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王慶華，杜婷婷，張智慧，季鳴，胡海宇，陳曉光*

(中國醫(yī)學科學院、北京協(xié)和醫(yī)學院藥物研究所，中國醫(yī)學科學院小分子腫瘤免疫治療藥物研究重點實驗室，北京100050)

摘要：近年來，對綠原酸(Chlorogenic acid，CGA)的研究發(fā)展較快，在醫(yī)藥、化工和食品等領域具有廣泛的應用，具有潛在的、廣闊的應用前景。其作為一種水溶性酚類化合物，在植物界中廣泛分布。具有較強的生物活性和廣泛的藥理作用。本文擬從抗菌、抗病毒、抗腫瘤、抗氧化和抗炎以及治療代謝類疾病等幾個方面對綠原酸的藥理作用及機制作一綜述，旨在為綠原酸作用機制的深入研究以及作用靶點的確證提供重要的理論依據(jù)。

關(guān)鍵詞：綠原酸；藥理作用；機制

A pharmacological review and further research of chlorogenic acid

Wang Qing-hua, Du Ting-ting, Zhang Zhi-hui, Ji Ming, Hu Hai-yu, Chen Xiao-guang*

(State Key Laboratory of Small Molecular Tumor Immunotherapy Drug Research, Chinese Academy of Medical Sciences, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China)

Abstract: In recent years, the research on chlorogenic acid (CGA) has developed rapidly, and has a wide range of applications in the fields of medicine, chemical industry and food. It has potential and broad application prospects. As a water-soluble phenolic compound, it is widely distributed in the plant kingdom. It has strong biological activity and a wide range of pharmacological effects. This article intends to review the pharmacological effects and mechanisms of chlorogenic acid from several aspects such as antibacterial, antiviral, antitumor, antioxidant and anti-inflammatory and treatment of metabolic diseases. The purpose is to provide important theoretical basis for the in-depth research on the mechanism of chlorogenic acid and confirming the action target.

Key words: chlorogenic acid; pharmacological action; mechanism

基金項目：重大新藥創(chuàng)制科技重大專項（ 2016ZX09101017）；創(chuàng)新工程-重大協(xié)同創(chuàng)新項目（2019-I2M-1-005）；中國醫(yī)學科學院醫(yī)學與健康科技創(chuàng)新工程（2017-I2M-2-004）；北京協(xié)和醫(yī)學院研究生創(chuàng)新基金（2019-1007-13）.

通訊作者Tel: 86-10-63165207, E-mail: chxg@imm.ac.cn

  綠原酸是由咖啡酸的羧基和奎尼酸的羥基縮合成縮酚酸，是植物細胞通過莽草酸途徑合成的一種苯丙素類物質(zhì)，其分子結(jié)構(gòu)中有酯鍵、不飽和雙鍵、多元酚和鄰二酚羥基[1, 2]。綠原酸在杜仲、金銀花、綠咖啡豆、土豆、蘋果以及茶葉等多種植物中含量很高[3-5]。具有抗氧化、抗菌、抗病毒、抗腫瘤、降血脂、降血糖和免疫調(diào)節(jié)等多方面的藥理作用[6-8]，在食品、醫(yī)藥和化工等領域都有廣泛的應用[9]（圖 1）。隨著科技的進步和研究的深入，綠原酸藥理作用機制逐漸被重視�，F(xiàn)對綠原酸的藥理作用和作用機制進行綜述，以期為綠原酸的藥用研究與開發(fā)提供參考。

Figure 1 The application of chlorogenic acid from green coffee beans in weight loss

1 綠原酸的藥理作用及機制

1.1 抗菌

  大量研究證明，綠原酸具有廣譜抗真菌和細菌的作用[7]。Martíne等[10]在2017年報道了綠原酸對多種植物致病真菌有抗真菌活性，具有生物殺真菌劑的潛力，其機制是通過抑制真菌孢子的早期透膜化來控制不同的植物病原真菌的生長。已有大量文獻報道，綠原酸是通過破壞肺炎鏈球菌(Streptococcus pneumoniae)，金黃色葡萄球菌(Staphylococcus aureus)和痢疾志賀氏菌（Shigella dysenteriae）的細胞膜，增加外膜和質(zhì)膜通透性, 導致細菌的屏障功能喪失，進而發(fā)揮其抗菌活性[11, 12]。Ren等[13]通過將綠原酸包被到聚二甲基硅氧烷（硅油）表面上起到對硅油的消毒作用，其抗菌作用的新機理是通過降低細菌細胞壁的硬度，減慢細菌的遷移和影響細菌細胞膜的穩(wěn)定性。Lee課題組[14]則闡明了綠原酸抑菌作用的機制是通過誘導活性氧耗竭進而引發(fā)大腸桿菌的類凋亡死亡。綜上所述，隨著綠原酸的抗菌機制深入研究為新型抗生素的研發(fā)奠定了堅實的基礎。

