动物营养学报 >

2025 , Vol. 37 >Issue 3: 1527 - 1538

DOI: https://doi.org/10.12418/CJAN2025.131

综述

槟榔中的主要活性物质及其生理功能研究进展

  • 蒋中二 , 1 ,
  • 李志青 1 ,
  • 候鹏霞 2 ,
  • 肖定福 , 1, *
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  • 1 湖南农业大学动物科学技术学院,岳麓山实验室,长沙 410128
  • 2 宁夏农林科学院动物科学研究所,银川 750002
*肖定福,教授,博士生导师,E-mail:

蒋中二(2000—),男,湖南娄底人,硕士研究生,动物营养与饲料科学专业。E-mail:

Copy editor: 菅景颖

收稿日期: 2024-09-04

  网络出版日期: 2025-03-13

基金资助

国家现代农业产业技术体系建设专项资助(CARS-37)

2024年宁夏特色产业重点研发专项“肉牛母带犊营养调控机制研究与集成示范”(2024BBF02016)

收起

Research Progress of Main Active Substances in Areca Nut and Their Physiological Functions

  • JIANG Zhonger , 1 ,
  • LI Zhiqing 1 ,
  • HOU Pengxia 2 ,
  • XIAO Dingfu , 1, *
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  • 1 Yuelushan Laboratory, College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
  • 2 Institute of Animal Science, Ningxia Academy of Agricultural and Forestry Science, Yinchuan 750002, China
*professor, E-mail:

Received date: 2024-09-04

  Online published: 2025-03-13

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摘要

槟榔是一种传统的中药材,含有槟榔碱、槟榔多酚等多种活性物质,具有抗氧化、抗炎症、抑制微生物活性、提高消化酶活性和促进骨骼生长等多种功效,能够改善动物健康,提高动物生产性能。本文综述了槟榔中的主要活性物质及其生理功能,以期为槟榔在动物生产中的广泛应用提供参考。

关键词： 槟榔; 槟榔提取物; 活性物质; 生理功能; 抗氧化; 抗炎症

本文引用格式

蒋中二 , 李志青 , 候鹏霞 , 肖定福 . 槟榔中的主要活性物质及其生理功能研究进展[J]. 动物营养学报, 2025 , 37(3) : 1527 -1538 . DOI: 10.12418/CJAN2025.131

Abstract

Areca nut is a traditional Chinese medicine, containing a variety of active substances such as areca nut and betel nut polyphenols, and it has many functions including antioxidant, anti-inflammatory, inhibition of microbial activity, improvement of digestive enzyme activity and promotion of bone growth, etc., which can improve animal health and improve animal performance. This review summarizes the main active substances in areca nut and their physiological functions, in order to provide a reference for the wide application of areca nut in animal production.

Key words： areca nut; areca nut extract; active substances; physiological functions; antioxidant; anti-inflammatory

槟榔树(Areca catechu L.)是一种常绿乔木,属于棕榈科槟榔属,主要分布在亚洲、非洲和欧洲的热带地区。槟榔(areca nut,AN)是槟榔树的成熟果实,其主要结构由果皮和果仁组成[1],被广泛用作许多传统中药制剂的重要成分[2]。槟榔在2003年被国际癌症研究机构(International Agency for Research on Cancer,IARC)列为一级致癌物,槟榔致癌原因是其中含有的大量纤维,在长期咀嚼过程中对口腔黏膜造成持续性的损伤,在此状态下,槟榔中的槟榔碱通过激活免疫细胞产生的大量细胞因子和生长因子导致胶原蛋白代谢异常,加重口腔黏膜纤维化等[3⇓-5],而在创口短期使用没有此类情况出现[6],且槟榔及相关制品不在《医疗用毒性药品管理办法》(国务院令第23号)收载的28种毒性药材之中。槟榔提取物(areca nut extracts,ANEs)是将槟榔通过浸提、抽提、超声提取、微波提取和超临界二氧化碳(CO2)等方法得到的提取物,随着研究深入,槟榔碱[7]、多酚[8]、单宁[9]、氨基酸[10]、多糖[11]、脂肪酸和皂苷等生物活性成分从槟榔中分离出[12]。槟榔中已有791种代谢产物通过超高效液相色谱-三重四极杆串联质谱法(ultra-performance liquid chromatography triple-quadrupole tandem mass spectrometry,UPLC-MS/MS)被鉴定出[13]。据调查,每年每棵槟榔树的槟榔产量为2.5~8 kg[14],槟榔中生物碱含量为0.38~1.3 mg/kg DM,总酚含量为108~216 mg GAE/g DM[15]。
由于槟榔具有祛痰、止咳、消食和醒酒等功效,有很高的药用价值,在中国、南亚和东南亚的国家中被广泛使用[16],并入编2020年的《中华人民共和国药典》[17]。近年来,随着研究不断细化,槟榔中所含的各种活性物质被证明具有抗氧化、抗菌、抗骨质疏松、抗抑郁、抗癌、消肿、止痛和降脂等作用[18],已有研究利用其抗菌活性在牙膏中发挥抗龋齿作用,且其效果优于市面上同类型含有植物抑菌成分的牙膏[19],使用槟榔提取物给纺织物染色,能提高其牢固、紫外防护、除臭和抑菌等多方面性能[20]。槟榔及其提取物在不同行业展现出了巨大的应用潜力。在全球经济下行的趋势下,提高畜禽生产力对畜牧业持续健康地发展至关重要[21],而槟榔作为一种天然植物,在饲料安全方面对比化工合成的添加剂更具有可靠性[22]。本文综述了槟榔中所含的主要活性物质及其在动物生理上的作用,以期为槟榔在动物生产中的应用提供参考。

