SIRT1氧化應(yīng)激通路與疾病的關(guān)系*
楊熙 綜述董文斌 審校
(四川醫(yī)科大學(xué)附屬醫(yī)院新生兒科, 四川 瀘州 646000)
【摘要】SIRT1是一類依賴煙堿腺嘌呤二核苷酸(nicotinamide adenine dinucleotide,NAD+)的第三類組蛋白去乙?;福@種蛋白從古細(xì)菌到人類都具有高度保守性。SIRT1在人體組織中廣泛表達(dá),運(yùn)動(dòng)、能量限制可以上調(diào)SIRT1表達(dá)。SIRT1通過(guò)組蛋白/非組蛋白去乙?;饔糜绊懟虻霓D(zhuǎn)錄,在抵抗各種應(yīng)激,調(diào)節(jié)細(xì)胞凋亡、細(xì)胞能量代謝以及細(xì)胞老化等方面發(fā)揮重要作用。目前,一些研究已經(jīng)證實(shí)SIRT1在與衰老相關(guān)性疾病中及氧化刺激中具有保護(hù)作用,如神經(jīng)退行性疾病、心血管系統(tǒng)疾病、腎臟系統(tǒng)疾病、內(nèi)分泌系統(tǒng)疾病等。
【關(guān)鍵詞】SIRT1; 氧化應(yīng)激; 疾病
【中圖分類號(hào)】R 446.69【文獻(xiàn)標(biāo)志碼】A
基金項(xiàng)目:中華兒科雜志第二屆雙鶴珂立蘇科研基金;四川省教育廳科研基金(08ZA150);四川省衛(wèi)生廳科研課題(90191)
通訊作者:董文斌,《西部醫(yī)學(xué)》編委,E-mail:DongWenbin2000@163.com
收稿日期:( 2015-01-19; 編輯: 張文秀)
The relationship between SIRT1 oxidative stress pathways and diseaseYANG Xireviewing, DONG Wenbinchecking
(DepartmentofNeonatology,TheAffiliatedHospitalofSichuanMedicalUniversity,Luzhou646000,Sichuan,China)
【Abstrat】SIRT1 is a highly conservative NAD+-dependent class Ⅲ histone deacetylase,whichis widely expressed in human tissues and motion, energy restriction can upregulate it's expression. SIRT1 can affect gene transcription via histone and non histone deacetylation,and play an important I role in against various stress, regulation of cell apoptosis, cell metabolism and cell senescence. At present, some studies have confirmed that SIRT1 has protective effects on aging related diseases and oxidation stimulation such as neurodegenerative disease,cardiovascular system disease, kidney system disease, endocrine system disease.
【Key words】SIRT1; Oxidative stress; Disease
