魏述永

（西南大學(xué)榮昌校區(qū)動(dòng)物醫(yī)學(xué)系，重慶 402460）

葛根及葛根素腦保護(hù)作用的研究進(jìn)展

魏述永

（西南大學(xué)榮昌校區(qū)動(dòng)物醫(yī)學(xué)系，重慶 402460）

葛根為我國(guó)傳統(tǒng)的藥食兩用植物，葛根素為其主要藥效成分之一。依據(jù)中醫(yī)藥理論，葛根具有解表退熱、生津止渴的功效?，F(xiàn)代藥理學(xué)研究表明，葛根及葛根素均具有顯著的腦保護(hù)活性，對(duì)阿爾茨海默病、帕金森病及腦卒中等模型動(dòng)物或細(xì)胞產(chǎn)生保護(hù)作用，其機(jī)制與調(diào)節(jié)GSK-3β/Nrf2、PI3K/Akt、cAMP/PKA等神經(jīng)細(xì)胞凋亡信號(hào)轉(zhuǎn)導(dǎo)通路有關(guān)。提示葛根具備開(kāi)發(fā)為抗神經(jīng)系統(tǒng)疾病保健食品的潛在價(jià)值。

葛根；葛根素；腦保護(hù)；保健食品

葛根為我國(guó)傳統(tǒng)藥食兩用植物，采挖自豆科植物野葛（Pueraria lobata（Willd.）Ohwi（Fabaceae））的干燥根，產(chǎn)地遍布我國(guó)南北各地，現(xiàn)已人工栽培。依據(jù)傳統(tǒng)理論，葛根具有解表退熱、生津止渴之功效，其藥效成分主要為葛根素、大豆苷、大豆苷元等[1]?，F(xiàn)代藥理學(xué)研究發(fā)現(xiàn)，葛根及葛根素對(duì)阿爾茨海默?。ˋlzheimer’s disease，AD）、帕金森?。≒arkinson’s disease，PD）及腦卒中等動(dòng)物及細(xì)胞模型具有顯著保護(hù)作用，給上述神經(jīng)系統(tǒng)“疑難雜癥”的治療帶來(lái)了福音。近年來(lái)，葛根及葛根素的各種制劑在國(guó)內(nèi)已經(jīng)被廣泛應(yīng)用于神經(jīng)系統(tǒng)疾病的臨床治療，但由于臨床實(shí)驗(yàn)設(shè)計(jì)及樣本的局限性，其療效仍存在爭(zhēng)議[2-6]，而作為傳統(tǒng)的藥食兩用物品，葛根作為腦保護(hù)保健食材的開(kāi)發(fā)尚未引起足夠重視。本文綜述了葛根及葛根素腦保護(hù)作用的研究進(jìn)展，為相關(guān)保健食品的開(kāi)發(fā)提供參考。

1 葛根的主要活性成分

葛根含有豐富的活性成分，主要包括異黃酮及其苷元、三萜類、香豆素類等，其中異黃酮及其苷元為主要活性成分，主要以葛根素、大豆苷、大豆苷元為主，因產(chǎn)地、品種、采收季節(jié)和生長(zhǎng)年限不同含量各異[7]；三萜類包括以葛根皂醇A、B、C命名的新型齊墩果烷型皂角精醇、大豆皂醇、槐二醇、大豆苷醇等；香豆素類主要包括6,7-二甲氧基香豆素及葛根香豆素[7-8]。另外，因?yàn)楹袚]發(fā)油成分，葛根具有輕微的甜味及酒味，揮發(fā)油中棕櫚酸甲酯占42.2%，硬脂酸甲酯占5.2%，2-乙酸甲氧乙酯占4.8%，乙酰甲醇占4.5%，正丁酸占4.1%[9]。葛根中還含有大量的微量組分，包括氯化膽堿、乙酰膽堿、D-甘露醇、花生酸、棕櫚酸、二丙酮胺及右旋松醇等[10-12]。