1 槟榔中的主要活性物质

槟榔中含有多种活性物质,到目前为止已从槟榔中分离和鉴定出超过59种活性物质,主要为多酚、类黄酮、生物碱、脂肪酸、单宁和萜类化合物等,具体如表1所示。图1展示了槟榔中几种主要的生物碱的化学结构[9]。
表1 槟榔中分离鉴定出的主要活性物质

Table 1 Main active substances isolated and identified from areca nut

分类
Classifies		 活性物质
Active substances		 参考文献
References
多酚Polyphenols 没食子酸、原儿茶酸、对羟基苯甲酸、咖啡酸、
丁香酸、对香豆酸、阿魏酸、芥子酸		 [15,23]
类黄酮Flavonoids 异鼠李素、金黄素、木犀草素、槲皮素、大黄酚、4',5'-二羟基-3',5',7'-
三甲氧基黄酮、5,7,4'-三羟基-3',5'-二甲氧基黄烷酮、甘草素		 [23-24]
单宁Tannins 儿茶酚、表儿茶素、表儿茶素没食子酸酯、槲皮素-3-
半乳糖苷、槲皮素-3-葡糖苷酸、山奈酚-3-葡萄糖苷、
槲皮素-3-鼠李糖苷、白藜芦醇、槲皮素、山奈酚		 [15,24]
生物碱Alkaloids 槟榔碱、槟榔次碱、去甲槟榔碱、去甲槟榔次碱、
槟榔啶、N-甲基-1,2,5,6-四氢吡啶-3-羧酸乙酯、烟酸甲酯、
烟酸乙酯、N-甲基哌啶-3-羧酸甲酯、N-甲基哌啶-3-
羧酸乙酯、尼古丁、异古瓦辛、高乳糖碱		 [7,15,23⇓-25]
脂肪酸Fatty acids 月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、油酸、癸酸、十二烯酸、十六碳烯酸 [24,26]
其他Others 对羟基苯甲酸、环氧针叶醇、4-[3'-(羟甲基)
环氧乙烷-2'-甲基]-2,6-二甲氧基苯酚、环亮氨酸、甘露糖、
半乳糖、木糖、阿拉伯糖、钙、磷、铁、维生素C、维生素B6		 [11,24,27]
图1 槟榔中几种主要的生物碱的化学结构

Arecoline:槟榔碱;Arecaidine:槟榔次碱;Guvacoline:去甲基槟榔碱;Guvacine:去甲基槟榔次碱;Arecolidine:槟榔碇。

