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        可可茶及其優(yōu)勢(shì)化學(xué)成分的健康功效研究進(jìn)展

        2021-10-16 05:57:22吳文亮童彤胡瑤周浩銀霞張曙光
        茶葉科學(xué) 2021年5期
        關(guān)鍵詞:研究

        吳文亮,童彤,胡瑤,周浩,銀霞,張曙光*

        可可茶及其優(yōu)勢(shì)化學(xué)成分的健康功效研究進(jìn)展

        吳文亮1,童彤1,胡瑤2,周浩1,銀霞1,張曙光1*

        1. 湖南省農(nóng)業(yè)科學(xué)院茶葉研究所,湖南 長(zhǎng)沙 410125;2. 湖南省農(nóng)業(yè)科學(xué)院核農(nóng)學(xué)與航天育種研究所,湖南 長(zhǎng)沙 410125

        可可茶為我國(guó)特異的茶樹資源,可可茶及其優(yōu)勢(shì)化學(xué)成分可可堿(TB)與沒食子兒茶素沒食子酸酯(GCG)具有多種健康功效。綜述了可可茶、TB和GCG對(duì)心血管疾病、癌癥、肥胖癥、糖尿病、神經(jīng)退行性疾病、牙科疾病、呼吸疾病和腎病等的干預(yù)作用,并簡(jiǎn)要分析了其作用機(jī)制,旨在為可可茶相關(guān)功能產(chǎn)品研發(fā)提供理論參考。

        可可茶;可可堿;沒食子兒茶素沒食子酸酯;健康功效

        可可茶(Chang)原名為南昆山毛葉茶,原始分布區(qū)在廣東的龍門、從化、增城三縣市交匯處的南昆山??煽刹璨铇滟Y源由植物分類學(xué)家張宏達(dá)教授發(fā)現(xiàn),并在1981年根據(jù)曾沛先生采集提供的標(biāo)本,發(fā)表了這個(gè)茶組植物新種,認(rèn)為可可茶在系統(tǒng)分類上屬于山茶科山茶屬茶亞屬茶組茶系,它和傳統(tǒng)的栽培茶樹有密切的親緣關(guān)系,均同屬于茶系的種[1-2]。自20世紀(jì)80年代末,張宏達(dá)、葉創(chuàng)興等研究團(tuán)隊(duì)對(duì)可可茶進(jìn)行了跟蹤研究,發(fā)現(xiàn)可可茶是我國(guó)一種特異的茶樹資源,其生物堿組分由可可堿(Theobromine,TB)占主導(dǎo),含量最高可達(dá)6.8%,約為傳統(tǒng)茶樹資源的18倍;兒茶素組分由沒食子兒茶素沒食子酸酯(Gallocatechin gallate,GCG)占主導(dǎo),含量最高可達(dá)9.88%,約為傳統(tǒng)茶樹資源的7倍[3]。可可茶具有一些健康功效,在整理前人研究成果的基礎(chǔ)上,本文綜述了可可茶及其優(yōu)勢(shì)化學(xué)成分TB與GCG健康功效的研究進(jìn)展及主要作用機(jī)制,為可可茶資源的創(chuàng)新利用或相關(guān)功能產(chǎn)品的研制提供一定的參考。

        1 可可茶的健康功效

        長(zhǎng)期以來,可可茶原產(chǎn)地百姓認(rèn)為其具有消炎、助消化、預(yù)防感冒等作用,目前大量研究證實(shí)了可可茶在抗癌、降脂減肥、抗氧化和消炎等方面的功效[4-17](表1)。

        1.1 可可茶的抗癌作用

        可可茶提取物具有抗癌作用。Peng等[4]通過體外試驗(yàn)發(fā)現(xiàn),可可茶能下調(diào)人前列腺癌細(xì)胞(PC-3)的腫瘤抑制基因(p21和p27)表達(dá),上調(diào)細(xì)胞凋亡途徑的Bax/Bcl-2基因比率,并抑制NF-κB活化,將癌細(xì)胞周期阻滯于G2/M期引起凋亡,從而顯著地抑制癌細(xì)胞生長(zhǎng);體內(nèi)試驗(yàn)發(fā)現(xiàn),可可茶處理組的裸鼠PC-3腫瘤的重量和體積均顯著低于對(duì)照組,表明可可茶在抗前列腺癌方面具有一定作用。Yang等[5]研究發(fā)現(xiàn),可可綠茶能下調(diào)人肝癌細(xì)胞(HepG2)細(xì)胞的腫瘤抑制基因(p53、p21和p27)表達(dá)和上調(diào)細(xì)胞凋亡途徑的Bax/Bcl-2基因比率,促使癌細(xì)胞凋亡和抑制癌細(xì)胞生長(zhǎng);體內(nèi)HepG2移植裸鼠模型試驗(yàn)發(fā)現(xiàn),可可綠茶處理組的裸鼠腫瘤的重量和體積以劑量依賴性方式顯著降低,表明可可茶具有一定的抗肝癌作用。Gao等[6]研究可可綠茶水提物對(duì)人結(jié)腸癌細(xì)胞(HCT116)和HCT116移植裸鼠的影響,發(fā)現(xiàn)與云南大葉種綠茶提取物相比,可可茶表現(xiàn)出更強(qiáng)的抗增殖和誘導(dǎo)細(xì)胞凋亡作用,且能顯著抑制HCT116腫瘤小鼠的腫瘤生長(zhǎng),其抗結(jié)腸癌的機(jī)制可能是上調(diào)細(xì)胞凋亡途徑的Bax/Bcl-2基因比率和下調(diào)PI3K/Akt信號(hào)通路,引起線粒體功能紊亂致使細(xì)胞凋亡。此外,可可茶對(duì)其他腫瘤也有抑制作用[7],如小鼠艾氏腹水癌細(xì)胞(EAC)、人宮頸癌細(xì)胞(HeLa)、人鼻咽癌細(xì)胞(CNE2)和艾氏腹水癌實(shí)體瘤(ESC)。