葛根素屬異黃酮類化合物，自20世紀(jì)50年代被分離鑒定以來(lái)[1]，其藥理活性已被廣泛研究。研究發(fā)現(xiàn)，葛根及葛根素具有腦保護(hù)、心血管保護(hù)、降糖、抗炎、抗骨質(zhì)疏松、保肝等廣泛的藥理活性[13-14]，其中，其腦保護(hù)機(jī)制與對(duì)抗AD、PD及腦卒中所引起的神經(jīng)細(xì)胞凋亡有關(guān)。鑒于上述疾病臨床治療較為困難，故對(duì)它們的預(yù)防就顯得尤為重要，然而其保健食品的開(kāi)發(fā)在國(guó)內(nèi)目前尚屬空白。葛根作為傳統(tǒng)的藥食兩用食材，具有顯著的腦保護(hù)活性，因此其在腦保健食品開(kāi)發(fā)上具有潛在價(jià)值。

2 葛根及葛根素的腦保護(hù)活性

2.1抗AD作用

AD是一種與年齡相關(guān)的神經(jīng)退行性疾病，海馬區(qū)神經(jīng)元線粒體損傷及氧化應(yīng)激所引起的三磷酸腺苷（adenosine triphosphate，ATP）合成障礙和細(xì)胞凋亡在AD的早期病變中起到重要作用[15-16]，以認(rèn)知和記憶功能不斷衰退為特征，其治療主要以保護(hù)神經(jīng)細(xì)胞緩和病情為主[17-18]。

2.1.1動(dòng)物實(shí)驗(yàn)

研究發(fā)現(xiàn)，葛根提取物對(duì)D-半乳糖誘導(dǎo)的AD小鼠學(xué)習(xí)記憶能力障礙具有改善作用，可顯著提高模型動(dòng)物自發(fā)性活動(dòng)及學(xué)習(xí)、記憶能力，其機(jī)制與提高腦組織超氧化物歧化酶（superoxide dismutase，SOD）活性而減輕氧化應(yīng)激損傷等有關(guān)[19]。另外，葛根素可改善去勢(shì)雌性小鼠的學(xué)習(xí)與記憶能力，其機(jī)制為改善谷氨酸/γ-氨基丁酸（glutamic acid/gamma amino acid butyric acid，Glu/GABA）比率[20]，改善海馬神經(jīng)元突觸重構(gòu)、增加突觸后蛋白（postsynaptic protein，PSD）-95表達(dá)及天冬氨酸受體亞單位（nmda receptor 2b，NR2B）的磷酸化[21]，而在全腦缺血-再灌注損傷大鼠模型中，葛根素改善學(xué)習(xí)記憶力的作用與上調(diào)B淋巴細(xì)胞瘤（B-cell lymphoma，Bcl）-2基因從而抑制細(xì)胞凋亡有關(guān)[22]。

2.1.2細(xì)胞實(shí)驗(yàn)

2.1.2.1β-淀粉樣蛋白誘導(dǎo)的細(xì)胞凋亡

β-淀粉樣蛋白（amyloid pepitide，Aβ）在AD的發(fā)病機(jī)制中起到重要作用，其沉積可導(dǎo)致神經(jīng)元死亡[23]。葛根提取物及葛根素可通過(guò)降低凋亡蛋白酶（caspase）-9的活性、激活絲氨酸/蘇氨酸激酶（serine/ threonine kinase，Akt）及增加Bcl-x1/Bcl-2相關(guān)死亡啟動(dòng)子（Bcl-x1/Bcl-2 related death promoter，Bad）的磷酸化而減少Aβ誘導(dǎo)的大鼠海馬神經(jīng)元的凋亡[24]，也可以通過(guò)清除自由基及抑制脂質(zhì)過(guò)氧化而減少原代培養(yǎng)大鼠海馬神經(jīng)元細(xì)胞的氧化應(yīng)激，其機(jī)制為誘導(dǎo)糖原合成酶激酶-3β（GSK-3β）9位絲氨酸的磷酸化而抑制GSK-3β/ NF-E2相關(guān)因子2（NF-E2-related factor 2，Nrf2）信號(hào)通路[25]，該作用可被GSK-3β抑制劑氯化鋰阻斷。進(jìn)一步研究表明，葛根素可激活蛋白激酶B（protein kinase B，PKB）/Akt，其為GSK-3β上游的重要激酶，從而引起GSK-3β的抑制作用[26]。通過(guò)增加p-Akt、Bcl-2和p-Bad的表達(dá)，降低Bcl-2相關(guān)X蛋白（Bcl-2 associated X protein，Bax）表達(dá)及細(xì)胞色素C的釋放，葛根素對(duì)Aβ誘導(dǎo)的PC12細(xì)胞凋亡產(chǎn)生保護(hù)作用，該作用可被磷脂酰肌醇3激酶（phosphatidyl inositol 3-kinase，PI3K）磷酸化作用抑制劑渥曼青霉素阻斷，提示其機(jī)制與PI3K信號(hào)通路有關(guān)[27]。

