2. 中国科学院亚热带农业生态研究所, 中国科学院 亚热带农业生态过程重点实验室, 湖南省畜禽健康养殖工程技术中心, 农业部中南动物营养与 饲料科学观测实验站, 长沙 410125;
3. 中国科学院研究生院, 北京 100049
2. Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock and Poultry, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China;
3. University of the Chinese Academy of Sciences, Beijing 10008, China
人和动物机体内由于细胞呼吸和能量代谢时刻发生着有氧氧化,在细胞中产生活性氧分子(reactive oxygen species,ROS),如超氧阴离子(·O-2)和羟自由基(·OH)等自由基。当细胞受到内外环境的刺激后,ROS产生增多,从而破坏了机体氧化与抗氧化系统之间的平衡,最终导致氧化应激(图1)[1, 2, 3]。过多的ROS能够激活核因子E2相关因子2(Nrf2)、核转录因子-κB(NF-κB)、丝裂原活化蛋白激酶(MAPKs)等,从而调节许多氧化物质和抗氧化物质相关基因的表达[4, 5]。不仅如此,蛋白质和DNA也是ROS的攻击靶标,ROS能够造成蛋白质结构突变或丧失生物活性、DNA链断裂、DNA位点突变、DNA双链畸变和原癌基因与肿瘤抑制基因突变,最终导致机体产生氧化损伤[6, 7]。DNA作为生物体最重要的遗传物质能够保持其自身一定的稳定性,但是DNA却经常发生内在的自发性损伤和遭受X射线、紫外线、烷化剂、嵌入剂等外在刺激而发生损伤,据统计每个细胞内的DNA在24 h内出现10 000次损伤。而DNA损伤能够加速细胞的衰老和凋亡、引起癌症和肿瘤等疾病。不仅如此,有研究报道DNA损伤也可以诱导ROS的产生[8],且对细胞死亡和自救有重要的作用[9],其原因可能是由于ROS能调节p53基因(一种抗癌基因)的活性[10, 11]。由此可见,ROS可引起DNA损伤,而DNA损伤也可以诱导产生ROS,因而氧化应激和DNA之间存在着一定的联系。
大量研究表明,ROS有2种来源:一种是内源性,线粒体呼吸链氧化磷酸化过程活性氧泄漏、过氧化酶体和被激活的炎性细胞等[12];另一种是外源性,例如外源物、病原体、促炎细胞因子和重金属等[13]。尽管细胞色素p450氧化酶也能产生ROS,但线粒体仍是细胞ROS最重要的来源。研究表明,在线粒体呼吸链辅酶还原型辅酶Ⅰ(NADH)、泛醌氧化还原酶和泛醌细胞色素C氧化还原酶的作用下,0.15%的氧被转化为ROS,其中主要是·O-2[12, 14],由于·O-2能攻击细胞内许多大分子(如脂质、蛋白质和DNA)且能通过酶催化反应产生其他ROS,如·OH和过氧化氢(H2O2)等,因而·O-2被视为“首要ROS”[15]。·O-2在超氧化物歧化酶(SOD)的催化作用下被转变为H2O2,H2O2通过过氧化氢酶、谷胱甘肽过氧化物酶(GPx)和Fenton反应被清除。其中过氧化氢酶能够通过歧化反应将2分子H2O2转化为1分子O2和2分子H2O,GPx利用一些还原剂将H2O2转化为2分子H2O,Fenton反应则是在Fe2+的催化下将H2O2分解生成·OH[1, 16]。尽管·OH的半衰期(大约10-9 s)非常短,但其活性很高,几乎对所有大分子(如碳水化合物、核酸、脂质和蛋白质)造成损伤[17](图2)。
