2. 内蒙古农业大学马属动物研究中心, 呼和浩特 010018;
3. 河北省牛羊胚胎工程技术研究中心, 保定 071000
2. Equine Research Center, Inner Mongolia Agricultural University, Hohhot 010018, China;
3. Research Center of Cattle and Sheep Embryo Engineering Technique of Hebei, Baoding 071000, China
哺乳动物Sirtuins是酵母转录抑制因子Sir2的同源基因，其实质为烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide，NAD+)依赖性的组蛋白去乙酰化酶[1]，包括SIRT1~SIRT7七种蛋白，广泛表达于哺乳动物的各个组织和器官。现有研究证实，SIRT1、SIRT2、SIRT3、SIRT4、SIRT6和SIRT7均与卵母细胞的减数分裂有关[2-5]。抑制SIRT1活性，会导致小鼠卵母细胞老化，而SIRT1活性上调可促进卵母细胞成熟[6]。SIRT2可通过调节卵母细胞内组蛋白4赖氨酸16(H4K16)和α微管蛋白乙酰化进而影响减数分裂进程，特异性敲除SIRT2会使微管和着丝粒的相互作用受损，导致纺锤体缺陷和染色体紊乱[7]。SIRT3则可抵抗小鼠体外受精(IVF)胚胎因氧化应激而导致的发育阻滞[8]。另外，特异性敲低SIRT7可导致小鼠卵母细胞减数分裂异常[4]。在大量查阅国内外Sirtuins相关研究文献的基础上，本文对Sirtuins与雌性哺乳动物生殖的关系进行了综述，为后期深入研究Sirtuins对雌性动物生殖生理的影响提供参考。
1 Sirtuins在雌性生殖细胞内分布及作用底物Sirtuins(SIRT1-SIRT7)广泛存在于哺乳动物卵母细胞内，每个成员均具有不同的组织特异性和亚细胞定位，SIRT1与SIRT2定位于细胞核和细胞质，并且SIRT1以细胞核为主，SIRT2以细胞质为主；SIRT3、SIRT4和SIRT5定位于细胞线粒体，SIRT6与SIRT7定位于细胞核(表 1)。Sirtuins各成员作用的底物存在着明显差异，因此, 其功能也具有较大差异，如SIRT1的底物为p53、FOXO3a、MnSOD等，与细胞氧化应激、细胞凋亡、能量代谢等功能相关[6, 11-12]；SIRT2的底物包括α-tublin、BubR1、H4K16等，与卵母细胞的减数分裂进程密切相关[7, 14]。总之，Sirtuins具有广泛的生物学功能，涉及细胞周期调控、细胞凋亡、氧化应激和线粒体代谢等多个方面。
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表 1 Sirtuins细胞定位及作用底物 Table 1 Location and substrates of Sirtuins in cells |
雌性哺乳动物出生时卵巢已经形成了供其一生使用的原始卵泡库，且原始卵泡的数量随年龄增加而下降，原始卵泡库的异常消耗可能会导致卵巢功能过早衰竭[18]。Sirtuins参与了原始卵泡发育的调控，研究发现，原始卵泡启动过程中，细胞核NADH/NAD+显著降低，能量供应由糖酵解向氧化磷酸化转变，卵母细胞核内SIRT1表达增加[19]；并且小鼠SIRT1过表达可通过激活FOXO3a抑制mTOR，以利于卵巢卵泡储备的维持[12]。另有研究证实，限制能量摄入有利于SIRT1和SIRT6在原始卵泡向生长卵泡过渡的过程中发挥重要作用，可通过促进卵泡生长延缓卵巢衰老[20]。Xiang等[21]发现限制能量摄入可促进小鼠内源性SIRT1表达增加，减少p53表达并抑制卵泡凋亡与闭锁。此外，SIRT3和SIRT6的表达与原始卵泡启动成正相关，而老龄小鼠卵巢储备降低与SIRT1、SIRT3、SIRT6的表达下降直接相关[22]，因此，SIRT1、SIRT3及SIRT6可作为卵巢储备及卵泡发育的潜在指标，为原始卵泡资源高效利用提供了依据。
2.2 Sirtuins对卵母细胞成熟的影响 2.2.1 卵母细胞染色质重塑染色质重塑是指染色质位置和结构的变化，主要涉及核小体的置换或重排，该过程增加了基因转录复合物与启动序列的可接近性，与组蛋白N端尾部修饰密切相关。Sirtuins可通过调节染色质的结构促进基因转录，提高卵母细胞发育潜力[19]。研究表明，生发泡(GV)期染色质形态、结构的重塑与Sirtuins密切相关[23]。在哺乳动物中，染色质致密化后期组蛋白乙酰化水平升高，卵母细胞成熟过程中可观察到组蛋白乙酰化的动态变化[24]。另有研究表明，SIRT1可通过组蛋白甲基转移酶Suv39h1促进H3K9甲基化，调控异染色质结构[25]，并且老龄小鼠GV期卵母细胞中染色质结构异常与SIRT1表达缺陷和H3K9甲基化水平降低有关[26]。迄今为止，Sirtuins家族其他成员对卵母细胞染色质重塑调控的影响未见报道。
2.2.2 卵母细胞线粒体合成线粒体可通过供能物质的氧化为细胞各种功能活动提供能量，Sirtuins与线粒体氧化功能有密切联系。细胞氧化磷酸化过程中，核内NADH减少，NAD+增多，SIRT1表达增加[19]。Sato等[27]研究猪卵母细胞线粒体DNA拷贝数与SIRT1表达关系时发现，在成熟液中添加Sirtuins激活剂白藜芦醇可促进SIRT1表达，并可通过增加ATP含量和线粒体膜电位增强线粒体功能；当加入SIRT1抑制剂Ex527时，线粒体DNA拷贝数减少。同样，在牛卵丘-卵母细胞复合体中加入白藜芦醇可增强SIRT1表达，增加体外培养卵母细胞线粒体DNA拷贝数及ATP含量，提高卵母细胞向囊胚发育的潜力[28]。SIRT3作为一种线粒体蛋白可调控能量的产生，SIRT3表达效率低下导致线粒体DNA拷贝数和生物发生减少，进而影响卵母细胞发育能力[29]。猪卵母细胞培养液中添加高浓度棕榈酸可诱导神经酰胺积累，下调SIRT3和磷酸化腺苷酸活化蛋白激酶(pAMPK)的表达可导致线粒体蛋白高乙酰化和卵母细胞功能障碍[30]。