2.1.2.2其他細(xì)胞模型

在過(guò)氧化氫（H2O2）誘導(dǎo)的PC12細(xì)胞模型中，葛根素可激活PI3K/Akt信號(hào)通路[28]。在活性氧（reactive oxygen species，ROS）超表達(dá)的線粒體轉(zhuǎn)基因神經(jīng)元雜交細(xì)胞模型中，葛根素可通過(guò)抑制Caspase-3、p38及Jun N末端激酶（jun N-terminal kinase，JNK）的活性并降低Bax/Bcl-2比率而減少線粒體氧化應(yīng)激引起的細(xì)胞凋亡[29]。在原代培養(yǎng)海馬神經(jīng)元細(xì)胞氧糖剝奪模型中，葛根素可降低細(xì)胞凋亡及壞死數(shù)量，其機(jī)制為減少谷氨酰胺釋放、細(xì)胞內(nèi)Ca2+濃度及NO合成引起的氧化應(yīng)激[30]。進(jìn)一步研究證實(shí)，在原代培養(yǎng)大鼠海馬神經(jīng)元細(xì)胞中，葛根素對(duì)細(xì)胞內(nèi)基礎(chǔ)Ca2+濃度沒(méi)有影響，但可通過(guò)雌激素受體增強(qiáng)KCl誘發(fā)的Ca2+釋放，雌激素受體拮抗劑ICI 182780、他莫西芬，蛋白激酶A（proteinkinase A，PKA）拮抗劑H89等均可阻斷該作用，提示其與環(huán)磷酸腺苷（cyclic adenosine monophosphate，cAMP）/PKA信號(hào)通路有關(guān)[31]。

2.2抗PD作用

PD以黑質(zhì)多巴胺能神經(jīng)元減少并退化成非多巴胺能神經(jīng)元為特征[32]，細(xì)胞凋亡是其重要的病理過(guò)程[33-34]。

2.2.1動(dòng)物實(shí)驗(yàn)

在去勢(shì)雌性大鼠黑質(zhì)神經(jīng)元中，葛根提取物及葛根素可提高細(xì)胞酪氨酸羥化酶（tyrosine hydroxylase，TH）陽(yáng)性率并降低凋亡細(xì)胞數(shù)量，提示其保護(hù)作用與抗細(xì)胞凋亡有關(guān)[35]。在6-羥多巴胺（6-hydroxy dopamine，6-OHDA）誘導(dǎo)的大鼠黑質(zhì)損傷模型中，腹腔注射葛根素（0.12 mg/（kg·d））10 d后可降低Bax水平，恢復(fù)多巴胺及其代謝物含量，提高細(xì)胞TH陽(yáng)性率及神經(jīng)膠質(zhì)細(xì)胞源性神經(jīng)營(yíng)養(yǎng)因子（neurotrophic factor，NTF）水平，因此推測(cè)其神經(jīng)細(xì)胞保護(hù)作用與抗凋亡及提高NTF水平有關(guān)[36]。

2.2.2細(xì)胞實(shí)驗(yàn)

在6-OHDA誘導(dǎo)的神經(jīng)生長(zhǎng)因子差異化的嗜鉻細(xì)胞瘤PC12細(xì)胞模型中，葛根提取物及葛根素可抑制Caspase-8并部分抑制Caspase-3活性從而抑制細(xì)胞凋亡[37]。葛根素也可保護(hù)1-甲基-4-苯基碘化吡啶（1-methyl-4-phenyl iodide pyridine，MPP+）誘導(dǎo)的PC12細(xì)胞的凋亡，其機(jī)制為降低絲裂原活化蛋白激酶激酶（mitogen-activated protein kinase kinase，MKK）7、JNK、c-Jun的磷酸化及細(xì)胞色素C的水平進(jìn)而抑制JNK信號(hào)通路[38]及線粒體依賴性Caspase級(jí)聯(lián)反應(yīng)[39]。在MPP+誘導(dǎo)的人神經(jīng)母細(xì)胞瘤SH-SY5Y株凋亡模型中，葛根素可激活PI3K/Akt信號(hào)通路、抑制細(xì)胞核p53蓄積及伴隨的Caspase-3依賴性細(xì)胞凋亡[40]，減少泛素結(jié)合蛋白的蓄積、增加Bcl-2/Bax比率以調(diào)節(jié)泛素蛋白酶系統(tǒng)[41]。

