簡(jiǎn)介：中文中文8900字出處出處BALATSOSNAA,DIMITRIOSV,PANAGIOTISM,ETALCOMPETITIVEINHIBITIONOFHUMANPOLYASPECIFICRIBONUCLEASEPARNBYSYNTHETICFLUOROPYRANOSYLNUCLEOSIDESJBIOCHEMISTRY,2009,4826604451本科畢業(yè)論文設(shè)計(jì)外文翻譯譯文譯文通過(guò)合成氟通過(guò)合成氟代嘧啶代嘧啶核苷競(jìng)爭(zhēng)性抑制人多聚核苷競(jìng)爭(zhēng)性抑制人多聚A特異性特異性核糖核酸酶核糖核酸酶PARNCOMPETITIVEINHIBITIONOFHUMANPOLYASPECIFICRIBONUCLEASEPARNBYSYNTHETICFLUOROPYRANOSYLNUCLEOSIDES摘要摘要聚（A）特異性核糖核酸酶（PARN是一種獲得性相互影響的脫腺苷，這個(gè)脫腺苷酶是居間的，和其它外切核酸酶類連接在一起，參與真核信使RNA的翻譯表達(dá)，因而它能積極參與有規(guī)律的基因的表達(dá)。到目前為止，氨基糖苷類和自然核苷酸是唯一報(bào)道的人類PARN活動(dòng)的調(diào)節(jié)器。在現(xiàn)在的研究中，我們發(fā)現(xiàn)合成的核苷類似物連接一個(gè)氟代嘧啶核苷的糖基和苯甲酰修飾的胞嘧啶或腺嘌呤作為基本官能團(tuán)能有效地抑制人類PARN。如以前所報(bào)道，當(dāng)對(duì)多種腫瘤細(xì)胞系進(jìn)行測(cè)試時(shí)，這種核苷類似物表現(xiàn)出很大的抑制作用。動(dòng)力學(xué)分析表明，對(duì)PARN的抑制是有競(jìng)爭(zhēng)性的，并不能通過(guò)改變外切核糖核酸酶類鎂（Ⅱ）的濃度來(lái)釋放。此外，用乙酰和/或糖基三苯甲基來(lái)替代糖基上2′，4′或6′的OH是抑制效果的關(guān)鍵。要了解核苷如何準(zhǔn)確的進(jìn)入PARN活性部位，通過(guò)分子動(dòng)力學(xué)模擬之后我們對(duì)分子進(jìn)行對(duì)接。在硅片分析表明，這些化合物能有效地進(jìn)入PARN活性中心。我們的研究結(jié)果支持這一想法即通過(guò)起催化作用的氨基酸殘基的相互作用使糖基介導(dǎo)的穩(wěn)定的核苷到達(dá)活躍的部位。兩者合計(jì)，在體外和硅片的數(shù)據(jù)表明，我們?nèi)祟怭ARN分子之間的目標(biāo)是通過(guò)降低信使RNM的周轉(zhuǎn)率而使這些化合物可發(fā)揮治療作用，從而解釋其在分子水平上的已知的體內(nèi)抑制作用。脫腺苷化是鎂（Ⅱ）依賴的外切核糖核酸酶類，它可以不斷裂解多聚（A）的末端，并釋放5′平滑肌磷酸酶1。在所有的脫腺苷，聚（A）特異性核糖核酸酶（PARN）是獨(dú)一無(wú)二的，因?yàn)樗梢栽诿撓佘栈陂g與5′帽結(jié)構(gòu)和可以進(jìn)入活動(dòng)現(xiàn)場(chǎng)。生化和在硅片的三維模型分析顯示這三個(gè)糖羥基在高效抑制作用方面是重要的角色。我們的數(shù)據(jù)表明，在本研究中所使用的類似物鉛化合物可作為服務(wù)于發(fā)展的新可能的PARN抑制劑和其他基本DEADENYLASES與新的治療方法的潛力用。材料與方法材料所有化學(xué)品包括嘌呤核苷酸和脫氧核苷酸，亞甲基藍(lán)，POLYADENYLIC酸鉀鹽（平均粒徑300腺苷，巴士A300）來(lái)自SIGMAALDRICH核苷類似物的合成。