李葆林，麻景梅，田宇柔，張鐵軍，牛麗穎*

甘草中新發(fā)現(xiàn)化學(xué)成分和藥理作用的研究進(jìn)展

李葆林1, 2, 3，麻景梅1, 2, 3，田宇柔1, 2, 3，張鐵軍4，牛麗穎1, 2, 3*

1. 河北中醫(yī)學(xué)院，河北 石家莊 050091 2. 河北省中藥配方顆粒創(chuàng)新中心，河北 石家莊 050091 3. 河北省中藥材品質(zhì)評(píng)價(jià)與標(biāo)準(zhǔn)化工程研究中心，河北 石家莊 050091 4. 天津藥物研究院 天津市中藥質(zhì)量標(biāo)志物重點(diǎn)實(shí)驗(yàn)室，天津 300462

甘草為臨床常用配伍藥材，在《神農(nóng)本草經(jīng)》中列為上品。甘草化學(xué)成分多樣，至今已發(fā)現(xiàn)黃酮、三萜、香豆素、二苯乙烯等化合物共400余種?，F(xiàn)代藥理學(xué)研究表明，甘草具有廣泛的抗腫瘤、抗炎、抗菌、抗病毒、神經(jīng)保護(hù)、肝臟保護(hù)等藥理作用。對(duì)甘草中新發(fā)現(xiàn)的化學(xué)成分、人工合成化學(xué)成分、炮制對(duì)化學(xué)成分的影響以及藥理作用的國內(nèi)外相關(guān)研究進(jìn)展進(jìn)行綜述，以期為甘草的進(jìn)一步開發(fā)利用提供參考。

甘草；化學(xué)成分；炮制；作用機(jī)制；抗腫瘤；新型冠狀病毒肺炎

甘草為豆科植物甘草Fisch.、脹果甘草Bat.或光果甘草L.的干燥根和根莖，具有補(bǔ)中益氣、緩急止痛、清熱解毒、化痰止咳、調(diào)和藥性之功效。其初載于《神農(nóng)本草經(jīng)》，列為上品，距今已有千載史長。據(jù)現(xiàn)代藥理學(xué)研究表明，有關(guān)甘草的研究方向已由藥效活性成分、藥效學(xué)研究逐漸向藥效機(jī)制研究過渡。本文總結(jié)近5年來國內(nèi)、外相關(guān)的研究進(jìn)展，對(duì)甘草中新發(fā)現(xiàn)化學(xué)成分、藥理作用及其機(jī)制進(jìn)行綜述，以期為進(jìn)一步研究提供數(shù)據(jù)上的支持和理論上的參考。

1 化學(xué)成分

古語有云，十方九草，無草不成方。甘草，歷經(jīng)千余年用藥實(shí)踐檢驗(yàn)，現(xiàn)流傳下來的經(jīng)典方劑搭配，如芍藥甘草湯、大黃甘草湯、甘草附子湯、枳殼甘草湯等枚不勝舉，均為其療效之佐證，僅《傷寒論》一部中所載方劑就有約74%的處方使用甘草，足以說明甘草的藥用價(jià)值[1-4]。

1.1 新發(fā)現(xiàn)的化學(xué)成分

據(jù)報(bào)道，甘草屬中已分離檢測(cè)出化學(xué)成分多達(dá)400余個(gè)，主要成分為黃酮類和三萜類化合物，同時(shí)含有香豆素類和二苯乙烯類化合物[5-9]。其常用研究模式主要為以HPLC、GC、pH區(qū)帶、大孔樹脂、硅膠、ODS、凝膠、IPL等色譜手段進(jìn)行分離，通過UV、MS、NMR等手段進(jìn)行檢測(cè)[10-16]。近5年來甘草中新發(fā)現(xiàn)的化學(xué)成分見表1。

