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褪黑素可消除 AKT 抑制剂 SH6 对牛卵母细胞和胚胎的抗发育作用。

Melatonin Abrogates the Anti-Developmental Effect of the AKT Inhibitor SH6 in Bovine Oocytes and Embryos.

机构信息

Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Korea.

Department of Microbial Biotechnology, Genetic Engineering and Biotechnology Division, National Research Centre, Dokki, Cairo 12622, Egypt.

出版信息

Int J Mol Sci. 2019 Jun 17;20(12):2956. doi: 10.3390/ijms20122956.

DOI:10.3390/ijms20122956
PMID:31212969
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6627520/
Abstract

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.

摘要

褪黑素是由松果体分泌的一种夜间抗氧化激素，AKT 是一种丝氨酸/苏氨酸特异性蛋白激酶，它们已被确定为几种对生殖至关重要的细胞过程的调节剂。本研究旨在探讨褪黑素和 AKT 在牛卵母细胞胚胎发育过程中的潜在相互作用。结果表明，在体外成熟（IVM）过程中加入特定的 AKT 抑制剂 SH6 会显著降低卵母细胞成熟、卵丘细胞扩展、分裂和囊胚发育，而添加褪黑素则可挽救这些过程。在有褪黑素存在的情况下用 SH6 处理的卵母细胞表现出较低水平的活性氧（ROS），囊胚发育时凋亡率较低，而与 SH6 处理组相比，线粒体谱显著改善。RT-qPCR 结果显示，成熟、线粒体和卵丘扩展相关基因的 mRNA 表达上调，包括 GDF-9、BMP-15、MARF1、ATPase、ATP5F1E、POLG2、HAS2、TNFAIP6 和 PTGS2，而与凋亡和细胞周期阻滞相关的基因 Bcl-2 相关 X 凋亡调节剂（BAX）、caspase 3 和 p21 的 mRNA 表达下调在褪黑素-SH6 共同处理组与 SH6 单独处理组相比。免疫荧光显示，与对照组和褪黑素-SH6 共同处理组相比，SH6 处理组中的 caspase 3 和 caspase 9 水平较高，AKT 磷酸化水平较低。总之，我们的研究结果表明褪黑素和 AKT 对整体胚胎发育过程都很重要，并且我们首次报道褪黑素可以中和 AKT 抑制的有害后果，这表明褪黑素在调节牛卵母细胞中的 AKT 信号通路方面可能发挥作用。

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