动物营养学报 >

2025 , Vol. 37 >Issue 4: 2200 - 2210

DOI: https://doi.org/10.12418/CJAN2025.187

综述

多酚类物质对奶牛乳腺上皮细胞凋亡、炎性和氧化损伤的缓解作用及其机制

  • 罗轶翾 ,
  • 邢媛媛 ,
  • 孙梅 ,
  • 李大彪 , *
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  • 内蒙古农业大学动物科学学院,内蒙古自治区高校动物营养与饲料科学重点实验室,呼和浩特 010018
* 李大彪,教授,博士生导师,E-mail:

罗轶翾(2000—),女,内蒙古鄂尔多斯人,硕士研究生,从事反刍动物营养研究。E-mail:

Copy editor: 田艳明

收稿日期: 2024-09-10

  网络出版日期: 2025-04-15

基金资助

中央引导地方科技发展资金项目(2022ZY0196)

内蒙古自治区直属高校基本科研业务费(BR22-13-13)

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Alleviating Effects and Mechanisms of Polyphenols on Apoptosis, Inflammation and Oxidative Damage in Bovine Mammary Epithelial Cells

  • LUO Yixuan ,
  • XING Yuanyuan ,
  • SUN Mei ,
  • LI Dabiao , *
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  • Key Laboratory of Animal Nutrition and Feed Science at University of Inner Mongolia Autonomous Region, College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010018, China
* professor, E-mail:

Received date: 2024-09-10

  Online published: 2025-04-15

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摘要

多酚类物质是由多个酚环构成的天然活性物质,其因对动物毒副作用在安全范围内,受到养殖业的广泛关注。目前,乳腺炎是影响奶牛生产效益的重要因素之一,对奶业发展以及人类健康造成严重危害。奶牛乳腺上皮细胞作为乳腺防御的第一道防线,近年来成为人们关注的重点。利用多酚类物质的抗氧化、抑菌、抗炎及抗凋亡等生物活性功能,可降低奶牛炎症反应,增强抗氧化功能,有效缓解奶牛乳腺炎。因此,本文根据国内外对多酚类物质缓解奶牛乳腺炎的研究现状,从奶牛乳腺炎的致病因素、多酚类物质的分类及多酚类物质缓解奶牛乳腺上皮细胞凋亡、炎性和氧化损伤的具体作用机制等方面进行综述,并提出尚需要进一步研究的问题和方向,以期为相关领域的研究提供理论依据和新视野。

关键词： 多酚类物质; 奶牛乳腺炎; 奶牛乳腺上皮细胞

本文引用格式

罗轶翾 , 邢媛媛 , 孙梅 , 李大彪 . 多酚类物质对奶牛乳腺上皮细胞凋亡、炎性和氧化损伤的缓解作用及其机制[J]. 动物营养学报, 2025 , 37(4) : 2200 -2210 . DOI: 10.12418/CJAN2025.187

Abstract

Polyphenols are natural active substances composed of multiple phenolic rings. Due to their safety profile within a tolerable range of toxic side effects in animals, they have attracted widespread attention in the livestock industry. Currently, bovine mastitis is one of the major factors affecting production efficiency, posing serious risks to the dairy industry and human health. In recent years, bovine mammary epithelial cells, as the first line of defense in the mammary gland, have become a focal point of attention. By utilizing the antioxidant, antibacterial, anti-inflammatory and anti-apoptotic bioactive functions of polyphenols, it is possible to reduce inflammatory responses in dairy cows, enhance antioxidant capacity and effectively alleviate bovine mastitis. Therefore, this paper provides a review based on the current research status both domestically and internationally on the alleviating effects of polyphenols on bovine mastitis. It focuses on the pathogenic causes of bovine mastitis, the classification of polyphenols, and the specific mechanisms through which polyphenols mitigate apoptosis, inflammation, and oxidative damage in bovine mammary epithelial cells. Unresolved issues requiring further investigation are proposed, with the aim of providing effective theoretical foundations and new perspectives for researchers in the relevant fields.