2.2.3 卵母细胞老化排卵后的卵母细胞在体内或体外会发生时间依赖性退化，即卵母细胞衰老。中年小鼠注射白藜芦醇可有效改善氧化应激诱导的卵母细胞衰老，增加抗衰老分子SIRT1表达，降低细胞内活性氧(ROS)水平，改善线粒体功能[31]，加入Ex527可抑制SIRT1活性，导致细胞内ROS增加[6]。研究表明，小鼠老化卵母细胞体外培养过程中SIRT1、SIRT2、SIRT3的表达均显著降低，在培养液中添加烟酰胺后，卵母细胞中SIRT1、SIRT2、SIRT3活性受到抑制，ROS产生增加，加速卵母细胞老化，而添加咖啡因可延缓SIRT1、SIRT2、SIRT3 mRNA水平的下降趋势，减慢细胞衰老进程[32]。Xu等[33]发现，卵母细胞在衰老过程中产生的ROS可通过抑制SIRT1的表达，抑制细胞内FOXO3a和SOD2生成，产生氧化应激。另外，研究证实，SIRT3过表达的小鼠不仅抵抗ROS的作用增强，还可延迟与年龄相关疾病的发生[34-35]。相反，敲除SIRT3的小鼠胚胎成纤维细胞中ROS产生增多、氧化磷酸化作用降低[36]。此外，SIRT4与细胞衰老进程也有密切联系，其介导的去乙酰化可通过调节谷氨酰胺代谢参与细胞衰老调控[37]，主要通过促进核苷酸合成应对DNA损伤[38]。但SIRT4对细胞衰老的影响尚存在争议，Zeng等[39]发现，老龄小鼠的卵母细胞中SIRT4表达上调，SIRT4表达的升高对线粒体功能有负调控作用，并可加快衰老进程。另有研究发现，将小鼠卵母细胞暴露于槲皮素(一种天然的抗氧化剂)中，可通过调控卵母细胞老化过程中Sirtuins的表达，减缓促成熟因子(MPF)活性下降，减少ROS的产生以及细胞凋亡的发生[40]。
2.2.4 卵母细胞减数分裂Sirtuins对于卵母细胞减数分裂的正常进行至关重要。减数分裂期间染色体的精确分离是卵母细胞成熟过程的关键步骤，从生发泡到第二次减数分裂的过程中纺锤体和染色体构型的精确变化，均是为卵母细胞受精和胚胎发育做准备，哺乳动物胚胎发育缺陷或着床失败主要是卵母细胞减数分裂期间染色体分离错误所致[41]。SIRT1、SIRT2是与减数分裂关系最密切的两个Sirtuins成员。抑制SIRT1导致核转录因子(Nrf2)表达降低，Nrf2缺失可通过抑制细胞周期蛋白B1(cyclin B1)的表达破坏纺锤体、染色体组织，影响卵母细胞成熟[10]。此外，使用SIRT1的特异性抑制剂Ex527会使小鼠卵母细胞ROS生成增加，导致第二次减数分裂中期分裂异常，表明SIRT1可能通过调节氧化还原状态和纺锤体正常组装参与卵母细胞成熟[6]。Qiu等[14]研究表明，SIRT2特异性缺失会破坏小鼠卵母细胞纺锤体、染色体组织和减数分裂进程。另有研究证实，在牛卵母细胞培养过程中加入SIRT2抑制剂，会影响减数分裂过程中皮质颗粒和线粒体正常分布以及染色体构型，阻碍卵母细胞成熟[42]。
2.3 Sirtuins对颗粒细胞的影响卵泡中的颗粒细胞包括壁层颗粒细胞和卵丘细胞，对卵母细胞的营养和成熟起着重要作用。SIRT1参与维持卵丘细胞端粒稳态, 并且能够作为卵巢衰老的生物标志物[43]，Han等[44]发现，SIRT1可通过调控细胞外调节蛋白激酶(ERK1/2)活性在人颗粒细胞凋亡过程中发挥抗凋亡作用。对SIRT3研究表明，SIRT3活性降低，线粒体酶如谷氨酸脱氢酶(GDH)的乙酰化水平增加，导致颗粒细胞衰老[17]，因此SIRT3被称作人类颗粒细胞和卵丘细胞代谢状态的重要传感器。此外，Sirtuins还与类固醇激素合成有关，在牛颗粒细胞培养过程中加入SIRT2抑制剂或使用siRNA干扰SIRT2表达后，PPARs/LXRα信号通路以及雌激素和睾酮的分泌受到抑制，表明SIRT2可能影响颗粒细胞内类固醇激素的合成[13]。
2.4 Sirtuins对胚胎发育的影响Sirtuins不仅对卵母细胞有积极影响，对受精后胚胎的发育同样具有重要作用。卵子在形成过程中便开始储备Sirtuins mRNA，为胚胎发育做准备。SIRT1可通过去乙酰化作用调节合子组蛋白编码，提高H3K9甲基化水平，从而促进猪胚胎着床前的发育[45]。Abe等[46]在体外胚胎培养液中加入白藜芦醇，提高了胚胎内pAMPK和ATP的水平，有效促进了胚胎发育以及耐冻性。而使用Sirtuin抑制剂(如NAM、Sirtinol)处理小鼠和猪体外胚胎均会降低囊胚形成，减少囊胚细胞数，导致SIRT2、SIRT3、POU5F1和Cdx2等重要基因下调[8, 47]。SIRT3可通过维持线粒体功能，保护体外受精胚胎培养过程免受氧化应激作用影响，SIRT3缺失的卵母细胞体外受精后囊胚发育率显著降低，这是因为氧化应激通过线粒体介导的ROS-p53途径导致体外胚胎发育停滞[8]。
3 Sirtuins影响雌性动物生殖功能的机制 3.1 Sirtuins与能量代谢Sirtuins在卵母细胞内的糖代谢、脂代谢等多方面均具有重要作用[48-50]。猪卵母细胞成熟过程中加入Sirtuins激活剂白藜芦醇可增强Sirtuins的表达，增加卵母细胞ATP含量，为卵母细胞的生长发育提供能量[51]。颗粒细胞糖酵解代谢产物NADH是卵母细胞发生氧化磷酸化的主要原料，Cinco等[52]研究发现，卵泡发育过程中卵母细胞核内SIRT1表达增加，游离/结合的NADH比值显著降低，说明NADH的消耗依赖于SIRT1的表达。胰岛素样生长因子-1(IGF-1)在机体的合成代谢途径中有重要作用，SIRT1激活可增强牛颗粒细胞中IGF-1诱导的类固醇生成并调控IGF-1受体信号通路，促进颗粒细胞代谢、分化，影响雄激素的分泌[53]。此外，SIRT1活性可影响脂肪酸降解和线粒体功能，并调节胆汁酸和胆固醇的动态平衡[54]。SIRT2在调节糖代谢途径中发挥着重要功能，可调控糖异生途径的限速酶——磷酸烯醇式丙酮酸羧基激酶1 (PEPCK1)，SIRT2可引起PEPCK1去乙酰化而实现对糖异生途径的调控[55]。SIRT3是研究最多的线粒体Sirtuin蛋白，影响关键的线粒体功能，如ATP的生产、ROS的调节等[56]，SIRT3 mRNA的高表达可提高人卵母细胞线粒体DNA的拷贝数，促进线粒体的生物合成[29]。另有研究表明，对SIRT3缺陷的小鼠进行饥饿试验，48 h后发现心脏中脂肪堆积异常且棕榈酸盐的氧化速率降低，脂肪酸β-氧化受到抑制[57]。SIRT6可通过修复DNA、调节糖脂代谢影响细胞稳态和糖尿病、肥胖症等疾病[58]。