表1 近5年來甘草中新發(fā)現(xiàn)的化學(xué)成分

1.2 人工修飾的化學(xué)成分

研究發(fā)現(xiàn)，通過特定化學(xué)成分生物合成相關(guān)酶編碼基因，結(jié)合基因組和轉(zhuǎn)錄組數(shù)據(jù)，可在體外利用前體化合物人工合成目標(biāo)產(chǎn)物，提高產(chǎn)物的產(chǎn)量和質(zhì)量分?jǐn)?shù)[25]。

同時(shí)，甘草中活性成分種類繁多，部分化合物的藥理效應(yīng)仍不盡理想，因此，通過人工修飾化合物并以此增強(qiáng)藥效成為中藥臨床應(yīng)用的又一突破口。Hu等[26]研究設(shè)計(jì)合成了一系列甘草素縮氨基硫脲衍生物，并通過體外試驗(yàn)對(duì)化合物抗腫瘤活性進(jìn)行檢測(cè)。結(jié)果表明，在甘草素骨架的4位引入縮氨基硫脲官能團(tuán)可顯著抗腫瘤活性，結(jié)構(gòu)見圖1中化合物1。Gaur等[27]在人工合成異甘草素和甘草素衍生物的過程中發(fā)現(xiàn)，引入醚基和酯基可顯著提高藥物的降糖活性，結(jié)構(gòu)見圖1中化合物2～7。Lin等[28]發(fā)現(xiàn)在甘草酸的糖苷處引入氨基酸殘基，可有效增強(qiáng)化合物的抗菌活性，結(jié)構(gòu)見圖1中化合物8。

圖1 近年來甘草中人工修飾的化學(xué)成分

1.3 炮制對(duì)化學(xué)成分的影響

中藥材化學(xué)成分受產(chǎn)地、氣候、土地環(huán)境、日照條件、采集方式、炮制方式、貯存條件等諸多影響因素。炮制，作為中藥特有的前處理方法，其經(jīng)熱、水、酒、蜜、醋等方式處理，可達(dá)到增效減毒，緩和藥性之功效。甘草常以生制、炒制、蜜炙為多，其成分含量受炮制方式不同而有所差異[29-31]。周倩等[32]研究發(fā)現(xiàn)蜜炙后甘草中化學(xué)成分比例發(fā)生改變，葡萄糖與果糖含量增加，新產(chǎn)生了5-羥甲基糠醛，增加了補(bǔ)脾作用。魯亞奇等[33]通過HPLC比較甘草炒制前后8個(gè)藥效成分的含量變化。研究發(fā)現(xiàn)，甘草炒制后，藥效成分較炮制前有所差異，其中異甘草苷、異甘草素均呈上升趨勢(shì)。Zhang等[34]采用UPLC-MS/MS法考察蜜炙前后甘草中6個(gè)生物活性成分體內(nèi)藥動(dòng)學(xué)差異，發(fā)現(xiàn)蜜炙后異甘草苷吸收減少，而異甘草素的吸收增加。

此外，同一炮制方法，可能也受其炮制過程的影響產(chǎn)生差異性變化。Ota等[35]以3批野生甘草藥材為原料，采用HPLC-ESI-IT-TOF-MSn對(duì)生品、炒制和蜜炙甘草樣品中的化學(xué)成分進(jìn)行了分析。發(fā)現(xiàn)共有41個(gè)峰的面積在加工過程中發(fā)生了明顯的變化，其中12個(gè)峰面積與炮制溫度呈正相關(guān)。

2 藥理作用

2.1 抗腫瘤作用

惡性腫瘤已成為嚴(yán)重威脅人類生命安全的重大疾病，其病因復(fù)雜，死亡率高、預(yù)后較差，暫無有效的治療手段?，F(xiàn)代醫(yī)學(xué)研究表明，甘草中藥效成分具有廣譜的抗腫瘤作用，可通過抑制腫瘤細(xì)胞的增殖減少遷移，促進(jìn)機(jī)體自噬等方式進(jìn)行治療，同時(shí)可通過修飾化學(xué)成分取代基達(dá)到增強(qiáng)藥效的作用[17,26,37]。各類抗腫瘤活性成分及藥效機(jī)制見表2。