Key words： polyphenols; bovine mastitis; bovine mammary epithelial cells

随着生活水平的提高,人们对于奶制品的需求逐年增加。为满足这一需求,养殖者采取集约化、标准化的饲养管理模式,以期提高奶牛生产效益。但与此同时,饲养管理方式的不到位导致奶牛乳腺炎频发,严重阻碍了奶牛养殖业的发展。多酚类物质具有抗氧化、抑菌、抗炎及抗凋亡等多种生物学功能[1],可提高奶牛抗氧化能力[2],并通过调控炎症与细胞凋亡信号通路,从而缓解奶牛乳腺炎。然而,目前的研究多集中于细胞水平,活体验证试验较少。因此,本文主要阐述了奶牛乳腺炎的致病因素,并从调控炎症、抗氧化信号通路和减少细胞凋亡角度阐述了多酚类物质缓解奶牛乳腺炎作用机制的最新研究进展,旨在从细胞水平揭示多酚类物质缓解奶牛乳腺炎的作用及其机制,为其实际应用和推广提供依据。

1 奶牛乳腺炎的致病因素

奶牛乳腺炎是目前规模化奶牛养殖场中多发病之一,可使奶牛乳腺功能受损,导致牛奶产量与质量下降,奶牛淘汰率提高。奶牛乳腺炎可能由单一因素引发,也可能由多种理化因素同时刺激导致,例如病原体微生物入侵、奶牛自身因素、饲养管理和环境卫生等[3]。奶牛乳腺上皮细胞(bovine mammary epithelial cells,BMEC)是抵御乳房感染的第一道防线,是先天性免疫的组成部分,对于乳腺的健康和疾病的防御至关重要。当奶牛发生乳腺炎后,BMEC将分泌炎性细胞因子和趋化因子[4],进而激活并调控免疫细胞发挥免疫防御功能。

1.1 氧化应激

围产期奶牛因泌乳量远大于干物质摄入量,常处于能量负平衡状态,能量负平衡引起机体动员大量脂质,显著增加活性氧(reactive oxygen species,ROS)含量,过量的ROS导致奶牛机体氧化应激[5]。研究发现,氧化应激损伤奶牛乳腺,导致奶牛产奶量下降,乳腺组织线粒体功能障碍[6],血乳屏障紊乱[7],引发奶牛乳腺炎。同时,血液中的丙二醛(malondialdehyde,MDA)含量提高,总抗氧化能力(total antioxidant capacity,T-AOC)及谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)和过氧化氢酶(catalase,CAT)活性降低[8]。此外,氧化应激诱导BMEC发生炎性反应,激活促炎信号传导途径,如丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)、核因子-κB(nuclear factor-κB,NF-κB)等,使促炎细胞因子白细胞介素-1β(interleukin-1β,IL-1β)、白细胞介素-6(interleukin-6,IL-6)和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)的mRNA表达量显著提高[9]。Ma等[10]研究表明,过量的ROS会激活半胱氨酸天冬氨酸蛋白酶(Caspase)和B细胞淋巴瘤-2(B-cell lymphoma-2,Bcl-2)家族相关基因的表达,上调促凋亡转录基因B细胞淋巴瘤-2相关X蛋白(B-cell lymphoma-2 associated X protein,Bax)的mRNA表达,导致BMEC凋亡,使奶牛乳腺免疫功能降低,导致奶牛乳腺炎的发生。

1.2 病原微生物感染

目前约有150种微生物可诱发奶牛乳腺炎[11],其中引起临床奶牛乳腺炎的病原体主要是大肠杆菌(Escherichia coli)、金黄色葡萄球菌(Staphylococcus aureus)、克雷伯氏菌属(Klebsiella)和无乳链球菌(Streptococcus agalactiae)等[12]。其中,大肠杆菌为革兰氏阴性菌,是临床乳腺炎的首要致病菌之一,其细胞壁所含的脂多糖(lipopolysaccharide,LPS)是一种内毒素,可激活Toll样受体4(Toll-like receptor 4,TLR4),并通过髓样分化因子88(myeloid differentiation factor 88,MyD88)作用,活化NF-κB信号通路,诱导炎性细胞因子IL-1β、IL-6和TNF-α的分泌[13],导致BMEC产生炎症反应。金黄色葡萄球菌为革兰氏阳性菌,通常引起亚临床型乳腺炎,其症状与大肠杆菌感染引起的乳腺炎相比较轻,甚至可能无症状,但其病程较长,对各类抗生素有明显的耐药性[14],导致奶牛乳腺持续性感染,给养殖业带来巨大损害。