Fig.1 Chemical structure of several main alkaloids in areca nut

2 槟榔中活性物质的主要作用

2.1 保护消化道健康

槟榔碱作为毒蕈碱受体(muscarinic acetylcholine receptor,mAChR)激活剂,能通过结合肠道平滑肌组织细胞中毒蕈碱受体M3,打开细胞膜上钙离子(Ca2+)通道使细胞外Ca2+内流,刺激消化道平滑肌内肌动蛋白收缩,促进肠道蠕动[28-29]。给小鼠、大鼠和犬类哺乳动物口服槟榔碱后,其通过肠壁细胞膜上质子偶联氨基酸转运蛋白1(H+-coupled amino acid transporter 1,PAT1)转运至细胞内[30],在血清中以槟榔碱、槟榔次碱、槟榔碱N-氧化物、槟榔碱基甘氨酸和槟榔碱巯基酸等9种代谢产物的形式存在,且能够通过泌尿系统排出体外[31⇓⇓-34]。
草鱼饲料中添加0.5~2.0 mg/kg槟榔碱可通过刺激毒蕈碱受体M3,增强胰蛋白酶、糜蛋白酶、脂肪酶和淀粉酶活性,提高神经肽P物质含量,通过脑-肠轴增加肠道中刷状缘酶的活性和胃肠道物质的转运速率,进而提高草鱼的消化能力,通过抑制Ras同源基因家族蛋白A(Ras homolog gene family member A,RhoA)/Rho相关卷曲螺旋蛋白激酶(Rho-associated coiled-coil forming protein kinase,ROCK)信号通路提高鱼体内紧密连接(tight junctions,TJs)和黏附连接(adherent junctions,AJs)相关蛋白的水平,保护肠道的结构完整性[35]。在文昌肉鸡饲粮中添加100~300 mg/kg槟榔提取物,可减少球虫感染引起的肠道黏膜损伤,降低盲肠病变评分[36]。在洛哌丁胺诱导小鼠便秘造成的肠道损伤模型中,口服30 mg/kg槟榔碱可通过减少生长抑制素(vasoactive intestinal peptide,VIP)和血管活性肽(somatostatin,SS)水平促进肠道蠕动,同时还改变了小鼠肠道菌群的组成和短链脂肪酸(short chain fatty acids,SCFAs)的组成和水平,下调了肿瘤坏死因子受体超家族成员17(tumor necrosis factor receptor superfamily member 17,Tnfrsf17)、溶质载体家族26成员3(solute carrier family 26 member 3,Slc26a3)和前蛋白转化酶枯草杆菌蛋白酶/kexin 4型(proprotein convertase subtilisin/kexin type 4,Pcsk4)等肠道疾病相关基因的表达,缓解了肠道的损伤程度[37]。图2总结了槟榔碱在肠道中吸收方式和在消化道中的主要作用。
图2 槟榔碱在肠道中的吸收方式和在消化道中的主要作用

Gut lumen:肠腔;protease:蛋白酶;lipase:脂肪酶;amylase:淀粉酶;AChR:乙酰胆碱受体 acetylcholine receptor;arecoline:槟榔碱;PAT1:质子偶联氨基酸转运蛋白1 H+-coupled amino acid transporter 1;TJs:紧密连接 tight junctions;ZO-1:闭锁小带蛋白-1 zonula occluden-1;occludin:闭合蛋白;claudin:密封蛋白;AJs:黏附连接 adherent junctions;cadherin:钙黏蛋白;catenin:连环蛋白;nectin:连接蛋白;afadin:胞黏蛋白;RhoA:Ras同源基因家族蛋白A Ras homolog gene family member A;ROCK:Rho相关卷曲螺旋蛋白激酶 Rho-associated coiled-coil forming protein kinase;Increase enzyme activity 提升酶活性;Promote intestinal peristalsis:促进肠道蠕动;Protective intestinal structure:保护肠道结构。

Fig.2 Intestinal absorption pattern of arecoline and its main roles in digestive tract[28⇓-30,35]

综上所述,槟榔中的活性物质在消化道内具有良好的吸收效果,能够通过刺激毒蕈碱受体M3促进消化道蠕动和提升消化酶活性,在应对寄生虫感染和便秘发生时能提高紧密连接和黏附连接相关蛋白的水平,有效保护肠道上皮完整,减少肠道损伤,达到提高饲料利用效率和生产性能的目的。