        表1 可可茶的健康功效

        注:“↑”表示上調(diào),“↓”表示下調(diào),“N/A”表示未明確。下同

        Note: “↑” and “↓” indicate up-regulation and down-regulation, respectively. “N/A” means that there is not available. The same below

        1.2 可可茶的降脂減肥作用

        可可茶具有降脂減肥效果。Yang等[8]以C57BL/6雄鼠為研究對(duì)象,將不同劑量的可可綠茶提取物添加到高脂食物中,研究可可茶對(duì)高脂飲食引起的代謝綜合征影響。結(jié)果表明,可可茶對(duì)小鼠的肥胖、肝脂肪變性和高脂血癥等均有改善效果,與高脂飲食組相比,高劑量可可茶能顯著降低過氧化物酶體增殖物激活受體(Peroxisome proliferators-activated receptors,PPAR)和3-羥基-3-甲基戊二單酰輔酶A還原酶(3-Hydroxy-3-methyl glutaryl coenzyme A reductase,HMGR)的mRNA水平,同時(shí)顯著升高低密度脂蛋白受體(Low-density lipoprotein receptor,LDLR)的mRNA水平。肥胖發(fā)生的典型特征是脂肪組織的增加,而脂肪組織增加是由脂肪細(xì)胞分化和增生引起的,因此,抑制脂肪細(xì)胞分化是控制肥胖的關(guān)鍵。Li等[9]采用3T3-L1前脂肪細(xì)胞探究可可茶對(duì)脂肪形成的抑制作用,結(jié)果發(fā)現(xiàn)可可茶可以顯著抑制細(xì)胞的脂滴積累和甘油三酯(Triglyceride,TG)產(chǎn)生,其機(jī)制是通過抑制p38分裂原激活的蛋白激酶(p38 mitogen-activated protein kinase,p38MAPK)、c-Jun氨基末端激酶(C-Jun N-terminal kinase,JNK)和細(xì)胞外信號(hào)調(diào)節(jié)激酶(Extracellular signal-regulated kinase1/2,ERK1/2)磷酸化來降低關(guān)鍵脂肪形成轉(zhuǎn)錄因子CAAT區(qū)/增強(qiáng)子結(jié)合蛋白(C/EBPα)、固醇調(diào)節(jié)元素結(jié)合蛋白1c(SREBP1c)和PPAR的mRNA水平,從而抑制脂肪形成。Kurihara等[10]認(rèn)為500?mg·kg-1的可可茶提取物可以明顯抑制小鼠高脂飲食后的血漿中TG水平,并通過體外試驗(yàn)證實(shí)可可茶提取物能抑制胰脂肪酶的活性。而Li等[11]研究發(fā)現(xiàn),400?mg·kg-1可可茶提取物在1個(gè)月內(nèi)能明顯降低高脂飲食誘導(dǎo)的肥胖小鼠的TC、TG和LDL-C水平,與陽(yáng)性對(duì)照組阿托伐他汀(Atorvastatin)治療效果相當(dāng)。

        1.3 可可茶的抗氧化和抗炎癥作用

        氧化應(yīng)激和炎癥都與一些慢性疾病有關(guān),如癌癥和肥胖癥等。因此,研究可可茶的抗氧化和抗炎特性有助于了解其抗肥胖和抗癌的作用。Li等[12]采用兩種抗氧化體系(FRAP法和DPPH法)評(píng)價(jià)可可茶與龍井茶、苦茶水提物的體外抗氧化活性,兩種測(cè)定方法均表明可可茶具有更強(qiáng)的抗氧化活性,抗氧化活性大小依次為可可茶>苦茶>龍井茶,與這3種茶的茶多酚含量多少規(guī)律一致,說明茶葉的抗氧化能力與茶多酚含量有一定的正相關(guān)。而彭力[13]采用3種抗氧化體系,即清除自由基能力(ABTS法和DPPH法)和抑制脂質(zhì)過氧化法(FTC法)評(píng)價(jià)可可茶與普通綠茶水提物的體外抗氧化活性,結(jié)果顯示抗氧化活性大小依次為可可茶>碧螺春>龍井茶。同樣,Peng等[14]也采用了ABTS法、DPPH法和FTC法測(cè)定了7種茶的抗氧化活性,3種測(cè)定方法結(jié)果均為可可白茶>可可綠茶>碧螺春>龍井>可可紅茶>英紅九號(hào)>祁門紅,HPLC檢測(cè)結(jié)果顯示,可可白茶的茶多酚含量最高。

        一氧化氮(Nitric oxide,NO)是炎癥反應(yīng)過程中的重要介質(zhì)和調(diào)節(jié)因子,能夠殺滅侵入機(jī)體的病原微生物,維持機(jī)體正常的免疫防御功能,但過量NO對(duì)宿主細(xì)胞也會(huì)產(chǎn)生損傷作用[15]。Lin等[16]通過脂多糖(LPS)誘導(dǎo)的巨噬細(xì)胞(RAW 264.7)建立炎癥細(xì)胞模型,比較可可茶與云南大葉茶的體外抗炎活性,發(fā)現(xiàn)可可茶比云南大葉茶更能抑制NO的產(chǎn)生,說明可可茶的抗炎活性強(qiáng)。研究已證實(shí)生物體內(nèi)NO生成的唯一途徑是由一氧化氮合酶(iNOS)催化-精氨酸合成,因此抑制iNOS的過量表達(dá)可以控制NO的水平[15]。Gao等[17]研究發(fā)現(xiàn),可可茶與云南大葉茶均能以劑量依賴性的方式抑制iNOS的表達(dá)水平,而且可可茶對(duì)iNOS的抑制效果比云南大葉茶更突出,說明可可茶能夠通過抑制iNOS表達(dá)來降低NO水平,從而起到抗炎的功效。