近年來(lái)隨著醫(yī)學(xué)的飛速發(fā)展,新型醫(yī)療技術(shù)的應(yīng)用在一定程度上提升了病人的搶救成功率及存活率。這也使機(jī)體更多的暴露在氧化應(yīng)激下,而氧化應(yīng)激可以誘導(dǎo)大量氧自由基生成導(dǎo)致細(xì)胞膜脂質(zhì)過(guò)氧化作用和蛋白質(zhì)氧化從而誘發(fā)細(xì)胞凋亡。在哺乳動(dòng)物中Sirtuin蛋白家族有七個(gè)成員,而SIRT1與酵母菌中Sir2同源性最高,也是目前研究最多的蛋白。大量研究證實(shí)SIRT1在抵抗氧化應(yīng)激中發(fā)揮了重要的保護(hù)作用,本文從SIRT1的生物性特性、SIRT1氧化應(yīng)激通路的調(diào)控、SIRT1氧化應(yīng)激通路在疾病中的作用進(jìn)行綜述。
1SIRT1生物性特性
Ivy[1]等在1986年從酵母中提取并分離出一種與細(xì)胞壽命相關(guān)的基因,隨后在線蟲和果蠅中也同樣發(fā)現(xiàn)這種基因,后來(lái)這種基因被命名為沉默信息調(diào)節(jié)因子2(silent information regulator2,Sir2)。Sir2相關(guān)酶類(sir2-related enzymes,Sirtuins)是一類依賴煙堿腺嘌呤二核苷酸(nicotinamide adenine dinucleotide,NAD+)的第三類組蛋白去乙?;?,這種蛋白從古細(xì)菌到人類都具有高度保守性。1999年,F(xiàn)rye[2-3]在人體中發(fā)現(xiàn)了與Sir2同源的五個(gè)基因(Sirt1-5),隨后研究者又相繼發(fā)現(xiàn)了Sirt6、Sirt7。哺乳動(dòng)物sirtuins蛋白亞細(xì)胞定位也不同。SIRT1在細(xì)胞核和細(xì)胞質(zhì)都有表達(dá),但以細(xì)胞核為主,SIRT2定位在細(xì)胞質(zhì),SIRT3、SIRT4、SIRT5定位在線粒體中,SIRT6、SIRT7定位在細(xì)胞核[4-7]。其中,SIRT1與酵母菌Sir2同源性最高,而對(duì)SIRT1的研究也是最多的[8]。
人類SIRT1基因定位與染色體10q22.1,基因長(zhǎng)度為33000bp,編碼的蛋白相對(duì)分子質(zhì)量為120000。由500個(gè)氨基酸殘基組成,包含9個(gè)外顯子和8個(gè)內(nèi)含子,全長(zhǎng)33kb,5、及3、端各有一個(gè)分別為53bp及1793bp的非編譯區(qū),由幾個(gè)基本結(jié)構(gòu)組成:一個(gè)大的結(jié)構(gòu)域,主要由Rossmann折疊構(gòu)成,其保守性較高;一個(gè)小的結(jié)構(gòu)域,包含一個(gè)鋅帶結(jié)構(gòu)(zinc ribbon)和一個(gè)螺旋構(gòu)件,其保守性較大結(jié)構(gòu)域要低得多,在大小結(jié)構(gòu)域之間形成一個(gè)裂隙,底物就結(jié)合于此并發(fā)生催化反應(yīng)[9]。
SIRT1在人體組織中廣泛表達(dá),運(yùn)動(dòng)、能量限制可以上調(diào)SIRT1表達(dá)[10,11]。SIRT1可以發(fā)揮其組蛋白/非組蛋白去乙?;淖饔糜绊懟虻霓D(zhuǎn)錄,還可以通過(guò)去乙?;恍┫掠伟谢颍瑥亩l(fā)揮抵抗各種應(yīng)激,調(diào)節(jié)細(xì)胞凋亡、調(diào)控細(xì)胞能量代謝以及細(xì)胞老化等。SIRT1具有組蛋白賴氨酸殘基去乙?;饔?,如將組蛋白H1的第26位、H3的第9位、H4的第16位賴氨酸去乙?;M(jìn)而調(diào)節(jié)基因的轉(zhuǎn)錄[12,13]。