UCPs是线粒体内膜上的一种具有调节质子跨膜作用的特殊蛋白质。目前在哺乳动物体内已经发现5种UCPs,分别为:UCP1、UCP2、UCP3、UCP4和UCP5[18, 19]。研究表明,在UCPs家族中,仅UCP2和UCP3能够对氧化应激起反馈调节的作用。例如,UCP2基因敲除的小鼠较正常小鼠大脑线粒体在氧化应激下能够产生更多的ROS[20],此外,UCP3基因的过度表达也能显著降低细胞衰老诱导的ROS的产生[21]。UCPs反馈调节ROS的机制是:UCPs通过降低质子电化学梯度,使呼吸作用中电子传递过程和ATP的合成解耦联,因此将储存的能量以热能的形式释放,并提高静息代谢率,其中UCPs通过调节质子泄漏(proton leak)以降低ROS的产量(图3)[22]。研究表明:呼吸链赋予质子的高运动能力,使给氧分子提供1个电子而变成·O-2的电子载体在稳定状态时的浓度升高,由此增加了·O-2的量;·O-2下游衍生物羟基壬烯酸激活电子漏,使膜电位降低,随后通过呼吸链刺激电子流量,使得给氧提供1个电子而变成·O-2的电子载体的在稳定状态时的浓度降低,因此UCPs对ROS的生成有一个负反馈机制,其功能是通过脂质过氧化产物来抵抗氧化应激,但是羟基壬烯酸在UCPs反馈调节ROS的机制尚不清楚[23, 24]。
氧化应激能够破坏细胞内氧化还原平衡,从而激活或抑制许多信号通路和一些信号介导分子,如核因子E2相关因子2-胞质伴侣蛋白(Nrf2/Keap1)信号通道[4]、NF-κB信号通道[5],MAPKs[25],激酶蛋白mTOR(一个蛋白质合成的关键调控子)[26]和蛋白激酶C(PKC)[27]等,最终调节相关基因的表达。其中Nrf2/Keap1是细胞内抵抗氧化应激和保持氧化还原平衡的重要信号通道之一[28],Nrf2是一种氧化应激基本表达的关键转录因子,存在于全身多个器官,它的缺失或激活障碍直接引起细胞对应激源的敏感性变化。因此,本文主要综述了ROS对Nrf2/Keap1信号通路的影响。
Keap1是Nrf2在细胞质中的富含半胱氨酸的结合蛋白,主要通过结合Nrf2使之无法进入细胞核,从而抑制Nrf2的活性,避免引起细胞对应激源的敏感性升高,例如敲除Keap1的基因导致Nrf2信号非常活跃[29, 30]。在无应激条件下,Nrf2在细胞质中通过与Keap1结合而被抑制,而当在氧化应激或过量ROS刺激时,半胱氨酸在Keap1中的残留量会增加,随后Keap1作为E3连接酶的活性变弱[31],Nrf2和Keap1之间的连接被打乱,导致Nrf2泛化和衰退减少,细胞质中自由的Nrf2增多,转移进细胞核的Nrf2增多[32, 33],进入细胞核的Nrf2与小Maf蛋白形成异源二聚体,并且和抗氧化反应元件(ARE)连接在一起。随后,ARE被激活并启动抗氧化基因的转录[34],从而使得抗氧化基因得以表达。但是Li等[32]研究报道:细胞内存在2种Nrf2蛋白,一种是游离Nrf2(fNrf2),另一种是与Keap1结合的Nrf2(kNrf2),在无应激状态下细胞质内绝大多数Nrf2是处于与Keap1结合的状态,只有少量fNrf2进入细胞核以保持氧化还原平衡;在ROS过量时,由于Keap1的自我泛素化使得Keap1与Nrf2的结合量达到饱和或减少[35, 36],从而fNrf2的量增多,进入细胞核强化抗氧化基因的表达[32]。这2种Nrf2/Keap1信号通道机制的关键不同之处是:前一种认为氧化还原信号是从Keap1到Nrf2的,而后一种认为Keap1和Nrf2都对氧化还原信号有高度的敏感性[32]。但是如前面叙述的细胞内在无应激状态下也时刻都产生ROS,因而细胞要保持氧化还原状态,也必须时刻都有fNrf2进入细胞核促使抗氧化基因表达,所以认为Li等[32]对Nrf2/Keap1信号通道机制的研究更为合理。