2.2 抑制微生物和寄生虫活性

单宁酸和三萜类化合物可通过螯合多种离子,抑制生物膜上葡萄糖基转移酶的活性,降低菌膜表面的疏水性,破坏菌膜的完整性,以抑制细菌的生长[38]。槟榔果皮中提取的化合物,可通过抑制真菌孢子的萌发、降低菌丝和胚管发育的速度抑制真菌的生长[39]。有研究发现,70~90 ℃下加氢蒸馏顶空固相微萃取的槟榔提取物对变形链球菌的最低抑菌浓度(minimum inhibitory concentration,MIC)为0.5 mg/mL[40]。使用己烷、乙酸乙酯和甲醇3种有机溶剂,从槟榔果皮提取铁烯醇、香豆甾醇和β-谷甾醇的混合物,浓度为100和200 mg/L时,在控制芒果采后炭疽病方面的效果显著优于杀菌剂苯甲酰[39]。槟榔提取物除了对金黄色葡萄球菌和白色念珠菌等普通致病菌有抑菌效果外,在对万古霉素和多种药物具有耐药性的菌种上同样有抑制作用[41]。表2总结了不同方式和溶剂提取的槟榔提取物能有效抑制的菌种,采取水醇混合提取或顶空固相微萃取的方式对活性物质中萜烯类等脂溶性抑菌成分具有更好的提取效率[26],可能会提高槟榔提取物的抑菌效果。
表2 槟榔提取物抑制的菌种

Table 2 Strains inhibited by areca nut extract

提取方法
Extraction methods		 抑制菌种
Inhibited bacteria		 参考文献
References
顶空固相微萃取
Headspace solid-phase microextraction		 枯草芽孢杆菌、粪肠球菌、大肠杆菌、铜绿假单胞菌、
金黄色葡萄球菌、无乳链球菌、犬链球菌、
酿脓链球菌、白色念珠菌		 [26]
顶空固相微萃取
Headspace solid-phase microextraction		 变形链球菌 [40]
顶空固相微萃取
Headspace solid-phase microextraction		 大肠杆菌、金黄色葡萄球菌、白色念珠菌 [46]
乙醇提取Ethanol extraction 变形链球菌 [19]
乙醇提取Ethanol extraction 金黄色葡萄球菌、大肠杆菌、结核分枝杆菌 [47]
水提取Water extraction 粪肠球菌属、万古霉素耐药肠球菌、铜绿假单胞菌、多重耐药
铜绿假单胞菌、鲍曼不动杆菌、多重耐药鲍曼不动杆菌		 [41]
水提取Water extraction 白色念珠菌、黄曲霉菌 [48]
甲醇及水提取
Methanol and water extraction		 金黄色葡萄球菌、变形链球菌、土垢分枝杆菌 [42]
乙醇及水提取
Ethanol and water extraction		 大肠杆菌、金黄色葡萄球菌、沙门氏菌、产气肠杆菌 [49]
槟榔提取物的抗寄生虫活性与所含的生物碱有关,槟榔碱作为毒蕈碱受体激活剂,可通过麻痹寄生虫神经系统,导致其失去活动能力,发挥抗寄生虫的作用[2]。在体外试验中,采用丁醇提取的槟榔提取物对恶性疟原虫的活性有显著的抑制作用,半数最大抑制浓度(half maximal inhibitory concentration,IC50)为18 μg/mL[42];乙醇提取的槟榔提取物能降低肝片吸虫和巨氏片吸虫的活性,由这2种寄生虫引起的片形吸虫病会导致牛的肝脏损伤,使产奶量和产肉量降低[43]。在体内试验中,灌服150 mg/(kg·d)槟榔提取物使伯氏疟原虫感染4 d的小鼠存活率提高了39.1%[44];在对文昌鸡的抗球虫试验中,添加100~300 mg/kg槟榔提取物能够降低球虫感染导致的肠道黏膜损伤,降低血清白细胞介素-2(interleukin-2,IL-2)含量,同时提高采食量和生长性能[36]。在蛋鸡的试验中,饲粮中添加0.5%~1.0%的槟榔仁粉可有效清除消化道内包括蛔虫在内的多种寄生虫,减少寄生虫引起的炎症反应[45]。
综上所述,槟榔中的活性物质具有抗菌和抑制寄生虫活性的功能,且对耐药性致病菌也具有抑制作用,能有效清除消化道内寄生虫和缓解寄生虫所引起炎症反应,在动物生产中可作为一种杀菌驱虫的添加剂或者药物使用。