3.2 Sirtuins与氧化应激氧化应激能通过氧化细胞内核酸、蛋白质等生物大分子导致细胞衰老[59]。氧化应激产生的ROS等活性物质可通过诱导或抑制Sirtuins基因表达、Sirtuins翻译后氧化修饰、改变NAD水平等多个方面不同程度影响Sirtuins的活性[60]。SIRT1可通过某些转录因子调控氧化还原状态，如介导p53激活抗氧化基因超氧化物歧化酶(SOD2)、谷胱甘肽过氧化物酶(GPx1)[61]，或介导FOXO3a上调SOD2和过氧化氢酶等的表达，消除ROS，诱导抗氧化反应[6, 62]。SIRT3与细胞的氧化应激同样有密切联系，卵母细胞中超氧化物歧化酶第68位赖氨酸位点(SOD2-K68)的乙酰化状态依赖于SIRT3，SIRT3过表达可抑制糖尿病小鼠卵母细胞SOD2-K68乙酰化水平的升高，保护卵母细胞免受氧化应激的不利影响[63]。Tao等[64]证实，SIRT3通过去乙酰化MnSOD第122位赖氨酸位点(MnSOD-K122)激活SOD2，提高线粒体清除ROS的效率。
3.3 Sirtuins与细胞分裂细胞分裂与微管动力学密切相关，微管由α-微管蛋白和β-微管蛋白形成的细胞骨架组成，其在维持细胞形态和细胞分裂过程中具有重要作用。微管蛋白乙酰化会影响微管稳定性、纺锤体形态和染色体排列[65]，而纺锤体的完整决定了减数分裂过程在时间和空间上的准确性[66]。SIRT2的消耗可破坏小鼠卵母细胞纺锤体、染色体组织，阻止微管附着着丝点。研究表明，SIRT2依赖性的BubR1去乙酰化参与卵母细胞减数分裂的调节，可降低卵母细胞纺锤体、染色体异常的发生[14]。Tang等[67]研究发现，驱动蛋白Kif18a可通过对卵母细胞减数分裂中微管蛋白乙酰化的调节影响纺锤体组织，敲除Kif18a后SIRT2表达降低，可见SIRT2介导的纺锤体微管蛋白乙酰化对减数分裂过程至关重要。另有试验表明，Sirtuins还有可能通过调控H4K16的乙酰化水平影响减数分裂进程，SIRT2的敲低引起α-tubulin和H4K16乙酰化水平提高，α-tubulin和H4K16的高度乙酰化会损害微管的稳定性和着丝粒的功能，导致卵母细胞减数分裂过程中纺锤体缺陷和染色体排列异常[7]。
4 结语Sirtuins作为一种多功能去乙酰化酶在维持卵巢储备、调控卵母细胞减数分裂、改善胚胎发育等方面具有重要功能。随着研究的深入，Sirtuins有望为延长卵巢寿命、减缓卵母细胞衰老、提高卵母细胞及胚胎质量等方面提供新思路。在人类医学领域，Sirtuins激活剂在改善女性多囊卵巢综合征、子宫内膜异位症以及因年龄引起的不孕症等方面已展示了广阔的应用前景[19]。SIRT2对维持老化卵母细胞减数分裂过程中纺锤体的功能至关重要，激活SIRT2有可能为家畜体外胚胎生产和人类试管婴儿技术程序的改进提供新方案。此外，在卵母细胞体外成熟和胚胎体外培养过程中会因氧化应激而影响其体外发育进程，SIRT3作为线粒体主要的去乙酰化酶，在对抗线粒体ROS的产生方面具有重要功能，有望利用SIRT3改善卵母细胞与胚胎的体外发育潜力，为临床治疗提供潜在的新靶点。
| [1] | CHANG H C, GUARENTE L. SIRT1 and other sirtuins in metabolism[J]. Trends Endocrinol Metab, 2014, 25(3): 138–145. DOI: 10.1016/j.tem.2013.12.001 |
| [2] | BENKHALIFA M, FERREIRA Y J, CHAHINE H, et al. Mitochondria:participation to infertility as source of energy and cause of senescence[J]. Int J Biochem Cell Biol, 2014, 55: 60–64. DOI: 10.1016/j.biocel.2014.08.011 |
| [3] | ZHANG L, HAN L S, MA R J, et al. Sirt3 prevents maternal obesity-associated oxidative stress and meiotic defects in mouse oocytes[J]. Cell Cycle, 2015, 14(18): 2959–2968. DOI: 10.1080/15384101.2015.1026517 |
| [4] | GAO M, LI X Y, HE Y F, et al. Sirt7 functions in redox homeostasis and cytoskeletal organization during oocyte maturation[J]. FASEB J, 2018, 32(11): 6228–6238. DOI: 10.1096/fj.201800078RR |
| [5] | HAN L S, GE J, ZHANG L, et al. Sirt6 depletion causes spindle defects and chromosome misalignment during meiosis of mouse oocyte[J]. Sci Rep, 2015, 5(1): 15366. DOI: 10.1038/srep15366 |
