动物营养学报    2022, Vol. 34 Issue (1): 59-67    PDF    
富勒烯[C60]抗氧化应激的研究进展及在畜禽生产中的应用前景
刘广1,2 , 罗友谊3 , 唐宇龙2 , 印遇龙1,2     
1. 湖南农业大学动物科学与技术学院, 长沙 410125;
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. 湖南省沅江市畜牧水产事务中心, 益阳 413100
摘要: 氧化应激损伤是指机体在遭受有害刺激时,体内高活性分子,如活性氧自由基(ROS)或活性氮自由基(RNS)产生过多,导致细胞、组织和动物机体受到严重损伤。畜禽在应激和疾病的条件下会造成氧化应激并引发各种炎症。减少氧化应激以提高畜禽生长性能、减少疾病发病率是畜禽生产中的重要研究内容。近年来,富勒烯[C60]被认为是一种强大的抗氧化剂,大量研究表明富勒烯[C60]及其衍生物在自由基清除和缓解机体氧化应激反应中发挥重要作用。本文对富勒烯[C60]及其衍生物的抗氧化作用和机制进行归纳总结,旨在为畜禽生产中抗氧化剂和抗生素替代物的开发利用找到新的方向,使富勒烯能应用到畜禽生产以代替抗生素解决食品安全问题,更好地发展绿色、健康、安全的养殖业。
关键词: 富勒烯[C60]    氧化应激    代替抗生素    
Research Progress on Antioxidant Stress of Fullerenes[C60] and Its Application Prospect in Livestock and Poultry Production
LIU Guang1,2 , LUO Youyi3 , TANG Yulong2 , YIN Yulong1,2     
1. College of Animal Science, Hunan Agricultural University, Changsha 410125, China;
2. Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South Central, Ministry of Agriculture, Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China;
3. Animal Husbandry and Aquatic Products Affairs Center of Hunan Province Yuanjiang, Yiyang 413100, China
Abstract: Oxidative stress injury refers to the excessive production of extremely reactive molecules within the body, like reactive oxygen species (ROS) or reactive nitrogen species (RNS), once the body is subjected to harmful stimuli, it causes serious harm to cells, tissues and animal's body. Livestock and poultry under stress and disease conditions can cause oxidative stress and various types of inflammation. Reducing oxidative stress is an important research component in livestock production to improve animal performance and reduce disease incidence. In recent years, fullerene is considered to be a powerful antioxidant, and numerous studies have shown that the fullerene[C60] and its derivatives play an important role in free radical scavenging and alleviation of oxidative stress in the body. In this paper, the antioxidant effect and mechanism of fullerene[C60] and its derivatives were summarized, to find a new direction for the development and utilization of antioxidants and antibiotic substitutes in animal production. The application of fullerene to livestock and poultry production can replace antibiotics to solve food safety problems, and can better develop the green, healthy and safe breeding industries.
Key words: fullerenes[C60]    oxidative stress    replace antibiotics    

富勒烯[C60](fullerenes C60)是由60个碳原子以12个五元环和20个六元环连接而成的具有30个共轭双键(C=C)的对称空心足球状分子,因此也被称为足球烯[1]。自1985年被发现以来就引起了科学家们的广泛关注,其中最主要的功能包括自由基清除、抗氧化、抗菌、抗病毒、DNA光裂解、肿瘤治疗以及药物控制递送等[2-3]。由于其独特的理化性质,在过去的几十年里,人们一直在努力通过各种反应使富勒烯[C60]官能化,改善其理化性质,以便更好地提高富勒烯[C60]在各个方面的生物学功能。目前最主要的研究领域是富勒烯[C60]与自由基的反应,在生物学中,富勒烯[C60]被证实是一种强大的抗氧化剂,它比目前主要的抗氧化剂维生素E与自由基的反应更加迅速,这种特性使得许多研究机构和大型制药公司投入大量经费研究和探索富勒烯[C60]控制氧化应激所引发的疾病。现在富勒烯[C60]与自由基高度亲和已经得到了公认,因此其被人们称为“自由基海绵”[4-5]。由于共轭双键夺取电子能力强,富勒烯[C60]对活性氧自由基(reactive oxygen species,ROS)的清除能力十分出色[6-7]。目前由于富勒烯[C60]不溶于水的特性,人们想办法增加其水溶性从而生产了一系列的富勒烯[C60]衍生物。如丙二酰羧基化富勒烯(图 1)[8-9]、六磺酰化富勒烯(图 2)、树突富勒烯(图 3)[10]和多羟基化富勒烯(富勒醇)等。这些富勒烯[C60]衍生物对某些核酸和蛋白质有更好的亲和力,在细胞和组织中具有比富勒烯[C60]更加出色的ROS清除能力。这些具有出色自由基清除能力的富勒烯[C60]及其衍生物已经有了大量的研究,本综述将介绍富勒烯[C60]的清除自由基反应、在治疗生物氧化应激疾病等各个领域的研究和畜禽生产中的应用前景。