2.1.1 抗肝癌 肝癌臨床癥狀不明顯，如食欲減退、身體消瘦、肝區(qū)疼痛等，其發(fā)病機(jī)制常與病毒性肝炎、肝硬化或其他致病物質(zhì)有關(guān)，是我國男性高發(fā)癌癥之一。Wang等[38-39]對(duì)甘草提取物對(duì)肝癌HCC細(xì)胞的潛在抗癌作用及其分子機(jī)制進(jìn)行了研究。結(jié)果發(fā)現(xiàn)，甘草苷可通過活性氧介導(dǎo)的MAPK/Akt/NF-κB信號(hào)通路誘導(dǎo)肝癌細(xì)胞周期阻滯和凋亡。同時(shí)，甘草素可通過活性氧介導(dǎo)的MAPK/STAT3/NF-κB信號(hào)通路誘導(dǎo)肝癌細(xì)胞凋亡，二者具有協(xié)同作用。

表2 甘草抗癌活性成分及作用機(jī)制

MAPK-絲裂原活化蛋白激酶 Akt-蛋白激酶B NF-κB-核轉(zhuǎn)錄因子-κB STAT3-信號(hào)傳導(dǎo)轉(zhuǎn)錄激活因子3 BRAF-絲氨酸/蘇氨酸激酶v-RAF鼠肉瘤病毒癌基因同源物B MEK-絲裂原活化蛋白/細(xì)胞外調(diào)節(jié)蛋白激酶 LRIG1-富含亮氨酸重復(fù)序列和免疫球蛋白樣結(jié)構(gòu)域1

MAPK-mitogen-activated protein kinase Akt-protein kinase B NF-κB-nuclear factor kappa-B STAT3-signal transducer and activator of transcription 3BRAF-the serine threonine kinase v-RAF murine sarcoma viral oncogene homologue B MEK-mitogen-activated protein kinase/ERK kinase LRIG1- leucine-rich repeats and immunoglobulin-like domains 1

Wang等[40]研究采用形狀篩選和誘導(dǎo)擬合對(duì)接的方法研究光甘草定的抗肝癌機(jī)制，發(fā)現(xiàn)光甘草定能抑制BRAF/MEK通路，減少M(fèi)EK1/2的磷酸化及其下游分子細(xì)胞外調(diào)節(jié)蛋白激酶1/2、轉(zhuǎn)錄激活因子1和環(huán)磷腺苷效應(yīng)元件結(jié)合蛋白的磷酸化水平，同時(shí)通過下調(diào)細(xì)胞周期蛋白D3、周期蛋白依賴性激酶2、4，使細(xì)胞周期阻滯在G1期，抑制肝癌HepG2細(xì)胞的增殖。Cai等[41]從蛋白質(zhì)組學(xué)和化學(xué)生物學(xué)的角度評(píng)價(jià)了甘草酸對(duì)肝癌細(xì)胞的影響，發(fā)現(xiàn)甘草酸可作用于c-Jun氨基末端激酶1，抑制肝癌干細(xì)胞特性，誘導(dǎo)分化。

2.1.2 抗胃癌 胃癌是發(fā)病率最高的消化道惡性腫瘤，其治療方式單一，預(yù)后較差，常伴隨有潰瘍、穿孔、食管阻梗等并發(fā)癥。Xie等[42]研究腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體聯(lián)合甘草苷的抗胃癌作用機(jī)制，發(fā)現(xiàn)當(dāng)2種藥物聯(lián)合使用時(shí)，二者共同作用于c-Jun氨基末端激酶，協(xié)同增強(qiáng)藥理效應(yīng)。Wei等[43]發(fā)現(xiàn)甘草苷通過下調(diào)細(xì)胞周期蛋白D1、細(xì)胞周期蛋白A和細(xì)胞周期蛋白依賴性激酶4水平，促進(jìn)、基因表達(dá)，抑制胃癌細(xì)胞增殖和遷移，進(jìn)而誘導(dǎo)凋亡和自噬。

