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綠原酸的藥理作用及機制研究進展
[ 來源:四川九章生物科技有限公司   發布日期:2020-05-26 05:45:01  責任編輯:  瀏覽次 ]

王慶華,杜婷婷,張智慧,季鳴,胡海宇,陳曉光*

(中國醫學科學院、北京協和醫學院藥物研究所,中國醫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)的研究發展較快,在醫藥、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。

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

通訊作者Tel: 86-10-63165207, E-mail: [email protected]

  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,其分子結構中有酯鍵、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、降血糖和免疫調節等多方面的藥理作用[6-8],在食品、醫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,增加外膜和質膜通透性, 導致細菌的屏障功能喪失,進而發揮其抗菌活性[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,綠原酸被發現具有抑制腫瘤的作用,從而引起了人們的廣泛關注[23]。此后,有關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)進而抑制腦膠質瘤生長[24]。Jiang課題組[25]報道了綠原酸對肝癌、肺癌和膠質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]研究發現綠原酸通過誘導活性氧的產生進而抑制結腸癌。Sapio等[27]報道綠原酸通過激活細胞外信號調節激酶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物,具有很強抗氧化和抗炎特性。兒茶酚結構的存在為自由基提供了結合位點[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]發現綠原酸可以抑制氧化應激誘導的腸上皮細胞中IL-8的產生來起到抗炎作用,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的產生。同年,Liang等[37]也指出綠原酸及其異構體可以通過抑制p38級聯磷酸化和上調NF-κB信號通路來抑制其上皮細胞(Caco-2)中IL-8產生。Gao等[38]在硫酸葡聚糖誘導的小鼠潰瘍性結腸炎模型中,發現綠原酸是通過調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節炎(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)啟動子區域的DNA結合能力,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相關因子2(Nuclear factor erythroid 2-related factor 2,Nrf2)信號通路并抑制核苷酸結合寡聚結構域,富含亮氨酸重復序列和含Pyrin結構域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。結果表明,綠原酸預處理可提高NAD-依賴性去乙;福⊿irtuin 1,SIRT1)活性水平,逆轉了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生功能障礙。其機制通過調節SIRT1和AMPK / PGC-1功能來抑制oxLDL誘導的內皮細胞凋亡。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調節的線粒體形態來預防飽和游離脂肪酸(Free fatty acid,FFA)誘導的脂毒性。結果表明。綠原酸通過減少ROS的產生以及增加線粒體質量和線粒體膜電位,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。神經退行性疾。ò柎暮D喜。ˋlzheimer disease,AD)和帕金森氏。≒arkinson’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元受損[45];诰G原酸具有較強的抗氧化和抗炎作用,很多學者發現它具有很好神經系統保護作用[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展現出很好的效果[47, 48]。Hermawati等[49]發現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-內皮細胞粘附分子CD31(Platelet endothelial cell adhesion molecule-1,PECAM-1/CD31)表達并降低內皮素(Endothelin-1,ET-1)表達來改善空間記憶并防止雙側頸總動脈閉塞后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誘導內源性抗氧化酶。因此,綠原酸可以作為潛在的神經保護藥物。