图 1 丙二酰羧基化富勒烯 Fig. 1 Malonyl carboxylated fullerenes[8-9]
图 2 六磺酰化富勒烯 Fig. 2 Hexasulfonyl fullerene
图 3 树突富勒烯 Fig. 3 Dendritic fullerenes[10]
1 氧化应激对畜禽生产的影响

ROS是生物代谢的正常副产物,正常情况下,机体通过酶或小的抗氧化分子来保护自己免受ROS的损害。动物在一些疾病和应激条件下会产生大量的ROS,导致细胞、组织和动物机体受到严重损伤,这种情况被称为氧化应激。当动物怀孕时会产生怀孕过程中必需的适量ROS,但随着孕期的进行,母体产生的ROS水平也将随之增加,在增加母体受到氧化应激损伤风险的同时也增加了胎儿长大后患代谢类疾病的概率,许多人类医学研究证明在妊娠后期出现的一些代谢疾病与氧化应激密切相关[11-13]

众所周知,在畜禽生产中仔猪断奶会引起应激,断奶应激会使仔猪的肠道功能受到损害,降低采食量;同时免疫功能遭到一定程度地破坏,导致仔猪抗病能力低,腹泻率大大增加,严重时甚至会导致仔猪死亡[14]。仔猪断奶应激的实质是断奶作为应激源诱发机体产生氧化应激,引起体内各种自由基激增、代谢紊乱,从而使得身体机能未完全发育的仔猪胃肠道受损,各分泌腺异常分泌,进而使其生长性能和养分利用率受到影响[15-16]

热应激同样能诱发氧化应激,热应激通过影响机体内代谢酶的活性来改变代谢水平,从而使机体产生过量的ROS和活性氮自由基(reactive nitrogen species,RNS),此时动物机体内的氧化-抗氧化平衡被打破,从而引发氧化应激反应,危害动物机体健康,影响动物生长性能[17-22]。据报道,长期处于高温高湿的环境时机体热应激会导致哺乳母猪乳中蛋白质含量下降和泌乳量减少,泌乳中期奶牛的产奶量减少30%~40%[23]。通过在高温环境下小鼠乳腺上皮细胞(mouse mammary epithelial cells,MMECs)和原代牛乳腺上皮细胞(bovine mammary epithelial cells,BMECs)培养发现,MMECs中超氧化物歧化酶(superoxide dismutase,SOD)活性降低和BMECs死亡率增加[24-26]。通过以上研究可以得出由热应激诱发的氧化应激是使母畜奶产量与质量降低、乳腺发病率增加的重要因素之一。

有研究表明氧化应激与免疫系统相互作用,氧化应激可能参与导致机体免疫功能紊乱发生的过程,而后者又进一步加重了氧化应激水平,周而复始,氧化应激可能在系统性红斑狼疮(systemic lupus erythematosus,SLE)的病理中发挥重要作用[27]。中性粒细胞通过多种机制参与SLE的发病机制,如中性粒细胞胞外陷阱网络(neutrophil extracellular-traps,NET),烟酰胺腺嘌呤二核苷酸磷酸氧化酶2(Nox2)基因缺陷的系统性红斑狼疮(MRL/lpr)小鼠不能产生抗氧化剂烟酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide phosphate,NADPH),使许多中性粒细胞不能正常产生和释放NET,从而加速SLE的疾病活动;同样线粒体中的ROS也能减少MRL/lpr小鼠的NET,使疾病活动增多[28-29]

在畜禽生产中出现的各种问题几乎都与氧化应激有着千丝万缕的联系,所有的细胞生物大分子,如脂类、DNA和蛋白质都很容易与ROS发生反应,生成比ROS对机体危害性更大的次级产物[30]。为了使畜禽生产中畜禽产品质量增加,使ROS给畜禽带来的伤害降低,寻找更加有效的抗氧化剂是很有必要的。