1.2  抗病毒

  很多文獻報道，綠原酸及其衍生物作為天然化合物，對多種不同類型的病毒有很好的抑制作用，其中包括艾滋病病毒（Human immunodeficiency virus，HIV），甲型流感病毒（H1N1/H3N2），單純皰疹病毒（Herpes simplex virus， HSVs），乙型肝炎病毒（Hepatitis B virus，HBV）等[15, 16]。1997年，Robinson等[17]報道了綠原酸可以抑制HIV-1整合酶。Tamura等[18]于2006年在人淋巴瘤細胞株MT-2上驗證了綠原酸可以有效地抑制HIV病毒，為HIV的新藥設計提供新的先導化合物。Nikolai課題組[19]在2016年首次報道了綠原酸及其衍生物具有抑制病毒的神經(jīng)氨酸酶活性。Ding等[20]也證明綠原酸在感染的后期可有效抑制甲型流感病毒（H1N1/H3N2）的感染。通過間接免疫熒光分析表明其下調(diào)了病毒核蛋白 (Nucleoprotein，NP)的表達，并在細胞水平和動物水平上證明綠原酸通過抑制神經(jīng)氨酸酶活性來抑制病毒感染。Zhao課題組[21]證明了加入綠原酸可以顯著提高HSV-1感染的小膠質(zhì)細胞（BV2）的存活率，同時抑制了感染細胞中TLR2 （Toll樣受體，Toll-like receptor，TLR）、TLR9和髓樣分化因子（Myeloid differentiation factor88，Myd88）的增加和降低了炎癥因子腫瘤壞死因子-α（Tumor necrosis factor-α，TNF-α）和IL -6（白細胞介素，Interleukin，IL）釋放。因此，證明了綠原酸可以通過有效地抑制病毒感染產(chǎn)生和炎癥反應來治療病毒感染。2009年，Wang等[22]以HepG2.2.15細胞和鴨乙型肝炎病毒感染模型證明了綠原酸可以抑制HBV-DNA復制以及乙型肝炎表面蛋白抗原（Hepatitis B surface antigen，HBsAg）的產(chǎn)生。由此可見，綠原酸有望成為一個潛在的廣譜抗病毒藥物。

1.3 抗腫瘤

  20世紀80年代，綠原酸被發(fā)現(xiàn)具有抑制腫瘤的作用，從而引起了人們的廣泛關(guān)注[23]。此后，有關(guān)其抑制不同類型腫瘤和機制研究越來越多。2017年我們課題組首次報道了綠原酸通過影響巨噬細胞的M1/M2極化分型（即促進M1型巨噬細胞和抑制M2表型巨噬細胞）進而抑制腦膠質(zhì)瘤生長[24]。Jiang課題組[25]報道了綠原酸對肝癌、肺癌和膠質(zhì)瘤都有明顯抑制作用，其機制不是通過直接的殺傷作用而是通過影響腫瘤細胞誘導分化來抑制腫瘤，并指出綠原酸有望成為一種安全有效的腫瘤分化誘導劑。Hou等[26]研究發(fā)現(xiàn)綠原酸通過誘導活性氧的產(chǎn)生進而抑制結(jié)腸癌。Sapio等[27]報道綠原酸通過激活細胞外信號調(diào)節(jié)激酶1/2（Extracellular regulated protein kinases，ERK1/2）抑制骨肉瘤細胞的增殖。Motoki Tagami課題組[28]報道了綠原酸通過影響細胞凋亡相關(guān)基因的表達起到抑制肺癌細胞的作用。盡管大量文獻報道了綠原酸抗腫瘤作用機制，但看法不盡一致。因此，潛在靶點的尋找和作用的機制有待進一步探索。