动物体内DNA经常受到来自体内外各种因素的刺激,例如:外源性的高温高压、紫外线、射线、重金属、强氧化剂、强酸和强碱等物理化学因素和内源性ROS、酸碱不平衡及DNA在复制和传递过程中出现的错误等,这些因素都将导致DNA损伤。DNA损伤的形式有多种,如DNA双链结构破坏(DSBs)[37]、DNA链断裂、碱基或碱基对被切除或替换等。此外,DNA损伤会引发多种细胞反应,包括DNA修复、细胞周期延迟或阻滞、细胞凋亡[38]等。由于DNA损伤的形式有多种,因而其损伤反应的机理也各不相同,由于DSBs出现在多种原因导致的DNA损伤中[39],本文主要介绍了DSBs诱发的反应。
DSBs是DNA损伤中最具有致命性作用的损伤之一,若DSBs没有被成功修复,不仅危及细胞的自我更新和分化能力,而且导致染色体组不稳定和疾病[39]。在哺乳动物细胞内,当MRN复合体(由Mre11、Rad50和Nbs1组成)感应到DSBs时,立即激活运动失调性毛细血管扩张症突变蛋白(ataxia telangiectasia mutated,ATM),磷脂酰肌醇-3-激酶β(phosphoinositide 3-kinase β,PI3Kβ)也是感应染色体结构完整性的一个重要感受器[40],PI3K相关激酶(PIKK)家族的成员参与组织DNA损伤反应[41, 42]。其中ATM能使细胞周期控制、DNA修复和染色体结构调节中的700多种蛋白质磷酸化,包括p53、细胞周期检测点激酶2(Chk2)和组蛋白家族成员X(H2AX)[43],并且有研究表明,ATM在氧化应激反应中也起到关键的作用[44]。被激活的ATM导致H2AX快速磷酸化形成γ-H2AX,从而在损伤处标定DNA损伤信号和积累修复蛋白,γ-H2AX能被小脑症蛋白(MCPH1)和DNA损伤调节蛋白1(MDC1)识别,MDC1通过磷酸酶和组蛋白交换因子的活动扩大依赖ATM的信号,与此同时也促进了其他DSBs信号和修复蛋白的积累,最终DNA损伤信号导致检查点蛋白激酶细胞周期检测点激酶1(Chk1)和Chk2被激活,Chk1和Chk2能修改细胞周期的部分机制使得细胞周期停止[45]。细胞在长期进化过程中产生细胞周期检测点(探测器包括Rad9和Rad17等)以保证细胞周期中DNA复制和染色体质量的机制,由于DNA损伤可以发生在细胞周期的任何时相,因而DNA损伤检查点又可分为:G1期、M期和S2期检查点[46]。若G1期发生DNA损伤,激活后的Chk1和Chk2可以磷酸化细胞分裂周期蛋白25A(Cdc25A),使其降解,即没有足够的Cdc25A清除细胞周期素依赖性激酶2(CDK2)上抑制其活性位点的磷酸基团,使得Cdc25A不能被激活,从而不能推动G1期向S期转换,引起细胞周期停滞[40];若S期发生DNA损伤,Chk1和Chk2抑制了CDK2活性,Cdc45不能组装到染色质上,Cdc45可以召集DNA聚合酶α,从而大大降低了DNA合成速度以延缓细胞周期[40, 47];若G2期发生DNA损伤,Cdc25A被泛素降解而不能激活细胞周期素依赖性激酶1(CDK1),且G2期检查点还会激活一条依赖p53的途径以停滞细胞周期[40, 48]。细胞周期停滞或延缓后,通过碱基切除修复、核酸切除修复、重组修复和错配修复等方式修复受损DNA,如损伤不能修复或不能正确完成,则启动凋亡或非凋亡性死亡程序,清除有损伤或病变倾向的细胞[49]。值得注意的是,有研究报道,表皮生长因子受体(EGFR)与细胞外调节蛋白激酶(ERK)和蛋白激酶B(PKB)串联的信号对依赖ATM修复DNA损伤的反应有积极影响[50, 51],并且修复DSBs有2条主要的途径,分别是同源重组(HR)和末端加入的非同源(non-homologous end-joining,NHEJ),这2条途径见的平衡是保持基因组稳定所必需的[52]。