1.3 高精料饲粮

为了提高奶牛产奶量,实现养殖效益最大化,养殖者通常会提高奶牛饲粮中的精料比,但长时间饲喂高精料饲粮会导致瘤胃内不饱和脂肪酸积累,pH降低,瘤胃菌群紊乱,引起亚急性瘤胃酸中毒(subacute ruminal acidosis,SARA)。在SARA状态下,瘤胃微生态平衡失调,革兰氏阴性菌释放大量LPS,并通过血液循环从乳管侵入乳腺,使BMEC发生凋亡,从而诱发奶牛乳腺炎[15]。Xie等[16]研究发现,给泌乳期奶牛饲喂高精料后,可显著提高乳中体细胞(somatic cells,SCC)数量和N-乙酰-D-氨基葡萄糖苷酶活性,显著降低乳蛋白率和支链氨基酸含量。此外,高精料饲粮会导致乳静脉血中LPS含量显著提高,同时乳腺组织中三酰甘油的含量和牛奶中乳脂的含量显著降低[17],奶牛乳腺中p38、细胞外信号调节激酶(extracellular signal-regulated kinase,ERK)、c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)的基因表达量以及IL-6、TNF-α、IL-1β基因表达量显著提高[18]。由此可知,长期给奶牛饲喂高精料,不仅影响奶牛机体健康,还会导致奶牛乳腺炎的发生,使乳成分含量下降。
除此之外,奶牛个体差异、血液循环障碍、饲养管理和环境卫生也会导致奶牛乳腺炎的发生[19]。在饲养过程中若操作不当且挤奶器械消毒不彻底,会引起奶牛乳房淤堵,产生炎性细胞,使乳房抵御病菌的能力下降,造成泌乳障碍。另外,当畜舍环境较差、养殖设备不完善导致舍内空气污浊时,常会引起奶牛免疫力降低,进一步提高奶牛乳腺炎发生的几率。
综上可知,不论是何种原因引起的奶牛乳腺炎,都与机体出现氧化应激和免疫反应息息相关,因此通过提高奶牛的免疫和抗氧化功能,以此来缓解奶牛乳腺炎是防治该病的关键措施。

2 多酚类物质的分类

多酚类物质指分子结构由多个羟基构成的酚类化合物,是一种有机次生代谢物,广泛存在于水果、蔬菜、谷物及茶等植物的根茎叶中。目前已在植物中发现8 000多种多酚类物质,根据其化学骨架可分为类黄酮与非类黄酮[2]。最常见的多酚类物质是类黄酮,共有15个碳构成,大致结构由2个芳环和3个碳原子组成,形成1个含氧杂环,因其功能受到该结构基团空间位置、羟基的数量和羟基相对位置的影响,可分为不同亚类,其中包括:黄酮醇、黄酮、黄烷酮、黄烷-3-醇、异黄酮和花青素。常见的非类黄酮则可分为:木脂素、酚酸和芷类。其中,酚酸常见于谷物,又可细分为羟基苯甲酸和羟基肉桂酸两大类;木脂素多见于亚麻籽和芝麻籽中,食物中大部分木脂素以开环异落叶松脂醇二葡萄糖苷存在;芪类则以白藜芦醇为代表,自然界中以正式和反式异构体以及共轭衍生物的形式出现[20-21]。

3 多酚类物质缓解BMEC凋亡、炎性和氧化损伤的作用机制

如何控制和治疗奶牛乳腺炎是全球乳制品行业的首要问题,目前治疗奶牛乳腺炎的常见方法是向乳腺内注射抗菌药物[22],然而抗生素的滥用会导致致病菌产生耐药性,同时也使奶产品中残留大量抗生素,进而危害人类健康,因此寻找并开发抗生素替代品已成为研究热点。大量研究表明,多酚类物质可以通过调控炎症、抗氧化和细胞凋亡机制,从而缓解奶牛乳腺炎,作为营养添加剂具有广泛的开发和应用前景。

