曾炫皓 章強(qiáng)強(qiáng)

(復(fù)旦大學(xué)附屬華山醫(yī)院皮膚科，上海 200040)

·綜述·

真菌提取物抗腫瘤研究進(jìn)展

曾炫皓 章強(qiáng)強(qiáng)

(復(fù)旦大學(xué)附屬華山醫(yī)院皮膚科，上海 200040)

本文總結(jié)了近幾年真菌提取物的抗癌作用相關(guān)的研究成果。一方面包括了最近幾年關(guān)于真菌提取物誘導(dǎo)癌細(xì)胞凋亡、抑制癌細(xì)胞增生、減少癌細(xì)胞血管生成的各種機(jī)制研究，另一方面歸納了多種真菌提取物對癌細(xì)胞抑制作用的研究結(jié)果。近幾年的研究結(jié)果顯示，真菌提取物能夠抑制多種腫瘤細(xì)胞的增殖，并誘導(dǎo)其凋亡，其機(jī)制與Wnt、NK-κB、MAPK、線粒體凋亡等多種信號通路相關(guān)，靶點包括了p38、bcl-2、c-jun、IκB、β-catenin、Akt等多種與細(xì)胞生物活動密切相關(guān)的蛋白。

真菌；腫瘤；機(jī)制；進(jìn)展

[Chin J Mycol，2017，12(3):184-192]

隨著世界人口老齡化，各種類型腫瘤的發(fā)病率不斷升高，嚴(yán)重威脅著人類的健康。真菌是大自然賦予人類的一座寶庫，從中我們提取出了大量的活性物質(zhì)用于治療各種不同類型的腫瘤。隨著對各種真菌研究的深入，一方面大量新的真菌活性物質(zhì)被發(fā)現(xiàn)，另一方面真菌活性物質(zhì)抗腫瘤的作用機(jī)制不斷被發(fā)現(xiàn)和完善。本文就近5 a發(fā)表的與抗癌真菌提取物相關(guān)的研究進(jìn)行總結(jié)和歸納。

1 真菌抗腫瘤活性物質(zhì)研究新進(jìn)展

1.1 真菌多糖

真菌多糖是一類10個以上的單糖以糖苷鍵連接而成的天然高分子多聚物，具有螺旋狀的立體構(gòu)型。近年來有多篇與真菌多糖研究進(jìn)展相關(guān)文章發(fā)表。其中Li等[1]報道了傳統(tǒng)中藥槐耳 (Huaier)的一種多糖類提取物TP-1對HCC SMMC-7721肝癌細(xì)胞的作用，其研究發(fā)現(xiàn)0.5、1和2 mg/kg劑量的TP-1能夠顯著抑制HCC SMMC-7721細(xì)胞的生長和轉(zhuǎn)移，并且對普通的細(xì)胞毒作用較弱。由于在試驗中發(fā)現(xiàn)TP-1能增加E-cadherin蛋白的表達(dá)，抑制N-cadherin蛋白的表達(dá)，他們認(rèn)為TP-1的抗腫瘤作用與其對AUF-1信號通路的調(diào)節(jié)作用相關(guān)。此外，TP-1還被發(fā)現(xiàn)可以通過抑制HIF-1α、VEGF、AUF-1以及AEG-1的表達(dá)，阻止腫瘤的血管生長。Zhang等[2]報道了一種從草莖點霉 (Phomaherbarum)YS4108的菌絲中提取出的真菌多糖YCP，YCP在實驗中能夠YCP能夠通過TLR2與TLR4相關(guān)機(jī)制來調(diào)節(jié)細(xì)胞內(nèi)p38、ERK、JNK、NF-κβ的表達(dá)，從而刺激B細(xì)胞產(chǎn)生更多的IgG抗體，并能在小鼠移植瘤模型上抑制Heps (肝癌細(xì)胞)、S180 (小鼠肉瘤細(xì)胞)、Lewis (肺癌細(xì)胞)腫瘤細(xì)胞的增殖。Li等[3]的研究發(fā)現(xiàn)姬松茸多糖 (A.blazeipolysaccharides)能夠影響HL-60 (人早幼粒白血病細(xì)胞)細(xì)胞線粒體膜電位，使線粒體釋放cytochrome c (細(xì)胞色素C)，從而誘導(dǎo)腫瘤細(xì)胞凋亡。