| [6] | DI EMIDIO G, FALONE S, VITTI M, et al. SIRT1 signalling protects mouse oocytes against oxidative stress and is deregulated during aging[J]. Hum Reprod, 2014, 29(9): 2006–2017. DOI: 10.1093/humrep/deu160 |
| [7] | ZHANG L, HOU X J, MA R J, et al. Sirt2 functions in spindle organization and chromosome alignment in mouse oocyte meiosis[J]. FASEB J, 2014, 28(3): 1435–1445. DOI: 10.1096/fj.13-244111 |
| [8] | KAWAMURA Y, UCHIJIMA Y, HORIKE N, et al. Sirt3 protects in vitro-fertilized mouse preimplantation embryos against oxidative stress-induced p53-mediated developmental arrest[J]. J Clin Invest, 2010, 120(8): 2817–2828. DOI: 10.1172/JCI42020 |
| [9] | SIROTKIN A V, DEKANOVÁ P, HARRATH A H, et al. Interrelationships between sirtuin 1 and transcription factors p53 and NF-κB (p50/p65) in the control of ovarian cell apoptosis and proliferation[J]. Cell Tissue Res, 2014, 358(2): 627–632. DOI: 10.1007/s00441-014-1940-7 |
| [10] | MA R J, LIANG W, SUN Q, et al. Sirt1/Nrf2 pathway is involved in oocyte aging by regulating Cyclin B1[J]. Aging (Albany NY), 2018, 10(10): 2991–3004. |
| [11] | YANG Q L, DAI S J, LUO X Y, et al. Melatonin attenuates postovulatory oocyte dysfunction by regulating SIRT1 expression[J]. Reproduction, 2018, 156(1): 81–92. DOI: 10.1530/REP-18-0211 |
| [12] | LONG G Y, YANG J Y, XU J J, et al. SIRT1 knock-in mice preserve ovarian reserve resembling caloric restriction[J]. Gene, 2019, 686: 194–202. DOI: 10.1016/j.gene.2018.10.040 |
| [13] | XU D J, HE H S, JIANG X H, et al. SIRT2 plays a novel role on progesterone, estradiol and testosterone synthesis via PPARs/LXRα pathways in bovine ovarian granular cells[J]. J Steroid Biochem Mol Biol, 2019, 185: 27–38. DOI: 10.1016/j.jsbmb.2018.07.005 |
| [14] | QIU D H, HOU X J, HAN L S, et al. Sirt2-BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality[J]. Aging Cell, 2018, 17(1): e12698. |
| [15] | HAN L S, WANG H C, LI L, et al. Melatonin protects against maternal obesity-associated oxidative stress and meiotic defects in oocytes via the SIRT3-SOD2-dependent pathway[J]. J Pineal Res, 2017, 63(3): e12431. DOI: 10.1111/jpi.12431 |
| [16] | JACOBS K M, PENNINGTON J D, BISHT K S, et al. SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression[J]. Int J Biol Sci, 2008, 4(5): 291–299. |
| [17] | PACELLA-INCE L, ZANDER-FOX D L, LANE M. Mitochondrial SIRT3 and its target glutamate dehydrogenase are altered in follicular cells of women with reduced ovarian reserve or advanced maternal age[J]. Hum Reprod, 2014, 29(7): 1490–1499. DOI: 10.1093/humrep/deu071 |