氟代嘧啶核苷合成如前所述（31）。簡(jiǎn)單地說(shuō)，凝結(jié)1′，2′，4′，6′四O乙?；?′脫氧3′氟葡萄糖胞嘧啶，SILYATEDN4苯甲酰胞嘧啶，或N6苯甲酰腺嘌呤造成的1的生產(chǎn)（2′，4′，6′三O乙?；?′脫氧3′氟ΒD吡喃葡萄糖N4苯甲酰胞嘧啶（5條）或9（2′，4′，6′三O乙?；?′脫氧3′氟ΒD吡喃葡萄糖）N6苯甲酰（±1）腺嘌呤，分別來(lái)說(shuō)，在場(chǎng)的三甲基硅三氟甲烷磺酸鈉和錫氯化物。脫保護(hù)的第5條與氫氧化鈉乙醇吡啶格A1分別產(chǎn)生1（3′，4′脫氧3′氟ΒD吡喃葡萄糖）胞嘧啶（C6）的，1（3′4′脫氧3′氟ΒD吡喃葡萄糖）N4苯甲酰胞嘧啶（A6的），或9（3′，4′脫氧3′氟ΒD吡喃葡萄糖）N6苯甲?；汆堰剩ˋ2）的。A2的治療和干2，2二甲氧基丙烷，N，N二甲基甲酰胺，通過(guò)乙?；蟮淖杂闪u基集團(tuán)在2′位的糖基醋酸酸酐/吡啶，去除異亞丙基，而且，最后，選擇性保護(hù)的主要6′羥基組一組取得了三苯甲基化合物A4。氧化的氟乙?；绑wA4與吡啶踵鉻酸鹽/乙酸酐給予9（3′脫氧3′氟6′O型三苯甲基ΒDGLYCEROHEX2′ENOPYRANOSYL4′ULOSE）N6苯甲?；汆堰剩ˋ3）。表達(dá)和純化重組PARN。質(zhì)粒編碼的全尺寸74KDA的人類PARN（VIRTANEN教授提供的，UPPSALAUNIVERSITY，瑞典）（用于N末端HIS6標(biāo)簽的多肽表達(dá)），被傳遞給BL21（DE3）細(xì)胞去表達(dá)重組蛋白，如前所述33，加入一些修改。簡(jiǎn)單地說(shuō)，菌落生長(zhǎng)在37℃過(guò)夜的卡那霉素（50UL/ML）。培養(yǎng)物在（1100）稀釋后在相同的37℃被異丙基1硫代Β的D半乳糖苷（IPTG）誘導(dǎo)的一個(gè)最終的濃度01MM的培養(yǎng)基中生長(zhǎng)。用于PARN表達(dá)的培養(yǎng)液被允許在37℃下培養(yǎng)3小時(shí)。在4℃下經(jīng)離心法收集細(xì)胞要20分鐘，和顆粒被凍結(jié)在70℃。表達(dá)了他的標(biāo)記可溶性蛋白進(jìn)行純化下列先前描述協(xié)議33。PARN活性測(cè)定和動(dòng)力學(xué)分析。如所述前34，酶的活性可以被亞甲藍(lán)所測(cè)定。作為時(shí)間函數(shù)脫腺苷酶率被確定用時(shí)間進(jìn)程分析（圖1）。亞甲藍(lán)是由12MG的亞甲藍(lán)溶解在100ML的3嗎啉基丙磺酸緩沖液中制備而成的（01M的3嗎啉基丙磺酸氫氧化鉀，PH值75和2MMEDTA）。標(biāo)準(zhǔn)反應(yīng)緩沖液含

簡(jiǎn)介：中文中文9326字出處出處BRITISHJOURNALOFPHARMACOLOGY,2009,1572195206譯文譯文傳病媒介設(shè)計(jì)與施藥綜述細(xì)胞滲透性肽二十年從分子機(jī)制到治療THEMEDSECTIONVECTORDESIGNANDDRUGDELIVERYREVIEWTWENTYYEARSOFCELLPENETRATINGPEPTIDESFROMMOLECULARMECHANISMSTOTHERAPEUTICSFREDERICHEITZ,MAYCATHERINEMORRISANDGILLSDIVITACENTREDERECHERCHESDEBIOCHIMIEMACROMOLECULAIRE,UMR5237,CNRS,UM1,UM2,CRBMDEPARTMENTOFMOLECULARBIOPHYSICSANDTHERAPEUTICS,1919ROUTEDEMENDE,MONTPELLIER,FRANCE摘要最近發(fā)現(xiàn)由于滲透功能欠佳以及低效的生物利用率而未用于臨床的新型有效治療分子，已經(jīng)成為了治療學(xué)發(fā)展的關(guān)鍵。