SIRT1也可以去乙酰化非組蛋白賴氨酸殘基完成不同的生理功能,如 p53 、叉頭蛋白(forkhead box O factor,FOXO),核因子κB(nuclear factor-kappa B,NF-κB).、Ku70、過(guò)氧化物酶體激活物受體γ(peroxisome proliferator-activated receptorγ,PPARγ)、PPARγ輔激活物1α(PPARγ coactivator 1α,PGC1α)、內(nèi)皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)、1型多聚ADP核糖合成酶[poly(ADP-ribose)polymerase 1,PARP1]、E2F轉(zhuǎn)錄因子1等。目前一些研究已經(jīng)證實(shí)SIRT1在與衰老相關(guān)性疾病中及氧化刺激中具有保護(hù)作用,如神經(jīng)退行性疾病、心血管系統(tǒng)疾病、腎臟系統(tǒng)疾病等[14]。
SIRT1的亞細(xì)胞定位受核漿穿梭機(jī)制調(diào)節(jié),以此參與細(xì)胞分化或細(xì)胞凋亡[4]。SIRT1一直以來(lái)都認(rèn)為是一種核蛋白,但隨后研究發(fā)現(xiàn),在某些特殊類型細(xì)胞當(dāng)中,其主要表達(dá)也可在細(xì)胞質(zhì)當(dāng)中。在新生小鼠心肌細(xì)胞當(dāng)中,SIRT1的表達(dá)在細(xì)胞核,但是在成年小鼠心肌細(xì)胞當(dāng)中,SIRT1在細(xì)胞質(zhì)也有表達(dá),并且以細(xì)胞質(zhì)為主[4]。研究發(fā)現(xiàn)定位在細(xì)胞核上的SIRT1主要起到抗凋亡作用,如以產(chǎn)生活性氧的抗毒素A處理細(xì)胞,其在細(xì)胞核中的SIRT1 表達(dá)增加,細(xì)胞凋亡減少[4]。而定位在細(xì)胞質(zhì)中的SIRT1作用還尚不清楚,有研究者根據(jù)對(duì)Ⅱ類去乙?;负?漿穿梭種的研究推測(cè):穿梭至細(xì)胞質(zhì)中的SIRT1可以增加細(xì)胞核中靶蛋白乙酰化水平并改變其活性,以此影響在細(xì)胞內(nèi)的功能[15]。
2SIRT1氧化應(yīng)激通路的調(diào)控
2.1SIRT1與P53P53是細(xì)胞中重要的腫瘤抑制因子,也是最早發(fā)現(xiàn)的SIRT1生理性底物[16],SIRT1與P53呈負(fù)性調(diào)節(jié)作用。當(dāng)細(xì)胞處于氧化應(yīng)激下時(shí),P53 N末端的多個(gè)位點(diǎn)磷酸化,C末端的多個(gè)賴氨酸位點(diǎn)乙酰化,P53活化刺激下游多個(gè)靶基因轉(zhuǎn)錄誘導(dǎo)細(xì)胞凋亡。SIRT1通過(guò)將P53蛋白第382位賴氨酸殘基去乙?;?,抑制P53活性,從而抑制下游依賴于P53的靶基因CDKNIA及BAX等的轉(zhuǎn)錄,從而減少細(xì)胞凋亡[17,18]。
2.2SIRT1與FOXOFOXO轉(zhuǎn)錄因子包括FOXO1、FOXO3a、FOXO4和FOXO6。FOXO蛋白家族主要參與調(diào)控細(xì)胞凋亡、細(xì)胞周期進(jìn)行和DNA損傷修復(fù)過(guò)程中所涉及的一系列基因的表達(dá)。SIRT1可以通過(guò)其去乙?;饔茫苯踊蛘唛g接調(diào)控FOXO1、FOXO3a、FOXO4的活性[19-20]。SIRT1可以使FOXO3a去乙?;?,使其促進(jìn)細(xì)胞周期調(diào)控相關(guān)的下游靶基因p27KIP和DNA修復(fù)相關(guān)的下游靶基因,從而抑制凋亡相關(guān)的下游靶基因如Fas ligand、Bim的表達(dá),進(jìn)而減少細(xì)胞凋亡[21,22]。SIRT1雙向調(diào)控FOXO:一方面誘導(dǎo)細(xì)胞周期停滯和增強(qiáng)抵抗應(yīng)激的能力;另一方面SIRT1使FOXO誘導(dǎo)細(xì)胞凋亡的能力減弱。