| [18] | NGUYEN Q N, ZERAFA N, LIEW S H, et al. Loss of PUMA protects the ovarian reserve during DNA-damaging chemotherapy and preserves fertility[J]. Cell Death Dis, 2018, 9(6): 618. DOI: 10.1038/s41419-018-0633-7 |
| [19] | TATONE C, DI EMIDIO G, BARBONETTI A, et al. Sirtuins in gamete biology and reproductive physiology:emerging roles and therapeutic potential in female and male infertility[J]. Hum Reprod Update, 2018, 24(3): 267–289. DOI: 10.1093/humupd/dmy003 |
| [20] | LUO L L, CHEN X C, FU Y C, et al. The effects of caloric restriction and a high-fat diet on ovarian lifespan and the expression of SIRT1 and SIRT6 proteins in rats[J]. Aging Clin Exp Res, 2012, 24(2): 125–133. |
| [21] | XIANG Y F, XU J J, LI L, et al. Calorie restriction increases primordial follicle reserve in mature female chemotherapy-treated rats[J]. Gene, 2012, 493(1): 77–82. DOI: 10.1016/j.gene.2011.11.019 |
| [22] | ZHANG J J, FANG L, LU Z Y, et al. Are sirtuins markers of ovarian aging?[J]. Gene, 2016, 575(2): 680–686. DOI: 10.1016/j.gene.2015.09.043 |
| [23] | DE LA FUENTE R. Chromatin modifications in the germinal vesicle (GV) of mammalian oocytes[J]. Dev Biol, 2006, 292(1): 1–12. DOI: 10.1016/j.ydbio.2006.01.008 |
| [24] | LODDE V, LUCIANO A M, FRANCIOSI F, et al.Accumulation of chromatin remodelling enzyme and histone transcripts in bovine oocytes[M]//KLOC M.Oocytes: Maternal Information and Functions.Cham: Springer, 2017: 223-255. |
| [25] | VAQUERO A, SCHER M, ERDJUMENT-BROMAGE H, et al. SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation[J]. Nature, 2007, 450(7168): 440–444. DOI: 10.1038/nature06268 |
| [26] | MANOSALVA I, GONZÁLEZ A. Aging changes the chromatin configuration and histone methylation of mouse oocytes at germinal vesicle stage[J]. Theriogenology, 2010, 74(9): 1539–1547. DOI: 10.1016/j.theriogenology.2010.06.024 |
| [27] | SATO D, ITAMI N, TASAKI H, et al. Relationship between mitochondrial DNA Copy Number and SIRT1 Expression in Porcine Oocytes[J]. PLoS One, 2014, 9(4): e94488. DOI: 10.1371/journal.pone.0094488 |
| [28] | SUGIYAMA M, KAWAHARA-MIKI R, KAWANA H, et al. Resveratrol-induced mitochondrial synthesis and autophagy in oocytes derived from early antral follicles of aged cows[J]. J Reprod Dev, 2015, 61(4): 251–259. DOI: 10.1262/jrd.2015-001 |
| [29] | ZHAO H C, DING T, REN Y, et al. Role of Sirt3 in mitochondrial biogenesis and developmental competence of human in vitro matured oocytes[J]. Hum Reprod, 2016, 31(3): 607–622. DOI: 10.1093/humrep/dev345 |
| [30] | ITAMI N, SHIRASUNA K, KUWAYAMA T, et al. Palmitic acid induces ceramide accumulation, mitochondrial protein hyperacetylation, and mitochondrial dysfunction in porcine oocytes[J]. Biol Reprod, 2018, 98(5): 644–653. DOI: 10.1093/biolre/ioy023 |