1.2 凝集素類

凝集素是普遍存在于自然界動植物和微生物中的一類非免疫來源的蛋白質(zhì)或糖蛋白，一般由2或4個相同亞基組成。Nagre等[4]從絲核菌 (Rhizoctoniabataticola)中分離出一種命名為RBL的凝集素，它的N端終點有獨特的氨基酸序列KKKAYSSRII，這與其他凝集素不同。RBL對人類卵巢癌細(xì)胞具有很強(qiáng)的細(xì)胞毒性作用，并且能與卵巢癌細(xì)胞標(biāo)記蛋白CA125結(jié)合，其具體的作用機(jī)制尚不明確。Barkeer等[5]報道了分離自齊整小核菌 (Sclerotiumrolfsii)的一種凝集素Sclerotiumrolfsiilectin (SRL)能夠通過調(diào)節(jié)c-JUN與SOCS，抑制MAPK信號通路與JAK/STAT信號系統(tǒng)，最終誘導(dǎo)HT-29細(xì)胞 (人結(jié)腸癌癌細(xì)胞)凋亡。此外，其作用還被發(fā)現(xiàn)與miRNA密切相關(guān)。

1.3 萜類

萜類是真菌中廣泛存在的一種化合物，具有多種生物活性。Cheng等[6]的研究發(fā)現(xiàn)茯苓酸 (Pachymic acid)的抗癌作用的機(jī)制與熱休克蛋白激活以及蛋白質(zhì)折疊相關(guān)基因的表達(dá)引起的內(nèi)質(zhì)網(wǎng)應(yīng)激有關(guān)，并且在應(yīng)用內(nèi)質(zhì)網(wǎng)應(yīng)激阻滯劑后，其抗癌作用顯著減弱。Yang等[7]最新的研究發(fā)現(xiàn)，從Chondrostereumsp.提取出的Hirsutanol A的作用機(jī)制與ROS和線粒體膜電位改變造成的線粒體損傷，并釋放細(xì)胞色素C，而導(dǎo)致的細(xì)胞凋亡相關(guān)。Deng等[8]從地花菌 (Albatrellusconfluens)分離出一種名為neoalbaconol (NA)的小分子萜類物質(zhì)。NA能夠通過PI3-K/HK2信號通路發(fā)揮抗癌活性，能有效抑制多種癌細(xì)胞的增生。Gill等[9]的研究闡述了靈芝 (Ganodermalucidum)中的萜類化合物靈芝酸 (Ganoderic Acid)通過Wnt信號通路殺傷腫瘤細(xì)胞的機(jī)制。

1.4 真菌次級代謝產(chǎn)物

Zhao等[10]分離出一種命名為alternariol (AOH)的化合物，并在研究中發(fā)現(xiàn)它能夠抑制NIH3T3 (小鼠胚胎成纖維細(xì)胞)細(xì)胞DNA pol-β的過度表達(dá)，通過p38激活MAPK信號通路，增加ATF2的表達(dá)量，進(jìn)而殺傷NIH3T3細(xì)胞。Koul等[11]報道了來自嗜松青霉 (Penicilliumpinophilum)的dicatenarin和skyrin誘導(dǎo)人類胰腺癌細(xì)胞凋亡的機(jī)制，其作用機(jī)制可能與線粒體膜滲透性改變引起的caspase-3蛋白的表達(dá)增加相關(guān)。Tao等[12]的研究描述了來自鐮刀菌No.DZ27 (Fusariumsp.No.DZ27)的beauvericin對KB (口腔癌細(xì)胞)和KBv200 (耐長春新堿的口腔癌細(xì)胞)細(xì)胞的增殖的抑制作用，與線粒體凋亡通路的聯(lián)系。Chen等[13]的研究發(fā)現(xiàn)來自Neosartoryapseufofischeri的gliotoxin (GTX)對腫瘤細(xì)胞的殺傷機(jī)制與Wnt和Caspase信號通路相關(guān)蛋白的激活密切相關(guān)。Kim等[14]從海洋藻類共生微生物中分離出名為Toluhydroquinone的化合物。Toluhydroquinone在實驗中能夠通過抑制β-catenin的激活，激活Ras/Raf/MEK/ERK信號通路相關(guān)蛋白質(zhì)，進(jìn)而誘導(dǎo)癌細(xì)胞凋亡。