2 富勒烯[C60]及其衍生物抗氧化应激的研究

自富勒烯[C60]及其衍生物被发现后,他们的抗氧化性质研究取得不断突破,许多研究团队根据研究侧重点不同对富勒烯[C60]及其衍生物抗氧化应激做了大量的研究,但在畜禽生产方向的研究很少。下面将分别对富勒烯[C60]及其衍生物在细胞、动物上的抗氧化应激研究进行概括,为证明使用富勒烯[C60]能减少在畜禽生产中氧化应激损伤是可行的提供文献参考。

2.1 富勒烯[C60]及其衍生物在细胞抗氧化应激方面的研究

富勒烯[C60]水溶液(FAS)能够有效抑制肝癌细胞(HepG2)中细胞角蛋白的表达,这种结构蛋白的抑制表达后使得HepG2细胞维持上皮组织的完整性及连续性被破坏[31]。在对Lewis肺癌(LLC)细胞的培养中发现,添加富勒烯[C60]后用于临床常用的化疗药物顺铂对肺癌细胞的毒性得到了显著加强[32]。丙二酰羧基化富勒烯是一种高效的神经保护剂,使用培养的新皮层细胞的体外试验表明一定剂量的丙二酰羧基化富勒烯可以抑制神经元死亡,而且丙二酰羧基化富勒烯的C3异构体比它的D3对称类似物更有效[33-35]。同时在超氧化物阴离子自由基的突变中,丙二酰羧基化富勒烯会表现出类似SOD的特性,从而保护神经细胞免受氧化损伤[36]。富勒醇C60(OH)12-26能增强被辐射后K562细胞抗氧化酶的活性[37]。富勒醇C60(OH)18-20有保护神经的功能,其通过阻断谷氨酸受体发挥保护神经的作用,使产生兴奋毒性和因血清剥夺凋亡的死亡神经元减少。在神经细胞培养中使用50 mmol/L的富勒醇处理神经细胞,因N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)导致的兴奋性神经元死亡减少了约80%[38]。树突富勒烯的自由基清除研究主要体现在放射性保护上,Daroczi等[39]使用斑马鱼胚胎作为体内模型来评估树突富勒烯的放射防护作用,他们将斑马鱼胚胎放置在电离辐射中,随着时间的变化会引起胚胎形态发生变化,但是经过树突富勒烯预处理的胚胎辐射损伤显著减少,其疗效可与目前作为癌症放疗中的细胞保护剂的氨基福汀相媲美,甚至当胚胎被辐射15 min之后使用树突富勒烯同样可以表现出明显的保护作用[40]

2.2 富勒烯[C60]及其衍生物在动物抗氧化应激方面的研究

将丙二酰羧基化富勒烯添加到SOD2基因缺陷小鼠的饲粮中,可以重建线粒体SOD保护,免受超氧化物自由基的伤害,并延长300%的寿命[36]。1 mmol/L富勒醇可使线虫的寿命延长8.4%[41]。此外,丙二酰羧基化富勒烯也被证明可以减少大脑氧化应激[42]。董润等[43]使用博来霉素诱导C57BL/6J小鼠后,通过腹腔注射水溶性富勒烯[C60]发现,治疗组能有效减少小鼠肺脏纤维化的病变程度。陈琪萍等[44]在X射线照射前后给予小鼠富勒烯[C60]大环多胺衍生物(CB)处理,发现CB能有效地干预线粒体内脂质过氧化物的合成,从而减少由辐射导致的线粒体氧化应激损伤。富勒烯[C60]及其衍生物的抗氧化研究不仅在细胞与小鼠上进行,也出现在许多其他动物上。例如:富勒醇C60(OH)12-26能提高被辐射大鼠的存活率[45],减少大鼠骨关节炎[46],保护贻贝棘尾虫免受辐射损伤[47]。在大鼠饲粮中添加富勒烯[C60]可以减轻肝脏纤维化、肺部炎症,预防和清除由过氧化氢和过氧化异丙苯引起的大鼠海马的氧化损伤[31-32],改善胰腺状态,使碱性磷酸酶和甘油三酯正常化[48]。另外一些富勒醇,如富勒醇C60(OH)22可以保护大鼠脑部微血管内皮细胞抵抗一氧化氮(NO)诱导的细胞骨架凋亡解聚和核损伤,并加速内皮细胞修复[49]。富勒醇C60(OH)24可通过减少氧化应激来防止阿霉素(Dox)诱导的大肠癌大鼠的慢性心脏和肝脏毒性,并且在体内能猝灭被NO介导线粒体产生的超氧自由基,并阻断其生物活性[50]。六磺酰化富勒烯能有效清除自由基,使冠状动脉堵塞缺血和疏通再灌注导致的氧化应激大鼠组织永久损伤与死亡显著减少[51]

