陳 暢，羅婉君，段飛鵬，王寓平，胥雄飛，楊萌楚，姜金鑄，謝永艷，黃錦偉*，黃麗萍*

·綜述·

基于應(yīng)激顆粒的中藥神經(jīng)保護(hù)研究設(shè)想

陳 暢1, 2, 3，羅婉君2，段飛鵬1，王寓平2，胥雄飛2，楊萌楚2，姜金鑄3，謝永艷1，黃錦偉2*，黃麗萍1*

1. 江西中醫(yī)藥大學(xué)藥學(xué)院，江西 南昌 330004 2. 澳門科技大學(xué)中藥質(zhì)量研究國家重點(diǎn)實(shí)驗(yàn)室，中國 澳門 999078 3. 中國中醫(yī)科學(xué)院中藥研究所，北京 100700

應(yīng)激顆粒是存在于胞質(zhì)的一種無膜致密顆粒，通過包裹mRNA、轉(zhuǎn)錄起始因子、RNA結(jié)合蛋白等翻譯起始階段的重要元件，使細(xì)胞在遭受不利刺激時(shí)出現(xiàn)短暫的蛋白翻譯阻滯，從而起到細(xì)胞保護(hù)作用。研究發(fā)現(xiàn)，應(yīng)激顆粒廣泛分布于海馬和皮層的神經(jīng)元細(xì)胞、星形膠質(zhì)細(xì)胞、小膠質(zhì)細(xì)胞和浦肯野細(xì)胞等神經(jīng)細(xì)胞中，生物過程涉及蛋白異常聚集、突觸的成熟和可塑性、免疫調(diào)節(jié)、抗氧化應(yīng)激反應(yīng)、抑制細(xì)胞凋亡等，在急性缺血性腦卒中和神經(jīng)退行性疾病的發(fā)生發(fā)展中發(fā)揮著重要作用。尤其是其多樣化的物質(zhì)組成和廣泛參與的生物過程，為中醫(yī)證候生物學(xué)及“同病異治”“整體調(diào)節(jié)”等中醫(yī)藥傳統(tǒng)理論和治法的研究提供了嶄新的思路和視野。對應(yīng)激顆粒的基本特征、神經(jīng)保護(hù)及研究方法等進(jìn)行系統(tǒng)的梳理，同時(shí)以急性缺血性腦卒中為范例，嘗試將應(yīng)激顆粒這一現(xiàn)代生物學(xué)現(xiàn)象納入到中醫(yī)藥現(xiàn)代研究中，提出研究設(shè)想和思路，以期用科學(xué)的語言闡釋傳統(tǒng)中醫(yī)藥相關(guān)理論與治法，也為行業(yè)同仁的相關(guān)研究提供參考。

應(yīng)激顆粒；腦缺血；RNA結(jié)合蛋白；Ras-GTPase活化蛋白SH3結(jié)構(gòu)域結(jié)合蛋白1；神經(jīng)保護(hù)

當(dāng)細(xì)胞受到不利環(huán)境（如紫外線照射、病毒感染、亞砷酸鹽刺激、熱休克、缺氧、饑餓）脅迫時(shí)，可出現(xiàn)短暫的蛋白質(zhì)翻譯阻滯，形成由翻譯起始階段mRNA等組成的一種致密性顆粒狀聚集體。當(dāng)脅迫消失后，該聚集體可解聚并釋放包裹的mRNA及相關(guān)蛋白，使細(xì)胞能夠繼續(xù)正常的蛋白質(zhì)翻譯過程。這種致密的顆粒狀聚集體即為應(yīng)激顆粒。應(yīng)激顆粒的形成是細(xì)胞應(yīng)對不利刺激時(shí)的一種自我保護(hù)機(jī)制，提高了細(xì)胞在不利環(huán)境下生存的能力。近年來，研究發(fā)現(xiàn)應(yīng)激顆粒參與了細(xì)胞的翻譯調(diào)控、蛋白質(zhì)錯(cuò)誤折疊等生物學(xué)過程，尤其是其動(dòng)態(tài)而快速的形成和解聚、調(diào)節(jié)蛋白異常聚集的特性，為急性缺血性腦卒中及神經(jīng)退行性疾病的治療提供了一種創(chuàng)新的思路。