2.1.3 抗婦科癌 婦科癌癥特指發(fā)病于女性的惡性腫瘤，常指包括宮頸癌、子宮內(nèi)膜癌、卵巢癌在內(nèi)的3大癌癥。Wu等[44]以人子宮內(nèi)膜基質(zhì)T-hESCs細(xì)胞系和人子宮內(nèi)膜癌Ishikawa、HEC-1A和RL95-2細(xì)胞為靶細(xì)胞，檢測(cè)異甘草素對(duì)細(xì)胞增殖、細(xì)胞周期調(diào)控、凋亡或自噬相關(guān)蛋白表達(dá)的影響。研究發(fā)現(xiàn)，異甘草素可誘導(dǎo)細(xì)胞周期阻滯于亞G1期或G2/M期，激活細(xì)胞外信號(hào)調(diào)節(jié)激酶信號(hào)通路，促進(jìn)天冬氨酸特異性半胱氨酸蛋白酶-7（cysteine-containing aspartate-specific protease-7，Caspase-7）/LC3BII蛋白的表達(dá)，誘導(dǎo)小鼠子宮內(nèi)膜癌細(xì)胞凋亡、自噬。

Chen等[45]發(fā)現(xiàn)異甘草素能夠通過抑制卵巢癌SKOV3、OVCAR5細(xì)胞的間充質(zhì)特征，抑制上皮細(xì)胞-間充質(zhì)轉(zhuǎn)化，阻斷癌細(xì)胞腹腔內(nèi)移，延長了荷瘤小鼠的生存時(shí)間。He等[46]研究發(fā)現(xiàn)甘草苷可通過激活Caspase-3和多聚多聚二磷酸腺苷-核糖聚合酶核糖聚合酶酶，誘導(dǎo)宮頸癌細(xì)胞凋亡，抑制宮頸癌細(xì)胞的遷移、侵襲和克隆能力。

2.1.4 抗皮膚癌 研究發(fā)現(xiàn)，異甘草素可以作用于黑色素瘤細(xì)胞代謝201條生化通路共計(jì)390個(gè)基因表達(dá)，誘導(dǎo)黑色素瘤B16F0細(xì)胞分化[47]。Xiang等[48]對(duì)異甘草素的抗黑色素瘤作用及其可能機(jī)制開展研究。結(jié)果顯示，異甘草素可通過抑制miR-301b/ LRIG1信號(hào)通路來抑制黑色素瘤細(xì)胞的增殖。Chen等[49]選用斑馬魚模型和分子對(duì)接技術(shù)研究了光甘草定對(duì)酪氨酸酶的抑制動(dòng)力學(xué)及其作用機(jī)制，發(fā)現(xiàn)光甘草定可通過形成穩(wěn)定的復(fù)合物方式，對(duì)酪氨酸酶產(chǎn)生非競(jìng)爭性抑制作用，影響黑色素的形成。

2.1.5 其他 Kim等[50]研究發(fā)現(xiàn)異甘草素可顯著降低人腎癌Caki細(xì)胞的存活率并誘導(dǎo)其凋亡，其機(jī)制為通過產(chǎn)生活性氧誘導(dǎo)Caki細(xì)胞凋亡，減少p53的表達(dá)，抑制STAT3信號(hào)通路。Zhang等[51]研究發(fā)現(xiàn)，異甘草素對(duì)人前列腺癌PC-3、22Rv1細(xì)胞有抗癌作用，機(jī)制可能與其使細(xì)胞周期阻滯于G2/M期相關(guān)。Zhang等[52]以結(jié)腸癌CT-26細(xì)胞建立荷瘤小鼠模型為研究對(duì)象，從腸道微生物區(qū)系的角度探討了甘草多糖的抗腫瘤作用機(jī)制。研究發(fā)現(xiàn)，治療14 d后，腫瘤質(zhì)量明顯減輕，其機(jī)制可能通過影響腸道菌群組成而發(fā)揮抗腫瘤作用。此外，已有研究證實(shí)，甘草中黃酮成分對(duì)鱗狀細(xì)胞癌也有治療作用[53-54]。

