., Ishii, S., and O’Neill, C. (2004). Trophic signals acting via phosphatidylinositol-3 kinase are required for normal pre-implantation mouse embryo development. J. Cell Sci. 117, 1567–1576.
Trophic signals acting via phosphatidylinositol-3 kinase are required for normal pre-implantation mouse embryo development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXjs1ynsr4%3D&md5=1ff3f549973c81dd281552779e10ce9eCAS | 15020683PubMed |

Malla, R., Ashby, C. R., Narayanan, N. K., Narayanan, B., Faridi, J. S., and Tiwari, A. K. (2015). Proline-rich AKT substrate of 40-kDa (PRAS40) in the pathophysiology of cancer. Biochem. Biophys. Res. Commun. 463, 161–166.
Proline-rich AKT substrate of 40-kDa (PRAS40) in the pathophysiology of cancer.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2MXptVSnsr8%3D&md5=dae9367d1ea48d5c7beed25b15628981CAS | 26003731PubMed |

Moncada, S., Gryglewski, R., Bunting, S., and Vane, J. R. (1976). An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263, 663–665.
An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE2sXmvVymsw%3D%3D&md5=9634b0ae56a6eaaf2a1419709850ffc8CAS | 802670PubMed |

Montes de Oca Luna, R., Wagner, D. S., and Lozano, G. (1995). Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378, 203–206.
Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK28%2FmvFOnsw%3D%3D&md5=d8951ac05272cee9d55572ddf77259abCAS | 7477326PubMed |

Namba, T., Oida, H., Sugimoto, Y., Kakizuka, A., Negishi, M., Ichikawa, A., and Narumiya, S. (1994). cDNA cloning of a mouse prostacyclin receptor. Multiple signaling pathways and expression in thymic medulla. J. Biol. Chem. 269, 9986–9992.
| 1:CAS:528:DyaK2cXkt12nt7g%3D&md5=aaf05268af9c15b103b8f12637b23140CAS | 7511597PubMed |

Navarrete Santos, A., Ramin, N., Tonack, S., and Fischer, B. (2008). Cell lineage-specific signaling of insulin and insulin-like growth factor I in rabbit blastocysts. Endocrinology 149, 515–524.
Cell lineage-specific signaling of insulin and insulin-like growth factor I in rabbit blastocysts.Crossref | GoogleScholarGoogle Scholar | 17962341PubMed |

Nitta, A., Zheng, W. H., and Quirion, R. (2004). Insulin-like growth factor 1 prevents neuronal cell death induced by corticosterone through activation of the PI3k/Akt pathway. J. Neurosci. Res. 76, 98–103.
Insulin-like growth factor 1 prevents neuronal cell death induced by corticosterone through activation of the PI3k/Akt pathway.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXjt1egtb4%3D&md5=d607c68634a98819d9c2401e2cfb5c38CAS | 15048933PubMed |

Noh, Y. H., Chob, H. S., Kim, D. H., Kim, O. H., Park, J., Lee, S. A., Yang, H. S., Sohn, D. S., Kim, W., Kim, D., Chung, Y. H., Kim, K. Y., Kim, S. S., and Lee, W. B. (2012). N-Acetylcysteine enhances neuronal differentiation of P19 embryonic stem cells via Akt and N-cadherin activation. Mol. Biol. (Mosk.) 46, 741–746.
| 1:STN:280:DC%2BC3s7jvVGhtw%3D%3D&md5=0977f32278ca3a2155c81b6ff2e171f4CAS | 23156673PubMed |

Ogawara, Y., Kishishita, S., Obata, T., Isazawa, Y., Suzuki, T., Tanaka, K., Masuyama, N., and Gotoh, Y. (2002). Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J. Biol. Chem. 277, 21 843–21 850.
Akt enhances Mdm2-mediated ubiquitination and degradation of p53.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38Xksl2jsLw%3D&md5=3f9d3e6bfb58963584baad33a45761eaCAS |