3.1 多酚类物质通过调控炎症反应缓解BMEC炎性损伤

炎症是机体应对感染、组织损伤等有害刺激的防御性反应,是维持稳态的基本机制[23]。通常情况下,可控的炎性反应有利于机体清除异物,保护自身免受侵害,但是严重的炎性反应会引起机体组织或器官病变,使免疫功能紊乱。多酚类物质通过调节机体免疫细胞活性,提高免疫球蛋白(immunoglobulin,Ig)含量,并减少促炎细胞因子表达和增强抗炎细胞因子表达,同时通过NF-κB、MAPK、Janus激酶(Janus kinase,JAK)-信号传导与转录激活因子(signal transducer and activator of transcription,STAT)信号通路改善免疫应答来缓解奶牛乳腺炎,从而发挥抗炎作用。构树中含有丰富的类黄酮,当给荷斯坦奶牛饲喂28 d含9.0%构树青贮饲粮后,血清中IgM含量显著升高,且随着饲喂天数的增加,血清中IgA和IgG含量显著升高[24],Ig含量的升高将进一步调节机体免疫作用[25]。Ma等[26]研究表明,通过给患有酮血症的奶牛补饲绿茶多酚可以显著降低血浆中促炎因子TNF-α、IL-1β、白细胞介素-2(interleukin-2,IL-2)、白细胞介素-8(interleukin-8,IL-8)和干扰素-γ(interferon-γ,IFN-γ)含量,显著提高血浆中抗炎因子白细胞介素-10(interleukin-10,IL-10)含量。Burmańczuk等[27]研究发现,通过给患有临床型奶牛乳腺炎的波兰荷斯坦奶牛乳区注射120 mg/(乳房·d)的黄芩苷,当试验天数达到第8天后,可显著降低奶牛SCC。随后,研究者以BMEC为模型进一步试验表明,当添加50 μmol/L表没食子儿茶素-3-没食子酸酯和羟基酪醇后,TNF-α、IL-1β和IL-6的基因表达量显著降低,IL-10的基因表达量显著提高[28]。由此可知,多酚类物质可以通过提高奶牛血浆中抗炎因子的表达和Ig的含量,同时降低促炎症因子的表达,从而发挥抗炎作用。
NF-κB是免疫系统的关键调节枢纽,其家族成员参与形成同源或异源二聚体后,与各类相关的DNA靶序列(κB位点)结合并调节细胞分化和凋亡[29]。核转录因子NF-κB的经典途径由p50/p65组成,正常情况下,NF-κB复合体与核因子-κB抑制因子(inhibitor of nuclear factor-κB,IκB)相互作用,在细胞质中处于失活状态;当受到外界刺激时,核因子-κB抑制因子激酶(inhibitor of nuclear factor-κB kinase,IKK)被激活,使IκB蛋白磷酸化,导致IκB的降解和NF-κB二聚体的释放,引起NF-κB复合体进入细胞核发挥转录作用,使得机体炎症进一步加重[30](图1)。Zhang等[31]以LPS诱导的小鼠乳腺炎为模型研究表明,白藜芦醇抑制IκBα的磷酸化,进而抑制NF-κB信号通路的激活。Liu等[32]研究表明,咖啡酸可以显著抑制LPS诱导的BMEC中NF-κB的激活。徐天乐等[33]研究发现,BMEC中的磷酸化p65在受到LPS刺激后蛋白表达量显著升高,但添加表没食子儿茶素没食子酸酯后,p65磷酸化水平显著降低,从而显著降低促炎因子TNF-α、IL-6和IL-1β基因表达量[34],使炎症得到缓解。姜黄素可以抑制泛素连接酶——肿瘤坏死因子受体相关因子6(tumor necrosis factor receptor associated factor 6,TRAF6)的活化,进而抑制其下游转化生长因子-β活化激酶1(transforming growth factor-β-activated kinase 1,TAK1)和IKK的磷酸化,维持NF-κB在细胞质内抑制形态[35]。绿原酸通过抑制MyD88/NF-κB信号通路的激活,来降低LPS诱导的BMEC中TLR4的表达[36]。咖啡酸可以抑制LPS诱导的BMEC中IκBα的降解[37],从而发挥抗炎作用。由此可知,当机体受到外界刺激后,IKK被激活从而使IκB蛋白磷酸化,激活NF-κB信号通路,进而导致促炎因子的大量生成与释放。而多酚类物质通过主动运输与被动扩散的方式进入细胞内[38],从而对NF-κB信号通路中多个位点发挥作用,抑制其被过度激活,有效缓解奶牛乳腺炎。
图1 多酚类物质调控炎症信号通路