        2 可可茶優(yōu)勢(shì)化學(xué)成分的健康功效

        可可茶有著突出的健康功效,這不僅與其茶多酚含量高有關(guān),也與其獨(dú)特的生物堿組成模式(以TB為代表)和兒茶素組成模式(以GCG為代表)有很大關(guān)系,現(xiàn)有研究均表明TB和GCG具有一定的保健功效。

        2.1 TB的健康功效

        大量研究表明,TB對(duì)心血管疾病、癌癥、肥胖癥、神經(jīng)退行性疾病、牙科疾病、呼吸疾病和腎病等有積極干預(yù)與治療作用[18-60](表2)。

        2.1.1 TB的保護(hù)心臟作用

        TB是一種血管舒張劑,能夠緩解由心絞痛引起的疼痛,在1959年就用于治療充血性心力衰竭和心絞痛綜合征[18]。在大規(guī)模的流行病學(xué)研究中發(fā)現(xiàn)血液中高密度脂蛋白膽固醇(HDL-C)濃度與患冠心病風(fēng)險(xiǎn)成反比[19],HDL-C具有膽固醇逆向運(yùn)輸作用[20],膽固醇逆向運(yùn)輸可以將過量的膽固醇從動(dòng)脈血管壁細(xì)胞排出體外來阻止泡沫細(xì)胞的形成,從而抑制動(dòng)脈粥樣硬化的發(fā)生(動(dòng)脈粥樣硬化主要發(fā)生在心臟部位)。血液中HDL-C含量的減少會(huì)帶來心血管疾病風(fēng)險(xiǎn),而研究發(fā)現(xiàn)TB有增加HDL-C水平的作用,其機(jī)制是TB通過抑制磷酸二酯酶(Phosphodiesterase,PDE)增加cAMP(Cyclic nucleotide phosphodiesterases)水平,細(xì)胞的cAMP會(huì)加強(qiáng)ATP結(jié)合盒轉(zhuǎn)運(yùn)蛋白A1(ATP-binding cassette transporter A1,ABCA1)的活性,ABCA1將磷脂和膽固醇在內(nèi)的脂類向細(xì)胞外運(yùn)輸,然后與細(xì)胞外的脂類受體載脂蛋白A-I(Apolipoprotein A-I,apoA-I)結(jié)合形成初生高密度脂蛋白(Nascent HDL)[21],通過這種方式,TB促使HDL-C水平升高發(fā)揮保護(hù)心臟的作用。Neufingerl等[22]研究表明,每天攝入850?mg的TB可使健康受試者的HDL-C濃度顯著增加0.16?mmol·L-1。

        2.1.2 TB的抗癌作用

        在抗癌方面,TB主要是干擾腫瘤的血管生成,減少新血管的形成,抑制腫瘤細(xì)胞轉(zhuǎn)移。血管生成在癌細(xì)胞的生長(zhǎng)和轉(zhuǎn)移中起著主要作用,Barcz等[23]研究結(jié)果顯示,TB對(duì)卵巢癌的血管生成活性有明顯的抑制作用,并減少了血管內(nèi)皮生長(zhǎng)因子(Vascular endothelial growth factor,VEGF)的產(chǎn)生,但對(duì)堿性成纖維細(xì)胞生長(zhǎng)因子(Basic fibroblast growth factor,bFGF)和白細(xì)胞介素-8(Interleukin-8,IL-8)的產(chǎn)生無(wú)影響,認(rèn)為TB可能是卵巢癌血管生成的有效抑制劑,其作用機(jī)制與抑制VEGF的產(chǎn)生有關(guān)。Skopińska-Rózewska等[24]在無(wú)免疫抑制的小鼠體內(nèi)接種人類肺癌細(xì)胞,發(fā)現(xiàn)TB明顯抑制了人類肺癌細(xì)胞VEGF和bFGF的生成。

        Gil等[25]通過研究腺苷受體拮抗劑蘇拉明(Suramin,SN)和TB在BALB/c小鼠皮內(nèi)接種E14/W肺癌細(xì)胞后的抗血管生成活性發(fā)現(xiàn),SN和TB都能抑制與腫瘤有關(guān)的血管生成,因此認(rèn)為TB可能是腺苷受體拮抗劑。Barcz等[26]研究發(fā)現(xiàn),TB作為腺苷受體拮抗劑,能抑制卵巢癌細(xì)胞以及從卵巢癌患者腹腔腹水中分離的CD45陽(yáng)性淋巴細(xì)胞的血管生成活性,通過使用合成的腺苷受體拮抗劑(8-苯基茶堿和8-環(huán)戊基-1,3-二丙基香堿),發(fā)現(xiàn)TB的抗血管生成特性依賴于與腺苷受體A2(Adenosine receptor A2,AR2)的相互作用。