Pomar, F. J., Teerds, K. J., Kidson, A., Colenbrander, B., Tharasanit, T., Aguilar, B., and Roelen, B. A. (2005). Differences in the incidence of apoptosis between in vivo and in vitro produced blastocysts of farm animal species: a comparative study. Theriogenology 63, 2254–2268.
Differences in the incidence of apoptosis between in vivo and in vitro produced blastocysts of farm animal species: a comparative study.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXjtFyrtbg%3D&md5=c8b624ed55a1f50dcbfa78e94bcc7682CAS | 15826688PubMed |

Redel, B. K., Tessanne, K. J., Spate, L. D., Murphy, C. N., and Prather, R. S. (2015). Arginine increases development of in vitro-produced porcine embryos and affects the protein arginine methyltransferase–dimethylarginine dimethylaminohydrolase–nitric oxide axis. Reprod. Fertil. Dev. 27, 655–666.
Arginine increases development of in vitro-produced porcine embryos and affects the protein arginine methyltransferase–dimethylarginine dimethylaminohydrolase–nitric oxide axis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2MXntVWnuro%3D&md5=08a2adf516e1541a04e0a48790d67ae9CAS | 25765074PubMed |

Riley, J. K., Carayannopoulos, M. O., Wyman, A. H., Chi, M., Ratajczak, C. K., and Moley, K. H. (2005). The PI3K/Akt pathway is present and functional in the preimplantation mouse embryo. Dev. Biol. 284, 377–386.
The PI3K/Akt pathway is present and functional in the preimplantation mouse embryo.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXpt1eksrY%3D&md5=09b4912e0d43abb30ad64a1c8cfea540CAS | 16005454PubMed |

Skeen, J. E., Bhaskar, P. T., Chen, C. C., Chen, W. S., Peng, X. D., Nogueira, V., Hahn-Windgassen, A., Kiyokawa, H., and Hay, N. (2006). Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. Cancer Cell 10, 269–280.
Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XhtFCgsbjN&md5=fbaebaa003e1b7533fd7a3e8da0ec190CAS | 17045205PubMed |

Smith, D. G., and Sturmey, R. G. (2013). Parallels between embryo and cancer cell metabolism. Biochem. Soc. Trans. 41, 664–669.
Parallels between embryo and cancer cell metabolism.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXksFWjtrs%3D&md5=4c387cf45b8b3d3fe2601bfc00f6ba76CAS | 23514173PubMed |

Song, G., Ouyang, G., and Bao, S. (2005). The activation of Akt/PKB signaling pathway and cell survival. J. Cell. Mol. Med. 9, 59–71.
The activation of Akt/PKB signaling pathway and cell survival.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXlt1eqtLo%3D&md5=776c5eb0cf2cc824c467281ea211230bCAS | 15784165PubMed |

Song, B. S., Kim, J. S., Kim, C. H., Han, Y. M., Lee, D. S., Lee, K. K., and Koo, D. B. (2009). Prostacyclin stimulates embryonic development via regulation of the cAMP response element-binding protein-cyclo-oxygenase-2 signalling pathway in cattle. Reprod. Fertil. Dev. 21, 400–407.
Prostacyclin stimulates embryonic development via regulation of the cAMP response element-binding protein-cyclo-oxygenase-2 signalling pathway in cattle.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXisFemsbg%3D&md5=30e807fef787fdac20b55c20091fa1fdCAS | 19261217PubMed |

Song, B. S., Kim, J. S., Kim, Y. H., Sim, B. W., Yoon, S. B., Cha, J. J., Choi, S. A., Yang, H. J., Mun, S. E., Park, Y. H., Jeong, K. J., Huh, J. W., Lee, S. R., Kim, S. H., Kim, S. U., and Chang, K. T. (2014). Induction of autophagy during in vitro maturation improves the nuclear and cytoplasmic maturation of porcine oocytes. Reprod. Fertil. Dev. 26, 974–981.
Induction of autophagy during in vitro maturation improves the nuclear and cytoplasmic maturation of porcine oocytes.Crossref | GoogleScholarGoogle Scholar | 23902659PubMed |