1 應(yīng)激顆粒的形成

應(yīng)激顆粒的形成分為經(jīng)典和非經(jīng)典2種途徑[1]。經(jīng)典途徑是應(yīng)激顆粒形成的主要方式，依賴于真核翻譯起始因子2α（eukaryotic initiation factor 2α，eIF2α）的磷酸化，非經(jīng)典途徑與破壞eIF4F復(fù)合物有關(guān)[2]。在哺乳動(dòng)物細(xì)胞中，目前已知至少有5種激酶[3]，包括蛋白激酶R（protein kinase R，PKR）、PKR樣內(nèi)質(zhì)網(wǎng)激酶（PKR-like endoplasmic reticulum kinase，PERK）、一般性控制非抑制性蛋白2（general control non-derepressible 2，GCN2）、血紅素調(diào)節(jié)抑制劑激酶（heme-regulated inhibitor kinase，HRI）和Z-DNA激酶[4]，可在細(xì)胞受到不同的刺激時(shí)激活，促進(jìn)eIF2α的磷酸化，進(jìn)而抑制eIF2與三磷酸鳥苷（guanosine triphosphate，GTP）結(jié)合，影響eIF2-GTP-tRNAMet復(fù)合物的形成，導(dǎo)致蛋白翻譯的暫時(shí)阻滯。在這一階段，翻譯起始階段的mRNA、翻譯起始因子、40S核糖體亞基和RNA結(jié)合蛋白等通過微管運(yùn)輸?shù)姆绞絒5]，以“核優(yōu)先”方式或“液-液相分離優(yōu)先”方式進(jìn)行裝配[6]，逐漸聚集并最終形成成熟的應(yīng)激顆粒。在組成應(yīng)激顆粒的組分中，超過50%為RNA結(jié)合蛋白[7]，雖然目前還未完全闡明這些蛋白各自的功能，但其中的Ras-GTPase活化蛋白SH3結(jié)構(gòu)域結(jié)合蛋白1（GTPase-activating protein SH3 domain binding protein 1，G3BP1）及T細(xì)胞胞質(zhì)內(nèi)抗原1（T-cell intracellular antigen 1，TIA1）對應(yīng)激顆粒的聚集起關(guān)鍵作用[8]。研究表明，缺乏G3BP1將不能形成應(yīng)激顆粒[9-11]，即便在沒有應(yīng)激的情況下，G3BP1也能誘導(dǎo)應(yīng)激顆粒的形成[8]。因此G3BP1也是被廣泛用于應(yīng)激顆粒形成的關(guān)鍵標(biāo)志性蛋白[12]。

2 應(yīng)激顆粒的解聚及影響因素

顯微觀察發(fā)現(xiàn)，盡管應(yīng)激顆粒是一個(gè)胞質(zhì)的無膜結(jié)構(gòu)，但其也有1個(gè)相對密集的“核”及1個(gè)具有潛在流動(dòng)性的“殼”，并呈現(xiàn)出液體一樣，組分快速交換的特點(diǎn)[7,13]。當(dāng)細(xì)胞所處的不利環(huán)境因素消失或減弱時(shí)，細(xì)胞中大部分的應(yīng)激顆?？稍跀?shù)分鐘內(nèi)同時(shí)解聚并消失，其解聚的過程表現(xiàn)為溶解而非分解為碎片[14-15]。應(yīng)激顆粒解聚后，一方面，釋放的mRNA及與翻譯相關(guān)的主要元件回到核糖體，重新啟動(dòng)正常的蛋白翻譯過程；另一方面，應(yīng)激顆粒的組分還可與胞質(zhì)中的另一種核糖核蛋白體，即P小體進(jìn)行物質(zhì)交換，mRNA進(jìn)入P小體發(fā)生降解或參與其他生物過程，RNA結(jié)合蛋白等則通過自噬的途徑予以清除[16-17]。