2.3SIRT1與eNOS在血管內(nèi)皮細(xì)胞中,SIRT1可以增加細(xì)胞抗氧化應(yīng)激能力,從而減少細(xì)胞凋亡。研究發(fā)現(xiàn)SIRT1使eNOS鈣調(diào)蛋白結(jié)合區(qū)域賴氨酸496位和506位去乙?;瘡亩せ頴NOS增加NO生成,從而改善內(nèi)皮依賴性的血管舒張活性。如果降低SIRT1的活性, NO生物功能下降[23]。SIRT1還能通過(guò)調(diào)節(jié)內(nèi)皮細(xì)胞的血管生成活性保護(hù)內(nèi)皮功能。Potente等發(fā)現(xiàn)SIRT1的去乙?;钚栽趦?nèi)皮細(xì)胞介導(dǎo)的血管生成過(guò)程中發(fā)揮重要作用。在體外研究中,如基因敲出SIRT1則可引起血管萌發(fā)障礙[24]。
2.4SIRT1與NF-KBNF-KB是一種異二聚體蛋白,在氧化應(yīng)激中扮演著非常重要的角色,控制細(xì)胞生存基因的表達(dá)[25]。各種促炎因素均可以激活動(dòng)脈壁NF-KB從而刺激線粒體產(chǎn)生大量氧自由基,SIRT1通過(guò)使NF-KB亞單位Rel/p65去乙酰化抑制其轉(zhuǎn)錄,減少氧自由基的產(chǎn)生,并且能夠抑制促進(jìn)動(dòng)脈粥樣硬化和心血管的主要病理因子,如腫瘤壞死因子(tumor necrosis factor,TNF)、單核細(xì)胞趨化蛋白-1(monocyte chemotactic protein-1)等,從而保護(hù)心臟[26]。
2.5SIRT1與Ku70在正常條件下,Bax在胞質(zhì)內(nèi)與DNA修復(fù)因子Ku70緊密結(jié)合,處于非活性狀態(tài)。但在氧化應(yīng)激條件下,Ku70 C末端的兩個(gè)重要賴氨酸殘基(K539、K542)乙?;?,Ku70與Bax的相互作用被破壞,Bax定位到線粒體,開啟細(xì)胞凋亡。乙酰化的Ku70可作為SIRT1的底物與其相互作用,使其兩個(gè)賴氨酸殘基去乙酰化,造成與Bax的作用加強(qiáng),使其不能移到線粒體上,以此抑制細(xì)胞凋亡[27]。
2.6SIRT1與SUMO化、去SUMO化SUMO(Small ubiquitin-related modifier)是類泛素蛋白家族的重要成員之一,它在結(jié)構(gòu)上與泛素分子相似,但其功能與泛素化修飾完全不同。SIRT1的第734位賴氨酸可以發(fā)生SUMO化修飾,實(shí)驗(yàn)表明,這一修飾將會(huì)增加SIRT1的去乙酰化活性。但在氧化應(yīng)激條件或者遺傳毒性物質(zhì)下,SIRT1又可以被SENP1(Sentrin-specific protease-1)去SUOM化,由此導(dǎo)致SIRT1的活性降低而p53介導(dǎo)的凋亡作用增強(qiáng)[28]。
3SIRT1氧化應(yīng)激通路在疾病中的作用