1.4 抗氧化和抗炎

  綠原酸是一種廣泛存在植物中的多酚類次生代謝產(chǎn)物，具有很強抗氧化和抗炎特性。兒茶酚結(jié)構(gòu)的存在為自由基提供了結(jié)合位點[29, 30]，綠原酸能夠螯合金屬離子和清除自由基 （超氧陰離子（O2-），過氧化氫（H2O2），羥基自由基（•OH），次氯酸（HOCl），過氧亞硝酸鹽陰離子（ONOO-）和一氧化氮（NO）） [31-33]。 Lu等[34]報道了綠原酸表現(xiàn)出很強的抗氧化活性，其清除DPPH自由基的活性是維生素C和E的2-3倍和清除超氧陰離子自由基的活性是維生素C和E的10-30倍。近年來，綠原酸的抗炎作用也備受關(guān)注。2006年，Dos Santos等[35]在脂多糖誘導大鼠炎癥模型上首次報道了綠原酸具有抗炎活性。隨后，有很多文獻對其抗炎機制進行了深入地探討。2018年，Hee等[36]發(fā)現(xiàn)綠原酸可以抑制氧化應激誘導的腸上皮細胞中IL-8的產(chǎn)生來起到抗炎作用，并闡明了其作用機制是通過清除細胞內(nèi)活性氧（Reactive oxygen species，ROS）進而通過蛋白激酶D-核因子κB（Protein kinase D -Nuclear factor kappa-B，PKD-NF-κB）信號通路的激活抑制IL-8的產(chǎn)生。同年，Liang等[37]也指出綠原酸及其異構(gòu)體可以通過抑制p38級聯(lián)磷酸化和上調(diào)NF-κB信號通路來抑制其上皮細胞（Caco-2）中IL-8產(chǎn)生。Gao等[38]在硫酸葡聚糖誘導的小鼠潰瘍性結(jié)腸炎模型中，發(fā)現(xiàn)綠原酸是通過調(diào)控絲裂原活化蛋白激酶（Mitogen-activated protein kinase，MAPK）/ERK/c-Jun氨基末端激酶（c-Jun N-terminal kinase，JNK）信號通路來降低組織的炎癥反應。Fu等[39]實驗證明綠原酸有望成為治療類風濕關(guān)節(jié)炎（Rheumatoid arthritis，RA）的新型治療劑，其機制是通過降低了NF-κB與B細胞活化因子（B cell-activating factor，BAFF）啟動子區(qū)域的DNA結(jié)合能力，并抑制了TNF-α刺激的MH7A細胞中NF-κB途徑的BAFF表達。Shi等[40]證明綠原酸可以有效降低CCl4誘導的急性肝損傷產(chǎn)生TNF-α，IL-6和IL-1β炎癥因子，其機制是通過活化核因子類紅細胞2相關(guān)因子2（Nuclear factor erythroid 2-related factor 2，Nrf2）信號通路并抑制核苷酸結(jié)合寡聚結(jié)構(gòu)域，富含亮氨酸重復序列和含Pyrin結(jié)構(gòu)域3（Nucleotide- binding oligomerization domain, leucine- rich repeat and pyrin domain- containing 3，NLRP3）炎癥小體激活來進行急性肝損傷的保護作用。Tsai等[41]在用綠原酸預處理的情況下，用氧化型低密度脂蛋白(Human Ox-LDL，oxLDL) 處理HUVEC細胞。