一些蛋白的磷酸化、甲基化修飾均能影響應(yīng)激顆粒的形成和解聚[18]。如G3BP1的磷酸化破壞了它形成多聚體的能力，而去磷酸化[8]和去甲基化[19]則有利于促進(jìn)應(yīng)激顆粒的組裝。其他如生長因子受體結(jié)合蛋白7和雙特異性酪氨酸磷酸化調(diào)節(jié)激酶3的磷酸化，也可促進(jìn)應(yīng)激顆粒的解聚。另外，三磷酸腺苷（adenosine triphosphate，ATP）可驅(qū)動(dòng)部分蛋白質(zhì)組分的交換，ATP酶可通過影響微管運(yùn)輸?shù)募?xì)胞轉(zhuǎn)運(yùn)，以及分子伴侶和RNA解螺旋酶的交互作用[5]，參與到應(yīng)激顆粒的運(yùn)動(dòng)中，暗示ATP可能參與驅(qū)動(dòng)應(yīng)激顆粒的形成[7]，在應(yīng)激顆粒的形成和解聚中扮演著重要的角色。此外，肌動(dòng)蛋白調(diào)節(jié)蛋白[20]、熱休克蛋白70等分子伴侶[21]及調(diào)節(jié)微管功能的相關(guān)蛋白如驅(qū)動(dòng)蛋白、動(dòng)力蛋白、組蛋白脫乙?；?、RhoA/ROCK1，也參與了應(yīng)激顆粒的形成和解聚過程[15,22-24]。

3 應(yīng)激顆粒的功能

應(yīng)激顆粒的形成，一方面促進(jìn)了某些組分的“聚集”，增強(qiáng)了細(xì)胞的天然免疫應(yīng)答等生物過程[25-27]；另一方面也可通過“隔離”相關(guān)信號分子，抑制細(xì)胞信號通路的轉(zhuǎn)導(dǎo)[28-29]。盡管目前對應(yīng)激顆粒的功能并不完全清楚，但已有證據(jù)表明，其可調(diào)節(jié)以下細(xì)胞生物學(xué)過程。

3.1 抗氧化

G3BP1及其綁定的配體泛素特異性蛋白酶10（ubiquitin-specific protease 10，USP10）在應(yīng)激顆粒的抗氧化作用中發(fā)揮著重要作用。研究表明，單獨(dú)的USP10并不具有抵抗過氧化氫導(dǎo)致的氧化損傷作用，而是在形成應(yīng)激顆粒后才能發(fā)揮此項(xiàng)功能[30]。在非應(yīng)激狀態(tài)下，USP10表達(dá)受到G3BP1的抑制，當(dāng)應(yīng)激顆粒形成后，G3BP1對USP10的抑制減弱，進(jìn)而發(fā)揮抗氧化功能。

3.2 抗凋亡

應(yīng)激顆粒的抗凋亡作用一方面與其抗氧化作用有關(guān)[30]，同時(shí)也可通過“隔離”誘導(dǎo)細(xì)胞凋亡的關(guān)鍵信號分子予以實(shí)現(xiàn)。研究表明，應(yīng)激顆粒除可通過抑制雷帕霉素復(fù)合物1通路的細(xì)胞凋亡外[31]，還可通過招募并“隔離”活化的蛋白激酶C1受體等關(guān)鍵信號分子，使其不能與其他因子相結(jié)合，進(jìn)而抑制了p38和c-Jun氨基末端激酶的激活，降低了細(xì)胞凋亡的發(fā)生[32]。此外，過表達(dá)的Fas活化絲氨酸/蘇氨酸激酶可與應(yīng)激顆粒中的重要RNA結(jié)合蛋白TIA1相互作用，降低TIA1對某些抗凋亡蛋白mRNA的抑制，從而促進(jìn)這些抗凋亡蛋白的表達(dá)[33]。