3.1SIRT1在心臟疾病中的作用心血管疾病以動(dòng)脈粥樣硬化(atherosclerosis,AS)為其主要病理基礎(chǔ)。研究表明血管內(nèi)皮細(xì)胞氧化應(yīng)激損傷是AS最主要的發(fā)病機(jī)制。氧化應(yīng)激主要與細(xì)胞內(nèi)活性氧(reactive oxyen species,ROS)生成增加和清除能力下降密切相關(guān)。Tanno發(fā)現(xiàn)白藜蘆醇在心衰小鼠的心肌細(xì)胞當(dāng)中,可以活化激動(dòng)SIRT1誘導(dǎo)Mn-SOD生成,減少氧化應(yīng)激下的心臟損傷[4]。Sakamoto等在實(shí)驗(yàn)中發(fā)現(xiàn)小鼠在胚胎時(shí)期,其SIRT1在心臟、大腦、脊髓以及神經(jīng)節(jié)后根都呈現(xiàn)高表達(dá)[29]。其在心臟生長(zhǎng)發(fā)育中發(fā)揮重要的作用。如果敲除小鼠的SIRT1基因,其常發(fā)生心臟發(fā)育不良并且伴有其他多器官發(fā)育畸形,存活率很低。Shinmura等發(fā)現(xiàn)在心肌缺血再灌注損傷中,SIRT1可以保護(hù)心肌細(xì)胞減少細(xì)胞凋亡[30]。Samuel等發(fā)現(xiàn)在心肌梗塞的大鼠中,SIRT1可以通過(guò)調(diào)控FOXO3a保護(hù)心臟減少細(xì)胞凋亡[31]。
3.2SIRT1在神經(jīng)退行性疾病中的作用神經(jīng)退行性疾病是指沒有特殊誘因而出現(xiàn)特定神經(jīng)元及相應(yīng)樹突、軸突和髓鞘逐漸變性、緩慢消耗和凋亡,但不伴有明顯組織和細(xì)胞反應(yīng)的一組疾病,主要包括阿爾茨海默病、帕金森病、亨廷頓氏舞蹈病、家族性震顫以及其他疾病。阿爾茨海默病其病理特征是淀粉樣斑塊,其由淀粉樣前體蛋白(amyloid precurosrprotein,APP)通過(guò)分泌酶和分泌酶連續(xù)溶蛋白性裂解產(chǎn)生。SIRT1通過(guò)抑制NF-KB從而抑制小神經(jīng)膠質(zhì)細(xì)胞依賴β-淀粉樣蛋白(Aβ)毒素,保護(hù)神經(jīng)細(xì)胞,如果敲出SIRT1基因,Aβ水平上升[32]。而錯(cuò)誤折疊的α-突觸核蛋白(SNCA)所組成的路易士小體的積累可以導(dǎo)致帕金森氏癥。Donmez等在實(shí)驗(yàn)中發(fā)現(xiàn)在帕金森氏癥動(dòng)物模型中,SIRT1過(guò)量表達(dá)可以抑制α-突觸核蛋白聚合體產(chǎn)生[33]。在亨廷頓氏舞蹈病中,突變的亨廷頓蛋白抑制PGC-1的表達(dá),導(dǎo)致線粒體功能障礙。實(shí)驗(yàn)發(fā)現(xiàn)SIRT1可以恢復(fù)亨廷頓蛋白(HTT)誘導(dǎo)的神經(jīng)元,達(dá)到神經(jīng)保護(hù)作用。如果將小鼠SIRT1基因敲除,小鼠會(huì)出現(xiàn)神經(jīng)發(fā)育缺陷如露腦[34-35]。
3.3SIRT1在腎臟疾病中的作用SIRT1在腎臟組織中廣泛表達(dá),在腎髓質(zhì)表達(dá)明顯高于皮質(zhì),尤其高表達(dá)于內(nèi)髓部,主要存在于系膜細(xì)胞、足細(xì)胞、腎小管上皮細(xì)胞以及腎髓間質(zhì)細(xì)胞,它能夠保護(hù)并維持腎臟細(xì)胞的功能。在氧化應(yīng)激損傷或毒性物質(zhì)損傷時(shí), SIRT1便會(huì)發(fā)揮強(qiáng)大的腎臟保護(hù)作用。He等發(fā)現(xiàn)SIRT1在小鼠腎髓間質(zhì)細(xì)胞中大量表達(dá),其提高細(xì)胞的抗氧化能力[36]。SIRT1可以保護(hù)腎小管細(xì)胞減少其凋亡。Hawegaw等發(fā)現(xiàn),在近端腎小管細(xì)胞中,SIRT1可以通過(guò)去乙?;疐OXO3抑制氧化應(yīng)激誘導(dǎo)的細(xì)胞凋亡[37]。同時(shí)Hasegawa等發(fā)現(xiàn)在轉(zhuǎn)基因小鼠中,SIRT1可以抵抗順鉑誘導(dǎo)的腎小管細(xì)胞損傷,并且還可以通過(guò)調(diào)控p53減少腎小管細(xì)胞凋亡[38]。在腎纖維化的發(fā)病機(jī)制中,TGF-β1/Smad3通路非常重要。Li等在單側(cè)輸尿管所誘發(fā)的腎臟纖維化中發(fā)現(xiàn),白藜蘆醇可以激活SIRT1,而SIRT1可以使Smad3去乙?;种芓GF-β1所誘導(dǎo)的腎臟纖維化,從而保護(hù)腎臟[39]。