1.5 治療代謝性疾病

  隨著社會的進步和人類物質生活水平的提高,代謝相關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]。隨著天然產物在治療代謝性疾病優勢的逐漸展現,人們又重新燃起了對天然產物的興趣。許多研究已經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,降低血漿中的脂質水平,并改變脂肪組織中脂肪生成和脂肪分解相關基因的mRNA表達。 此外,綠原酸改善HFD誘發的腸道菌群失調,也有助于改善HFD誘發的肥胖。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子泄漏,上調了葡萄糖轉運蛋白2(Glucose transporter type 2,GLUT2)和磷酸果糖激酶(Phosphofructokinase,PFK)來促進葡萄糖的吸收,增加了線粒體的數量和功能。2019年,Xu等[55]研究了綠原酸和咖啡因對高脂飲食誘導的肥胖小鼠脂質代謝的聯合作用機理。飼喂綠原酸和咖啡因的聯合使用可有效降低增加的體重、腹膜內脂肪組織重量、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,并增加血清脂聯素水平,促進了AMPKα的磷酸化,抑制了轉錄調節因子固醇調節元件結合蛋白-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,FAS)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。結果表明,綠原酸和咖啡因的聯用,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節脂質代謝。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果,綠原酸以劑量依賴性方式抑制體內和內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 %的減少是體內脂肪,而普通速溶咖啡的參與者減少體重和體內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]發現綠原酸以劑量依賴性方式抑制高脂飲食誘導的血清脂質水平。Wan等[61]研究了綠原酸對大鼠高膽固醇血癥的影響。發現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,發現白桑樹的葉提取物、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障模型來確定綠原酸對糖性白內障的影響。實驗顯示,持續兩周口服綠原酸可以有效阻止糖性白內障的發展。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,發現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,結果顯示,綠原酸有效降低腸道葡萄糖吸收率,對葡萄糖轉運具有拮抗作用。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。發現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;诰G原酸對人體的糖代謝障礙具有調節作用,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結構域,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)和叉頭框轉錄因子O亞族1(Forkhead box O1, FOXO1),從而發揮葡萄糖代謝調節作用。

  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現綠原酸的預防和治療對肥胖癥及與肥胖有關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服用4個月,其體重、體重指數、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。


  在治療心血管系統和血栓栓塞性疾病方面,綠原酸顯現出很好的療效,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 %)和脂肪酸轉運蛋白(Fatty acid transporters,FATP)(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中活性氧過量的產生來降低氧化應激和提高一氧化氮的生物利用度,進而減輕了自發性高血壓大鼠的內皮功能障礙,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,發現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、內皮功能和血壓的急性影響。結果顯示,給予綠原酸的受試者的收縮壓和舒張壓均明顯降低,一氧化氮的狀態和內皮功能未受到明顯影響。綠原酸可用于預防糖尿病引發的心血管系統損害[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,Fuentes等[79]證明綠原酸抑制血小板A2A受體/腺苷酸環化酶/環磷酸腺苷(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,現對綠原酸治療代謝性疾病的作用機制進行總結(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

  近年來,有關綠原酸的研究報道越來越多,業已成為天然產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腦膠質母細胞瘤的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。

References

[1] Kühnl T, Koch U, Heller W, et al. Chlorogenic acid biosynthesis: characterization of a light-induced microsomal 5-O-(4-coumaroyl)-D-quinate/shikimate 3'-hydroxylase from carrot (Daucus carota L.) cell suspension cultures [J]. Arch Biochem Biophys, 1987, 258(1): 226-232.

[2] Lallemand L A, Zubieta C, Lee S G, et al. A structural basis for the biosynthesis of the major chlorogenic acids found in coffee [J]. Plant Physiol, 2012, 160(1):249-260.

[3] Lepelley M, Cheminade G, Tremillon N, et al. Chlorogenic acid synthesis in coffee: An analysis of CGA content and real-time RT-PCR expression of HCT, HQT, C3H1, and CCoAOMT1 genes during grain development in C. canephora [J]. Plant Sci, 2007, 172(5): 978-996.

[4] Duarte G S, Pereira A A, Farah A. Chlorogenic acids and other relevant compounds in Brazilian coffees processed by semi-dry and wet post-harvesting methods [J]. Food Chem, 2010, 118(3):851-855.

[5] Wang Z, Clifford M N. Comparison of the profiles of chlorogenic acids and their derivatives from three Chinese traditional herbs by LC-MSn [J]. Acta Pharm Sin, 2008, 43(2):185-190.

[6] Naveed M, Hejazi V, Abbas M, et al. Chlorogenic acid (CGA): A pharmacological review and call for further research [J]. Biomed Pharmacother, 2018, 97:67-74.

[7] Bagdas D, Gul Z, Meade J A, et al. Pharmacologic Overview of Chlorogenic Acid and its Metabolites in Chronic Pain and Inflammation [J]. Curr Neuropharmacol, 2020, 18(3):216-228.

[8] Li Y, Wang Q, Yao X, et al. Induction of CYP3A4 and MDR1 gene expression by baicalin, baicalein, chlorogenic acid, and ginsenoside Rf through constitutive androstane receptor- and pregnane X receptor-mediated pathways [J]. Eur J Pharmacol, 2010, 640(1-3):46-54.