| [31] | LIANG Q X, LIN Y H, ZHANG C H, et al. Resveratrol increases resistance of mouse oocytes to postovulatory aging in vivo[J]. Aging (Albany NY), 2018, 10(7): 1586–1596. |
| [32] | ZHANG T, ZHOU Y, LI L, et al. SIRT1, 2, 3 protect mouse oocytes from postovulatory aging[J]. Aging (Albany NY), 2016, 8(4): 685–696. |
| [33] | XU W D, LI L J, SUN J W, et al. Putrescine delays postovulatory aging of mouse oocytes by upregulating PDK4 expression and improving mitochondrial activity[J]. Aging (Albany NY), 2018, 10(12): 4093–4106. |
| [34] | SUNDARESAN N R, GUPTA M, KIM G, et al. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice[J]. J Clin Invest, 2009, 119(9): 2758–2771. |
| [35] | SUNDARESAN N R, BINDU S, PILLAI V B, et al. SIRT3 blocks aging-associated tissue fibrosis in mice by deacetylating and activating glycogen synthase kinase 3β[J]. Mol Cell Biol, 2015, 36(5): 678–692. |
| [36] | KIM H S, PATEL K, MULDOON-JACOBS K, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress[J]. Cancer Cell, 2010, 17(1): 41–52. DOI: 10.1016/j.ccr.2009.11.023 |
| [37] | RAUH D, FISCHER F, GERTZ M, et al. An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms[J]. Nat Commun, 2013, 4(1): 2327. |
| [38] | JEONG S M, XIAO C Y, FINLEY L W S, et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism[J]. Cancer Cell, 2013, 23(4): 450–463. DOI: 10.1016/j.ccr.2013.02.024 |
| [39] | ZENG J, JIANG M X, WU X H, et al. SIRT4 is essential for metabolic control and meiotic structure during mouse oocyte maturation[J]. Aging Cell, 2018, 17(4): e12789. DOI: 10.1111/acel.12789 |
| [40] | WANG H, JO Y J, OH J S, et al. Quercetin delays postovulatory aging of mouse oocytes by regulating SIRT expression and MPF activity[J]. Oncotarget, 2017, 8(24): 38631–38641. |
| [41] | FRANCIOSI F, GOUDET G, TESSARO I, et al. In vitro maturation affects chromosome segregation, spindle morphology and acetylation of lysine 16 on histone H4 in horse oocytes[J]. Reprod Fertil Dev, 2017, 29(4): 721–730. DOI: 10.1071/RD15350 |
| [42] | XU D J, WU L, JIANG X H, et al. SIRT2 inhibition results in meiotic arrest, mitochondrial dysfunction, and disturbance of redox Homeostasis during Bovine Oocyte Maturation[J]. Int J Mol Sci, 2019, 20(6): 1365. DOI: 10.3390/ijms20061365 |
| [43] | VALERIO D, LUDDI A, DE LEO V, et al. SA1/SA2 cohesion proteins and SIRT1-NAD+ deacetylase modulate telomere homeostasis in cumulus cells and are eligible biomarkers of ovarian aging[J]. Hum Reprod, 2018, 33(5): 887–894. DOI: 10.1093/humrep/dey035 |