LPS:脂多糖 lipopolysaccharide;CD14:单核细胞分化抗原CD14 monocyte differentiation antigen CD14;polyphenols:多酚类物质;P:磷酸化 phosphorylation;JAK:Janus激酶 Janus kinase;STAT:信号传导与转录激活因子 signal transducer and activator of transcription;Cytoplasm:细胞质;Nucleus:细胞核;Raf:Raf原癌基因丝氨酸/苏氨酸蛋白激酶 Raf proto-oncogene serine/threonine-protein kinase;MEK1/2:丝裂原活化蛋白激酶激酶1/2 mitogen-activated protein kinase kinase 1/2;ERK1/2:细胞外信号调节激酶 extracellular signal-regulated kinase 1/2;MAP3K:丝裂原活化蛋白激酶激酶激酶 mitogen-activated protein kinase kinase kinase;MAP2K:丝裂原活化蛋白激酶激酶 mitogen-activated protein kinase kinase;JNK:c-Jun氨基末端激酶 c-Jun N-terminal kinase;AP-1:激活蛋白-1 activator protein-1;TRAF6:肿瘤坏死因子受体相关因子6 tumor necrosis factor receptor associated factor 6;TAK1:转化生长因子-β活化激酶1 transforming growth factor-β-activated kinase 1;IKK:核因子-κB抑制因子激酶 inhibitor of nuclear factor-κB kinase;IκBα:核因子-κB抑制因子α inhibitor of nuclear factor-κB α;Ub:泛素 ubiquitin;COX-2:环氧化酶-2 cyclooxygenase-2;iNOS:诱导型一氧化氮合酶 inducible nitric oxide synthase;Cytokines:细胞因子。