2.3抗腦缺血再灌注損傷

腦缺血后常引起嚴(yán)重的組織損傷，其病理過(guò)程與興奮性毒性、炎癥反應(yīng)、自由基釋放等因素密切相關(guān)[42]，再灌注后，隨著ROS及NO的釋放，腦組織損傷加重[43]，因此，減少興奮性氨基酸、炎癥反應(yīng)及自由基釋放引起的氧化應(yīng)激反應(yīng)可對(duì)腦組織產(chǎn)生保護(hù)作用[44]。葛根及葛根素對(duì)缺血再灌注損傷的保護(hù)作用主要體現(xiàn)在上述三方面。

2.3.1減輕興奮性毒性

葛根及葛根素對(duì)大腦中動(dòng)脈栓塞模型（middle cerebral artery occlusion，MCAO）大鼠缺血再灌注損傷具有保護(hù)作用，其機(jī)制與減輕Glu過(guò)度釋放引起的興奮性毒性有關(guān)。造模前腹腔注射葛根素（100 mg/kg），缺血60 min后再灌注24 h，可降低紋狀體Glu/GABA比率，并降低Glu誘導(dǎo)的海馬神經(jīng)元細(xì)胞的凋亡和壞死[45]。

2.3.2抗炎

大腦中動(dòng)脈栓塞前10 min，腹腔注射葛根素（50 mg/kg）可降低缺血組織梗死區(qū)面積，缺氧誘導(dǎo)因子（hypoxia inducible factor，HIF）-1α、腫瘤壞死因子（tumor necrosis factor，TNF）-α表達(dá)，并抑制誘導(dǎo)型一氧化氮合酶（inducible nitric oxide synthases，iNOS）、中性粒細(xì)胞及Caspase-3活性，從而減輕炎癥反應(yīng)及細(xì)胞凋亡[46-47]，也可通過(guò)降低MCAO大鼠腦組織白細(xì)胞介素（interleukin，IL）-1β水平而產(chǎn)生抗炎作用[48]。

2.3.3抗氧化應(yīng)激

葛根提取物及葛根素可降低MCAO大鼠缺血組織丙二醛（malonaldehyde，MDA）、NO含量，增加超氧化物歧化酶（superoxide dismutase，SOD）[48]、促紅細(xì)胞生成素（erythropoietin，EPO）[49]活性及突觸素水平[48]，改善局灶性腦缺血再灌注損傷大鼠熱休克蛋白（heat shock protein，HSP）70含量并降低凋亡相關(guān)因子（factor associated suicide，F(xiàn)as）水平[50]。葛根素也可以減輕新西蘭A大白兔[51]和大鼠[6]短暫性脊髓缺血損傷，其機(jī)制可能與增加氧硫還原蛋白轉(zhuǎn)錄及抑制凋亡有關(guān)。

2.4其他腦保護(hù)作用

葛根素對(duì)Glu、天冬氨酸及紅藻氨酸誘導(dǎo)的神經(jīng)損傷具有保護(hù)作用[52]，可降低酸中毒引起的海馬神經(jīng)元酸敏感離子通道電流[53]，減輕背根神經(jīng)節(jié)P2X3受體介導(dǎo)的偏頭痛[54]，抑制Ca2+內(nèi)流及周期蛋白依賴性激酶（cyclin dependent kinase，Cdk）5活性而保護(hù)Glu誘導(dǎo)的神經(jīng)絲軸突轉(zhuǎn)運(yùn)損害[55]，通過(guò)糖基化修飾作用抑制脂多糖（lipopolysaccharide，LPS）誘導(dǎo)的小膠質(zhì)細(xì)胞iNOS及伴隨的NO、ROS表達(dá)[56]，并具有促進(jìn)神經(jīng)生長(zhǎng)作用[57]。