        另外,TB在惡性膠質(zhì)母細(xì)胞瘤的增殖中顯示出抗腫瘤潛力,這種作用由磷酸二酯酶4(PDE4)的負(fù)調(diào)控引起,促進(jìn)cAMP水平升高,降低p38 MAPK和JNK活性,同時(shí)減弱p44/42細(xì)胞外信號(hào)調(diào)節(jié)激酶(p44/42-ERK)活性和抑制蛋白激酶B(Protein kinase B,PKB)/雷帕霉素靶蛋白(Mammalian target ofrapamycin,mTOR)/核因子-κB(NF-κB)信號(hào)途徑[27]。TB也可以通過調(diào)控與生長(zhǎng)途徑有關(guān)的凋亡基因來控制腫瘤細(xì)胞的增殖,Bcl-2(B-cell lymphoma-2)基因是細(xì)胞凋亡抑制基因,而Bax(BCL2-Associated X)基因是促進(jìn)細(xì)胞凋亡的功能基因。Carla-Cadoná等[28]發(fā)現(xiàn)TB對(duì)人結(jié)腸癌細(xì)胞(HT-29)具有抗增殖活性,在暴露于TB的HT-29細(xì)胞中,癌細(xì)胞的增殖速率降低,細(xì)胞凋亡途徑的基因Bax/Bcl-2上調(diào)。

        表2 可可堿的健康功效

        TB對(duì)大腸腫瘤的化學(xué)預(yù)防也有效果。Shojaei-Zarghani等[29]研究了TB對(duì)二甲基肼(Dimethylhydrazine,DMH)誘發(fā)的雄性Wistar大鼠結(jié)腸癌的影響,發(fā)現(xiàn)TB在200?mg·kg-1的劑量下,能減少腫瘤的體積和數(shù)量,抑制蛋白激酶B(PKB)和糖原合成酶激酶-3(Glycogen synthase kinase-3,GSK3)的磷酸化,同時(shí)增加腺瘤性結(jié)腸息肉?。ˋdenomatous polyposis coli,APC)腫瘤抑制因子的表達(dá)。隨后該研究團(tuán)隊(duì)評(píng)估了單獨(dú)使用和聯(lián)合使用茶氨酸、TB對(duì)DMH誘導(dǎo)的雄性Wistar大鼠結(jié)腸癌的化學(xué)預(yù)防作用,結(jié)果表明,茶氨酸、TB以及聯(lián)合給藥都可以預(yù)防DMH誘導(dǎo)的結(jié)腸癌發(fā)生,與單獨(dú)服用茶氨酸或TB相比,同時(shí)服用茶氨酸和TB后,PKB和mTOR的mRNA及蛋白表達(dá)水平明顯降低;與茶氨酸相比,TB處理對(duì)細(xì)胞增殖標(biāo)記蛋白(Ki-67)和PKB/mTOR抑制表達(dá)效果更好[30]。

        2.1.3 TB的降脂減肥作用

        肥胖癥被認(rèn)為是慢性炎癥狀態(tài)。巨噬細(xì)胞和促炎性細(xì)胞因子在脂肪組織炎癥中的作用受到越來越多的關(guān)注。Fuggetta等[31]在體外脂肪組織炎癥模型中分析TB對(duì)脂肪生成和促炎性細(xì)胞因子的影響,結(jié)果顯示,TB能顯著抑制前脂肪細(xì)胞向成熟脂肪細(xì)胞分化,并降低單核細(xì)胞趨化蛋白-1(Monocyte chemotactic protein 1,MCP-1)和白細(xì)胞介素-1(Interleukin-1,IL-1)等促炎性細(xì)胞因子水平;MCP-1可以激活巨噬細(xì)胞,TB則通過降低MCP-1水平來控制巨噬細(xì)胞在脂肪組織中的浸潤(rùn),對(duì)治療肥胖癥有潛在的作用。

        另外,TB能夠通過抑制脂肪生成等相關(guān)因素來抑制3T3-L1小鼠細(xì)胞的脂肪生成和分化。Jang等[32]研究了TB抑制3T3-L1前脂肪細(xì)胞分化的作用機(jī)制,發(fā)現(xiàn)TB通過細(xì)胞外信號(hào)調(diào)節(jié)激酶/c-Jun氨基末端激酶(ERK/JNK)信號(hào)途徑抑制3T3-L1前脂肪細(xì)胞中的PPAR活性和C/EBP的表達(dá),從而在脂肪生成的早期階段抑制脂肪細(xì)胞的分化。Mitani等[33]研究表明,TB能減弱小鼠體重和附睪脂肪組織重量的增加趨勢(shì),并抑制小鼠脂肪組織中脂肪生成相關(guān)基因的表達(dá);在3T3-L1前脂肪細(xì)胞中,TB通過腺苷受體A1(AR1)途徑引起C/EBP蛋白降解,TB選擇性地與AR1相互作用,AR1的敲除可解除TB引起的C/EBP降解。

        肥胖通常被認(rèn)為是脂肪細(xì)胞(白色脂肪細(xì)胞)在體內(nèi)積聚過多而形成的一種慢性疾病,哺乳動(dòng)物體內(nèi)主要存在3種類型的脂肪細(xì)胞,即白色脂肪細(xì)胞、棕色脂肪細(xì)胞和米色脂肪細(xì)胞。研究顯示白色脂肪細(xì)胞向棕色脂肪細(xì)胞轉(zhuǎn)變會(huì)增加脂肪產(chǎn)熱和促進(jìn)能量消耗,同時(shí)激活棕色脂肪細(xì)胞和米色脂肪細(xì)胞產(chǎn)熱耗能,進(jìn)而抵抗肥胖[34]。Jang等[35]通過3T3-L1白色脂肪細(xì)胞和HIB1B棕色脂肪細(xì)胞模型研究表明,TB可誘導(dǎo)白色脂肪細(xì)胞向棕色脂肪細(xì)胞轉(zhuǎn)變,抑制白色脂肪細(xì)胞中關(guān)鍵的脂肪生成轉(zhuǎn)錄因子C/EBP和PPAR的表達(dá),并在這兩種類型脂肪細(xì)胞中通過-腎上腺素受體(-Adrenergic receptor,3-AR)和AMPK途徑進(jìn)行脂質(zhì)分解代謝。隨后Jang等[36]在肥胖C57BL/6小鼠模型中發(fā)現(xiàn),TB可以通過3-AR靶點(diǎn)來抑制PDE活性,調(diào)節(jié)相關(guān)生化反應(yīng),誘導(dǎo)白色脂肪細(xì)胞的棕色化,并激活了棕色脂肪細(xì)胞的脂肪分解和產(chǎn)熱,抵抗肥胖。