3.3 參與免疫調(diào)節(jié)

cGAS/string天然免疫信號通路可識別由于衰老或損傷等所產(chǎn)生的胞質(zhì)DNA碎片，啟動(dòng)I型干擾素表達(dá)，幫助細(xì)胞進(jìn)行免疫防御。研究顯示，G3BP1可通過幫助cGAS聚集發(fā)生相分離，增強(qiáng)其對DNA的敏感性和結(jié)合能力，進(jìn)而促進(jìn)cGAS的激活[34]。G3BP1缺失將導(dǎo)致cGAS不能有效結(jié)合DNA，從而抑制cGAS介導(dǎo)的I型干擾素的產(chǎn)生[35]。除此之外，應(yīng)激顆粒的聚集可抑制腫瘤壞死因子-α（tumor necrosis factor-α，TNF-α）介導(dǎo)的核因子-κB通路的活化[36]；組成蛋白CUGBP2及HuR可調(diào)控前炎癥刺激物環(huán)氧合酶-2的表達(dá)等[37-38]。

4 應(yīng)激顆粒與神經(jīng)保護(hù)

4.1 應(yīng)激顆粒與缺血性腦卒中

急性缺血性腦卒中后損傷部位蛋白翻譯的暫時(shí)阻滯與應(yīng)激顆粒的聚集關(guān)系密切[39]，在腦缺血?jiǎng)游锬Ｐ偷拇竽X皮層和海馬均可觀察到大量應(yīng)激顆粒的產(chǎn)生。研究表明[40]，大腦皮層應(yīng)激顆粒的形成在腦缺血再灌注后6 h達(dá)到峰值，在再灌注后24 h下降，而細(xì)胞凋亡水平和腦梗死體積在再灌注后6 h最低，24 h最高。提示應(yīng)激顆粒的形成與凋亡水平呈負(fù)相關(guān)趨勢，再灌注24 h是研究應(yīng)激顆粒形成與細(xì)胞凋亡水平相關(guān)性的最佳觀測時(shí)間點(diǎn)，同時(shí)也表明應(yīng)激顆粒具有動(dòng)態(tài)結(jié)構(gòu)和抗凋亡作用。體外細(xì)胞實(shí)驗(yàn)也證明，通過促進(jìn)糖氧剝奪/復(fù)氧的PC細(xì)胞應(yīng)激顆粒的生成，可明顯抑制細(xì)胞的凋亡水平[41-43]。除此之外，腦缺血可導(dǎo)致海馬CA3區(qū)、hilar區(qū)、齒狀回等神經(jīng)元eIF2α迅速磷酸化，應(yīng)激顆粒明顯增加[44]。然而海馬CA1區(qū)相對難以形成應(yīng)激顆粒[45-46]，因此當(dāng)血流恢復(fù)灌注后，除CA1區(qū)外其他腦區(qū)的蛋白合成大多可逐步恢復(fù)[47-48]，這也可以解釋為何有的研究表明CA1區(qū)比CA3區(qū)對缺血更為敏感[49-50]。腦缺血后應(yīng)激顆粒的形成也可通過不依賴于eIF2α磷酸化的途徑產(chǎn)生，該過程與eIF4F復(fù)合物有關(guān)[51]。

4.2 應(yīng)激顆粒與神經(jīng)退行性疾病

神經(jīng)退行性疾病的發(fā)生除與應(yīng)激顆粒關(guān)鍵蛋白G3BP1關(guān)系密切外[52]，還與一些蛋白的異常聚集有關(guān)。如β淀粉樣蛋白、tau蛋白、α突觸核蛋白（α-synuclein）、TAR DNA結(jié)合蛋白-43（TAR DNA binding protein-43，TDP-43）及FUS的異常聚集被認(rèn)為是阿爾茨海默病、帕金森癥、肌萎縮性脊髓側(cè)索硬化癥等神經(jīng)退行性疾病的重要病理標(biāo)志。這在形態(tài)學(xué)上與應(yīng)激顆粒形成過程中，RNA結(jié)合蛋白高度聚集形成致密顆粒非常相似，這一病理過程已被證明與應(yīng)激顆粒形成有關(guān)[53]。研究表明，內(nèi)質(zhì)網(wǎng)內(nèi)未正確折疊蛋白的積累，可激活位于內(nèi)質(zhì)網(wǎng)的激酶PERK，引起eIF2α磷酸化，進(jìn)而促進(jìn)應(yīng)激顆粒形成[54]。報(bào)道顯示，用siRNA敲減TDP-43后[55]，應(yīng)激顆粒形成減少，提示TDP-43參與了應(yīng)激顆粒的生成[56-58]。與神經(jīng)退行性疾病相關(guān)的許多蛋白，如tau[59]、FUS[60]、ataxin-2[61]、運(yùn)動(dòng)神經(jīng)元生存蛋白[62]、血管穩(wěn)定蛋白[63]等，在應(yīng)激發(fā)生時(shí)，也可被招募到應(yīng)激顆粒中參與應(yīng)激顆粒的形成[64]。