結(jié)果表明，綠原酸預處理可提高NAD-依賴性去乙�；�酶（Sirtuin 1，SIRT1）活性水平，逆轉(zhuǎn)了oxLDL受損的SIRT1和AMP激活的蛋白激酶（AMP-activated protein kinase，AMPK）/過氧化物酶體增殖物受體γ共激活因子1（Peroxisome proliferator-activated receptor-gamma coactivator-1，PGC-1）活性，并減輕了oxLDL誘導的氧化應激和線粒體生物發(fā)生功能障礙。其機制通過調(diào)節(jié)SIRT1和AMPK / PGC-1功能來抑制oxLDL誘導的內(nèi)皮細胞凋亡。因此，使沉默SIRT1，AMPK和PGC-1會減弱綠原酸抵御氧化應激的能力。Yang等[42]報道了綠原酸通過激活SIRT1調(diào)節(jié)的線粒體形態(tài)來預防飽和游離脂肪酸（Free fatty acid，F(xiàn)FA）誘導的脂毒性。結(jié)果表明。綠原酸通過減少ROS的產(chǎn)生以及增加線粒體質(zhì)量和線粒體膜電位，減輕了氧化應激和線粒體功能障礙；顯著降低促細胞凋亡蛋白Bax（Bcl2 associated X，Bax）表達，從而減少線粒體介導的caspase依賴性細胞凋亡。在機制上，通過抑制動力蛋白相關(guān)蛋白1（Dynamin-relatedprotein1，Drp1）和增強線粒體融合蛋白 2（Mitofusin 2，Mfn2）表達來減弱ROS誘導的線粒體片段化；激活SIRT1阻止了綠原酸對線粒體ROS和Drp1的抑制作用。Ali等[43]研究表明綠原酸具有肝保護作用，其機制通過增加抑制細胞凋亡Bcl2（B淋巴細胞瘤-2，B-cell lymphoma-2，Bcl2）表達并抑制環(huán)氧化酶-2（Cyclooxygenase-2，Cox-2）、誘導型一氧化氮合酶（Inducible nitric oxide synthase，iNOS）、Bax和Caspases 3、9介導的炎癥反應和細胞凋亡來降低甲氨蝶呤（Methotrexate，MTX）誘導的肝毒性。Wang等[44]研究表明綠原酸通過影響肝星狀LX2細胞系中IL-13/microRNA-21（miR-21）/Smad7信號傳導相互作用抑制血吸蟲病誘導的肝纖維化，因此，綠原酸有望成為用于治療血吸蟲病肝纖維化的抗肝纖維化類藥物。神經(jīng)退行性疾�。ò�爾茨海默氏病（Alzheimer disease，AD）和帕金森氏病（Parkinson’s disease，PD））的病理學研究表明慢性氧化應激和促炎機制會導致神經(jīng)元受損[45]�；�于綠原酸具有較強的抗氧化和抗炎作用，很多學者發(fā)現(xiàn)它具有很好神經(jīng)系統(tǒng)保護作用[46]。在一些臨床和臨床前研究表明咖啡提取物（主要成分綠原酸）對AD和PD展現(xiàn)出很好的效果[47, 48]。Hermawati等[49]發(fā)現(xiàn)綠原酸可以改善記憶力減退和海馬細胞短暫性全腦缺血后死亡，其機制是通過增加Bcl2、超氧化物歧化酶2（Superoxide dismutase 2，SOD2）和血小板-內(nèi)皮細胞粘附分子CD31（Platelet endothelial cell adhesion molecule-1，PECAM-1/CD31）表達并降低內(nèi)皮素（Endothelin-1，ET-1）表達來改善空間記憶并防止雙側(cè)頸總動脈閉塞后CA1錐體細胞死亡。Fang課題組[50]研究表明，綠原酸作為一種有效的自由基清除劑，可以顯著保護PC12細胞免受氧化損傷。其機制包括直接的ROS猝滅活性和通過激活Nrf2誘導內(nèi)源性抗氧化酶。因此，綠原酸可以作為潛在的神經(jīng)保護藥物。