2.2 抗炎作用

2.2.1 廣譜抗炎及機(jī)制 甘草活性成分通過作用于源性代謝物質(zhì)，如亞油酸、鞘氨醇、色胺、皮質(zhì)酮和白三烯B4等，影響到機(jī)體內(nèi)花生四烯酸代謝，鞘脂、色氨酸和脂肪酸的代謝以及磷脂的合成等多種途徑，表現(xiàn)出廣泛地抗炎作用，現(xiàn)已應(yīng)用于臨床治療肺損傷和哮喘等疾病[36,55-56]，見表3。

2.2.2 抗病毒作用 2020年1月，全球爆發(fā)新型冠狀病毒肺炎（coronavirus disease 2019，COVID-19），其發(fā)病速度之快，傳染能力之強(qiáng)，實(shí)屬罕見。在COVID-19臨床診治過程中，目前仍無明確特效藥物，中醫(yī)藥在預(yù)防和治療中發(fā)揮了不可或缺的重要作用。楊璐等[69]基于網(wǎng)絡(luò)藥理學(xué)，對(duì)小柴胡湯治療COVID-19發(fā)熱的可行性進(jìn)行了研究，運(yùn)用分子對(duì)接技術(shù)將小柴胡湯中柴胡、黃芩、甘草等成分和作用靶點(diǎn)與COVID-19感染受體進(jìn)行擬合，初步探討了甘草抑制COVID-19發(fā)熱的可能性。

周珊珊等[70]基于網(wǎng)絡(luò)藥理學(xué)和分子對(duì)接技術(shù)，探討了清肺達(dá)原顆粒治療COVID-19的作用機(jī)制，驗(yàn)證了甘草酸可能作為抗新型冠狀病毒的潛在活性成分，推測(cè)了COVID-19的治療機(jī)制可能與調(diào)節(jié)炎癥和免疫相關(guān)的信號(hào)通路有關(guān)。

表3 甘草的抗炎作用及機(jī)制

IL-白細(xì)胞介素 IgE-免疫球蛋白E COX-2-環(huán)氧化酶-2 TNF-α-腫瘤壞死因子-α

IL-interleukin IgE-immunoglobulin E COX-2-cyclooxygenase-2 TNF-α-tumor necrosis factor-α

2.3 神經(jīng)系統(tǒng)作用

2.3.1 神經(jīng)保護(hù) Zhu等[71]建立了大鼠認(rèn)知障礙模型，通過異甘草素處理，對(duì)模型小鼠的認(rèn)知功能、海馬損傷、突觸蛋白等進(jìn)行了評(píng)價(jià)。結(jié)果表明，異甘草素可通過磷酸化降低糖原合成酶激酶-3β（glycogen synthase kinase 3β，GSK-3β）活性，增強(qiáng)核因子E2相關(guān)因子2（nuclea factor erythroid-2-related factor 2，NRF2）表達(dá)，降低NF-κB響應(yīng)，抑制神經(jīng)炎癥，對(duì)認(rèn)知損傷和神經(jīng)元損傷進(jìn)行保護(hù)。