1.5 近幾年新發(fā)現(xiàn)的真菌活性物質(zhì)

Ramos等[15]分別從N.laciniosaKUFC 7896以及soilfungusN.fischeriKUFC 6344提取出的乙酸乙酯混合物E2和E3對多種腫瘤細(xì)胞有細(xì)胞毒性作用。Kim等[16]從Cordyceps提取出的Cordyceps pruinosa butanol fraction (CPBF)能通過多個細(xì)胞信號通路誘導(dǎo)Hela細(xì)胞 (實驗用增殖表皮癌細(xì)胞)的凋亡。Harms等[17]分離出化學(xué)式為C15H16N2O5S的化合物，這種化合物能夠抑制K562細(xì)胞的增殖，并且這種作用與TNF相關(guān)的NF-κB信號通路密切相關(guān)。Ai等[18]從裙帶菜內(nèi)生真菌KcF8 (Guignardiasp.KcF8)提取的幾種化合物顯示出了對多種腫瘤細(xì)胞增殖的抑制作用。

2 真菌抗癌相關(guān)作用機(jī)制研究進(jìn)展

近幾年真菌提取物抗癌機(jī)制研究的進(jìn)展總結(jié)見表1。

如表1所示，真菌提取物抗癌機(jī)制常常與多個信號通路相關(guān)，下文就真菌提取物對腫瘤細(xì)胞作用的幾個主要途徑進(jìn)行敘述。

2.1 調(diào)節(jié)Wnt信號通路

如圖1所示，Wnt/β-catenin信號由Wnt蛋白、跨膜受體胞質(zhì)蛋白、核內(nèi)轉(zhuǎn)錄因子、下游靶基因等組成，包括：①經(jīng)典Wnt/β-catenin信號通路。②Wnt/Ca2+信號通路。③c-Jun N端激酶介導(dǎo)的細(xì)胞集性信號通路。Wnt信號通路在細(xì)胞增殖、轉(zhuǎn)化、黏附、存活、和凋亡等都有重要作用。目前，較為明確的是經(jīng)典Wnt信號通路。通常情況下β-catenin與軸蛋白、APC、GSK-3β組成多蛋白復(fù)合體結(jié)合后被磷酸，進(jìn)而被泛素化降解，保持β-catenin處于較低水平。但當(dāng)Wnt信號激活的時候，會抑制下游蛋白復(fù)合體磷酸化，促進(jìn)β-catenin釋放。在腫瘤細(xì)胞中，Wnt異常持續(xù)激活導(dǎo)致大量β-catenin進(jìn)入細(xì)胞核，從而導(dǎo)致腫瘤細(xì)胞增殖異常[42]。近幾年的研究中發(fā)現(xiàn)Cordycepin可以通過增強(qiáng)GSK-3β介導(dǎo)的β-catenin磷酸化，抑制腫瘤細(xì)胞增殖[23]；真菌化合物Ganoderic acid、gliotoxin (GTX)、Toluhydroquinone、Antrodia camphorata (AC)能夠通過調(diào)節(jié)參與Wnt信號通路的蛋白質(zhì)，抑制β-catenin的激活，從而抑制腫瘤細(xì)胞的增殖[9,13-14,37]。