[9] Santana-Gálvez Jesús, Luis C Z, Jacobo-Velázquez Daniel. Chlorogenic acid: recent advances on its dual role as a food additive and a nutraceutical against metabolic syndrome [J]. Molecules, 2017, 22(3):358.

[10] Martínez G, Regente M, Jacobi S, et al. Chlorogenic acid is a fungicide active against phytopathogenic fungi [J]. Pestic Biochem Physiol, 2017, 140:30-35.

[11] Lou Z, Wang H, Zhu S, et al. Antibacterial activity and mechanism of action of chlorogenic acid [J]. J Food Sci, 2011, 76:M398-M403.

[12] Li G, Wang X, Xu Y, et al. Antimicrobial effect and mode of action of chlorogenic acid on Staphylococcus aureus [J]. Eur Food Res Technol, 2014, 238:589-596.

[13] Ren S, Wu M, Guo J, et al. Sterilization of polydimethylsiloxane surface with Chinese herb extract: a new antibiotic mechanism of chlorogenic acid [J]. Sci Rep, 2015, 5:10464.

[14] Lee B, Lee D G. Depletion of reactive oxygen species induced by chlorogenic acid triggers apoptosis-like death in Escherichia coli [J]. Free Radic Res, 2018, 52(5):1-11.

[15] Neamati N, Hong H, Sunder S, et al. Potent inhibitors of human Immunodeficiency virus type 1 integrase: identification of a novel four-point pharmacophore and tetracyclines as novel inhibitors [J]. Mol Pharmacol, 1997, 52(6):1041.

[16] Utsunomiya H, Ichinose M, Uozaki M, et al. Antiviral activities of coffee extracts in vitro [J]. Food Chem Toxicol, 2008, 46(6):1919-1924.

[17] Robinson W E, Cordeiro M, Abdel-Malek S, et al. Dicaffeoylquinic acid inhibitors of human immunodeficiency virus integrase: Inhibition of the core catalytic domain of human immunodeficiency virus integrase [J]. Mol Pharmacol, 1996, 50(4):846-855.

[18] Tamura H, Akioka T, Ueno K, et al. Anti-human immunodeficiency virus activity of 3,4,5-tricaffeoylquinic acid in cultured cells of lettuce leaves [J]. Mol Nutr Food Res, 2006, 50(4-5): 396-400.

[19] Karar M G E, Matei M F, Jaiswal R, et al. Neuraminidase inhibition of dietary chlorogenic acids and derivatives-potential antivirals from dietary sources [J]. Food Funct, 2016, 7: 2052-2059.

[20] Ding Y, Cao Z, Cao L, et al. Antiviral activity of chlorogenic acid against influenza A (H1N1/H3N2) virus and its inhibition of neuraminidase [J]. Sci Rep, 2017, 7:45723.

[21] Guo Y J, Luo T, Wu F, et al. Involvement of TLR2 and TLR9 in the anti-inflammatory effects of chlorogenic acid in HSV-1-infected microglia [J]. Life Sciences, 2015, 127:12-18.

[22] Wang G F, Shi L P, Ren Y D, et al. Anti-hepatitis B virus activity of chlorogenic acid, quinic acid and caffeic acid in vivo and in vitro [J]. Antiviral Res, 2009, 83(2):186-190.

[23] Huang M T, Smart R C, Wong C Q, et al. Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate[J]. Cancer Res. 1988, 48(21):5941-5946.

[24] Xue N, Zhou Q, Ji M, et al. Chlorogenic acid inhibits glioblastoma growth through repolarizating macrophage from M2 to M1 phenotype [J]. Sci Rep, 2017, 7:39011.

[25] Huang S, Wang L L, Xue N N, et al. Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation [J]. Theranostics. 2019, 9(23): 6745-6763.

[26] Hou N, Liu N, Han J, et al. Chlorogenic acid induces reactive oxygen species generation and inhibits the viability of human colon cancer cells [J]. Anti-Cancer Drugs, 2016, 28(1):1.