大量研究表明,ROS能够引起氧化损伤,并攻击蛋白质和DNA,会引起包括DNA链断裂、DNA位点突变、DNA双链畸变和原癌基因与肿瘤抑制基因突变等形式的DNA损伤[6],例如,嗜中性粒细胞和巨噬细胞引起的ROS能直接导致DNA脱氨基和碱基氧化[53]。不仅如此,DNA损伤可以提升细胞内ROS水平[8],且DNA损伤诱导的ROS在调节细胞的死亡和自救中起到很重要的作用[9]。由此说明DNA损伤和ROS引起的氧化应激之间存在着一定的联系。
过多的ROS引起的氧化损伤会导致包括DNA链断裂、DNA位点突变、DNA双链畸变等形式的DNA损伤,但是与核DNA(nDNA)相比,线粒体DNA(mtDNA)更容易遭受氧化伤害[54]。有报道称,ROS对mtDNA突变影响更大[55]。大多数mtDNA突变的形式是:胸腺嘧啶(T)转变为胞嘧啶(C),鸟嘌呤(G)转变为腺嘌呤(A)[56]。而ROS可使G氧化为8-氧鸟嘌呤(8-oxoG),而8-oxoG不再与C配对,反而与A配对,使得G转变为A[57]。此外,Fenton反应分解H2O2生成的高活性·OH能高效地损伤DNA,包括:DNA链断裂、DNA位点突变、DNA双链畸变。并且线粒体呼吸链产生的ROS导致的mtDNA损伤和突变能反过来使呼吸链功能失效,从而进一步促进ROS的产生[58]。由此说明,ROS引起的氧化应激与DNA损伤之间有相互促进作用。
在细胞培养中,DNA损伤已被证明可以刺激细胞中ROS产生[59],如·O-2、H2O2和·OH[60]。DNA损伤后的2 h内ROS量迅速增加,2.0~3.5 h逐渐减少,3.5~5.0 h内出现第2次迅速增加[61],但其机制仍不清楚。有研究表明,DNA损伤通过H2AX-还原型辅酶Ⅱ氧化酶1(Nox1)/Rac1通道诱导ROS产生,H2AX的超量表达和基因敲除都证明H2AX能调节ROS的产生[61],其原因可能是由于DNA损伤后导致H2AX被磷酸化的量增加,H2AX通过掩蔽14-3-3zeta[14-3-3zeta蛋白是14-3-3家族的一个成员,通常以二聚体的形式存在,在真核细胞中普遍存在,它能同时接受2个配体(如受体蛋白和激酶等),是信号传导通路中的重要接头蛋白[60]],激活Rac1、GTP酶和Nox1,从而引起细胞内ROS的量增加。其中,Nox1是gp91(phox)(一个NADPH氧化酶的亚单位)的同源分子,其基因可在非噬细胞(上皮细胞和内皮细胞等)内表达,能被Rac1(细胞内重要的信号转导分子)激活。研究表明,减少Rac1的生成能减少依赖Nox1产生的ROS量[62]。
综上所述,若ROS引起的氧化应激和各种原因诱导的DNA损伤超过了动物机体细胞自我修复的能力,将会对动物机体造成各种损伤,如肿瘤、癌症、细胞衰老甚至凋亡等,并且DNA损伤和氧化应激之间存在着必然的联系。但是一些细胞自我修复和抵抗各种应激与ROS和DNA损伤的机制尚不清楚,并且氧化应激和DNA损伤对机体细胞造成损伤的广泛性及其在动物生产中产生的影响需要做进一步的研究。
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