表1 真菌提取物抗癌作用相關(guān)作用機(jī)制和信號通路

圖1 Wnt信號通路示意以及真菌提取物作用位點

Fig.1 Wnt signal pathway and the targets of anti-cancer fungal extracts

2.2 調(diào)節(jié)NF-κB信號通路

NF-κB的激活機(jī)制主要依賴于IκB蛋白磷酸化所導(dǎo)致的泛素化蛋白的水解作用。通常，細(xì)胞質(zhì)中的NF-κB與其抑制蛋白IκB相結(jié)合而處于失活狀態(tài)，IκB激酶 (IκK)在接受到有效的刺激后激活，誘使IκB發(fā)生磷酸化，進(jìn)而IκB被泛素連接酶所識別而發(fā)生泛素化。IκB在泛素化后水解，解除了其對NF-κB的抑制作用，其NLS的重新暴露使其迅速與細(xì)胞核κB位點發(fā)生特異結(jié)合，實現(xiàn)對相關(guān)基因表達(dá)的調(diào)控作用。該通路的異?；罨c腫瘤細(xì)胞的增生、侵襲和轉(zhuǎn)移都有密切的聯(lián)系[42]。近年發(fā)現(xiàn)的多種真菌提取物均能通過干擾該通路，達(dá)到抗癌效果。如表1所示，ascochlorin (ASC)能夠與NF-κB結(jié)合，而阻止其對DNA的調(diào)控作用[21]；Allantopyrone A通過調(diào)節(jié)TNF-α的表達(dá)對TNF-R1-TRADD-RIP通路進(jìn)行調(diào)節(jié)，最終通過RIP抑制NF-κB的激活[24]；6-acetylmonodethiogliotoxin除了調(diào)節(jié)TNF-α，還可以通過直接阻止NF-κB p65進(jìn)入DNA[17];isosclerone可以通過降低Iκk活性，減少IκB磷酸化，從而抑制NF-κB的激活[31]；isotetrahydro-auroglaucin與flavoglaucin能夠直接抑制IκB-α磷酸化，也可以抑制NF-κB p65與DNA的連接[30]；Trichothecin (TCN)能夠通過抑制IκK-β的磷酸化，阻止NF-κB的激活[34]。

2.3 調(diào)節(jié)caspase家族蛋白

含半胱氨酸的天冬氨酸蛋白水解酶 (Caspase)家族與哺乳動物的細(xì)胞凋亡密切相關(guān)。其中caspase-8 (MACH)參與細(xì)胞凋亡的起始，它既可以自我活化也可以在顆粒酶B的剪切下活化?；罨蟮腸aspase-8可以剪切PARP，還參與caspase3或caspase8的活化過程。在Fas、DR4、DR5等介導(dǎo)的外源性細(xì)胞凋亡中，caspase-8能夠引發(fā)caspase蛋白酶的級聯(lián)反應(yīng)。同時caspase也可以裂解促細(xì)胞凋亡因子蛋白 (BH3 interacting domain death agonist protein，Bid)，其裂解產(chǎn)生的羧基端片段tBid能夠誘導(dǎo)線粒體釋放細(xì)胞色素c。caspase-3是細(xì)胞凋亡主要的終末剪切酶，是細(xì)胞凋亡的執(zhí)行者，其激活是細(xì)胞凋亡進(jìn)入不可逆階段的標(biāo)志。Caspase最主要的作用機(jī)制包括：①降解調(diào)節(jié)死亡蛋白bcl-2。②催化RARP的裂解。③活化核酸內(nèi)切酶DFF、CAD[43]。如表1所示，在實驗中多種真菌提取物作用于癌細(xì)胞后都可以引起caspase3以及caspase8表達(dá)的增加，以及bcl-2和RARP的減少。

2.4 調(diào)節(jié)線粒體凋亡通路

線粒體凋亡通路包括內(nèi)源性線粒體凋亡通路以及外源性死亡受體通路。內(nèi)源性的線粒體死亡受體通路：各種刺激導(dǎo)致的線粒體損傷，引起線粒體細(xì)胞色素C釋放，從而激活caspase蛋白，誘導(dǎo)細(xì)胞凋亡。外源性死亡受體通路包括：①由系列級聯(lián)反應(yīng)導(dǎo)致的caspase-3激活，如Fas/FasL介導(dǎo)的死亡結(jié)構(gòu)域蛋白激活。②由于Bid、bcl-2等活性變化導(dǎo)致的線粒體外膜通透性改變所引起的caspase-3激活[44]。

近幾年的研究發(fā)現(xiàn)多種真菌提取物能夠通過上述兩種途徑介導(dǎo)細(xì)胞凋亡。如表1所示，dicatenarin、skyrin物質(zhì)等能夠改變線粒體膜，導(dǎo)致細(xì)胞色素C釋放，激活caspase3而引起細(xì)胞凋亡[11]；A.blazeipolysaccharides (ABP)能夠通過影響線粒體膜電位改變引起細(xì)胞色素C，而導(dǎo)致細(xì)胞凋亡[3]。Verrucarin A (VA)能夠通過影響ROS的濃度導(dǎo)致線粒體損傷[35]。Cordycepspruinosabutanol fraction (CPBF)通過調(diào)節(jié)bcl-2蛋白，引起線粒體膜通透性改變而導(dǎo)致caspase-3激活[16]。