[27] Sapio L, Salzillo A, Illiano M, et al. Chlorogenic acid activates ERK1/2 and inhibits proliferation of osteosarcoma cells [J]. J Cell Physiol. 2020, 235:3741-3752.

[28] Yamagata K, Izawa Y, Onodera D, et al. Chlorogenic acid regulates apoptosis and stem cell marker-related gene expression in A549 human lung cancer cells [J]. Mol and Cell Biochem, 2018, 441: 9-19.

[29] Kono Y, Kobayashi K, Tagawa S, et al. Antioxidant activity of polyphenolics in diets. Rate constants of reactions of chlorogenic acid and caffeic acid with reactive species of oxygen and nitrogen [J]. Biochim Biophys Acta, 1997, 1335(3): 335-342.

[30] Riceevans C A, Miller N J, Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids [J]. Free Radic Biol Med, 1996, 20(7): 933-956.

[31] Sato, Y, Itagaki, S, Kurokawa, T, et al. In vitro and in vivo antioxidant properties of chlorogenic acid and caeic acid [J]. Int J Pharm, 2011, 403: 136-138.

[32] Kono Y, Kobayashi K, Tagawa S, et al. Antioxidant activity of polyphenolics in diets. Rate constants of reactions of chlorogenic acid and caffeic acid with reactive species of oxygen and nitrogen [J]. Biochim Biophys Acta, 1997, 1335(3): 335.

[33] Zhang L Y, Cosma G, Gardner H, et al. Effect of chlorogenic acid on hydroxyl radical [J]. Mol Cell Biochem, 2003, 247: 205–210.

[34] Lu Y, Foo L Y. Antioxidant and radical scavenging activities of polyphenols from apple pomace [J]. Food Chem, 68(1): p81-85.

[35] Dos Santos M D, Almeida M C, Lopes N P, et al. Evaluation of the Anti-inflammatory, Analgesic and Antipyretic Activities of the Natural Polyphenol Chlorogenic Acid [J]. Biol Pharm Bull, 2006, 29(11): 2236-2240.

[36] Hee S, Hideo S, Min-Jung B, et al. Catechol groups enable reactive oxygen species scavenging-mediated suppression of PKD-NFkappaB-IL-8 signaling pathway by chlorogenic and caffeic acids in human intestinal cells [J]. Nutrients, 2017, 9(2): 165.

[37] Liang N, D. Kitts D. Chlorogenic acid (CGA) isomers alleviate interleukin 8 (IL-8) production in Caco-2 cells by decreasing phosphorylation of p38 and increasing cell integrity[J]. Int J Mol Sci, 2018, 19: 3873.

[38] Gao W, Wang C, Yu L, et al. Chlorogenic Acid Attenuates Dextran Sodium Sulfate-Induced Ulcerative Colitis in Mice through MAPK/ERK/JNK Pathway [J]. BioMed Res Internat, 2019, 6769789.

[39] Fu X, Lyu X, Liu H, et al. Chlorogenic acid inhibits BAFF expression in collagen-induced arthritis and human synoviocyte MH7A cells by modulating the activation of the NF-κB signaling pathway [J]. J Immunol Res, 2019, 8042097.

[40] Shi A, Shi H, Wang Y, et al. Activation of Nrf2 pathway and inhibition of NLRP3 inflammasome activation contribute to the protective effect of chlorogenic acid on acute liver injury [J]. Int Immunopharmacol, 2018, 54:125-130.

[41] Tsai K L, Hung C H, Chan S H, et al. Chlorogenic acid protects against oxLDL-induced oxidative damage and mitochondrial dysfunction by modulating SIRT1 in endothelial cells [J]. Mol Nutr Food Res, 2018, 1700928.

[42] Yang L, Wei J, Sheng F, et al. Attenuation of palmitic acid-Induced lipotoxicity by chlorogenic acid through activation of SIRT1 in hepatocytes [J]. Mol Nutr Food Res, 2019, 63 (14): 1801432.

[43] Ali N, Rashid S, Nafees S, et al. Protective effect of chlorogenic acid against methotrexate induced oxidative stress inflammation and apoptosis in rat liver: An experimental approach [J]. Chem Biol Interact, 2017, 272: 80-91.