1.5 治療代謝性疾病

  隨著社會的進步和人類物質(zhì)生活水平的提高，代謝相關(guān)性疾病已成為全球影響人類健康的重要問題。其中包括血脂異常、高血壓、高空腹血糖水平、胰島素抵抗、慢性炎證和血栓形成等[51]。隨著天然產(chǎn)物在治療代謝性疾病優(yōu)勢的逐漸展現(xiàn)，人們又重新燃起了對天然產(chǎn)物的興趣。許多研究已經(jīng)評估綠原酸對代謝類疾病的影響，其中包括肥胖、血脂異常、糖尿病、高血壓、代謝綜合征和保護心血管等[52]。

  在治療肥胖方面，Wang等[53]喂食高脂飲食（High fat diet，HFD）小鼠用綠原酸治療6周。結(jié)果表明，給予綠原酸可顯著降低小鼠的體重，降低血漿中的脂質(zhì)水平，并改變脂肪組織中脂肪生成和脂肪分解相關(guān)基因的mRNA表達。 此外，綠原酸改善HFD誘發(fā)的腸道菌群失調(diào)，也有助于改善HFD誘發(fā)的肥胖。Han等[54] 研究表明綠原酸通過促進葡萄糖的攝取和線粒體的功能來刺激褐色脂肪細胞的生熱。其機制增強了棕色脂肪細胞的生熱和質(zhì)子泄漏，上調(diào)了葡萄糖轉(zhuǎn)運蛋白2（Glucose transporter type 2，GLUT2）和磷酸果糖激酶（Phosphofructokinase，PFK）來促進葡萄糖的吸收，增加了線粒體的數(shù)量和功能。2019年，Xu等[55]研究了綠原酸和咖啡因?qū)Ω咧�飲食誘導的肥胖小鼠脂質(zhì)代謝的聯(lián)合作用機理。飼喂綠原酸和咖啡因的聯(lián)合使用可有效降低增加的體重、腹膜內(nèi)脂肪組織重量、血清LDL-c、FFA、總膽固醇（Totalcholesterol，TC）、三酸甘油脂 （Triglyceride，TG）、瘦素、IL-6濃度以及肝TG和TC水平，并增加血清脂聯(lián)素水平，促進了AMPKα的磷酸化，抑制了轉(zhuǎn)錄調(diào)節(jié)因子固醇調(diào)節(jié)元件結(jié)合蛋白-1c（Sterol regulatory element-binding protein-1c，SREBP-1c）和肝X受體α（Liver X receptor α，LXRα）的表達，并降低了脂肪酸合成(Fatty acid synthesis，F(xiàn)AS)和3-羥基3-甲基戊二酰輔酶A還原酶（HMG-CoA Reductase，HMGR）的表達。此外，增加了脂肪組織甘油三酯水解酶（Adipose triglyceride lipase，ATGL）和激素敏感脂肪酶（Hormone-sensitive lipase，HSL）的表達。結(jié)果表明，綠原酸和咖啡因的聯(lián)用，可以激活AMPKα-LXRα/ SREBP-1c信號通路對高脂飲食誘導的肥胖小鼠具有抗肥胖作用和調(diào)節(jié)脂質(zhì)代謝。同年Kumar等[56]也報道了綠原酸通過激活AMPK，抑制HMGR，增強肉堿棕櫚酰轉(zhuǎn)移酶 (Carnitine palmitoyltransferase 1，CPT1) 的活性控制肥胖。Cho等[57]研究了綠原酸對高脂飲食誘導肥胖小鼠的體重、體脂和肥胖相關(guān)激素的影響。與高脂飲食對照組相比，綠原酸和咖啡酸均顯著降低體重、內(nèi)臟脂肪量、血漿瘦素和胰島素水平、肝臟和心臟中的甘油三酸酯以及脂肪組織和心臟中的膽固醇。Huang等[58]在大鼠實驗中獲得了相似的結(jié)果，綠原酸以劑量依賴性方式抑制體內(nèi)和內(nèi)臟脂肪的增加和高脂飲食誘導的游離脂肪酸。同樣人體研究也顯示富含綠原酸的食物具有抗肥胖作用。Thom[59]給予30名超重受試者12周，每天五杯普通速溶咖啡或Coffee Slender®（富含綠原酸）。喝Coffee Slender®參與者明顯減少了體重，其中80 %的減少是體內(nèi)脂肪，而普通速溶咖啡的參與者減少體重和體內(nèi)脂肪的作用并不顯著。此外，Soga等[60]研究了綠原酸對人體能量代謝的影響。18名健康男性受試者每天食用185 ml含或不含綠原酸的測試飲料（329 mg），持續(xù)4周，間接量熱法顯示與對照飲料相比含有綠原酸的飲料可顯著提高餐后能量的利用，并且飲用含綠原酸飲料的受試者餐后脂肪利用率更高。

  在控制血脂異常方面，Cho等[57]觀察到綠原酸和咖啡酸均顯著降低小鼠血漿中的游離脂肪酸、甘油三酸酯和膽固醇，與高脂對照組相比顯著提高了高密度脂蛋白膽固醇/總膽固醇的比率。Huang等[58]發(fā)現(xiàn)綠原酸以劑量依賴性方式抑制高脂飲食誘導的血清脂質(zhì)水平。Wan等[61]研究了綠原酸對大鼠高膽固醇血癥的影響。發(fā)現(xiàn)綠原酸可顯著降低總膽固醇和低密度脂蛋白膽固醇，并增加高密度脂蛋白膽固醇；此外，還改善了動脈粥樣硬化指數(shù)和心臟危險因素。