2.5 調(diào)節(jié)MAPK信號通路

絲裂原活化蛋白激酶 (MAPK)信號通路是在真核細(xì)胞中廣泛存在的一類絲/蘇氨酸蛋白激酶，MAPKs家族包括了p38 MAPK、ERK、BML/ERK5、ERK27、NLK、ERK8,具體分為3種類型：①ERK通路。②p38 MAPK通路。③JNK/SAPK通路。其中ERK的激活與細(xì)胞增殖相關(guān)，JNK與細(xì)胞應(yīng)激與凋亡相關(guān)，p38與炎癥密切相關(guān)。在多種腫瘤的發(fā)生發(fā)展中均可以檢測到MAPK信號通路的異常激活[45]。此外，MAPK信號通路還與腫瘤新生血管的生成有密切聯(lián)系[46]。Lee等的研究發(fā)現(xiàn)ascochlorin能夠調(diào)節(jié)ERK1/2與p38的磷酸化水平，進(jìn)而抑制MAPK信號通路的激活。如表1所示，Zhao等[10]在實驗中發(fā)現(xiàn)Alternariol能夠通過促進(jìn)p38 MAPK磷酸化，抑制腫瘤細(xì)胞中DNA-pol β的過度表達(dá)。Barkeer等[5]在實驗中發(fā)現(xiàn)Sclerotiumrolfsiilectin (SRL)能夠顯著降低c-JUN在細(xì)胞中的濃度，并且引起多種MAPK通路相關(guān)蛋白濃度的變化。Kim等[14]的研究發(fā)現(xiàn)Toluhydroquinone能夠抑制MEK1/2和ERK1/2的磷酸化，并且可以抑制Rac1的表達(dá)。Xia等[38]在實驗中發(fā)現(xiàn)Mycoepoxydiene可以抑制ERK、c-jun、JNK、p38等MAPK相關(guān)蛋白的磷酸化。此外，部分真菌提取物可以通過MAPK信號通路影響腫瘤的血管生成，如Ascochlorin、TP-1、Compound (3)[1,21,40]。

2.6 其他機(jī)制

Song等[27]的研究發(fā)現(xiàn)diaporine A能夠通過上調(diào)mTOR的靶向性作用因子miR-99a，影響腫瘤細(xì)胞的增殖。Cheng等[6]的研究發(fā)現(xiàn)Pachymic acid能夠通過增加XBP-1s、ATF4、Hsp70、CHOP和phospho-eIF2α的表達(dá)，引起內(nèi)質(zhì)網(wǎng)應(yīng)激，進(jìn)而抑制腫瘤細(xì)胞增殖。Deng等[8]的研究發(fā)現(xiàn)neoalbaconol (NA)通過調(diào)節(jié)磷脂酰肌醇-3-羥激酶 (phosphatidylinositol 3-hydroxy kinase，PI3K)與蛋白激酶B (protein kinase B，AKT)的磷酸化，引起己糖激酶2 (hexokinase 2，HK2)的活性的降低，抑制腫瘤細(xì)胞的增殖。

3 真菌提取物抗癌作用實驗匯總

2012～2016年40篇文章報道的真菌提取物對各種不同癌細(xì)胞的抑制作用總結(jié)見表2。從表2可以看出，不同的真菌提取物對不同類型的腫瘤細(xì)胞有抑制作用，并且部分真菌提取物在抑制腫瘤細(xì)胞的同時，對正常細(xì)胞的毒性較小。除外少數(shù)幾種真菌提取物只在相對較高的劑量時才能顯著抑制腫瘤細(xì)胞生長，大部分真菌提取物都能在較低濃度下顯著抑制腫瘤細(xì)胞生長，表現(xiàn)出顯著的抗癌作用。

4 小 結(jié)