        2.1.4 TB改善神經(jīng)退行性疾病作用

        TB具有穿越血腦屏障的能力,對(duì)神經(jīng)元功能會(huì)產(chǎn)生明顯的影響。阿爾茨海默?。ˋlzheimer’s disease,AD)引起癡呆的主要病理學(xué)特征是腦內(nèi)和腦外淀粉樣蛋白(A)和tau蛋白的累積,AD可分為散發(fā)性和家族性兩類,散發(fā)性AD主要是由脂蛋白E的增加引起,脂蛋白E作為乳糜微粒的組成部分,是大腦中膽固醇的運(yùn)輸工具[37]。研究表明,高脂質(zhì)水平,特別是膽固醇水平,與AD形成有關(guān),AR1可能參與了對(duì)神經(jīng)遞質(zhì)釋放的抑制[38-39]。Mendiola-Precoma[40]等研究富含豬油的飲食(Lard-enriched diet,LED)對(duì)成年大鼠(6月齡)認(rèn)知和記憶過程的影響,結(jié)果表明,長(zhǎng)期富含脂肪的飲食會(huì)降低成年大鼠的認(rèn)知和記憶功能,生化與基因方面表現(xiàn)為A、IL-1蛋白水平增加和AR1基因表達(dá)水平上升;而飼喂TB能改善LED誘導(dǎo)的神經(jīng)變性和記憶損傷,回調(diào)AR1基因水平。

        cAMP-反應(yīng)元件結(jié)合蛋白(cAMP-response element-binding protein,CREB)是一種轉(zhuǎn)錄因子,可以被細(xì)胞質(zhì)中增加的cAMP和Ca2+激活,參與不同的大腦神經(jīng)過程,包括誘導(dǎo)腦源性神經(jīng)營(yíng)養(yǎng)因子(Brain-derived neurotropic factor,BDNF)的產(chǎn)生;鈣調(diào)素依賴型蛋白激酶Ⅱ(Ca2+/calmodulin-dependent protein kinase Ⅱ,CaMKⅡ)是一種在學(xué)習(xí)和記憶形成機(jī)制中具有重要作用的蛋白激酶[41]。Islam等[42]研究發(fā)現(xiàn)TB通過上調(diào)CaMKII/CREB/BDNF途徑增強(qiáng)了大鼠認(rèn)知和學(xué)習(xí)功能;而Yoneda等[43]發(fā)現(xiàn)了另一條TB增強(qiáng)工作記憶的途徑——cAMP/CREB/BDNF途徑,TB作為PDE抑制劑,可以使細(xì)胞內(nèi)的cAMP水平升高,cAMP激活CREB產(chǎn)生BDNF,從而增強(qiáng)小鼠的工作記憶。

        2.1.5 TB改善牙本質(zhì)過敏和牙釉質(zhì)損傷作用

        齲病是一種多因素、呈動(dòng)態(tài)變化的疾病過程,可引起脫礦與再礦化失衡,導(dǎo)致牙體硬組織脫礦[44]。據(jù)報(bào)道,在倉(cāng)鼠的飲食中添加TB能抑制倉(cāng)鼠的齲齒[45]。與氟化鈉相比,TB可以提高牙釉質(zhì)表面微硬度,并有助于表面再結(jié)晶[46]。Kargul等[47]收集24顆新拔出的人類第三磨牙,并用一定濃度的TB進(jìn)行處理,結(jié)果顯示,未經(jīng)TB處理的對(duì)照組牙釉質(zhì)表面總體上呈現(xiàn)光滑和稍有凹陷,并有小坑線,而TB處理組則表現(xiàn)在牙釉質(zhì)的表面形成沉淀物,起到更好的保護(hù)作用,牙釉質(zhì)的表面有硬度。

        牙本質(zhì)過敏(Dentin hypersensitivity,DH)是指牙齒在受到外界的刺激,如溫度(冷、熱)、化學(xué)物質(zhì)(酸、甜)以及機(jī)械作用(磨擦或咬硬物)等所引起的牙齒酸、軟、痛等癥狀[48]。牙本質(zhì)過敏癥的治療方法一般是閉塞牙本質(zhì)小管或進(jìn)行神經(jīng)脫敏,Amaechi等[49]發(fā)現(xiàn)與Novamin牙膏相比,含TB的牙膏促進(jìn)了牙本質(zhì)小管的閉合,緩解了DH。A·賽之霍普爾等[50]申請(qǐng)了含有TB的組合物用于治療牙齒過敏癥的專利(CN201380032101.0),提供了用于減輕哺乳動(dòng)物口腔敏感性,堵塞哺乳動(dòng)物牙齒中的牙本質(zhì)小管的方法。Nassar等[51]研究發(fā)現(xiàn)TB具有降低牙本質(zhì)過敏性和增強(qiáng)牙釉質(zhì)損傷再硬化的潛力。