Teng等[72]研究發(fā)現(xiàn)甘草苷可作用于ERK和AKT/GSK-3β通路，增強(qiáng)細(xì)胞外信號(hào)調(diào)節(jié)激酶AKT和GSK3β的磷酸化水平，使谷氨酸誘導(dǎo)的大鼠嗜鉻細(xì)胞瘤PC12細(xì)胞的存活率顯著提高。Rashedinia等[73]研究發(fā)現(xiàn)甘草酸可通過維持線粒體功能，促進(jìn)能量代謝和線粒體生物合成，發(fā)揮其細(xì)胞保護(hù)作用。

2.3.2 抗抑郁 抑郁癥生理變化主要表現(xiàn)為機(jī)體內(nèi)5-羥色胺或去甲腎上腺素分泌減少。Wang等[74]采用強(qiáng)迫游泳試驗(yàn)和懸尾試驗(yàn)評(píng)價(jià)了甘草苷和異甘草苷的抗抑郁活性。結(jié)果發(fā)現(xiàn)，2種化合物均能顯著增加海馬、下丘腦和皮層中主要神經(jīng)遞質(zhì)5-羥色胺和去甲腎上腺素的濃度，具有明顯的抗抑郁作用。

Su等[75]對(duì)甘草素減輕脂多糖誘導(dǎo)的小鼠抑郁樣行為進(jìn)行了研究，結(jié)果發(fā)現(xiàn)，甘草素能有效降低促炎細(xì)胞因子水平，降低NF-κB/p-p65和p-IκBα表達(dá)，上調(diào)海馬腦源性神經(jīng)營養(yǎng)因子（brain derived neurotrophic factor，BDNF）和酪氨酸激酶受體B（tyrosine kinase receptor B，TrkB）的含量。Tao等[76]發(fā)現(xiàn)甘草素可通過PI3K/Akt/mTOR介導(dǎo)的BDNF/TrkB通路治療慢性抑郁癥，具有明顯改善抑郁癥狀。

2.3.3 治療神經(jīng)退行性疾病 神經(jīng)退行性疾病臨床表現(xiàn)為大腦和脊髓的細(xì)胞神經(jīng)元喪失的疾病狀態(tài)，包括阿爾茨海默病、帕金森癥等。Mirza等[77]通過文獻(xiàn)調(diào)研，篩選出40種具有抗帕金森病活性的植物化學(xué)物質(zhì)，使用AutoDock和AutoDockVina將配體受體信息對(duì)接，分析了這些化合物的藥動(dòng)學(xué)情況。研究發(fā)現(xiàn)，甘草次酸和白藜蘆醇苷是具有較高結(jié)合能的強(qiáng)效化合物，可作為抗帕金森病的潛在藥物。Abdel Bar等[78]合成了14個(gè)甘草次酸類乙酰膽堿酯酶抑制劑衍生物，具有明顯的乙酰膽堿酯酶抑制活性，可增加乙酰膽堿的水平和作用時(shí)間，從而減輕阿爾茨海默病的癥狀。此外，研究發(fā)現(xiàn)，甘草素具有增強(qiáng)記憶的作用，可用于治療學(xué)習(xí)和記憶障礙[79]。

2.4 心腦血管系統(tǒng)保護(hù)作用

研究發(fā)現(xiàn)，甘草次酸可與11β-羥基類固醇脫氫酶-2相互作用，具有顯著的降壓作用。同時(shí)，甘草甜素和甘草次酸可作為凝血因子Xa和凝血酶抑制劑，具有抗血栓作用，可用于顱內(nèi)出血性中風(fēng)的治療[80]。Qi等[81]研究發(fā)現(xiàn)，異甘草素可以減輕模型小鼠動(dòng)脈粥樣硬化病變，降低血脂水平，抑制瞬時(shí)受體電位通道5的表達(dá)。

Xu等[82]發(fā)現(xiàn)，甘草酸可激活心肌Nrf2/血紅素加氧酶-1（heme oxygenase，HO-1），抑制NF-κB信號(hào)通路，改善心肌缺血性損傷，對(duì)心肌梗死有保護(hù)作用。Zhang等[83]研究發(fā)現(xiàn)，甘草苷通過抑制NF-kB和MAPKs信號(hào)通路對(duì)高糖誘導(dǎo)的心肌纖維化具有保護(hù)作用。