  在治療糖尿病方面，Ong等[62]觀察到綠原酸抑制Leprdb/db糖尿病小鼠的肝中葡萄糖6-磷酸酶（Glucose-6-phosphatase，G-6-P）表達和活性，減少肝脂肪變性，改善脂質(zhì)分布和骨骼肌葡萄糖攝取，從而改善空腹血糖水平、葡萄糖耐量、胰島素敏感性和血脂異常。Attila等[63]研究了白桑樹的葉提取物及其三種主要成分（綠原酸、蘆丁和異槲皮素）的抗糖尿病活性。在鏈脲霉素誘導糖尿病大鼠模型，發(fā)現(xiàn)白桑樹的葉提取物、綠原酸和蘆丁的非空腹血糖水平呈劑量依賴性降低，而異槲皮素則未見。Jin等[64]研究了綠原酸對晚期糖尿病小鼠葡萄糖和脂質(zhì)代謝的影響。與對照組相比，綠原酸組的體脂，空腹血糖和糖基化血紅蛋白（Hemoglobin A1c，HbA1c）百分比顯著降低。Kim等[65]通過大鼠半乳糖性白內(nèi)障模型來確定綠原酸對糖性白內(nèi)障的影響。實驗顯示，持續(xù)兩周口服綠原酸可以有效阻止糖性白內(nèi)障的發(fā)展。Bagdas等[66]研究了綠原酸治療對大鼠糖尿病傷口愈合的影響，使用鏈脲霉素誘導糖尿病大鼠模型并在其背部形成傷口，通過觀察傷口愈合的時間，發(fā)現(xiàn)綠原酸加速傷口愈合。Johnston等[67]評估了咖啡中綠原酸抗糖尿病作用。實驗結(jié)果表明綠原酸可以顯著降低葡萄糖依賴性促胰島素多肽（Glucose-dependent insulinotropic polypeptide，GIP），顯著增加胰高血糖素樣肽1（Glucagon-like peptide-1，GLP-1）的分泌，結(jié)果顯示，綠原酸有效降低腸道葡萄糖吸收率，對葡萄糖轉(zhuǎn)運具有拮抗作用。同樣Iwai等[68]通過對45位受試者評估了富含綠原酸的不含咖啡因的綠咖啡豆提取物的降血糖作用。發(fā)現(xiàn)攝入含有綠原酸飲料后血漿葡萄糖顯著降低，但未觀察到血漿胰島素譜有顯著變化。Ahrens[69]研究了Emulin™（綠原酸，楊梅素和槲皮素的專利混合物）的抗糖尿病作用。對40位2型糖尿病患者進行治療。結(jié)果顯示，如果定期食用EmulinTM，不僅具有降低食物血糖的急性作用，而且可以長期降低2型糖尿病患者的血糖水平。基于綠原酸對人體的糖代謝障礙具有調(diào)節(jié)作用，Gao等[70]通過綠原酸修飾的功能化磁微球蛋白尋找了綠原酸的靶點為蛋白激酶B（Protein kinase B，AKT）。并通過綠原酸分子探針的免疫熒光進一步證明了綠原酸與AKT的共定位。同時闡明了其作用機制是通過直接靶向AKT的PH結(jié)構(gòu)域，激活AKT在Ser-473上的磷酸化，誘導下游分子的磷酸化，糖原合酶激酶3（Glycogen synthase kinase 3, GSK3）和叉頭框轉(zhuǎn)錄因子O亞族1（Forkhead box O1, FOXO1），從而發(fā)揮葡萄糖代謝調(diào)節(jié)作用。

  在治療代謝綜合征方面，Ma等[71]研究評估綠原酸在代謝綜合征中的作用時發(fā)現(xiàn)綠原酸的預防和治療對肥胖癥及與肥胖有關(guān)的小鼠肝臟脂肪變性和胰島素抵抗有很好的療效。綠原酸有效防止體重增加，抑制肝脂肪變性的發(fā)展，并減低高脂飲食誘導的胰島素抵抗。Patti等[52]評價了一個含有綠原酸的天然補品對代謝綜合征患者的影響。78名患有代謝綜合征的患者持續(xù)服用4個月，其體重、體重指數(shù)、腰圍、空腹血糖和體重顯著降低，也觀察到總膽固醇也得到有效地降低。