用于提高治療分子細(xì)胞的吸收技術(shù)已經(jīng)設(shè)計(jì)出來(lái)，其中包括細(xì)胞滲透性肽（CPPS）。對(duì)若干蛋白質(zhì)進(jìn)入細(xì)胞的能力進(jìn)行研究中首次發(fā)現(xiàn)了CPPS。迄今為止，大量CPPS已被發(fā)現(xiàn)，并可分為2個(gè)主要類別，第一個(gè)要求通過(guò)細(xì)胞內(nèi)攝作用與藥物進(jìn)行化學(xué)銜接，第二個(gè)包括與藥物形成穩(wěn)定的非共價(jià)化合物?，F(xiàn)今，CPPS成為了用于非攻擊性進(jìn)入細(xì)胞的理想工具，并成功用于不同于小型化學(xué)分子，核酸類，蛋白質(zhì)類，肽類，脂質(zhì)體與顆粒的治療分子體外與體內(nèi)的遞送物質(zhì)。這篇綜述集中于結(jié)構(gòu)/功能以及日常給藥過(guò)程中CPPS的細(xì)胞攝取機(jī)制。我們也會(huì)強(qiáng)調(diào)用于治療分子遞送的多肽載體運(yùn)用，并提供最新臨床評(píng)價(jià)。這篇文章是傳病媒介設(shè)計(jì)與施藥綜述的一部分，此章節(jié)中出現(xiàn)的所有文章以列于論文最后。關(guān)鍵詞細(xì)胞滲透性肽；非共價(jià)遞藥系統(tǒng)；低分子反意核糖核酸；納米顆粒；施藥；分子機(jī)制；治療學(xué)縮寫(xiě)詞CPP細(xì)胞滲透性肽；GAG葡糖胺聚糖；NLS核定為系列；PMO磷酸類嗎琳代低聚物；PNA核酸肽；PTD蛋白質(zhì)轉(zhuǎn)導(dǎo)域引言施藥的挑戰(zhàn)過(guò)去10多年，為了突破小型分子和基因治療的局限性，我們已經(jīng)證明最新的大型治療分子并沒(méi)有遵循利平斯基的規(guī)則，這是一個(gè)極大的促進(jìn)因素，比如蛋白毒液肽相銜接POOGAETAL,1998。自此，設(shè)計(jì)出許多其他能夠觸發(fā)介質(zhì)穿透細(xì)胞膜進(jìn)入細(xì)胞質(zhì)的CPPSJ?RVERANDLANGEL,2004JOLIOTANDPROCHIANTZ,2004DESHAYESETAL,2005SNYDERANDDOWDY,2005。CPPS是一種普遍少于30種氨基酸類肽，基于天然和非天然蛋白或者是嵌合序列，并且能夠再細(xì)分成2類。第一類要求化學(xué)與介質(zhì)鏈接，第二類則包括穩(wěn)定結(jié)構(gòu)和非共價(jià)配合物。CPPS也能與結(jié)構(gòu)的觀點(diǎn)相區(qū)分，例如隨便哪個(gè)聚陽(yáng)離子，本質(zhì)上存在于基本序列或者兼性的聚精氨酸族。代表性的CPPS在表格1中已列明。雖然這份綜述主要關(guān)注于基于天然氨基酸類CPPS，但是現(xiàn)今關(guān)于CPPS的新觀念包含非天然的和改良的，為了提高穩(wěn)定性或者運(yùn)輸效率而被提倡。FARRERASINFREUETAL,2007共價(jià)策略基于科學(xué)技術(shù)上的細(xì)胞穿透肽的描述，到目前為止主要包括介質(zhì)與化學(xué)交聯(lián)或是跟在CPP融合蛋白標(biāo)記物表達(dá)式之后的克隆所獲得的對(duì)肽載體之間共價(jià)結(jié)合形成結(jié)構(gòu)NAGAHARAETAL,1998GAIT,2003MOULTONANDMOULTON,2004ZATSEPINETAL,2005。