3 葛根及葛根素的毒副作用

葛根在我國(guó)食用的歷史悠久，并未發(fā)現(xiàn)其嚴(yán)重的不良反應(yīng)，但隨著葛根素特別是其注射劑在臨床上的廣泛使用，其引起的發(fā)熱、過(guò)敏性休克、溶血、肝腎損害等不良反應(yīng)日益引起廣泛關(guān)注，也極大制約了該制劑的臨床價(jià)值[58]，而將葛根開(kāi)發(fā)為腦保護(hù)保健食品，在有效利用其藥理活性的同時(shí)，可以避免葛根素制劑的各種不良反應(yīng)，可謂一舉兩得。

3.1對(duì)實(shí)驗(yàn)動(dòng)物的毒性作用

動(dòng)物實(shí)驗(yàn)表明，葛根的毒副作用較低。葛根醇提物5 g/（kg·d）（相當(dāng)于葛根素500 mg/（kg·d））灌胃大鼠21 d，與正常對(duì)照組相比，肝、腎、胰腺及脾臟組織未見(jiàn)病變，肌酐、肌酐激酶、丙氨酸氨基轉(zhuǎn)移酶（alanine aminotransferase，ALT）、天冬氨酸氨基轉(zhuǎn)移酶（aspartic transaminase，AST）及γ-谷氨酰轉(zhuǎn)移酶等血清生化指標(biāo)未見(jiàn)異常[59]。葛根總黃酮肌內(nèi)注射對(duì)大鼠的半數(shù)致死量（median lethal dose，LD50）為5.97 g/kg，葛根素靜脈注射對(duì)小鼠的LD50為700～800 mg/kg[60]。大鼠肌內(nèi)或靜脈注射葛根素50 mg/（kg·d）持續(xù)50 d及犬肌內(nèi)或靜脈注射葛根素10 mg/（kg·d）持續(xù)30 d未引起重要組織器官形態(tài)及功能改變[5]。

3.2臨床治療中的毒副作用

口服500 mg葛根提取物（含葛根素19%，大豆苷4%）每天3次持續(xù)7 d，在治療期間及其后4周內(nèi)肝功能、血液學(xué)及尿液分析等生命體征無(wú)顯著變化[61]。另有報(bào)道顯示，持續(xù)給予100名患者葛根及丹參水提物（7∶3，m/m）3 g/d 24周，日常血液學(xué)及生化檢驗(yàn)未見(jiàn)顯著影響，8名患者（其中6名為安慰劑組，2名為治療組）出現(xiàn)胸痛、坐骨神經(jīng)痛、胃腸道出血等副作用[62]。在臨床治療中，葛根素注射劑可能出現(xiàn)發(fā)熱、頭痛、頭暈、過(guò)敏性休克、皮疹、咽喉腫痛、溶血性貧血、肝腎損傷等副作用，其毒理學(xué)機(jī)制研究尚待深入進(jìn)行[58]。

4 葛根保健食品的開(kāi)發(fā)現(xiàn)狀

日本較早地將葛根的活性成分葛根黃素、葛根黃苷等類黃酮物質(zhì)用作治療心血管病的藥物及加工為保健食品，如葛根口服液、葛根罐頭、葛根飲料等，以滿足特殊人群的需要，產(chǎn)品十分暢銷，幾乎成為老人和產(chǎn)婦必備的食品[63]。美國(guó)在葛根素的提取、藥效方面研究較多，尤其注重葛根黃酮的抗氧化性和雌激素效應(yīng)的研究[64]，致力于開(kāi)發(fā)出抗衰老、調(diào)節(jié)女性更年期不適癥的保健食品，生產(chǎn)出葛根與咖啡、蘆筍、蘆薈配制而成的飲料，并有葛根凍罐頭、葛根混合晶、葛根口服液、葛粉紅腸等新產(chǎn)品，深受消費(fèi)者喜愛(ài)[63]。

雖然我國(guó)為葛根資源產(chǎn)地，但大多數(shù)地區(qū)對(duì)于葛根的生產(chǎn)加工仍處于較粗放狀態(tài)，如簡(jiǎn)單加工成葛根粉、葛根粒等，經(jīng)濟(jì)效益較低。近10a來(lái)，隨著人們對(duì)保健食品的日益重視，國(guó)內(nèi)葛根保健食品的開(kāi)發(fā)也得以較快發(fā)展，目前已經(jīng)研制出防治高血壓、高血脂、冠心病、糖尿病等的葛根變性淀粉、葛根掛面、葛根果晶、葛根軟糖、葛根飲料、葛根低聚糖、葛根麥芽糊精、葛奶、葛根保健糊等初級(jí)和深加工產(chǎn)品[63]，但尚少見(jiàn)葛根腦保健食品的相關(guān)報(bào)道。