Fig.1 Polyphenols regulate inflammatory signaling pathways

哺乳动物中的MAPK是一组高度保守的的丝氨酸/苏氨酸蛋白激酶,包括ERK1/2、JNK和p38[39]。MAPK信号级联由丝裂原活化蛋白激酶激酶激酶(mitogen-activated protein kinase kinase kinase,MAP3K)、丝裂原活化蛋白激酶激酶(mitogen-activated protein kinase kinase,MAP2K)和MAPK 3层激酶组成,当细胞膜受到外界刺激时,激活MAPK 3级级联调控,活化的MAPK磷酸化多种分子,从而诱导相关炎症基因的表达[40](图1)。Jiang等[41]研究表明,白藜芦醇苷显著降低小鼠乳腺组织中MyD88和TRAF6蛋白表达量以及MAP2K3/6和p38的磷酸化,磷酸化JNK和磷酸化ERK蛋白表达量则无显著性。杜鹃素通过下调ERK1/2、p38、NF-κB p65的磷酸化来抑制促炎因子的产生,从而防止LPS诱导的小鼠乳腺炎进一步发展[42]。孔令浩[43]研究发现,与热应激处理的BMEC相比,绿原酸显著降低了Ras和磷酸化MAP2K的蛋白表达量,表明绿原酸可以抑制热应激对Raf原癌基因丝氨酸/苏氨酸蛋白激酶(Raf proto-oncogene serine/threonine-protein kinase,Raf)-丝裂原活化蛋白激酶激酶1/2(mitogen-activated protein kinase kinase 1/2,MEK1/2)-ERK1/2通路的活化。Liu等[32]用LPS刺激BMEC后,MAPK信号通路被激活,激活蛋白-1(activator protein-1,AP-1)蛋白表达量显著升高;当添加咖啡酸后AP-1蛋白和基因表达量均显著降低,表明咖啡酸能通过阻断MAPK信号通路的激活,从而干扰炎症级联反应。综上所述,多酚类物质可以调控乳腺组织和乳腺细胞内MAPK通路,与此同时NF-κB通路相关蛋白也被激活,共同调控炎症反应,从而缓解奶牛乳腺炎的发生。
JAK家族包括JAK1、JAK2、JAK3和酪氨酸激酶2(tyrosine kinase 2,TYK2),能够活化STAT家族[44]。JAK-STAT途径既受干扰素、LPS或生长因子调节,又可以介导促炎细胞因子的产生,当炎性细胞因子与其细胞表面受体结合后,相关JAK被激活,磷酸化STAT上的酪氨酸激酶,活化后的STAT易位到细胞核中,介导靶基因的转录,引发奶牛乳腺炎[45](图1)。Tsugami等[46]研究表明,向小鼠乳腺细胞中添加25 μmol/L的染料木黄酮,磷酸化JAK2、磷酸化STAT5和STAT5的蛋白表达量显著降低。LPS可以诱导巨噬细胞释放大量炎性介质,损伤BMEC的结构与功能,向RAW 264.7巨噬细胞中加入滨蓟黄甙后,可以显著下调JAK-STAT通路的磷酸化,抑制诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)和环氧合酶-2(cyclooxygenase-2,COX-2)的mRNA表达[47]。Guo等[48]从橙子皮不溶性膳食纤维中提取出结合多酚,可有效地抑制LPS诱导的JAK1和STAT3蛋白的磷酸化,并通过阻断LPS诱导的RAW 264.7细胞中JAK-STAT通路的激活来抑制IL-1β、IL-6和iNOS的蛋白表达。由此可知,多酚类物质可以通过调控动物机体JAK-STAT信号通路,降低促炎因子的表达,但多酚类物质通过调控BMEC中JAK-STAT信号通路缓解奶牛乳腺炎的研究未见报道。
综上所述,多酚类物质通过调控NF-κB、MAPK和JAK-STAT等炎症信号通路来缓解炎症反应,而对于多酚类物质如何通过上述信号通路共同调节机体炎症,协同发挥免疫功能,仍需进一步研究。