大多數(shù)著作報(bào)道了TAT上的肽類FAWELLETAL,1994VIVESETAL,1997FRANKELANDPABO,1988,穿膜肽DEROSSIETAL,1994,聚精氨酸肽ARG8序列WENDERETAL,2000FUTAKIETAL,2001和傳輸POOGAETAL,1998其他衍生蛋白肽類，例如來(lái)自純單皰疹病毒的VP22蛋白ELLIOTTANDO’HARE,1997,PVECELMQUISTETAL,2001,降鈣素衍生肽SCHMIDTETAL,1998KRAUSSETAL,2004,抗生物肽BUFORINI和SYNBPARKETAL,1998PARKETAL,2000,此外還有聚脯氨酸SAP多肽PUJALSETAL,2006也被成功地用于提高與介質(zhì)的共價(jià)鏈接轉(zhuǎn)導(dǎo)JOLIOTANDPROCHIANTZ,2004ELANDALOUSSIETAL,2005MURRIELANDDOWDY,2006。最近，CPPS的新世代，提出了結(jié)合不同的轉(zhuǎn)導(dǎo)基序ABESETAL,2007或者是與蛋白或低聚核苷酸結(jié)合域串聯(lián)的轉(zhuǎn)導(dǎo)域MEADEANDDOWDY,2007。不同的化學(xué)物質(zhì)已被涉及，用來(lái)穩(wěn)定或裂解主要的二硫鍵或硫代酯聯(lián)在內(nèi)的共軛體系。根據(jù)介質(zhì)的穩(wěn)定性和效率，有幾個(gè)參數(shù)需要考慮，包括聯(lián)動(dòng)化學(xué)類型，隔離物的本質(zhì)GAIT,2003ZATSEPINETAL,2005共價(jià)策略，大體上報(bào)告了DNA模仿分子或寡核苷酸立體的遞送，其中包括PNAKOPPELHUS

簡(jiǎn)介：中文中文6395字出處出處NATUREBIOTECHNOLOGY,2000,181111511155本科畢業(yè)論文設(shè)計(jì)外文翻譯學(xué)院專業(yè)藥學(xué)藥學(xué)姓名學(xué)號(hào)指導(dǎo)老師指導(dǎo)老師職稱合作老師合作老師職稱外文題目（原文）外文題目（原文）TRANSGENICTRANSGENICPLANTSPLANTSASASFACTORIESFACTORIESFORFORBIOPHARMACEUTICALSBIOPHARMACEUTICALS譯文譯文轉(zhuǎn)基因植物轉(zhuǎn)基因植物生物醫(yī)藥的生產(chǎn)工廠生物醫(yī)藥的生產(chǎn)工廠GLYNISGIDDINGS,GORDONALLISON,DOUGLASBROOKS,ANDADRIANCARTERINSTITUTEOFBIOLOGICALSCIENCES,UNIVERSITYOFWALES,ABERYSTWYTH,CLEDWYNBUILDING,ABERYSTWYTHCEREDIGIONSY233DD,UKCORRESPONDINGAUTHORGDGABERACUKRECEIVED12NOVEMBER1999ACCEPTED11AUGUST2000由于容易轉(zhuǎn)化且能為蛋白質(zhì)提供廉價(jià)來(lái)源，植物在蛋白質(zhì)和多肽等生物藥物生產(chǎn)中具著巨大潛力。在第一個(gè)植物來(lái)源的生物藥物正在進(jìn)行臨床試驗(yàn)的同時(shí)，許多生物技術(shù)公司正積極開(kāi)發(fā)，進(jìn)行大田試驗(yàn)，并獲得植物表達(dá)系統(tǒng)的專利。