2.3 抗氧化活性

自由基是分子内不成对的电子,进入细胞内造成氧化损伤导致疾病,体内主要存在于羟基、过氧化物和超氧化物中[50],而具有抗氧化活性的物质可保护细胞免受侵害[51]。槟榔中含有大量的还原糖、多酚和黄酮类活性物质,有抗氧化和自由基清除功能[52]。表3展示了槟榔中不同成分的抗氧化能力。
表3 槟榔中不同成分的抗氧化能力

Table 3 Antioxidant ability of different components in areca nut

成分
Ingredients		 添加量
Additive amounts		 试验对象
Test objects		 结果
Results		 参考文献
References
槟榔多糖(水提)
Areca polysaccharide
(water extraction)		 0.2~2 mg/mL DPPH、
羟基自由基		 DPPH、羟基自由清除率随
添加量增加而上升,2 mg/mL时清除
率分别为23.61%和30.14%		 [11]
槟榔提取物(水提)
Areca nut extract
(water extract)		 300 mg/kg BW 卵巢切除导致
骨质疏松小鼠		 降低血清H2O2和MDA含量,提高GSH
含量和CAT活性,通过抑制ROS释放、降
低RANKL/OPG比值和骨吸收治疗骨质疏松		 [53]
槟榔提取物(水/乙醇/氯仿等)
Areca extract (water/ethanol/
chloroform, etc.)		 — H2O2、
DPPH、NO		 H2O2-IC50=83.14 μg/mL、DPPH-IC50=
181.42 μg/mL、NO-IC50=152.13 μg/mL		 [46,52,54]
槟榔提取物(水提)
Areca nut extract
(water extract)		 500~2 000 mg/kg BW 肝损伤
大鼠模型		 显著降低了大鼠血清中ALT、
AST活性和MDA含量		 [55]
槟榔提取物(水提)
Areca nut extract
(water extract)		 50 μg/mL DPPH、FRAP、
HGF细胞、
亚油酸		 DPPH-IC50=6.4 μg/mL、FRAP-IC50=
(5 717.8±537.6) μmol Fe2+/mg,细胞
保护活性113.5%,脂质过氧化抑制率83%		 [15,56]
槟榔提取物(水提)
Areca nut extract
(water extract)		 6.25~12.5 μg/mL PMN细胞 抑制细胞松弛素B和fMLP
诱导的ROS和MPO释放		 [57]
槟榔多酚(50%乙醇提取)
Areca polyphenol
(50% ethanol extraction)		 160~320 μg/mL RAW264.7细胞 降低LPS刺激的RAW264.7细胞中
ROS水平,增强Nrf2和HO-1的表达		 [51]
槟榔多酚(80%丙酮提取)
Areca polyphenol
(80% acetone extraction)		 0.1~1 μg/mL SAS细胞 降低诱导剂TPA诱导的COX-2
表达和ERK磷酸化		 [58]
槟榔碱
Arecoline		 0.5~0.25 mg/kg 草鱼 激活Keap1a/Nrf2信号通路,降低
肠道内MDA、PC和ROS生成量		 [35]
槟榔仁粉
Areca nut powder		 0.25%~1% 蛋鸡 降低血清转氨酶活性 [45]

DPPH:1,1-二苯基-2-三硝基苯肼 1,1-diphenyl-2-picylhydrazyl;H2O2:过氧化氢 hydrogen peroxide;MDA:丙二醛 malondialdehyde;GSH:谷胱甘肽 glutathione;CAT:过氧化氢酶 catalase;ROS:活性氧 reactive oxygen species;NO:一氧化氮 nitric oxide;IC50:半数最大抑制浓度 half maximal inhibitory concentration;ALT:谷丙转氨酶 alanine aminotransferase;AST:谷草转氨酶 aspartate aminotransferase;FRAP:铁离子还原/抗氧化能力 ferric ion reducing antioxidant power;fMLP:N-甲酰-蛋氨酸-亮氨酸-苯丙氨酸 N-formyl-methionylleucyl-phenylalanine;MPO:髓过氧化物酶 myeloperoxidase;LPS:脂多糖 lipopolysaccharide;Nrf2:核红细胞2相关因子2 nuclear erythroid 2-related factor 2;HO-1:血红素氧合酶-1 hemeoxygenase-1;TPA:12-O-十四烷酰佛波醇-13-乙酸酯 12-O-tetradecanoylphorbol-13-acetate;COX-2:环氧合酶-2 cyclooxygenase-2;ERK:细胞外调节蛋白激酶 extracellular regulated protein kinases;Keap1a:Kelch样环氧氯丙烷相关蛋白1a Kelch-like ECH-associated protein 1a;PC:蛋白质羰基 protein carbonyl。