| [44] | HAN Y, LUO H N, WANG H, et al. SIRT1 induces resistance to apoptosis in human granulosa cells by activating the ERK pathway and inhibiting NF-κB signaling with anti-inflammatory functions[J]. Apoptosis, 2017, 22(10): 1260–1272. DOI: 10.1007/s10495-017-1386-y |
| [45] | ADAMKOVA K, YI Y J, PETR J, et al. SIRT1-dependent modulation of methylation and acetylation of histone H3 on lysine 9 (H3K9) in the zygotic pronuclei improves porcine embryo development[J]. J Anim Sci Biotechnol, 2017, 8(1): 83. DOI: 10.1186/s40104-017-0214-0 |
| [46] | ABE T, KAWAHARA-MIKI R, HARA T, et al. Modification of mitochondrial function, cytoplasmic lipid content and cryosensitivity of bovine embryos by resveratrol[J]. J Reprod Dev, 2017, 63(5): 455–461. DOI: 10.1262/jrd.2016-182 |
| [47] | KWAK S S, CHEONG S A, YOON J D, et al. Expression patterns of sirtuin genes in porcine preimplantation embryos and effects of sirtuin inhibitors on in vitro embryonic development after parthenogenetic activation and in vitro fertilization[J]. Theriogenology, 2012, 78(7): 1597–1610. DOI: 10.1016/j.theriogenology.2012.07.006 |
| [48] | ZHANG M M, PAN Y D, DORFMAN R G, et al. Sirtinol promotes PEPCK1 degradation and inhibits gluconeogenesis by inhibiting deacetylase SIRT2[J]. Sci Rep, 2017, 7(1): 7. |
| [49] | MARTIN A N, ALEXANDER-MILLER M, YOZA B K, et al. Sirtuin1 targeting reverses innate and adaptive immune tolerance in septic mice[J]. J Immunol Res, 2018, 2018: 2402593. |
| [50] | SONG J, YANG B, JIA X B, et al. Distinctive roles of sirtuins on diabetes, protective or detrimental?[J]. Front Endocrinol (Lausanne), 2018, 9: 724. DOI: 10.3389/fendo.2018.00724 |
| [51] | ITAMI N, SHIRASUNA K, KUWAYAMA T, et al. Resveratrol improves the quality of pig oocytes derived from early antral follicles through sirtuin 1 activation[J]. Theriogenology, 2015, 83(8): 1360–1367. DOI: 10.1016/j.theriogenology.2015.01.029 |
| [52] | CINCO R, DIGMAN M A, GRATTON E, et al. Spatial characterization of bioenergetics and metabolism of primordial to preovulatory follicles in whole Ex Vivo murine ovary[J]. Biol Reprod, 2016, 95(6): 129. DOI: 10.1095/biolreprod.116.142141 |
| [53] | REVERCHON M, RAME C, BUNEL A, et al. VISFATIN (NAMPT) Improves in vitro IGF1-induced steroidogenesis and IGF1 receptor signaling through SIRT1 in Bovine Granulosa Cells[J]. Biol Reprod, 2016, 94(3): 54. |
| [54] | KUPIS W, PAŁYGA J, TOMAL E, et al. The role of sirtuins in cellular homeostasis[J]. J Physiol Biochem, 2016, 72(3): 371–380. DOI: 10.1007/s13105-016-0492-6 |