水蛭素是一個(gè)轉(zhuǎn)基因植物生物藥品，目前首次在加拿大進(jìn)行了商業(yè)化生產(chǎn)。但產(chǎn)物的純化是一昂貴的過(guò)程，目前開(kāi)發(fā)了多種方法解決這個(gè)問(wèn)題，包括油體膜蛋白融合技術(shù)，使提取油體的方法獲得目的蛋白。在某些情況下，我們可以利用直接消化經(jīng)修飾的植物來(lái)進(jìn)行生物制藥產(chǎn)品的給藥，這種情況下，就可能消除對(duì)純化步驟的需要。這種生物藥品和可食疫苗可以存儲(chǔ)和分布在種子，塊莖，或水果中，使得發(fā)展中國(guó)家的管理部分可以更便宜和容易實(shí)施免疫計(jì)劃。通過(guò)轉(zhuǎn)基因植物生產(chǎn)可以使一些如葡糖腦苷脂酶等有限使用的昂貴生物培養(yǎng)生產(chǎn)的外源蛋白綜述，見(jiàn)（REF14）進(jìn)行概述。農(nóng)業(yè)生產(chǎn)系統(tǒng)通常使用兩種轉(zhuǎn)化方法在植物里生產(chǎn)重組藥品。第一種利用農(nóng)桿菌穩(wěn)定轉(zhuǎn)化，基因槍法，或其他標(biāo)準(zhǔn)的轉(zhuǎn)化技術(shù)來(lái)生產(chǎn)轉(zhuǎn)基因植物。煙草被廣泛用作模型表達(dá)系統(tǒng)，其他一些植物也已被使用，其中包括煙草，擬南芥，番茄，香蕉，蘿卜，豇豆（黑眼豆），油菜，埃塞俄比亞芥菜，馬鈴薯，水稻，小麥和玉米。第二種是當(dāng)重組病毒在非轉(zhuǎn)基因植物宿主中表達(dá)和復(fù)制時(shí)感染非轉(zhuǎn)基因植物。最常用的主要病毒系統(tǒng)是煙草花葉病毒（TMV）和豇豆花葉病毒（CPMV）。雖然產(chǎn)量類似于轉(zhuǎn)化植株，但他們產(chǎn)量可以更高。煙草花葉病毒衍生載體已被用于在番茄和煙草生產(chǎn)口服降血壓肽（血管緊張素1轉(zhuǎn)換酶抑制劑），以及在NBETHAMIANA中生產(chǎn)艾滋病毒抑制劑（Α天花粉蛋白）。嵌合CPMV顆粒，顯性人類鼻病毒14和HIV1，已從轉(zhuǎn)基因豇豆植物中分離出來(lái)。他們被發(fā)現(xiàn)可以在艾滋病毒嵌合體的情況下引起抗體的產(chǎn)生，以消除在體內(nèi)由HIV1病毒感染的T細(xì)胞。第二種方法對(duì)于疫苗生產(chǎn)可能是很有用的。疫苗可以防范疾病，保護(hù)機(jī)體，他們通過(guò)刺激胃腸道的相關(guān)淋巴組織來(lái)促使免疫球蛋白A的產(chǎn)生。進(jìn)入病毒顆粒、或?qū)⑵浜筒《镜鞍祖溄拥目乖砦坏谋磉_(dá)促進(jìn)這一進(jìn)程。轉(zhuǎn)基因植物藥物蛋白的表達(dá)主要是由組成型CAMV35S啟動(dòng)的。然而，可能會(huì)導(dǎo)致低產(chǎn)量，例如，人血清白蛋白占可溶性總蛋白的002（TSP）和人類蛋白C為0001％（見(jiàn)13）。種子限制表達(dá)可以帶來(lái)更高的產(chǎn)量。種子表達(dá)的腦啡肽，例如，TSP可以累積到29％。種子的表達(dá)已通過(guò)外源基因引入谷蛋白（GT3）信號(hào)肽序列和GT3啟動(dòng)子作用下轉(zhuǎn)錄實(shí)現(xiàn)了。在煙草中轉(zhuǎn)基因免疫球蛋白的轉(zhuǎn)錄也由種子特異性，發(fā)育調(diào)節(jié)，豆素B4的啟動(dòng)子控制。