        2.1.6 TB的止咳作用

        TB是一種支氣管擴(kuò)張劑,可以改善哮喘病人的支氣管擴(kuò)張。Usmani等[52]研究顯示,TB能有效地抑制由檸檬酸引起的豚鼠咳嗽和辣椒素引起的人體咳嗽,且沒有不良反應(yīng),這是由于TB對(duì)外源誘導(dǎo)的傳入神經(jīng)激活有抑制作用。TB通過抑制傳入神經(jīng)通路來抑制咳嗽,這種作用可能是通過抑制支氣管的PDE和AR1的活性而引起的,但也可能涉及其他作用方式(如激活Ca2-K+通道)[52-53]。另外,TB的止咳作用不會(huì)引起像其他止咳藥所顯示的副作用,可作為一類新止咳藥[52]。

        2.1.7 TB改善腎病作用

        腎結(jié)石是一種高發(fā)疾病,一部分腎結(jié)石由尿酸結(jié)晶組成,血液中的尿酸鹽含量高是一種病理狀況,可導(dǎo)致尿酸結(jié)晶體產(chǎn)生[54]。Grases等[55]研究了甲基黃嘌呤(咖啡因、茶堿、TB和副黃嘌呤)抑制尿酸結(jié)晶的能力,并評(píng)估它們?cè)谥委熌蛩嵝阅I結(jié)石中的應(yīng)用潛力,結(jié)果顯示在所研究的甲基黃嘌呤中,TB能明顯地抑制尿酸結(jié)晶成核,可作為尿酸結(jié)晶抑制劑,在治療和預(yù)防尿酸性腎結(jié)石方面具有很高的臨床潛力。糖尿病腎病被認(rèn)為是慢性腎衰竭的主要原因,糖尿病中過量的活性氧(Reactive oxygen species,ROS)可導(dǎo)致細(xì)胞外基質(zhì)(Extracellular matrix,ECM)基因的表達(dá)增加,并逐漸發(fā)展為腎臟纖維化和終末期腎病。據(jù)報(bào)道,TB在糖尿病腎病方面具有治療潛力,可通過對(duì)沉默信息調(diào)節(jié)因子2相關(guān)酶1(Sirtuin1,Sirt-1)的激活,減少糖尿病大鼠腎臟中ECM的積累,降低ROS水平[56]。

        2.1.8 TB的其他作用

        TB還可以預(yù)防骨關(guān)節(jié)炎,軟骨細(xì)胞的功能失調(diào)是骨關(guān)節(jié)炎發(fā)生的一個(gè)重要因素,TB對(duì)白細(xì)胞介素-1(IL-1)引起的軟骨細(xì)胞功能障礙具有預(yù)防作用,其機(jī)制是TB通過下調(diào)NF-κB途徑抑制IL-1誘導(dǎo)的IκB激活、NF-κB蛋白p65的積累和NF-κB啟動(dòng)子活性[57]。在腸道微生物與炎癥關(guān)聯(lián)方面,TB能顯著調(diào)節(jié)腸道微生物的組成和豐度,降低雙歧桿菌(spp.)、鏈球菌(spp.)的菌落豐度;另外TB增加短鏈脂肪酸(SCFAs)的產(chǎn)量,SCFAs具有下調(diào)某些促炎因子(IL-6、IL-12)的表達(dá),抑制炎癥的產(chǎn)生[58]。也有報(bào)道稱過量的可可堿有一定毒性,狗、馬和新西蘭海雀等動(dòng)物代謝可可堿的能力非常有限,體內(nèi)可可堿的累積會(huì)成為潛在致命毒物,100~200?mg的可可堿就可以使狗致命[59];而對(duì)于人類,可可堿似乎比咖啡堿更安全,其口服致死劑量更高[60]。

        2.2 GCG的健康功效

        EGCG是茶樹()資源兒茶素的主要成分,而GCG是可可茶樹資源兒茶素的主要成分,GCG在市場(chǎng)上的價(jià)格是EGCG的10~100倍。已有研究證實(shí)GCG具有多種生物活性[61],包括降血糖、抗氧化、抑菌消炎、抗脂和抗腫瘤[62-80](表3),GCG在某些方面作用效果甚強(qiáng)于EGCG。

        2.2.1 GCG的降脂、降血糖作用

        兒茶素可以加速膽固醇代謝,促進(jìn)膽固醇排泄。Ikeda等[62]通過體外試驗(yàn)比較了GCG與EGCG在膽固醇膠束中的溶解度,結(jié)果顯示GCG降低膽汁膠束中膽固醇的作用明顯。隨后該研究團(tuán)隊(duì)通過大鼠試驗(yàn)比較GCG與EGCG對(duì)血清膽固醇濃度的影響,結(jié)果表明,GCG與EGCG都是通過抑制腸道對(duì)膽固醇的吸收來降低血清膽固醇濃度,并且效果差異不顯著[63]。Lee等[64]用富含GCG的兒茶素混合物(∶=1∶1)飼喂高糖飲食誘導(dǎo)的高脂血癥大鼠,發(fā)現(xiàn)大鼠肝臟中的膽固醇(TC)和TG濃度顯著下降,表明富含GCG的兒茶素混合物具有降血脂作用;隨后在HepG2細(xì)胞水平上比較純化的GCG與EGCG單體對(duì)LDLR活性的作用(LDLR是調(diào)節(jié)膽固醇濃度的關(guān)鍵因素),結(jié)果顯示,與EGCG相比,純化的GCG更能提高LDLR蛋白水平和活性。Lu等[65]發(fā)現(xiàn)兒茶素單體組分對(duì)HepG2細(xì)胞模型中膽固醇生物合成的抑制能力依次為GCG>EGCG>ECG(Epicatechin gallate)>GA(Gallic acid)>EGC(Epigallocatechin)>C(Catechin)>EC(Epicatechin)。