[44] Wang Y, Yang A F, Xue B J, et al. Antischistosomiasis liver fibrosis effects of chlorogenic acid through IL-13/miR-21/Smad7 signaling interactions in vivo and in vitro [J]. Antimicrob Agents Chemother, 2016, 61(2): e01347-16.

[45] Nabavi S M, Manayi A, Daglia M, et al. Chlorogenic acid and mental diseases: from chemistry to medicine [J]. Curr Neuropharmacol, 2017, 15(4): 471-479.

[46] Lin M T, Beal M F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases [J]. Nature, 2006, 443(7113): 787-795.

[47] Ascherio A, Chen H, Schwarzschild M A, et al. Caffeine, postmenopausal estrogen, and risk of Parkinsons disease. Neurology, 2003, 60(5), 790-795.

[48] Arendash G W, Schleif W, Rezai-Zadeh K, et al. Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production [J]. Neuroscience, 2006, 142(4): 941-952.

[49] Hermawati E, Arfian N, Mustofa, et al. Chlorogenic acid ameliorates memory loss and hippocampal cell death after transient global ischemia [J]. Eur J Neurosci, 2020, 51: 651–669.

[50] Juan Y, Peng S, Xu J, et al. Reversing ROS-mediated neurotoxicity by chlorogenic acid involves its direct antioxidant activity and activation of Nrf2-ARE signaling pathway [J]. Biofactors, 2019, 45(4):616-626.

[51] Gregory K, Panagiota P, Eva K, et al. Metabolic syndrome: definitions and controversies [J]. BMC Med, 2011, 9(1):48-48.

[52] Patti A M, Al-Rasadi K, Katsiki N, et al. Effect of a natural supplement containing Curcuma longa, Guggul, and chlorogenic acid in patients with metabolic syndrome [J]. Angiology, 2015, 66, 856-861.

[53] Wang Z, Lam K L, Hu J, et al. Chlorogenic acid alleviates obesity and modulates gut microbiota in high-fat-fed mice [J]. Food Sci Nutr, 2019, 7(2): 579-588.

[54] Han X, Zhang Y, Guo J, et al. Chlorogenic acid stimulates the thermogenesis of brown adipocytes by promoting the uptake of glucose and the function of mitochondria [J]. J Food Sci, 2019, 84 (12): 3815-3824.

[55] Xu M, Yang L, Zhu Y, et al. Collaborative effects of chlorogenic acid and caffeine on lipid metabolism via the AMPKα-LXRα/SREBP-1c pathway in high-fat diet-induced obese mice [J]. Food Funct, 2019, 10: 7489-7497.

[56] Kumar R, Sharma A, Iqbal M S, et al. Therapeutic promises of Chlorogenic acid with special emphasis on its anti-obesity property [J]. Curr Mol Pharmacol, 2020, 13(1):7-16

[57] Cho A S, Jeon S M, Kim M J, et al. Chlorogenic acid exhibits anti-obesity property and improves lipid metabolism in high-fat diet-induced-obese mice [J]. Food Chem Toxicol, 2010, 48(3): 937-943.

[58] Huang K, Liang X C, Zhong Y L, et al. 5-Caffeoylquinic acid decreases diet-induced obesity in rats by modulating PPARα and LXRα transcription [J]. Journal of the Science of Food and Agriculture, 2015, 95(9):1903-1910.

[59] Thom, E. The effect of chlorogenic acid enriched coffee on glucose absorption in healthy volunteers and its effect on body mass when used long-term in overweight and obese people [J]. J Int Med Res, 2007, 35(6): 900–908.

[60] Soga S, Ota N, Shimotoyodome A. Stimulation of postprandial fat utilization in healthy humans by daily consumption of chlorogenic acids [J]. Biosci Biotechnol Biochem, 2013, 77, 1633-1636.

[61] Wan, C W, Wong C N, Pin W K, et al. Chlorogenic acid exhibits cholesterol lowering and fatty liver attenuating properties by up-regulating the gene expression of PPAR-α in hypercholesterolemic rats induced with a high-cholesterol diet [J]. Phytother Res, 2013, 27, 545–551.