Trigal, B., Gomez, E., Diez, C., Caamano, J. N., Martin, D., Carrocera, S., and Munoz, M. (2011). In vitro development of bovine embryos cultured with activin A. Theriogenology 75, 584–588.
In vitro development of bovine embryos cultured with activin A.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXjs1KmtA%3D%3D&md5=879ad6b45865367b3da1ae70abcdf2e3CAS | 21040964PubMed |

Wasielak, M., Fujii, T., Ohsaki, T., Hashizume, T., Bogacki, M., and Sawai, K. (2013). Transcript abundance and apoptosis in Day-7 porcine blastocyst cultured with exogenous insulin-like growth factor-I. Reprod. Biol. 13, 58–65.
Transcript abundance and apoptosis in Day-7 porcine blastocyst cultured with exogenous insulin-like growth factor-I.Crossref | GoogleScholarGoogle Scholar | 23522072PubMed |

Xu, R., Shang, C., Zhao, J., Han, Y., Liu, J., Chen, K., and Shi, W. (2015). Activation of M3 muscarinic receptor by acetylcholine promotes non-small cell lung cancer cell proliferation and invasion via EGFR/PI3K/AKT pathway. Tumour Biol. 36, 4091–4100.
Activation of M3 muscarinic receptor by acetylcholine promotes non-small cell lung cancer cell proliferation and invasion via EGFR/PI3K/AKT pathway.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2MXotFejsL0%3D&md5=eff18e075bc3d4856c5848888506e6c8CAS | 25964092PubMed |

Yeung, W. S., Ho, P. C., Lau, E. Y., and Chan, S. T. (1992). Improved development of human embryos in vitro by a human oviductal cell co-culture system. Hum. Reprod. 7, 1144–1149.
| 1:STN:280:DyaK3s%2Fhs1Ojsg%3D%3D&md5=7ed78803d731960fbf95292daeb27f62CAS | 1400940PubMed |

Yin, X. J., Lee, H. S., Jeon, J. T., and Kong, I. K. (2007). Effect of culture medium and prostaglandin I(2) (PGI(2)) analogue on in vitro development of parthenogenetically activated cat oocytes. J. Reprod. Dev. 53, 1053–1058.
Effect of culture medium and prostaglandin I(2) (PGI(2)) analogue on in vitro development of parthenogenetically activated cat oocytes.Crossref | GoogleScholarGoogle Scholar | 17587771PubMed |

Yoon, S. B., Choi, S. A., Sim, B. W., Kim, J. S., Mun, S. E., Jeong, P. S., Yang, H. J., Lee, Y., Park, Y. H., Song, B. S., Kim, Y. H., Jeong, K. J., Huh, J. W., Lee, S. R., Kim, S. U., and Chang, K. T. (2014). Developmental competence of bovine early embryos depends on the coupled response between oxidative and endoplasmic reticulum stress. Biol. Reprod. 90, 104.
Developmental competence of bovine early embryos depends on the coupled response between oxidative and endoplasmic reticulum stress.Crossref | GoogleScholarGoogle Scholar | 24695629PubMed |

Yoshioka, K., Suzuki, C., Tanaka, A., Anas, I. M., and Iwamura, S. (2002). Birth of piglets derived from porcine zygotes cultured in a chemically defined medium. Biol. Reprod. 66, 112–119.
Birth of piglets derived from porcine zygotes cultured in a chemically defined medium.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38Xht1yksQ%3D%3D&md5=c7abf1bbab15424abb6e46120e16675cCAS | 11751272PubMed |

Zhang, J. Y., Diao, Y. F., Oqani, R. K., Han, R. X., and Jin, D. I. (2012). Effect of endoplasmic reticulum stress on porcine oocyte maturation and parthenogenetic embryonic development in vitro. Biol. Reprod. 86, 128.
Effect of endoplasmic reticulum stress on porcine oocyte maturation and parthenogenetic embryonic development in vitro.Crossref | GoogleScholarGoogle Scholar | 22190710PubMed |