真菌是大自然賦予人類的一座寶庫，從真菌中篩選抗癌天然物質(zhì)的潛力巨大。一方面，真菌提取物的種類繁多，既能找到針對癌癥發(fā)生的共同機(jī)制和信號通路發(fā)揮作用的物質(zhì)，也能找到針對特殊類型的癌癥機(jī)制發(fā)揮作用的物質(zhì)。另一方面，從生物體中篩選天然藥物相比通過化學(xué)合成藥物更為方便和快捷，并且不會存在化學(xué)合成藥物的諸多限制[50]。隨著研究技術(shù)的不斷提高，越來越多的真菌提取物的作用機(jī)制被揭示。近幾年研究的真菌提取物的抗癌作用機(jī)制主要為通過調(diào)節(jié)MAPK、Wnt、NK-κB等信號通路抑制腫瘤細(xì)胞增殖，以及通過線粒體直接或間接激活caspase家族蛋白誘導(dǎo)癌細(xì)胞凋亡。真菌提取物抗癌的有效性與可靠性已經(jīng)在大量的細(xì)胞實驗中被證實，但是大量真菌提取物在活體中的作用還有待進(jìn)一步的研究。真菌提取物用作抗癌藥物有巨大前景，對其進(jìn)一步研究有助我們發(fā)現(xiàn)新的抗腫瘤藥物。

表2 真菌提取物對各類腫瘤細(xì)胞的抑制作用

名稱來源菌種腫瘤細(xì)胞名稱效果參考文獻(xiàn)cephalochrominCosmosporaviliorYMJ89051501A549對Hep3B,Caco-2,HT1080,Huh7,SW1353,A549的24hIC50值分別是(14.31±0.14),(12.40±0.05),(4.98±1.49),(4.64±0.29),(3.54±0.36),(2.72±0.42)μmol/L[29]isoscleroneAspergillusfumigatusMCF-7對MCF-7的IC50值為63.92μmol/L附近[31]Compounds5-7Guignardiasp.KcF8K562;A549;Huh-7;H197;MCF-7;U937;BGC823;HL60;HeLa;MOLT-4對多種腫瘤細(xì)胞的LD50值波動在0.05～39.2μmol/L[18]A.cinnamomeaAntrodiacinnamomeaSK-HEP-1對SK-HEP-1的24hIC50值在500μg/mL附近[32]FumigaclavineCAspergillusfumigatusMCF-7對MCF-7的24hIC50值在60μmol/L附近[33]neoalbaconol(NA)AlbatrellusconfluensC666-1;HK1NPC;ZR-75-1對C666-,HK1NPC,ZR-75-1的24hIC50值分別是10μmol/L,18μmol/L和7.5μmol/L[8]Trichothecin(TCN)endophyticfun-gusoftheherb-alplantMayte-nushookeriLoesHL-60;HepG2;A549;PANC-1對HL-60,HepG2,A549,PANC-1的24hIC50值分別是0.18μmol/L,0.82μmol/L,0.39μmol/L,0.28μmol/L[34]VerrucarinA(VA)MyrotheciumverrucariaMDA-MB-231;T47D對MDA-MB-231和T47D的24hIC50值在400ng/mL附近[35]Ganodermatsugae(GT)GanodermaSKOV-3;OVCAR-3對SKOV-3的24hIC50值在1mg/mL附近,而對OVCAR-3作用不明顯[36]Antrodiacamphorata(AC)AntrodiacamphorataSKOV-3對SKOV-3的24hIC50值在196μg/mL附近[37]HirsutanolAChondrostereumsp.SW620對SW620和MDA-MB-231的24hIC50值分別是13.43μmol/L和35.67μmol/L[7]

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[本文編輯] 王 飛

·消息·

The recent progresses of anti-cancer fungal extracts

ZENG Xuan-hao,ZHANG Qiang-qiang

(DepartmentofDermatology，HuaShanHospital，F(xiàn)udanUniversity，Shanghai200040，China)

This review summaries theadvance in anti-cancer fungal extracts in recent years.On the one hand,related multiple mechanisms might include the anti-cancer fungal extracts inducing apoptosis,inhibiting proliferation and angiogenesis.On the other hand,the anti-cancer effects of various anti-cancer fungal extracts in cancer cells are also reviewed.These study show that anti-cancer fungal extracts can inhibit the proliferation of cancer cells and induce apoptosis in cancer cells.The mechanisms of those functions involved various signal pathways,including Wnt,NK-κB,MAPK and Mitochondria related apoptosis signal pathways,and related to various proteins related to biological activity such as p38,bcl-2,c-jun,IκB,β-catenin,Akt.

fungus;cancer;mechanisms;progresses

國家自然科學(xué)基金 (81573056)

曾炫皓，男 (漢族)，碩士研究生在讀.E-mail:969358560@qq.com

章強(qiáng)強(qiáng),E-mail:zhangqq8@163.com

R 979.1

A

1673-3827(2017)12-0184-09

2016-10-24