在連接應(yīng)激顆粒與神經(jīng)退行性疾病的RNA結(jié)合蛋白中，TDP-43的研究相對更為深入。TDB-43是一種DNA和RNA結(jié)合蛋白，病理性TDP-43被認(rèn)為是額顳葉變性和肌萎縮側(cè)索硬化癥的主要病理標(biāo)志物，后來也發(fā)現(xiàn)其參與了阿爾茨海默病、帕金森癥及亨廷頓病等神經(jīng)退行性疾病的病理過程[65-66]。正常情況下，應(yīng)激發(fā)生后，位于細(xì)胞核的TDP-43迅速轉(zhuǎn)移到胞質(zhì)中，參與應(yīng)激顆粒的形成并起細(xì)胞保護(hù)作用[57,67]。然而病理狀態(tài)下，目前已知最少有4種情況可導(dǎo)致TDP-43的異常聚集，進(jìn)而表現(xiàn)出TDP-43蛋白病的特征。①RNA結(jié)合功能缺陷的TDP-43因不能被募集到應(yīng)激顆粒中，而在胞質(zhì)中形成磷酸化和P62陽性TDP-43顆粒[68]。②當(dāng)應(yīng)激消失后，病理性的TDP-43聚集物并不隨著應(yīng)激顆粒的解體而解聚[69]。③應(yīng)激顆粒異常解體時(shí)，TDP-43從應(yīng)激顆粒釋放至胞質(zhì)，并發(fā)生磷酸化，進(jìn)而發(fā)生液-液相分離形成病理性聚集體[70-71]。④TDP-43突變導(dǎo)致胞質(zhì)TDP-43永久性聚集，進(jìn)而增加了應(yīng)激顆粒的穩(wěn)定性，阻礙了應(yīng)激顆粒本身的動(dòng)態(tài)物質(zhì)交換過程[72]。

深入研究發(fā)現(xiàn)，富含甘氨酸、天冬酰胺、谷氨酰胺和酪氨酸的朊蛋白樣結(jié)構(gòu)域[73-74]，重點(diǎn)調(diào)節(jié)了TDP-43的剪接活性及與應(yīng)激顆粒等的相互作用。

4.3 應(yīng)激顆粒參與其他神經(jīng)保護(hù)功能

G3BP1和TIA1是形成應(yīng)激顆粒的關(guān)鍵RNA結(jié)合蛋白，基因敲除或其功能異常均會(huì)影響應(yīng)激顆粒的正常聚集。G3BP1高表達(dá)于大腦海馬、額葉皮層、小腦浦肯野細(xì)胞等部位[75]。基因敲除后，小鼠腦組織海馬區(qū)鈣離子穩(wěn)態(tài)失衡，神經(jīng)突觸傳遞功能障礙，皮層及內(nèi)囊神經(jīng)元大量細(xì)胞凋亡，小腦浦肯野細(xì)胞數(shù)量明顯減少，可出現(xiàn)記憶力減退及運(yùn)動(dòng)功能障礙等癥狀[75-78]。G3BP1復(fù)合物還可在小鼠腦組織中參與到內(nèi)含子保留的轉(zhuǎn)錄調(diào)控中，并進(jìn)一步調(diào)節(jié)谷氨酸神經(jīng)元的相關(guān)功能，影響神經(jīng)突觸可塑性[78]。另外，TIA1的降低或敲除可促進(jìn)小膠質(zhì)細(xì)胞的增殖、活化與吞噬，白細(xì)胞介素-1β及TNF-α釋放增多，氧化應(yīng)激水平提高，神經(jīng)突觸丟失增加，加重了tau蛋白疾病發(fā)展[79]。富甘氨酸序列的冷誘導(dǎo)RNA結(jié)合蛋白也可參與應(yīng)激顆粒的形成[80]。研究表明，在原代大鼠海馬神經(jīng)元細(xì)胞模型中，亞低溫處理可通過上調(diào)冷誘導(dǎo)RNA結(jié)合蛋白的表達(dá)，抑制細(xì)胞內(nèi)氧自由基的生成，從而直接或間接地抑制了氧自由基誘導(dǎo)的神經(jīng)元細(xì)胞凋亡，進(jìn)而起到海馬神經(jīng)元的保護(hù)作用[81]。