有研究对比了70种药用植物乙醇提取物对1,1-二苯基-2-三硝基苯肼(1,1-diphenyl-2-picylhydrazyl,DPPH)自由基清除活性,IC50低于50 μg/mL的有11种,其中槟榔提取物的清除活性最高,最低清除浓度为4.5 μg/mL[59]。在对槟榔中多糖的抗氧化研究中,分离出一种新型多糖PAP1b,主要由甘露糖、半乳糖、木糖和阿拉伯糖组成,体外试验表明,这种多糖能够清除DPPH和羟基自由基,具有抗氧化活性[11]。在槟榔中多酚的抗氧化研究中,0.1或1 μg/mL槟榔多酚可通过降低SAS细胞内激活蛋白-1(activating protein-1,AP-1)和核因子-κB(nuclear factor kappa-B,NF-κB)基因表达,降低炎症诱导剂12-O-十四烷酰佛波醇-13-乙酸酯(12-O-tetradecanoylphorbol-13-acetate,TPA)诱导的环氧合酶-2(cyclooxygenase-2,COX-2)表达和细胞外调节蛋白激酶(extracellular regulated protein kinases,ERK)磷酸化,抑制相关因子的表达[58],而高剂量槟榔多酚却有相反的表现,会通过丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)和NF-κB途径,诱导COX-2表达[60]。在对槟榔中生物碱的抗氧化研究中,在成年草鱼饲粮中添加1 mg/kg槟榔碱,可通过激活Kelch样环氧氯丙烷相关蛋白1a(Kelch-like ECH-associated protein 1a,Keap1a)和核红细胞2相关因子2(nuclear erythroid 2-related factor 2,Nrf2)信号通路,提高肠道中GPx4b、GPx1b和过氧化氢酶(catalase,CAT)的mRNA丰度,显著降低肠道内丙二醛(malondialdehyde,MDA)、蛋白质羰基(protein carbonyl,PC)和活性氧(reactive oxygen species,ROS)的生成量,且在0.5~1.5 mg/kg浓度范围内肠道内超氧化物歧化酶(superoxide dismutase,SOD)、CAT活性和谷胱甘肽(glutathione,GSH)含量随饲粮中槟榔碱添加量的增加而上升[35],而高剂量的槟榔碱会导致氧化和抗氧化系统的失衡,在体内主要表现为ROS水平增加,GSH被耗尽,对组织造成氧化损伤[61]。
综上所述,槟榔中的多糖、多酚和槟榔碱等以及槟榔提取物具有清除自由基的功能,可通过调控AP-1/NF-κB信号通路降低环氧合酶活性,且槟榔碱可通过激活Keap1a/Nrf2信号通路,提高抗氧化酶的活性,降低ROS和MDA水平。但不管是槟榔多酚还是槟榔碱,在体内随添加剂量的上升均出现加重氧化损伤现象,其不同剂量下影响的机制和适宜的添加量还有待进一步研究。