2.3 富勒烯[C60]及其衍生物在畜禽抗氧化应激方面的研究进展

富勒烯[C60]及其衍生物的功能是缓解氧化应激引发的疾病,畜禽生产中由于饲养管理技术、环境以及畜禽自身原因导致的大部分应激实质上均为氧化应激,而富勒烯[C60]作为抗氧化剂在畜禽生产方面的研究却较少。目前已经证实在饲粮中添加N-乙酰半胱氨酸(N-acetyl cysteine,NAC)修饰的富勒烯[C60]可以提高肉用仔鸡肝脏和肾脏中抗氧化能力[52]。4 ℃保存的猪精子中加入羧基化富勒烯[C60]能够显著降低精子氧化应激和相关的并发症,为富勒烯[C60]在公猪精液保存的应用提供了可靠的理论基础[53]

本实验室通过了解富勒烯[C60]在细胞和动物上的研究进展,推测富勒烯[C60]在畜禽生产上有广阔的应用前景,并通过试验证明了其可行性。试验在3周龄雄性C57BL/6小鼠的饮水中添加呕吐毒素(deoxynivalenol,DON)模拟在畜禽生产中由于霉菌毒素引起畜禽生长性能、免疫功能降低和机体氧化-抗氧化平衡破坏[54];结果表明在小鼠饲粮中添加富勒烯[C60]可以改善小鼠的生长性能,提高肠道绒毛高度和紧密连接蛋白表达量,降低血清炎症因子和脂多糖含量,提高肠道和肝脏中总抗氧化能力(total antioxidant capacity,T-AOC)以及SOD和谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)活性。T-AOC是生物机体内各种活性抗氧化分子的总水平,通过抗氧化分子总水平来表示机体总的抗氧化能力大小,其中SOD与GSH-Px是T-AOC中的2类抗氧化分子,SOD可以使对机体有害的自由基快速分解并且降低细胞脂质过氧化。GSH-Px是一种广泛存在于机体中的过氧化物分解酶,可以有效清除机体中脂质过氧化物、过氧化氢等有害过氧化物。由此可以得出富勒烯[C60]能改善由DON诱导的肠道氧化应激状态的结论,应用富勒烯[C60]减少畜禽生产中氧化应激带来的损伤是可行的。

3 富勒烯[C60]及其衍生物抗氧化损伤的作用机制

通过对细胞凋亡研究发现氧自由基是诱导凋亡的重要因素,其存在的机制是线粒体被氧自由基攻击释放细胞色素C,随后含半胱氨酸的天冬氨酸蛋白水解酶(cysteinyl aspartate specific proteinase,Caspase)蛋白酶被激活,从而引起细胞的凋亡[55-57]。当细胞遭受到氧化应激损伤时,会调节细胞内的GSH-Px、SOD、过氧化氢酶(catalase,CAT)和其他非酶性抗氧化物质的生成,从而达到清除体内ROS的目的。有研究表明,在加入富勒烯[C60]预处理细胞之后,能有效减少NO对细胞的氧化损伤,并且能够维持线粒体的正常形态,减少细胞凋亡率[51, 58-60]

3.1 富勒烯[C60]及其衍生物直接抗氧化损伤

富勒烯[C60]及其衍生物对机体氧化应激的保护作用与机体内原有的抗氧化物质抗氧化应激有相似之处,已知的许多抗氧化剂可以与ROS和ROS诱导的自由基中间体直接反应来阻止ROS诱导的损伤[61]。从富勒烯[C60]的结构来看,30个共轭双键的存在可以结合60个自由基,改性的富勒烯[C60]衍生物则能够通过附加化学基团数量和位置或少或多地结合自由基。丙二酰羧基化富勒烯在小鼠体内表现出类似于锰超氧化物歧化酶(MnSOD)模拟物的生物活性,可以有效地清除超氧阴离子。尽管清除速度慢于生物自身的SOD1和SOD2,但是在含金属SOD模拟物清除超氧阴离子速度范围内[36]。同时,富勒烯[C60]还表现出类似细胞色素C过氧化物酶(cytochrome C peroxidase,CcP)的活性,主要参与细胞中过氧化氢的降解过程[62]。在预防糖尿病的研究中发现,富勒烯[C60]对缓解超氧化物和羟基自由基引起的脂质过氧化作用略强于维生素E[63],富勒烯[C60]类似于SOD、CcP、维生素E等生物抗氧化剂的能力使其参与细胞中氧化还原循环。超氧化物的电子会先通过氧化还原链转移到富勒烯[C60],使得富勒烯[C60]被还原成富勒烯[C60]阴离子之后再将多余的电子转移到另一种超氧化物上,使其还原成过氧化物阴离子,直接减少机体受到氧化损伤的风险[64]