5 應(yīng)激顆粒的觀察和檢測

對應(yīng)激顆粒標(biāo)簽蛋白如G3BP1或TIA1的檢測，是當(dāng)前表征應(yīng)激顆粒的主要手段[82]。在細(xì)胞水平，采用熒光顯微鏡或激光共聚焦顯微鏡觀測技術(shù)，以免疫熒光法檢測TIA1或G3BP1，已被用于觀察毒胡蘿卜素誘導(dǎo)海馬神經(jīng)元HT22細(xì)胞[83]及缺氧誘導(dǎo)的人小膠質(zhì)HMC3細(xì)胞[84]應(yīng)激顆粒的形成。若采用G3BP1與微管關(guān)聯(lián)蛋白等神經(jīng)細(xì)胞標(biāo)記蛋白共同觀察，還可考察應(yīng)激顆粒的細(xì)胞定位[75]。為增加對應(yīng)激顆粒檢測的準(zhǔn)確性，有研究同時(shí)采用了G3BP1及TIA1 2種標(biāo)簽蛋白，對缺氧/復(fù)氧的原代皮層神經(jīng)元細(xì)胞或神經(jīng)細(xì)胞PC12中的應(yīng)激顆粒進(jìn)行表征[43]。除此之外，以紅色熒光蛋白、綠色熒光蛋白分別對G3BP1、TIA1進(jìn)行標(biāo)記，還可動(dòng)態(tài)觀察細(xì)胞受亞砷酸鹽刺激后應(yīng)激顆粒的形成過程[46,84]。在組織水平，除可采用免疫組化法對TIA1等標(biāo)簽蛋白進(jìn)行定量的方法外[40]，也可用免疫熒光法，以G3BP1或TIA1為標(biāo)記，對大鼠腦缺血后缺血組織的應(yīng)激顆粒進(jìn)行形態(tài)學(xué)表征[41]。

盡管G3BP1和TIA1均可作為應(yīng)激顆粒的標(biāo)簽蛋白，但在非應(yīng)激狀態(tài)下，TIA1主要位于細(xì)胞核內(nèi)，應(yīng)激發(fā)生后部分遷移到胞質(zhì)中[85]。而G3BP1主要分散于細(xì)胞質(zhì)中，熒光標(biāo)記的G3BP1在應(yīng)激發(fā)生后更容易觀察到特異性的點(diǎn)狀熒光[82,86]。因此有學(xué)者認(rèn)為與TIA相比，G3BP1更適合作為應(yīng)激顆粒的標(biāo)志物[12]。

由于應(yīng)激顆粒是一種無膜的亞細(xì)胞結(jié)構(gòu)，且存在動(dòng)態(tài)而迅速的物質(zhì)交換過程，因此對其內(nèi)部組成的研究還存在許多技術(shù)瓶頸[87]。目前相關(guān)的研究手段包括熒光漂白恢復(fù)技術(shù)[88]、高分辨顯微技術(shù)[7]、蛋白組學(xué)分析[7]、差速離心及免疫純化[24]、體外模擬[89]及數(shù)學(xué)建模[90]等。