2.4 抗炎症

槟榔中的活性物质可通过激活和抑制多种信号通路,调节相关炎症因子的转录和活性,改善炎症反应造成的损伤。槟榔碱同时也是烟碱乙酰胆碱受体(nicotinic acetylcholine receptor,nAChR)的激动剂,在非洲爪蛙卵母细胞模型中,浓度为30~100 μmol/L的槟榔碱可大量激活α7 nAChR受体[62],而α7 nAChR受体激活剂能通过调节下游通路抗炎症因子的表达在体内发挥抗炎症作用[63]。小鼠口服300 mg/kg槟榔提取物可通过抑制肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)的表达和丝裂原活化蛋白激酶ERK1/2的激活,抑制肥大细胞脱颗粒,减少炎症因子的产生[64]。在不同细胞、器官和动物的炎症模型中,槟榔中活性物质均表现出抗炎作用,其中在脂多糖(lipopolysaccharide,LPS)诱导RAW264.7细胞炎症模型,槟榔碱降低了缺氧诱导因子-1α(hypoxia inducible factor-1α,HIF-1α)的表达,减少了LPS造成的氧化损伤,小鼠注射LPS会导致炎症因子白细胞介素-1β(IL-1β)和TNF-α水平升高,注射5~15 mg/(kg·d)槟榔碱可降低小鼠IL-1β的转录和分泌,增加脾脏中的CD4+和CD8+ T淋巴细胞的比例和脾脏的重量,血清中免疫球蛋白A(IgA)、免疫球蛋白M(IgM)和免疫球蛋白G(IgG)水平也得到提高[65]。在蔚蓝素诱导的胰腺炎小鼠模型试验中,腹膜内注射50~200 mg/kg槟榔提取物可抑制胰腺萎缩和胶原蛋白沉积,通过抑制Smad2蛋白磷酸化来抑制转化生长因子-β(transforming growth factor-β,TGF-β)信号传导,减少胰腺组织和胰腺星状细胞(pancreatic stellate cells,PSCs)外基质中α-平滑肌肌动蛋白(alpha-smooth muscle actin,α-SMA)、I型胶原和纤连蛋白1(fibronectin 1,FN1),缓解胰腺炎导致的胰腺纤维化[66]。在注射甘油三硝酸酯导致大鼠脑膜血浆蛋白外渗的头痛模型中,口服250~500 mg/kg槟榔提取物可通过抑制脑膜巨噬细胞一氧化氮合酶(iNOS)的表达,减少血浆蛋白外渗,抑制炎症反应[67]。在大鼠前肢注射卡拉胶(50 μL,1%)、前列腺素E2(100 μL,0.01 μg/mL)、花生四烯酸(100 μL,0.5%)、组胺(100 μL,1 mg/mL)和5-羟色胺(100 μL,1 mg/mL)诱导炎症导致的组织水肿模型中,口服10~50 mg/kg槟榔提取物可抑制水肿的程度[68]。
综上所述,槟榔中的活性物质具有抗炎活性,可通过MAPK、TNF-α和nAChR受体等多种信号通路发挥抗炎作用,其中的生物碱和多酚可能是槟榔中发挥抗炎作用的主要成分,通过神经和体液调节炎症反应,但在不同器官中发挥的抗炎作用和适宜的剂量仍有待考究。

2.5 增强骨质

生物碱具有通过NF-κB配体受体激活因子(receptor activator of nuclear factor κB ligand,RANKL)依赖性通路[包括TRAF6、NF-κB、MAPK和活化T细胞核因子c1(nuclear factor of activated T-cells c1,NFATc1)信号通路]减少破骨细胞生成,促进间充质干细胞分化、成骨细胞增殖和刺激成骨细胞自噬的功能[69]。槟榔碱还能增加细胞膜上Na+-Ca2+转运载体的数量,提高细胞内Ca2+的浓度[70]。槟榔中不仅含有生物碱,且其中含有的半乳甘露聚糖和黄酮类活性物质有助于骨骼健康,是一种天然绿色且无副作用的潜在防止骨质疏松和骨关节炎的药物[71]。在LPS诱导的小鼠骨质流失模型中,通过注射10 mg/kg BW槟榔碱可增加股骨小梁数量(Tb.N)和小梁厚度(Tb.Th),减少小梁间距(Tb.Sp)[53]。有研究表明,50~100 μmol/L槟榔碱减缓了抗酒石酸酸性磷酸酶(tartrate-resistant acid phosphatase,TRAP)阳性多核破骨细胞的生长,通过减少RANKL巨噬细胞集落刺激因子(macrophage colony stimulating factor,M-CSF)的表达,减少骨髓巨噬细胞(bone marrow-derived macrophages,BMM)中吸收坑的形成,给小鼠注射槟榔碱恢复了股骨流失,增加了MC3T3-E1成骨细胞中碱性磷酸酶(alkaline phosphatase,ALP)活性、骨矿化以及ALP、Runt-相关转录因子-2(Runt-related transcription factor 2,Runx2)等成骨细胞分化相关基因表达[72]。除了槟榔碱,槟榔多酚具有同样的功效,在卵巢切除大鼠骨质疏松模型中,槟榔多酚通过骨形态发生蛋白2(bone morphogenetic protein 2,BMP2)控制成骨细胞的增殖来促进骨骼形成,调节与骨形成有关的肠道源性血清素的表达来改善骨质疏松症[73]。除此之外,槟榔多酚还可通过维持小肠中提供防卫功能的潘氏细胞数量和溶菌酶活性,减少大鼠肠道微生物组中对骨代谢有负面影响的菌群另枝菌属(Alistipes)的丰度,增强骨质[74]。
综上所述,槟榔中的槟榔碱能增加细胞膜上Na+-Ca2+转运载体的数量,提高细胞内Ca2+的浓度,通过干扰NFATc1、MAPK和NF-κB激活通路,抑制破骨细胞分化相关基因的表达和易位,增强成骨细胞活性。槟榔中的槟榔多酚除可增强成骨细胞活性外,还可通过调节消化道微生物组增强肠道免疫力,减少对骨代谢有负面作用的菌群的丰度来增强骨质。