  在治療心血管系統(tǒng)和血栓栓塞性疾病方面，綠原酸顯現(xiàn)出很好的療效，在細胞水平，Sancheza等[72]研究表明用200 mM 綠原酸處理3T3-L1脂肪細胞后，細胞內(nèi)鈣濃度相對于對照增加了9倍，同時也促進了胰島素的分泌，同時顯著提高了PPARg （過氧化物酶體增殖劑激活受體，Peroxisome proliferator-activated receptor，PPAR）（150 %）和GLUT4（220 %）以及PPARa（40 %）和脂肪酸轉(zhuǎn)運蛋白（Fatty acid transporters，F(xiàn)ATP）（25 %）的mRNA表達。因此，可作為刺激胰島素的增敏劑和降脂劑。在整體動物，Suzuki等[73]報道了綠原酸對減低自發(fā)性高血壓大鼠的血壓和改善血管功能。其機制通過抑制血管系統(tǒng)中活性氧過量的產(chǎn)生來降低氧化應激和提高一氧化氮的生物利用度，進而減輕了自發(fā)性高血壓大鼠的內(nèi)皮功能障礙，血管肥大和高血壓。在人體，純綠原酸和綠原酸含量很高食物可以對血壓產(chǎn)生積極影響。Kozuma等[74]針對117名輕度的高血壓健康男性。分組給予28天了不同濃度綠原酸，發(fā)現(xiàn)綠原酸可以有效降低收縮壓（Systolic blood pressure，SBP）和舒張壓（Diastolic blood pressure，DBP），其原因綠原酸具有抗氧化特性，改善內(nèi)皮功能障礙并降低血壓。Watanabe等[75]也同樣證明了綠原酸有效降低患有高血壓患者的血壓。Mubarak等[76]研究了綠原酸對一氧化氮狀態(tài)、內(nèi)皮功能和血壓的急性影響。結(jié)果顯示，給予綠原酸的受試者的收縮壓和舒張壓均明顯降低，一氧化氮的狀態(tài)和內(nèi)皮功能未受到明顯影響。綠原酸可用于預防糖尿病引發(fā)的心血管系統(tǒng)損害[77]。Stefanello等[78]研究表明綠原酸作為抗凝劑，當糖尿病大鼠的血小板在激動劑二磷酸腺苷（Adenosine diphosphate，ADP）刺激下，綠原酸治療30天血小板聚集可明顯減少。此外，F(xiàn)uentes等[79]證明綠原酸抑制血小板A2A受體/腺苷酸環(huán)化酶/環(huán)磷酸腺苷（Cyclic adenosine phosphate，cAMP）/ 蛋白激酶A（Protein kinase A，PKA）信號激活途徑進而抑制小鼠動脈血栓形成。綜述所述，現(xiàn)對綠原酸治療代謝性疾病的作用機制進行總結(jié)（圖 2）。

Figure 2 Mechanisms of action of chlorogenic acid over metabolic diseases. Abbreviations: AMPK = AMP-activated protein kinase, CPT1 = Carnitine palmitoyltransferase 1, FAS = Fatty acid synthase, FFA = Free fatty acid, GLUT2=Glucose transporter type 2, G-6-P = Glucose-6-phosphatase, GIP = Glucose-dependent insulinotropic polypeptide, GLP-1=Glucagon-like peptide-1, HMGCR = 3-hydroxy-3-methylglutaryl CoA reductase, LXR = Liver X receptor, NO = Nitric oxide, PFK = Phosphofructokinase, PPAR = Peroxisome proliferator-activated receptor, ROS = Reactive oxygen species, SREBP-1c = Sterol regulatory element-binding protein 1c

2 總結(jié)

  近年來，有關(guān)綠原酸的研究報道越來越多，業(yè)已成為天然產(chǎn)物領域研究熱點之一。綠原酸作為金銀花、杜仲、咖啡、茵陳等許多中草藥的主要有效成分之一，隨著其生物活性的不斷深入研究，它的應用愈加廣泛。在國外已將綠原酸作為減肥的保健品出售。在我們國家，綠原酸也作為抗腫瘤藥物進行晚期復發(fā)腦膠質(zhì)母細胞瘤的II期臨床研究。但值得注意地是, 雖然我國對含有綠原酸及其衍生物的中藥的使用有著悠久的歷史, 但是我們對綠原酸分子機制的探索和靶點驗證仍然存在很大的不足, 這也是我們今后著力解決的問題。

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圖文摘要：

  綠原酸在抗菌、抗病毒、抗腫瘤、抗氧化和抗炎以及治療代謝類疾病等方面的藥理作用及機制研究

The pharmacological effects and mechanisms of chlorogenic acid from several aspects such as antibacterial, antiviral, antitumor, antioxidant and anti-inflammatory and treatment of metabolic diseases.