3.4SIRT1與糖尿病SIRT1也參與胰島素分泌,SIRT1超表達(dá)正向調(diào)節(jié)胰島β細(xì)胞。氧化應(yīng)激損傷胰島素信號(hào)通路,導(dǎo)致胰島素抵抗[40]。Lee 等報(bào)道,在氧化應(yīng)激下SIRT1通過(guò)抑制NF-KB信號(hào)保護(hù)β細(xì)胞[41]。在β細(xì)胞特異SIRT1轉(zhuǎn)基因小鼠模型中,SIRT1可以在胰島β細(xì)胞專一性的高表達(dá),而小鼠耐糖量及糖刺激的胰島素分泌得到明顯改善[42]。解偶聯(lián)蛋白2(uncoupling protein 2)是線粒體內(nèi)膜額一種解耦聯(lián)蛋白,具有解離呼吸鏈氧化磷酸化耦聯(lián)的能力,減弱β細(xì)胞將葡萄糖轉(zhuǎn)化為ATP的能力,并將ATP的能量轉(zhuǎn)化為熱量。SIRT1可以抑制線粒體ATP產(chǎn)生UCP2表達(dá),從而導(dǎo)致K+通道關(guān)閉和胰島素分泌[43]。
4小結(jié)與展望
氧化應(yīng)激被認(rèn)為是細(xì)胞損傷的重要因素,氧自由基會(huì)導(dǎo)致細(xì)胞膜脂質(zhì)過(guò)氧化作用和蛋白質(zhì)氧化而破壞細(xì)胞的完整性,誘發(fā)細(xì)胞凋亡。SIRT1是依賴NAD+的去乙?;福ㄟ^(guò)組蛋白/非組蛋白去乙?;淖饔冒l(fā)揮其抗氧化應(yīng)激、抗炎、抑制細(xì)胞凋亡等作用。大量研究發(fā)現(xiàn)SIRT1在神經(jīng)退行性疾病、心血管系統(tǒng)疾病、腎臟系統(tǒng)疾病中具有強(qiáng)大的抗氧化應(yīng)激作用,但其機(jī)制尚不清楚,還需進(jìn)一步探討。
白藜蘆醇是一種存在于葡萄、虎杖、花生等天然植物及果實(shí)中的植物多酚類化合物。白藜蘆醇是現(xiàn)在發(fā)現(xiàn)在自然界中SIRT1最有效的激動(dòng)劑[44]。1989年在世界衛(wèi)生組織對(duì)心血管疾病調(diào)查中發(fā)現(xiàn),同樣以三高飲食為主的法國(guó)人,其心血管系統(tǒng)疾病的發(fā)病率卻低于周邊國(guó)家。后來(lái)研究發(fā)現(xiàn),這與法國(guó)人喜愛喝葡萄酒有關(guān),而葡萄酒中含有大量的白藜蘆醇。Howitz[44]等發(fā)現(xiàn)白藜蘆醇是通過(guò)激活細(xì)胞內(nèi)的SIRT1從而發(fā)揮其保護(hù)心血管及抗炎等方面的作用。Park等發(fā)現(xiàn)白藜蘆醇可以通過(guò)AMPK信號(hào)通路激活SIRT1[45]。Price等證實(shí)中等量的白藜蘆醇可以首先激活SIRT1,然后誘導(dǎo)肝臟激酶B去乙?;虯MPK信號(hào)通路活化,而增加線粒體的作用[46]??梢?,將白藜蘆醇用于上述疾病的防治具有廣闊的前景。
【參考文獻(xiàn)】
[1]Ivy JM, Klar AJ, Hicks JB.Cloning and characterization of four SIR genes of saceharomyces cerevisiae [J].Mol Cell Biol,1986,6(2):688-702.