2.6 其他

2.6.1 影响繁殖性能

给雄性大鼠口服150 mg/kg槟榔提取物可减少射精间隔,增加性活动频率,且对其他方面无任何负面影响[75]。但是给小鼠注射10 mg/kg槟榔碱时会降低其精子数量和活力,维生素C和维生素E处理有缓解作用[76],这可能与高浓度槟榔碱会导致氧化与抗氧化失衡有关[61]。

2.6.2 镇痛

在福尔马林诱导小鼠疼痛的舔舐行为中,口服10~100 mg/kg槟榔提取物在外周释放缓激肽和前列腺素等各种炎症介质的痛感发生第2阶段,对疼痛的抑制作用与阿司匹林的作用相当,在乙酸诱导的小鼠胃疼痛扭动模型中,口服10~100 mg/kg槟榔提取物可显著抑制小鼠的扭动行为,且对扭动行为呈剂量依赖性[68]。50~400 mg/kg槟榔提取物对乙酸诱导的小鼠胃疼痛扭动抑制率达88.5%,即便在低浓度50 mg/kg下也与400 mg/kg阿司匹林的抑制程度相当[77]。

2.6.3 抗抑郁

在对槟榔代谢物的抗抑郁网络药理学预测中,共有L-苯丙氨酸、原儿茶酸、苯佐卡因、环氧苷和3,4-二羟基苯甲醛等93中代谢物可靶向141个抑郁症相关基因[23]。10 mg/L的槟榔碱急性治疗可减少斑马鱼的抑郁行为,提高脑去甲肾上腺素和血清素水平,降低血清素周转率,提高斑马鱼的社交频率,1 mg/L的慢性治疗能提高小胶质细胞特异性生物标志基因egr2和ym1的脑表达,提高抗抑郁的潜力[78]。

2.6.4 促进创面愈合

在印度,槟榔是用于皮肤溃疡的传统药物,有试验表明口服槟榔提取物可加速大鼠烧伤创面愈合,并缓解地塞米松对创面收缩率和上皮形成期的抑制作用[79]。外用也具有同样效果,用含5%~10%槟榔提取物的软膏治疗有烧伤创口的大鼠,其伤口收缩率显著高于用磺胺嘧啶银软膏处理的对照组[80]。有研究认为这可能与其中含有的类黄酮、单宁、皂苷和生物碱等活性物质的抗菌活性有关[81]。

3 小结与展望

槟榔中的活性物质具有抗氧化、抗炎症以及抑菌等功能,有些还具有增强骨质的作用,能够有效减少养殖过程中的动物健康问题。槟榔碱是一种毒蕈碱受体M3激动剂,能通过刺激消化道蠕动和提高消化酶活性提高饲料利用效率,提高动物生产力。但是,由于对槟榔诱导口腔癌的问题存在固有印象,槟榔相关产品的开发存在一定阻力。此外,在动物生产的应用研究中,仅在水产动物与家禽中有研究,在其他动物中的应用研究仍处于空白状态,且其在不同动物以及生长阶段的使用效果受到使用剂量和使用形式等多种因素的影响,而且在高剂量时槟榔提取物在动物体内表现出负面作用。因此,进一步研究槟榔中活性物质在畜禽实际生产中的适宜使用量和主要作用机制,制定槟榔提取物生产流程标准并对有效成分进行定量是槟榔活性物质开发使用的研究重点。

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