6 基于應(yīng)激顆粒的中醫(yī)藥現(xiàn)代研究設(shè)想

結(jié)構(gòu)決定功能是當(dāng)前生物學(xué)研究的基本認(rèn)識。研究應(yīng)激顆粒的組分構(gòu)成對其功能的研究意義重大。報(bào)道顯示，細(xì)胞受到不同的壓力刺激時(shí)，所產(chǎn)生的應(yīng)激顆粒組分不同[3]。如在釀酒的酵母中，eIF3在熱應(yīng)激誘導(dǎo)的應(yīng)激顆粒中被發(fā)現(xiàn)，而葡萄糖缺乏誘導(dǎo)的應(yīng)激顆粒中卻無eIF3[91-93]。功能上看，同一類型細(xì)胞所產(chǎn)生的應(yīng)激顆粒，也可能產(chǎn)生完全相反的生物效應(yīng)。如在腫瘤細(xì)胞中，應(yīng)激顆粒一方面可通過絲裂原活化蛋白激酶途徑抑制腫瘤細(xì)胞凋亡[32]；也可通過包裹住缺氧誘導(dǎo)因子-1α mRNA，使血管內(nèi)皮細(xì)胞生長因子無法被激活，進(jìn)而提高腫瘤的治療效果[94]。

應(yīng)激顆粒組成成分和功能的深入研究，為藥物開發(fā)提供了一個(gè)全新的領(lǐng)域。在中藥神經(jīng)保護(hù)領(lǐng)域，盡管當(dāng)前只有少數(shù)研究報(bào)道了中藥（成分）可通過促進(jìn)應(yīng)激顆粒生成發(fā)揮腦保護(hù)作用[40,95]，但應(yīng)激顆粒介導(dǎo)的中藥神經(jīng)保護(hù)策略，已展示出創(chuàng)新的研究思路和廣闊的研發(fā)前景，尤其是應(yīng)激顆粒動(dòng)態(tài)的物質(zhì)組成與功能特征，更是與中醫(yī)藥的一些治療理念不謀而合。首先，細(xì)胞受不同刺激導(dǎo)致的損傷，與傳統(tǒng)中醫(yī)認(rèn)為的機(jī)體由于不同證候?qū)е碌募膊∮兄T多相似之處。如中醫(yī)認(rèn)為“中風(fēng)”的基本病因有氣虛、血瘀、痰濕、熱毒等，這些中醫(yī)學(xué)上的不同病因與細(xì)胞受到的不同環(huán)境刺激在損傷原理上非常相似。其次，應(yīng)激顆粒受到不同刺激從而有不同的物質(zhì)組成這一特性，一方面可為闡釋中醫(yī)的證候生物學(xué)提供科學(xué)載體和物質(zhì)條件；同時(shí)采用不同的治法如補(bǔ)氣、活血、化痰、清熱等對應(yīng)激顆粒不同的物質(zhì)組成進(jìn)行“糾偏”，也可為研究“同病異治”這一傳統(tǒng)中醫(yī)治法提供創(chuàng)新的思路和方法。另外，應(yīng)激顆粒的形成，包裹和隔離了諸多細(xì)胞信號傳遞因子，對細(xì)胞的生物過程如凋亡、氧化應(yīng)激、免疫調(diào)節(jié)等產(chǎn)生重大影響。盡管尚不清楚應(yīng)激顆粒在不同情況下其確切的物質(zhì)組成，但其對細(xì)胞生物過程的多方位調(diào)控，也為研究中藥多成分如何調(diào)節(jié)機(jī)體的多個(gè)生物學(xué)效應(yīng)，開創(chuàng)了一個(gè)全新的研究方向。以缺血性腦卒中為例，應(yīng)激顆粒介導(dǎo)的中醫(yī)證候生物學(xué)、“同病異治”及“整體調(diào)節(jié)”研究設(shè)想可簡要概括為圖1的研究思路和框架。

圖1 基于應(yīng)激顆粒的中醫(yī)藥現(xiàn)代研究設(shè)想(以缺血性腦卒中為例)