3.2 多酚类物质通过提高抗氧化功能缓解BMEC氧化损伤

当ROS含量高于机体抗氧化防御能力时,自由基不能及时被清除,导致机体代谢紊乱,引起奶牛乳腺氧化损伤。利用多酚类物质的抗氧化作用,可有效防止氧化应激损伤,其主要影响机制为:一方面,多酚类物质结构中的羟基与苯环形成的共轭体系可防止新自由基的产生,阻止ROS进一步的扩散,并通过螯合金属离子、抑制氧化酶活性从而起到对生物组织的保护作用[49];另一方面,多酚类物质可以激活抗氧化防御系统与机体核因子红系2相关因子2(nuclear factor erythroid 2-related factor 2,Nrf2)途径,介导抗氧化反应,进而保护奶牛机体健康。Liu等[50]以经产荷斯坦奶牛为试验动物,当辣木叶黄酮添加量为50 mg/kg BW时,可显著降低血浆中MDA含量,显著提高血浆中T-AOC和总超氧化物歧化酶(total superoxide dismutase,T-SOD)活性,对血浆中GSH-Px和CAT活性无显著影响。Zhan等[51]以紫花苜蓿黄酮饲喂荷斯坦奶牛,得到与Liu等[50]类似的试验结果。原花青素广泛存在于各类植物中,有研究表明,在泌乳早期奶牛饲粮中添加40 mg/(kg BW·d)的葡萄籽原花青素,可有效改善奶牛乳汁抗氧化性能,提高奶牛乳汁中GSH-Px活性[52]。Kan等[53]用过氧化氢(H2O2)刺激BMEC建立氧化应激模型,当杨梅素添加量为20 μmol/L时可以显著抑制ROS和MDA的产生,并增加SOD活性和T-AOC。由此可知,多酚类物质对提高奶牛抗氧化能力、增强机体适应性和缓解奶牛乳腺炎有积极作用。
Nrf2是Cap‘n’collar(CNC)转录因子家族成员,由7个高度保守的Nrf2-ECH同源结构域(Nrf2-ECH homology,Neh)组成[54],在诱导机体的抗氧化应答中起着重要作用。正常生理条件下,大部分Nrf2以抑制状态存在于细胞质中,当受到氧化应激或炎症反应时,Nrf2被Kelch样环氧氯丙烷相关蛋白1(Kelch-like ECH-associated protein 1,Keap1)释放并易位到细胞核中,与抗氧化反应元件(antioxidant response element,ARE)结合[55],并激活下游抗氧化基因血红素氧合酶-1(heme oxygenase-1,HO-1)和还原型辅酶Ⅰ(Ⅱ)醌脱氢酶-1[NAD(P)H quinone oxidoreductase-1,NQO-1]转录,有效减少氧化损伤(图2)。Li等[56]研究表明,信号蛋白p62与Nrf2为竞争性关系,既可以激活Nrf2,又受Nrf2诱导,槲皮素通过诱导p62蛋白表达,抑制Keap1与Nrf2的结合,使Nrf2发生核易位,导致包括p62在内的下游抗氧化基因的转录激活,缓解氧化应激。He等[57]向小鼠乳腺细胞内加入ML385(Nrf2/HO-1信号通路的特异性抑制剂)后,黄芩素抗氧化作用被抑制,使Nrf2与HO-1蛋白表达量显著降低,验证了Nrf2是发挥抗氧化作用的关键信号通路。Fusco等[58]研究发现,羟基酪醇能够预防LPS诱导的BMEC氧化应激,抑制促炎因子的增加并增强内源性抗氧化系统(Nrf2、HO-1和NQO-1)基因的表达,显着提高BMEC的抗氧化防御能力。向BMEC中加入H2O2,发现细胞出现氧化应激,加入橙皮素后CAT活性与对照组相比显著升高,同时Keap1的蛋白表达量显著降低[59]。沉默Nrf2基因后,BMEC抗氧化能力被显著抑制[60],进一步说明了多酚类物质通过Nrf2信号通路缓解H2O2诱导的BMEC氧化应激(图2)。
图2 多酚类物质调控抗氧化信号通路

LPS:脂多糖 lipopolysaccharide;polyphenols:多酚类物质;H2O2:过氧化氢 hydrogen peroxide;Cul3:Cullin-Ring E3泛素连接酶 Cullin-Ring E3 ubiquitin ligase;Keap1:Kelch样环氧氯丙烷相关蛋白1 Kelch-like ECH-associated protein 1;Nrf2:核因子红系2相关因子2 nuclear factor erythroid 2-related factor 2;Ub:泛素 ubiquitin;Oxidative Stress:氧化应激;Cytoplasm:细胞质;Nucleus:细胞核;P:磷酸化 phosphorylation;ARE:抗氧化反应元件 antioxidant response element;HO-1:血红素氧合酶-1 heme oxygenase-1;NQO-1:还原型辅酶Ⅰ(Ⅱ)醌脱氢酶-1 NAD(P)H quinone oxidoreductase-1。

Fig.2 Polyphenols regulate antioxidant signaling pathways

不过,尽管多酚类物质已被反复证明具有较强的抗氧化特性,但尚未完全阐明该作用的确切机制,同时,目前在解释多酚类物质如何通过Nrf2信号通路调节机体氧化应激方面,仍然缺乏应用活体动物作为试验对象的相关研究。