[62] Ong K W, Hsu A, Tan B K H. Anti-diabetic and anti-lipidemic effects of chlorogenic acid are mediated by ampk activation [J]. Biochemn Pharmacol, 2013, 85(9):1341-1351.

[63] Attila H, Ana M, Tusty-Jiuan H, et al. Chlorogenic acid and rutin play a major role in the in vivo antidiabetic activity of Morus alba leaf extract on type II diabetic rats [J]. PloS One, 2012, 7(11): e50619.

[64] Jin S, Chang C, Zhang L, et al. Chlorogenic acid improves late diabetes through adiponectin receptor signaling pathways in db/db mice[J]. PloS One, 2015, 10(4): e0120842.

[65] Kim C S, Kim J, Lee Y M, et al. Inhibitory effects of chlorogenic acid on aldose reductase activity in vitro and cataractogenesis in galactose-fed rats[J]. Arch Pharm Res, 2011, 34(5):847-852.

[66] Bagdas D, Etoz B C, Gul Z, et al. In vivo systemic chlorogenic acid therapy under diabetic conditions: Wound healing effects and cytotoxicity/genotoxicity profile [J]. Food Chem Toxicol, 2015, 81:54-61.

[67] Johnston K L, Clifford M N, Morgan L M. Coffee acutely modifies gastrointestinal hormone secretion and glucose tolerance in humans: glycemic effects of chlorogenic acid and caffeine [J]. Am J Clin Nutr, 2003, 78(4):728-733.

[68] Iwai K, Narita Y, Fukunaga T, et al. Study on the postprandial glucose responses to a chlorogenic acid-rich extract of decaffeinated green coffee beans in rats and healthy human subjects [J]. Food Sci Technol Res. 2012, 18: 849-860.

[69] Ahrens, M J, Thompson D L, et al. Effect of emulin on blood glucose in type 2 diabetics [J]. J Med Food, 2013, 16:1-6.

[70] Gao J, He X, Ma Y, et al. Chlorogenic acid targeting of the AKT PH domain activates AKT/GSK3β/FOXO1 signaling and improves glucose metabolism[J]. Nutrients, 2018, 10(10). 10(10): 1366.

[71] Ma Y, Gao M, Liu D. Chlorogenic acid improves high fat diet-induced hepatic steatosis and insulin resistance in mice [J]. Pharm Res, 2015, 32, 1200-1209.

[72] Sancheza M B, Miranda-Pereza E, Gomez J C, et al. Potential of the chlorogenic acid as multitarget agent: Insulin-secretagogue and PPAR a/g dual agonist [J]. Biomed Pharmacother, 2017, 94:169.

[73] Suzuki A, Yamamoto N, Jokura H, et al. Chlorogenic acid attenuates hypertension and improves endothelial function in spontaneously hypertensive rats [J]. J Hypertens, 2006, 24:1065-1073.

[74] Kozuma K, Tsuchiya S, Kohori J, et al. Antihypertensive effect of green coffee bean extract on mildly hypertensive subjects [J]. Hypertens Res, 2005, 28, 711–718.

[75] Watanabe T, Arai Y, Mitsui Y, et al. The blood pressure-lowering effect and safety of chlorogenic acid from green coffee bean extract in essential hypertension [J]. Clin Exp Hypertens, 2006, 28: 439-449.

[76] Mubarak A, Bondonno C P, Liu A H, et al. Acute effects of chlorogenic acid on nitric oxide status, endothelial function, and blood pressure in healthy volunteers: A randomized trial [J]. J Agric Food Chem, 2012, 60, 9130-9136

[77] Stefanelloa N, Spanevellob R M, Passamontic S, et al. Coffee, caffeine, chlorogenic acid, and the purinergic system [J]. Food and Chem Toxicol, 2019, 123: 298-313.

[78] Stefanello N, Schmatz R, Pereira L B, et al. Effects of chlorogenic acid, caffeine and coffee on components of the purinergic system of streptozotocin-induced diabetic rats [J]. J Nutr Biochem, 2016, 38,145-153.

[79] Fuentes E, Caballero J, Alarcón M, et al. Chlorogenic acid inhibits human platelet activation and thrombus formation [J]. PLoS One, 2014, 9e: 90699.

 

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.




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