7 結(jié)語

當(dāng)前對應(yīng)激顆粒的研究和認(rèn)識還不全面，相信隨著現(xiàn)代生物學(xué)的進(jìn)步，應(yīng)激顆粒的物質(zhì)組成和功能將逐漸被揭示，這為基于應(yīng)激顆粒的創(chuàng)新藥物研究開啟了嶄新的一頁。尤其是當(dāng)不利刺激發(fā)生時(shí)胞質(zhì)成分快速聚集，刺激消失后迅速解聚的特性，為急性缺血性腦卒中等急性腦損傷的研究提供了良好的載體；其調(diào)控RNA蛋白的錯(cuò)誤折疊和異常聚集，也為神經(jīng)退行性疾病的研究開拓了新的思路和方法。

利益沖突 所有作者均聲明不存在利益沖突

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Inspiration of neuroprotection of traditional Chinese medicine (TCM) based on stress granules

CHEN Chang1, 2, 3, Betty Yuen Kwan Law2, DUAN Fei-peng1, WANG Yu-ping2, XU Xiong-fei2, YANG Meng-chu2, JIANG Jing-zhu3, XIE Yong-yan1, Vincent Kam Wai Wong2, HUANG Li-ping1

1. School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, China 2. State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China 3. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China

Stress granules (SG) are membrane-free dense granules present in the cytoplasm that act as cytoprotective agents by wrapping mRNA, transcription initiation factors, and RNA-binding proteins and other important components of the translation initiation phase, resulting in a transient protein translation block when cells are subjected to adverse stimuli. This cellular process is a self-protection mechanism for cells. It was found that SG were widely distributed in neurons, astrocytes, microglia, purkinje cell in the hippocampus and cortex, and the biological processes involve abnormal protein aggregation, synaptic maturation and plasticity, immune regulation, antioxidant stress response, and inhibition of apoptosis. For instance, SG participate the misfolding and abnormal accumulation of the essential protein, synaptic maturation and plasticity, it also exhibits immunoregulation, anti-oxidation and prevention of cell apoptosis in neuronal cells, so as to contribute to the neuronal function recovery. Accordingly, SG are considered as an alternative approach for treatment of stroke and neurodegenerative disease. In particular, its diversified substance composition and widely involved biological process provide a new vision for the study of TCM syndrome biology and the traditional treatments of TCM such as “different treatment of the same disease” and “holistic regulation”. Here, the principal character, neuroprotective functions and related research methods are systematically reviewed. At the same time, taking acute ischemic stroke as an example, the modern biological phenomenon of SG is tried to incorporate into the modern research of TCM, and research inspiration and ideas are put forward in order to explain the relevant theories and treatments of TCM in a scientific way and provide reference for other researchers.

stress granules; cerebral ischemia; RNA-binding proteins; G3BP1; neuroprotection

R285

A

0253 - 2670(2022)16 - 5185 - 08

10.7501/j.issn.0253-2670.2022.16.028

2022-02-18

國家自然科學(xué)基金資助項(xiàng)目（82060759）；國家自然科學(xué)基金資助項(xiàng)目（81660713）；澳門科技發(fā)展基金資助項(xiàng)目（0048/2018/A2）；中國中醫(yī)科學(xué)院科技創(chuàng)新工程項(xiàng)目（CI2021A00916，CI2021A04404，CI2021A04405）；江西中醫(yī)藥大學(xué)研究生境外訪學(xué)基金資助項(xiàng)目

陳 暢，副研究員，碩士生導(dǎo)師，研究方向?yàn)橹兴幧窠?jīng)藥理學(xué)。E-mail: cchen@icmm.ac.cn

黃麗萍，教授，博士生導(dǎo)師，研究方向?yàn)橹兴幧窠?jīng)藥理學(xué)。E-mail:jxnchlp@163.com

黃錦偉，教授，博士生導(dǎo)師，研究方向?yàn)橹兴幩幚韺W(xué)。E-mail: kawwong@must.edu.mo

[責(zé)任編輯 崔艷麗]