5 結(jié) 語(yǔ)

葛根用于卒中等腦部疾病的治療在我國(guó)已有1 000多年的歷史，如唐代《千金方》中所載“獨(dú)活湯”用于治療卒中、痹癥?，F(xiàn)代藥理學(xué)研究也表明，葛根及葛根素具有顯著的神經(jīng)保護(hù)活性，其機(jī)制與調(diào)節(jié)PKB/Akt、GSK-3β/Nrf2[25-26]、PI3K/Akt[27-28,40]、JNK[29,38]、cAMP/PKA[31]等細(xì)胞凋亡信號(hào)轉(zhuǎn)導(dǎo)通路有關(guān)。鑒于腦部疾病如AD、PD、卒中等治療難度極大、療效欠佳，加強(qiáng)疾病預(yù)防就顯得尤為重要，因而相關(guān)保健食品的開(kāi)發(fā)前景巨大。

雖然目前葛根保健食品的種類眾多，但尚少見(jiàn)腦保護(hù)相關(guān)的保健食品，且葛根保健食品的開(kāi)發(fā)仍存在諸多問(wèn)題，如：1）食品的保健功能尚無(wú)客觀、準(zhǔn)確的評(píng)價(jià)標(biāo)準(zhǔn)，相關(guān)產(chǎn)品的質(zhì)量良莠不齊，影響了其市場(chǎng)認(rèn)可度。2）產(chǎn)品的保健功能界定不清或盲目擴(kuò)大，缺乏針對(duì)各種疾病特點(diǎn)的特色產(chǎn)品的開(kāi)發(fā)。3）產(chǎn)品生產(chǎn)中，缺乏針對(duì)各種成分特點(diǎn)的工藝設(shè)計(jì)，缺乏有效成分含量的嚴(yán)格標(biāo)準(zhǔn)。因此葛根保健食品特別是腦保健食品的開(kāi)發(fā)特別是質(zhì)量標(biāo)準(zhǔn)的制定與完善仍需要深入研究。

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Progress in Cerebral Protection of Pueraria lobata (Willd.) Ohwi (Fabaceae) and Puerarin

WEI Shuyong
(
Department of Veterinary Medicine, Rongchang Campus, Southwest University, Chongqing 402460, China)

Pueraria lobata(Willd.) Ohwi (Fabaceae), a traditional edible and medicinal plant in China, is used in in traditional Chinese medicine. Puerarin is one of its most important and effective components. According to the traditional Chinese medicinal theory, the roots ofPueraria lobata(Willd.) Ohwi (Fabaceae) have many functions such as relieving exterior syndrome, reducing fervescence, promoting the secretion of saliva or body fluid, and quenching thirst. Modern pharmacological research suggest that bothPueraria lobata(Willd.) Ohwi (Fabaceae) and puerarin exert cerebral protections in animal or cell models of Alzheimer’s disease, Parkinson’s disease and stroke, and the mechanisms involved may be associated with regulating the GSK-3β/Nrf2, PI3K/Akt and cAMP/PKA apoptosis signal pathways. These results indicate thatPueraria lobata(Willd.) Ohwi (Fabaceae) has the potential to be developed into health foods against nervous system diseases.

Pueraria lobata(Willd.) Ohwi (Fabaceae); puerarin; cerebral protection; health food

R285.5

1002-6630（2015）17-0259-05

10.7506/spkx1002-6630-201517048

2014-11-22

國(guó)家自然科學(xué)基金青年科學(xué)基金項(xiàng)目（31402237）；重慶市基礎(chǔ)與前沿研究計(jì)劃項(xiàng)目（cstc2014jcyjA80023）；中央高?；究蒲袠I(yè)務(wù)費(fèi)專項(xiàng)資金項(xiàng)目（XDJK2014C058）

魏述永（1980—），男，講師，博士，研究方向?yàn)橹兴幩幚砼c新藥研發(fā)。E-mail：shuyongwei013@163.com