2.5 其他作用

2.5.1 肝臟保護(hù) 體外研究發(fā)現(xiàn)，甘草中黃酮、二苯乙烯、游離酚類化合物，可參與到體內(nèi)代謝之中，改善肝組織病理表征，調(diào)節(jié)總膽固醇、總?cè)８视?、高密度脂蛋白膽固醇和低密度脂蛋白膽固醇，具有肝臟保護(hù)活性，其機(jī)制可能與上調(diào)Nrf2通路有關(guān)[23,84-86]。Huo等[87]研究發(fā)現(xiàn)，甘草酸不同構(gòu)型配比可以體現(xiàn)不同的肝臟保護(hù)活性，其中以18α--甘草酸與18β--甘草酸配比為4∶6時(shí)活性最強(qiáng)，其機(jī)制與調(diào)節(jié)氧化應(yīng)激和脂質(zhì)代謝有關(guān)。

2.5.2 抗糖尿病 Sawada等[88]研究發(fā)現(xiàn)，光甘草定可通過調(diào)節(jié)骨骼肌細(xì)胞內(nèi)的一磷酸腺苷活化蛋白激酶途徑刺激L6肌管攝取葡萄糖，對(duì)糖尿病、高血糖等代謝紊亂有一定的治療作用。Gaur等[27]通過合成異甘草素和甘草素衍生物，并對(duì)其口服葡萄糖耐量進(jìn)行篩選，發(fā)現(xiàn)在衍生物中引入醚基和酯基可顯著提高其抗糖活性。

2.5.3 解毒 在傳統(tǒng)經(jīng)方中，甘草常作為解毒良方與部分毒性中藥，如草烏、附子、雷公藤、牛黃等配伍使用[89]，其機(jī)制可能與調(diào)節(jié)P糖蛋白、乳腺癌耐藥蛋白和多藥耐藥相關(guān)蛋白2等外排轉(zhuǎn)運(yùn)蛋白的表達(dá)，抑制腸道吸收，促進(jìn)外排轉(zhuǎn)運(yùn)有關(guān)[90-91]。

2.5.4 抗骨質(zhì)疏松 Choi等[92]研究發(fā)現(xiàn)，光甘草定可通過改善線粒體功能，保護(hù)成骨細(xì)胞免受抗霉素A誘導(dǎo)影響，減少骨細(xì)胞衰老過程中引起的線粒體功能障礙，防止成骨細(xì)胞損傷。Uchino等[93]研究發(fā)現(xiàn)，甘草素同時(shí)具有促進(jìn)成骨細(xì)胞分化和抑制破骨細(xì)胞分化的雙重作用，可用于進(jìn)一步開發(fā)治療和預(yù)防骨質(zhì)疏松癥的新藥研究。

2.5.5 免疫調(diào)節(jié) Han等[94]發(fā)現(xiàn)，甘草酸通過調(diào)節(jié)過敏相關(guān)免疫細(xì)胞，對(duì)IgE介導(dǎo)的變態(tài)反應(yīng)具有抗過敏作用。Ayeka等[95]以CT26荷瘤BALB/c小鼠為試驗(yàn)動(dòng)物，以甘草多糖作用后免疫器官質(zhì)量和指數(shù)、免疫器官指數(shù)、免疫細(xì)胞數(shù)量和血清細(xì)胞因子水平的變化為評(píng)價(jià)指標(biāo)，驗(yàn)證了甘草多糖可提高試驗(yàn)動(dòng)物的免疫器官指數(shù)，具有免疫調(diào)節(jié)作用。