由于在細(xì)胞質(zhì)中免疫球蛋白經(jīng)常干擾細(xì)胞的功能，最好是將它們分泌到非共質(zhì)體系，或定位到內(nèi)質(zhì)網(wǎng)處，在那里他們積累到更多比例（15％）。定位可通過(guò)豆球蛋白B4的信號(hào)序列實(shí)現(xiàn)。雖然由于上述生產(chǎn)系統(tǒng)易轉(zhuǎn)化、易于應(yīng)用它們已被廣泛應(yīng)用于研究和驗(yàn)證概念的研究，但并不是用于商業(yè)或其他大鬼魅應(yīng)用的理想選擇。從這些植物分離純化重組蛋白將是低效和昂貴的，而且需要去除各種代謝物，包括尼古丁。此外，種子只占煙草植物中很一小部分比重，將必須使用營(yíng)養(yǎng)組織。商業(yè)生產(chǎn)中從含水高的組織中提取蛋白質(zhì)可能導(dǎo)致蛋白質(zhì)的損失，而且降低了處理效率

簡(jiǎn)介：中文中文38003800字譯文譯文實(shí)驗(yàn)性腎衰竭對(duì)頭孢噻利誘導(dǎo)大鼠癲癇發(fā)作的藥效學(xué)實(shí)驗(yàn)性腎衰竭對(duì)頭孢噻利誘導(dǎo)大鼠癲癇發(fā)作的藥效學(xué)影響影響EFFECTOFEXPERIMENTALRENALFAILUREONTHEPHARMACODYNAMICSOFCEFOSELISINDUCEDSEIZURESINRATSMASASHINAGATAANDMASATOYASUHARA我們調(diào)查了輸液速度和實(shí)驗(yàn)性腎衰竭對(duì)頭孢噻利（CFSL）誘導(dǎo)大鼠癲癇發(fā)作的藥效學(xué)影響，作為CFSL誘導(dǎo)癲癇發(fā)作的動(dòng)物模型，給雄性WISTAR大鼠靜脈注射了來(lái)自三個(gè)不同國(guó)家之一的CFSL（1458G/H/RAT），直到最大癲癇發(fā)作（其發(fā)生在輸液后的80到360分鐘）。當(dāng)停止滴入CSFL后，腦脊液（CSF），血液（血清）以及腦中均可檢測(cè)出其成分。CSFL誘導(dǎo)癲癇發(fā)作的血藥濃度隨著輸液速度的增加而增加，但是腦組織液以及腦脊液中癲癇發(fā)作的血藥濃度將不受輸液速度的影響。給輸尿管結(jié)扎（UL）以及對(duì)照組大鼠以14G/H/RAT的速度靜脈注射CFSL直到癲癇發(fā)作，然后以相同的步驟來(lái)確定輸液速度對(duì)CFSL的血藥濃度的影響。腎衰竭對(duì)CFSL誘導(dǎo)癲癇發(fā)作的要求在伴隨著一個(gè)在規(guī)定的數(shù)額顯著下降。輸尿管結(jié)扎的大鼠的血清，腦液以及CSF中的血藥濃度明顯比對(duì)照組大鼠的低。結(jié)果表明，實(shí)驗(yàn)策略和動(dòng)物模型在這個(gè)調(diào)查中用來(lái)評(píng)估疾病的影響還有CFSL誘導(dǎo)大鼠癲癇發(fā)作的其他各種藥效學(xué)影響是有用的，而腎功能衰竭是影響CFSL神經(jīng)毒性最危險(xiǎn)的因素之一。關(guān)鍵詞關(guān)鍵詞頭孢噻利；腎功能衰竭；癲癇；藥效學(xué)頭孢噻利（CSFL），第四代頭孢菌素抗生素，已經(jīng)于1998年9月引入日本市場(chǎng)在同年12月，因中樞神經(jīng)系統(tǒng)CNS產(chǎn)生的副作用如癲癇發(fā)作和恍惚狀態(tài)被警告列入CSFL的標(biāo)簽。在很多情況下，這些不良反應(yīng)已經(jīng)在老年人和/或者腎功能衰竭患者中被觀察出來(lái)。因此，腎功能衰竭被認(rèn)為是影響CFSL神經(jīng)毒性最危險(xiǎn)的因素之一。