[2]Frye RA. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity[J]. Biochem Biophys Res Commun, 1999,260:273-279.
[3]Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins[J]. Biochem. Biophys. Res. Commun, 2000,273:793-798.
[4]Tanno M, Sakamoto J, Miura T,etal. Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1[J]. J. Biol. Chem,2007,282:6823-6832.
[5]North B J, Verdin E. Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis[J]. PLoS ONE. 2007,2:e784.
[6]Sundaresan N R, Samant S A, Pillai V B,etal. SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70[J].Mol. Cell. Biol, 2008,28:6384-6401.
[7]Michishita E, Park JY, Burneskis JM,etal. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol. Biol. Cell. 2005;16:4623-4635.
[8]Kelly GS. A review of the sirtuin system, its clinical implications, and the potential role of dietary activators like resveratrol: part2[J]. Altern Med Rev, 2010,15(4):313-328.
[9]Wang C, Chen L, Hou X,etal. Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage [J]. Nat Cell Biol,2006,8(9):1025-1031.
[10] Bell EL, Guarente L. The SirT3 divining rod points to oxidative stress[J].Mol Cell, 2011,42:561-568.
[11] Little JP, Safdar A, Wilkin GP,etal. A practical model of lowvolume high-intensity interval training induces mitochondrial biogenesis in human skeletal. muscle:potential mechanisms[J].J Physiol, 2010,588:1011-1022.
[12] Imai S, Armstrong CM, Kaeberlein M.,etal. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase[J]. Nature.,2000,403:795-800.
[13] Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P., Reinberg D. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin[J]. Mol. Cell, 2004,16:93-105.
[14] Schemies J, Uciechowska U, Sippl W,etal. NAD(+) -dependent histone deacetylases (sirtuins) as novel therapeutic targets[J]. Med Res Rev, 2010,30(6):861-889.
[15] Verdin E, Dequiedt F,Kasler HG. ClassⅡ histone deacetylases:versatile regulators. Trends Genet,2003,19(5):286-293.
[16] Gu W, Roeder RG. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain[J]. Cell, 1997,90(4):595-606.
[17] Vaziri H, Dessain SK, Ng Eaton E,etal. HSIR2(SIRT1) functions as an NAD+-dependent p53 deacetylase. Cell,2001, 107(2):149-159.
[18] Luo J, Nikolaev AY, Imai S,etal. Negative control of p53 by Sir2alpha promotes cell survival under stress[J]. Cell,2001, 107(2):137-148.
[19] Maiese K, Chong ZZ, Shang YC. "Sly as a FOXO": New paths with Forkhead signaling in the brain[J]. Curr Neurovasc Res, 2007,4(4):295-302.
[20] Maiese K, Chong ZZ, Shang YC. OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins[J]. Trends Mol Med, 2008,14(5):219-227.
[21] Maiese K, Chong ZZ, Shang YC,etal. Rogue proliferation versus restorative protection: where do we draw the line for Wnt and forkhead signaling[J]? Expert opinion on therapeutic targets, 2008,12(7):905-916.
[22] Storz P. Forkhead homeobox type O transcription factors in the responses to oxidative stress[J]. Antioxid Redox Signal,2011,14(4):593-605.
[23] Mattagajasingh I, Kim CS, Naqvi A,etal. SIRT1 promotes endothelium-dependent vascular relaxation by activatingendothelial nitric oxide synthase[J]. Proc Natl Acad Sci USA, 2007, 104(37):14855-14860.
[24] Potente M, Ghaeni L, Baldessari D,etal. SIRT1 controls endothelial angiogenie functions during vascular growth[J]. Genes Dev, 2007, 21(20) :2644-2658.