3.3 多酚类物质通过调控细胞凋亡缓解BMEC程序性死亡

细胞凋亡是一种程序性死亡机制,受特定基因调控,可去除受损或不需要的细胞,对于维持内环境稳态具有重要意义[61]。当BMEC受到外界刺激时会引起线粒体损伤,触发内源性凋亡途径,严重时会导致奶牛乳腺炎的发生。多酚类物质通过诱导细胞自噬、刺激细胞凋亡信号通路等方式预防和治疗奶牛乳腺炎[29]。蒲公英富含丰富的类黄酮和酚酸,可有效缓解LPS诱导的细胞凋亡,提高BMEC的细胞活力[62]。Liu等[63]向BMEC中加入H2O2后发现,细胞体积缩小并形成囊泡和凋亡小体,同时染色质凝集,加入辣木叶黄酮后,细胞凋亡程度有所缓解。Liu等[64]研究发现,LPS处理BMEC后线粒体膜电位(mitochondrial membrane potential,MMP)显著降低,当加入阿魏酸后这一现象有所缓解,表明阿魏酸通过保护线粒体膜电位,从而有效减少细胞凋亡。与此同时,Bcl-2家族分子主要通过线粒体途径调控细胞凋亡,Bcl-2和Bax是细胞存活和凋亡的重要调节因子,当Bax蛋白表达水平升高时,Bcl-2/Bax比值降低,线粒体膜的通透性改变并释放细胞色素C[65],使下游Caspase-3活化,引起细胞凋亡。Grewal等[66]研究姜黄素对热应激造成的BMEC凋亡的影响发现,较低浓度的姜黄素(5和10 μmol/L)可显著提高Bcl-2的mRNA表达量,使Bcl-2/Bax比值降低,抑制下游基因Caspase-3的活化。与H2O2组相比,橙皮苷加H2O2组可显著提高BMEC中抗凋亡因子Bcl-2的蛋白表达量,显著降低促凋亡因子Bax的蛋白表达量[67],表明内源性凋亡通路被抑制。
此外有研究表明,多酚类物质通过调控磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase,PI3K)-蛋白激酶B(AKT)信号通路,抑制细胞凋亡,从而缓解乳腺炎。当外界刺激PI3K激活后在质膜上催化磷脂酰肌醇4,5-二磷酸(phosphatidylinositol 4,5-bisphosphate,PIP2)产生第二信使磷脂酰肌醇3,4,5-三磷酸(phosphatidylinositol 3,4, 5-triphosphate,PIP3),在3-磷酸肌醇依赖蛋白激酶-1(3-phosphoinositide-dependent protein kinase-1,PDK-1)作用下AKT与PIP3结合,AKT被激活,活化的AKT可抑制下游分子Caspase-9。Jiang等[68]以患有乳腺炎的小鼠为试验模型,证明了桑色素可显著增加LPS诱导的PI3K和AKT的磷酸化水平,激活PI3K-AKT信号通路来抑制小鼠乳腺炎。但Li等[42]研究发现,杜鹃素可以显著降低LPS诱导的小鼠乳腺细胞中AKT的磷酸化,缓解细胞炎性反应,进而缓解细胞凋亡。不过,多酚类物质如何调控PI3K-AKT通路达到缓解乳腺炎的机制尚不完全明确,同时,前人对于多酚类物质通过PI3K-AKT信号通路调控BMEC的凋亡还未见报道,值得进一步研究。
综上所述,多酚类物质通过调控凋亡通路相关蛋白表达,有效抑制氧化应激以及LPS等引起的BMEC凋亡,极大程度上保护细胞,从而防止因大量细胞凋亡而造成的奶牛乳腺炎。

4 小结与展望

奶牛乳腺炎作为影响我国奶业发展的三大疾病之一,常常给养殖场带来较大的经济损失。近年来,探究绿色安全的天然活性物质治疗奶牛乳腺炎成为研究热点,多酚类物质因其抗氧化、抗炎及抗肿瘤等生物活性受到广泛关注,大量体外与体内研究表明多酚类物质可以通过NF-κB、MAPK、JAK-STAT、Nrf2、Bcl-2/Bax-Caspase以及PI3K-AKT等信号通路缓解奶牛乳腺炎,其未来的研究前景十分广阔。但目前大部分的研究集中在细胞水平上,且试验动物多以小鼠为主,仍缺少在奶牛活体水平的验证。在之后的研究中,可以利用活体奶牛、乳腺组织以及BMEC为试验模型,深入探究多酚类物质缓解奶牛乳腺炎的作用效果以及调控机制,探明各信号通路之间的相互联系,从而有助于发掘多酚类物质防治奶牛乳腺炎的关键靶点,为多酚类物质在养殖业中的实际应用和推广提供依据。

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