2.5.6 其他 Choi等[96]研究發(fā)現(xiàn)異甘草素在潰瘍小鼠體內(nèi)具有胃黏膜保護(hù)作用，其機(jī)制為藥物生物利用度較低，在胃中分布較高，繼而增強(qiáng)胃黏膜分泌，降低COX-2活性，起到保護(hù)作用。Zhao等[97]研究發(fā)現(xiàn)，大鼠服用甘草酸后，可誘導(dǎo)P-gp和細(xì)胞色素P450酶活性，提高大鼠肝臟清除率，減少對(duì)扁蒴藤素的吸收，影響其藥動(dòng)學(xué)特性。此外，甘草提取物還具有抗菌、抗病毒、改善發(fā)育、增強(qiáng)肌肉質(zhì)量等藥理作用[98-104]。

3 結(jié)語

甘草的化學(xué)成分復(fù)雜，藥效作用廣泛，如何進(jìn)一步開展甘草藥效成分系統(tǒng)研究和藥理作用機(jī)制研究，對(duì)于中藥藥效物質(zhì)基礎(chǔ)研究、掌握中藥材禁忌配伍和臨床不良反應(yīng)、指導(dǎo)臨床用藥均有重大意義[105]。當(dāng)前，研究方向已由提取分離有效成分、臨床療效評(píng)價(jià)轉(zhuǎn)為修飾甘草藥效成分、優(yōu)化藥理作用、研究藥效機(jī)制。隨著現(xiàn)代分析手段，如分子生物學(xué)、代謝組學(xué)、網(wǎng)絡(luò)藥理學(xué)等的不斷發(fā)展，甘草的藥用價(jià)值還有進(jìn)一步挖掘的客觀需求，對(duì)于COVID-19的治療作用仍有待進(jìn)一步研究與驗(yàn)證。

利益沖突 所有作者均聲明不存在利益沖突

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Research progress on newly discovered chemical constituents and pharmacological effects ofet

LI Bao-lin1, 2, 3, MA Jing-mei1, 2, 3, TIAN Yu-rou1, 2, 3, ZHANG Tie-jun4, NIU Li-ying1, 2, 3

1. Hebei University of Chinese Medicine, Shijiazhuang 050091, China 2. Hebei TCM Formula Granule Innovation Center, Shijiazhuang 050091, China 3. Hebei TCM Quality Evaluation & Standardization Engineering Research Center, Shijiazhuang 050091, China 4. Tianjin Key Laboratory of Quality Marker of Traditional Chinese Medicine, Tianjin Institute of Pharmaceutical Research, Tianjin 300462, China

etis a commonly used clinical compatible Chinese herbal medicine, which is listed as one of the highest grade herb in.ethas a variety of chemical constituents, and more than 400 kinds of flavonoids, triterpenoids, coumarins, stilbenoids and other kinds of compounds have been found so far. Modern pharmacological studies have shown thatethas a wide range of anti-tumor, anti-inflammatory, antibacterial, antiviral, neuroprotective, liver protective, and other pharmacological effects. Related research progress on newly discovered chemical components, artificially modified chemical constituents, effects of processing on chemical components, and pharmacological effects at home and abroad in recent years are reviewed in this paper, which will provide references for the further development ofet.

et; chemical constituents; processing; mechanism of action; antitumor; COVID-19

R282.71

A

0253 - 2670(2021)08 - 2438 - 11

10.7501/j.issn.0253-2670.2021.08.029

2020-08-04

河北省自然科學(xué)基金資助項(xiàng)目（H2019423050）；河北省中醫(yī)藥管理局科研計(jì)劃項(xiàng)目（2017014）

李葆林，助理研究員，博士研究生，研究方向?yàn)橹兴幏治黾八幮镔|(zhì)基礎(chǔ)研究。Tel: (0311)89926750 E-mail: libaol2016@163.com

牛麗穎，教授。Tel: (0311)89926548 E-mail: niuliyingyy@163.com

[責(zé)任編輯 崔艷麗]