        表3 沒食子兒茶素沒食子酸酯的健康功效

        茶葉中的兒茶素對(duì)與高血糖癥有關(guān)的-淀粉酶(-Amylase)和-葡萄糖苷酶(-Glucosidase)有抑制作用[66]。Wu等[67]研究發(fā)現(xiàn),糖尿病患者的餐后高血糖水平與碳水化合物消化酶(-淀粉酶和-葡萄糖苷酶)有關(guān),GCG能對(duì)-淀粉酶和-葡萄糖苷酶有強(qiáng)抑制作用,可有效地控制餐后的血糖水平,其機(jī)制是GCG與-淀粉酶和-葡萄糖苷酶結(jié)合形成復(fù)合物,從而誘發(fā)這兩種消化酶的構(gòu)象變化,導(dǎo)致酶活性下降。此外,GCG在-淀粉酶和-葡萄糖苷酶上的結(jié)合部位不同,氫鍵和范德華力主導(dǎo)GCG與-淀粉酶的相互作用,而氫鍵和疏水作用則促進(jìn)GCG--葡萄糖苷酶復(fù)合物的穩(wěn)定性。Xie等[68]使用鏈脲霉素誘導(dǎo)的糖尿病大鼠模型,通過葡萄糖耐量試驗(yàn)和測(cè)定血漿中的葡萄糖、胰島素、甘油三酯、游離脂肪酸水平來評(píng)估GCG和EGCG的抗糖尿病活性,發(fā)現(xiàn)GCG作用效果比EGCG好。

        2.2.2 GCG的抗氧化作用

        兒茶素被認(rèn)為是有效的抗氧化劑,因?yàn)樗鼈兙哂星宄钚匝鹾妥杂苫饶芰?。Wu等[69]研究發(fā)現(xiàn),GCG對(duì)蛋白質(zhì)的氧化和羰基化具有保護(hù)作用,能改善甲基乙二醛(Methylglyoxal,MGO)介導(dǎo)的晚期糖基化終末產(chǎn)物(Advanced glycation end products,AGEs),AGEs的形成和積累被認(rèn)為是糖尿病并發(fā)癥發(fā)生和發(fā)展的致病因素,GCG對(duì)MGO引起的蛋白質(zhì)羰基化的分子機(jī)制可能是由于其對(duì)羥自由基(Hydroxyl radical,·OH)和超氧自由基(Superoxide free radicals,·O2-)的清除。谷氨酸鹽(Glutamate)是一種神經(jīng)遞質(zhì),神經(jīng)細(xì)胞用它來發(fā)送信號(hào),然而谷氨酸鹽的過度積累會(huì)導(dǎo)致中樞神經(jīng)系統(tǒng)的興奮性中毒,發(fā)生氧化應(yīng)激。Park等[70]發(fā)現(xiàn)兒茶素對(duì)谷氨酸鹽誘導(dǎo)的小鼠海馬神經(jīng)元細(xì)胞株(HT22)氧化應(yīng)激有保護(hù)作用,5種兒茶素(EGCG、GCG、GC、ECG和EC)都顯示出強(qiáng)烈的抗氧化作用,GCG表現(xiàn)最好,其作用機(jī)制可能是通過調(diào)節(jié)ERK/JNK信號(hào)途徑,同時(shí)降低活性氧(ROS)水平,從而有效地抑制谷氨酸鹽引起的HT22細(xì)胞的氧化應(yīng)激。另一些研究也表明,基于GCG與EGCG的化學(xué)結(jié)構(gòu)、酶結(jié)合親和力等因素,GCG的抗氧化活性高于EGCG[71-72]。

        2.2.3 GCG的抑菌、消炎、抗脂作用

        GCG具有抗細(xì)菌作用。GCG與EGCG都能抑制肉毒桿菌()和蠟樣芽孢桿菌()的無(wú)性生長(zhǎng),但與EGCG相比,GCG對(duì)蠟樣芽孢桿菌顯示出更好的抑制活性[73]。Sugita-Konishi等[74]研究EGCG、GCG、EGC、ECG、EC和C等6種兒茶素單體對(duì)腸出血性大腸桿菌(,EHEC)產(chǎn)生Vero毒素的影響,結(jié)果發(fā)現(xiàn)培養(yǎng)基中的EGCG和GCG能明顯地抑制EHEC向培養(yǎng)上清液中釋放Vero毒素,GCG在0.05?mg·mL-1濃度時(shí)可抑制EHEC釋放Vero毒素。

        2--甲基--赤蘚糖醇4-磷酸(2--methyl--erythritol 4-phosphate,MEP)途徑是萜類生物合成途徑,這種途徑只在微生物中起作用。因此,阻斷MEP途徑已被視為篩選抗菌劑的目標(biāo),而1-脫氧--木酮糖-5-磷酸還原異構(gòu)化酶(1-deoxy--xylulose 5-phosphate reductoisomerase,DXR)是MEP途徑中萜類生物合成的第一個(gè)關(guān)鍵酶。Hui等[75]發(fā)現(xiàn)GCG是DXR的抑制劑,可以作用在DXR上,有效抑制細(xì)菌生長(zhǎng)。GCG還能抑制炎癥,Li等[76]研究發(fā)現(xiàn)GCG可以降低3T3-L1前脂肪細(xì)胞內(nèi)ROS的積累,并下調(diào)3T3-L1前脂肪細(xì)胞分化中NF-κB途徑,降低LPS誘導(dǎo)的IL-6和MCP-1產(chǎn)生,抑制脂肪細(xì)胞的炎癥反應(yīng)。