[25] Shang YC, Chong ZZ, Hou J,etal. Wnt1, FoxO3a, and NF-kappaB oversee microglial integrity and activation during oxidant stress[J]. Cell Signal, 2010,22(9):1317-1329.
[26] Yeung F, Hoberg JE, Ramsey CS,etal. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase[J]. Embo J, 2004,23(12):2369-2380.
[27] Cohen HY, Lavu S, Bitterman KJ,etal.Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis[J]. Mol Cell, 2004, 13: 627-638.
[28] Yang Y, Fu W, Chen J,etal. SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress[J]. Nat Cell Biol, 2007, 9(11): 1253-1262.
[29] Sakamoto J, Miura T, Shimamoto K,etal. Predominant expression of Sir2 alpha, an NAD-dependent histone deacetylase in the embryonic mouse heart and brain [J].FEBS Lett,2004,556(3):281-286.
[30] Shinmura K, Tamaki K, Bolli R. Impact of 6-mocloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1 [J]. Am J Physiol Heart Circ Physiol, 2008,295(6):H2348-H2355.
[31] Samuel S M, Thirunavukarasu M, Penumathsa S V,etal.Akt/FOXO3a/SIRT1-mediated cardiopretection by n-tyrosol against ischemic stress in rat in vivo model of myocardial infarction: switching gears toward survival and longevity [J]. J Agric Food Chem,2008,56(20) :9692-9698.
[32] Chen J, Zhou Y, Mueller-Steiner S, Chen LF,etal.SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappB signaling[J].Biol Chem,2005,280(40):364-374.Donmez G, Gurente L. Aging and disease:connections to sirtuins[J]. Aging Cell,2010(9):285-290.
[33] Spillantini MG, Schmidt ML. Lee VM,etal.Alpha-synuclein in Lewy bodies[J].Nature,1997(388):839-840.
[34] Jiang M, Wang J, Fu J,etal. Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets [J].Nat Med,2012(18):153-158.
[35] Parker JA, Arango M, Abderrahmane S,etal. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons[J]. Med Sci (Paris),2005(37):349-350.
[36] He W, Wang Y, Zhang MZ,etal.Sirt1 activation protects the mouse renal medulla from oxidative injury[J]. J. Clin. Invest, 2010,120:1056-1068.
[37] Hasegawa K, Wakino S, Yoshioka K,etal. Sirt1 protects against oxidative stress-induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression[J]. Biochem. Biophys. Res. Commun, 2008,372:51-56.
[38] Hasegawa K, Wakino S, Yoshioka K,etal. Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function[J]. J. Biol. Chem,2010,285:13045-13056.
[39] Li J, Qu X, Ricardo SD,etal. Resveratrol inhibits renal fibrosis in the obstructed kidney: potential role in deacetylation of Smad3[J]. Am. J. Pathol.2010;177:1065-1071
[40] Kitada M, Kume S, Kanasaki K,etal. Sirtuins as possible drug targets in type 2 diabetes[J]. Curr Drug Targets, 2013,14:622-636.
[41] Lee JH, Song MY, Song EK,etal.Overexpression of SIRT1 protects pancreatic beta-cells against cytokine toxicity by suppressing the nuclear factor-kappaB signaling pathway[J]. Diabetes, 2009,58:344-351.
[42] Moynihan KA, Grimm AA, Plueger MM,etal. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice[J]. Cell Metab, 2005,2:105-117.
[43] Moynihan KA, Grimm AA, Plueger M. M.,etal. Increased dosage of mammalian Sir2 in pancreatic β cells enhances glucose-stimulated insulin secretion in mice[J]. Cell Metab, 2005,2:105-117.
[44] Howitz KT, Bitterman KJ, Cohen HY,etal. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan[J]. Nature,2003,425(6954):191-196.
[45] Park SJ, Ahmad F, Philp A,etal. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases[J]. Cell,2012,148:421-433.
[46] Price NL, Gomes AP, Ling AJ,etal. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function[J].Cell Metab, 2012,15:675-690.