| [55] | JIANG W Q, WANG S W, XIAO M T, et al. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase[J]. Mol Cell, 2011, 43(1): 33–44. DOI: 10.1016/j.molcel.2011.04.028 |
| [56] | LOMBARD D B, ZWAANS B M M. SIRT3:as simple as it seems?[J]. Gerontology, 2014, 60(1): 56–64. DOI: 10.1159/000354382 |
| [57] | CHEN T S, LIU J N, LI N, et al. Mouse SIRT3 attenuates hypertrophy-related lipid accumulation in the heart through the deacetylation of LCAD[J]. PLoS One, 2015, 10(3): e0118909. DOI: 10.1371/journal.pone.0118909 |
| [58] | KUGEL S, MOSTOSLAVSKY R. Chromatin and beyond:the multitasking roles for SIRT6[J]. Trends Biochem Sci, 2014, 39(2): 72–81. DOI: 10.1016/j.tibs.2013.12.002 |
| [59] |
胡德宝, 张宝修, 张也, 等. 氧化应激与胚胎的氧化还原调节[J]. 畜牧兽医学报, 2014, 45(7): 1038–1043.
HU D B, ZHANG B X, ZHANG Y, et al. Oxidative stress and redox regulation of embryonic[J]. Acta Veterinaria et Zootechnica Sinica, 2014, 45(7): 1038–1043. (in Chinese) |
| [60] | SANTOS L, ESCANDE C, DENICOLA A. Potential modulation of sirtuins by oxidative stress[J]. Oxid Med Cell Longev, 2016, 2016: 9831825. |
| [61] | SABLINA A A, BUDANOV A V, ILYINSKAYA G V, et al. The antioxidant function of the p53 tumor suppressor[J]. Nat Med, 2005, 11(12): 1306–1313. DOI: 10.1038/nm1320 |
| [62] | HASEGAWA K, WAKINO S, YOSHIOKA K, et al. Sirt1 protects against oxidative stress-induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression[J]. Biochem Biophys Res Commun, 2008, 372(1): 51–56. DOI: 10.1016/j.bbrc.2008.04.176 |
| [63] | LIU X H, ZHANG L, WANG P, et al. Sirt3-dependent deacetylation of SOD2 plays a protective role against oxidative stress in oocytes from diabetic mice[J]. Cell Cycle, 2017, 16(13): 1302–1308. DOI: 10.1080/15384101.2017.1320004 |
| [64] | TAO R D, COLEMAN M C, PENNINGTON J D, et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress[J]. Mol Cell, 2010, 40(6): 893–904. DOI: 10.1016/j.molcel.2010.12.013 |
| [65] | ZHANG M Q, DAI X X, SUN Y L, et al. Stag3 regulates microtubule stability to maintain euploidy during mouse oocyte meiotic maturation[J]. Oncotarget, 2017, 8(1): 1593–1602. |
| [66] | MAJUMDAR S, BASU D, GHOSH DASTIDAR S. Conformational states of E7010 is complemented by microclusters of water inside the α, β-Tubulin core[J]. J Chem Inf Model, 2019, 59(5): 2274–2286. DOI: 10.1021/acs.jcim.8b00538 |
| [67] | TANG F, PAN M H, WAN X, et al. Kif18a regulates Sirt2-mediated tubulin acetylation for spindle organization during mouse oocyte meiosis[J]. Cell Div, 2018, 13(1): 9. DOI: 10.1186/s13008-018-0042-4 |