        2.2.4 GCG的抗腫瘤作用

        據(jù)報(bào)道,基質(zhì)金屬蛋白酶(Matrix metalloproteinases,MMPs)的過度表達(dá)會(huì)導(dǎo)致細(xì)胞外基質(zhì)破壞,容易發(fā)生如癌細(xì)胞的入侵和轉(zhuǎn)移等病理情況[77]。而GCG可以通過調(diào)節(jié)NF-κB途徑降低基質(zhì)金屬蛋白酶-9(MMP-9)的啟動(dòng)子活性和其mRNA表達(dá)水平來減少M(fèi)MP-9的分泌,預(yù)防腫瘤發(fā)生[78]。cAMP介導(dǎo)的cAMP-反應(yīng)元件結(jié)合蛋白(CREB)等信號(hào)通路參與了黑色素細(xì)胞中黑色素的合成,小眼球相關(guān)轉(zhuǎn)錄因子(Microphthalmia-associated transcription factor,MITF)是這些途徑中最重要的分子靶點(diǎn)[79]。Zhang等[80]發(fā)現(xiàn)GCG作為抗黑色素生成劑,保護(hù)細(xì)胞免受異常黑色素生成的影響,通過抑制cAMP下調(diào)CREB磷酸化水平,減少M(fèi)ITF表達(dá),隨后黑色素細(xì)胞的酪氨酸酶水平也降低,減少了黑色素的合成。

        3 總結(jié)與展望

        本文歸納了國(guó)內(nèi)外學(xué)者研究可可茶及其優(yōu)勢(shì)化學(xué)成分TB與GCG的多種健康功效,其主要作用機(jī)制如圖1所示。

        TB作為一種腺苷受體(AR1和AR2)拮抗劑,在抑制血管生成、抑制脂肪分化和增強(qiáng)記憶方面發(fā)揮重要作用。GCG下調(diào)cAMP濃度,抑制CREB磷酸化水平,進(jìn)而減少M(fèi)ITF的表達(dá),保護(hù)細(xì)胞免受異常黑色素生成的影響。TB和GCG的部分作用機(jī)理具有相似性,比如都可抑制JNK/ERK/P38MAPK途徑及下游的PKB/mTOR/NF-κB信號(hào)通路,下調(diào)IL-6、IL-1、MCP-1和MMP-9的表達(dá),發(fā)揮抗炎和抗腫瘤作用,同樣可可茶、TB和GCG部分作用機(jī)理也具有相似性(圖1)。目前,可可茶、TB和GCG的保健功效研究還處在細(xì)胞和動(dòng)物試驗(yàn)階段,鮮有臨床干預(yù)試驗(yàn)和流行病學(xué)調(diào)查,其功效機(jī)理的系統(tǒng)性研究還有待進(jìn)一步拓展。

        圖1 可可茶、TB與GCG的保健功效的主要作用機(jī)制

        另外,TB與咖啡堿(CAF)的化學(xué)結(jié)構(gòu)相似,因此它們的生理活性也有很大的相似性,吳命燕等[81]綜述報(bào)道,CAF對(duì)心血管疾病、癌癥、神經(jīng)疾病和呼吸疾病也有干預(yù)治療作用。而TB具有CAF沒有的生理功能是抗牙本質(zhì)過敏、修復(fù)牙釉質(zhì)損傷作用。GCG是EGCG表型異構(gòu)體,兩者的生物利用度有差異,張梁等[82]分析發(fā)現(xiàn),小鼠體內(nèi)的EGCG相對(duì)生物利用度明顯高于大鼠,并通過推算EGCG在人體內(nèi)的相對(duì)生物利用度并不低于小鼠。Xie等[83]通過建立體外胃腸道消化模型試驗(yàn),發(fā)現(xiàn)EGCG的降解明顯大于GCG,說明GCG比EGCG的生物利用度還低。通過整理分析發(fā)現(xiàn),目前可可茶的優(yōu)勢(shì)化學(xué)成分TB、GCG的健康功能相關(guān)研究較多,而可可茶的健康功效報(bào)道較少,主要體現(xiàn)在抗腫瘤、降脂和抗氧化抗炎3個(gè)方面,其他方面功效研究有待深入挖掘,因此TB和GCG的現(xiàn)有功效研究成果可以為可可茶尚未開展的功效試驗(yàn)提供理論依據(jù),也為可可茶相關(guān)功能產(chǎn)品的研制提供一定的參考。

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        and Specific Chemical Components, Theirs Health Beneficial Effects

        WU Wenliang1, TONG Tong1, HU Yao2, ZHOU Hao1, YIN Xia1, ZHANG Shuguang1*

        1. Tea Research Institute, Hunan Academy of Agricultural Sciences, Changsha 410125, China; 2. Nuclear Agronomy and Aerospace Breeding Research Institute, Hunan Academy of Agricultural Sciences, Changsha 410125, China

        Cocoa tea (Chang) is a specific tea resource in China, and theobromine (TB) and gallocatechin gallate (GCG), as the dominant chemical components of cocoa tea, have various health effects. This paper summarized intervention effects and mechanisms of cocoa tea, TB and GCG on cardiovascular diseases, cancers, obesity, diabetes, neurodegenerative diseases, dental diseases, respiratory diseases and kidney diseases, etc. This review would provide a theoretical reference for the development of functional cocoa tea products.

        , theobromine, gallocatechin gallate, health effects

        S571.1

        A

        1000-369X(2021)05-593-15

        2021-07-30

        2021-08-23

        湖南省重點(diǎn)領(lǐng)域研發(fā)計(jì)劃(2020NK2047)、湖南省農(nóng)業(yè)科技創(chuàng)新資金(2020CX36)、湖南省自然科學(xué)基金(2020JJ5277)

        吳文亮,男,博士后,主要從事茶葉品質(zhì)化學(xué)與營(yíng)養(yǎng)健康的研究。*通信作者:suglezhang@126.com

        (責(zé)任編輯:黃晨)

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