3.2 富勒烯[C60]及其衍生物调节信号通路减少氧化损伤

生物机体为了控制ROS水平,防止ROS积累导致损伤,形成了完善的抗氧化体系,拥有一系列的转录因子调控细胞内相关的抗氧化酶表达,改善机体氧化应激状态,减少氧化应激损伤,使机体维持氧化还原稳态。大量的研究发现,自然界中许多天然化合物能够调节抗氧化相关转录因子的活性,从而达到抗氧化的目的[65]。如白藜芦醇和紫檀芪等天然化合物都能够激活转录因子NF-E2相关因子2(NF-E2-related factor 2,Nrf2)[66-67],减少机体氧化应激损伤[68],Nrf2的激活可显著抑制白细胞介素-1(interleukin-1,IL-1)DNA诱导的外源性和内源性凋亡途径的激活,激活细胞外信号调节激酶1/2(extracellular signal-regulated kinase,ERK1/2),调控含ETS结构域的蛋白(ETS domain-containing protein,Elk-1)转录因子发挥作用[69],而富勒醇的抗氧化机制与白藜芦醇等一些抗氧化物的研究结果[70-71]是一致的。Pei等[46]研究发现,富勒醇可以有效地抑制p38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38 MAPK)磷酸化、降低核内核因子-κB(nuclear factor kappa-B,NF-κB)和叉头框蛋白O1(forkhead box protein O1,FoxO1)2种转录因子的水平,减少氧化损伤和抑制炎症反应。在通过采用DAF-16基因敲除株CF1038来研究线虫在应激环境中的寿命时发现,富勒醇在应激条件下可增加SOD3和热休克蛋白16.2(heat shock proteins 16.2,HSP-16.2)的表达,这2个蛋白是DAF-16调控的2个靶点,可以在应激环境增强维持生命的进程。同时富勒醇促进DAF-16更多的核定位,以实现其抗氧化应激活性,降低了内源性ROS水平,从而提高了线虫的寿命[55]

综上所述,富勒烯[C60]可能是通过调节细胞外调节蛋白激酶(extracellular regulated protein kinases,Erk)、p38 MAPK等酶活性激活Nrf2、NF-κB和FoxO1等转录因子,通过这些信号通路发挥效应间接减少机体受到的氧化损伤。

4 小结与展望

在畜禽生产中抗氧化剂的使用十分常见,使用效果更好的抗氧化剂可以减轻生产中畜禽的氧化应激,在保障畜禽健康的同时还可以提高生长性能。根据富勒烯[C60]及其衍生物大量抗氧化作用和少量对畜禽生长性能影响的研究,证明富勒烯[C60]可以研发成更加有效的抗氧化剂。我国在长期使用促生长类抗生素作为饲料添加剂后发现抗生素不止是提高畜禽生长性能、保障畜禽健康,而且会导致病原菌产生耐药性和畜禽产品中抗生素残留等问题,在全面禁止畜禽饲料中添加抗生素的背景下,急需寻找到能够代替抗生素作为提高畜禽生长性能、保障畜禽健康的新型添加剂。富勒烯[C60]及其衍生物在自由基清除和抗氧化活性的报道很多,将富勒烯[C60]产品推广到畜禽生产和疾病预防与治疗,能为代替抗生素找到新的方向。目前越来越多新的富勒烯[C60]衍生物被合成出来,由于纳米材料的合成工艺的复杂以及富勒烯[C60]自身不溶于水的特性,富勒烯[C60]如何与特定基团连结并使其产生特定功能获得生物活性仍然是富勒烯[C60]热点研究方向。由于特定功能的水溶性富勒烯[C60]衍生物合成复杂,导致价格偏高,不利于其在畜禽生产上的推广应用,现阶段基本处于试验研究。富勒烯[C60]的研究并不能只专注于研发新的富勒烯[C60]衍生产品,同时应该优化制备方法,降低成本,富勒醇产品将会有广阔的应用前景和市场。将富勒烯[C60]应用到畜禽生产代替抗生素能解决食品安全问题,更好地发展绿色、健康、安全的养殖业。

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