CFSL主要經(jīng)腎臟排泄，腎功能衰竭患者可增加CFSL的血藥濃度。另外，關(guān)于腎衰竭能否改變CFSL誘導(dǎo)大鼠癲癇發(fā)作的藥效學(xué)還是未知數(shù)。的濃度，用BIORAD蛋白分析法NIPPONBIORADLABORATORIES,JAPAN測(cè)定CSF中的蛋白濃度，使用牛血清白蛋白作為參照物。CFSLCFSL血藥濃度的分析血藥濃度的分析用HPLC測(cè)定CFSL的血藥濃度。測(cè)定條件，100ΜL（01M）的血清以及鈉和10ΜL鉀磷酸鹽緩沖液PH70，100MG/ML的硫酸頭孢匹羅和100ΜL乙腈混合，渦旋10S，離心（13000轉(zhuǎn)/MIN）2MIN后作為內(nèi)標(biāo)物取上清液100ΜL（002M）鈉和鉀磷酸鹽緩沖液（PH25）400ΜL，混合，渦旋10S，取5ΜL注入HPLC色譜柱。分析30ΜLCSF，內(nèi)標(biāo)物的濃度減少到1MG/ML，以及注射量為50ΜL。測(cè)定腦內(nèi)的CFSL濃度，準(zhǔn)確稱量右半球，用生理鹽水勻漿（量為右半球重量的5倍），取勻漿200ΜL（01M），鈉和鉀磷酸鹽緩沖液PH7020ΜL，1MG/ML硫酸頭孢匹羅和200ΜL乙腈混合，渦旋10S，作為內(nèi)標(biāo)物，最終混合成50ΜL注入HPLC色譜柱。HPLC色譜儀器為L(zhǎng)C9A（SHIMADZU,JAPAN），254NM的SPD6A分光光度計(jì)，色譜柱TSKGELODS80TM5MM,46MMID315CM,TOSOH,JAPAN流動(dòng)相為0065V/V的乙腈溶液，002M的鈉和鉀磷酸鹽緩沖液PH25，流速為10ML/MIN數(shù)據(jù)分析數(shù)據(jù)分析所有結(jié)果表示平均±SD評(píng)價(jià)不同的樣品組分意味著在UL和對(duì)照組大鼠中使用F試驗(yàn)判斷平等差異，其次是學(xué)生T試驗(yàn)或者WELCH的T試驗(yàn)。TUKEY–KRAMER試驗(yàn)用來(lái)分析其他實(shí)驗(yàn)結(jié)果。結(jié)果結(jié)果輸液速度對(duì)血液、腦以及輸液速度對(duì)血液、腦以及CSF中致最大癲癇發(fā)作的藥物濃度的影響中致最大癲癇發(fā)作的藥物濃度的影響從表1中可看出，根據(jù)不同的藥物輸注速率1458G/H/RAT靜脈注射CFSL產(chǎn)生的使大鼠最大癲癇發(fā)作的時(shí)間在80607AND360651MIN。全部動(dòng)物的給藥劑量在29603TO34605G/KG，并隨著輸液速度的增加而減少。在血清中到達(dá)最大癲癇發(fā)作的CFSL藥物濃度明顯受到藥物輸液速度的影響，藥物濃度隨著輸液速度的增加而增加；在腦和CSF中到達(dá)最大癲癇發(fā)作的CFSL藥物濃度不受藥物輸液速度的影響。

簡(jiǎn)介：中文中文18萬(wàn)字萬(wàn)字出處出處BEENKENA,MOHAMMADIMTHEFGFFAMILYBIOLOGY,PATHOPHYSIOLOGYANDTHERAPYJNATUREREVIEWSDRUGDISCOVERY,2009,83235253本科畢業(yè)論文設(shè)計(jì)外文翻譯譯文譯文FGF家族生物學(xué)，病理生理學(xué)和治療學(xué)簡(jiǎn)述家族生物學(xué)，病理生理學(xué)和治療學(xué)簡(jiǎn)述THEFGFFAMILYBIOLOGY,PATHOPHYSIOLOGYANDTHERAPY摘要摘要成纖維細(xì)胞生長(zhǎng)因子家族（FGFS）中的各個(gè)因子調(diào)控著一系列的發(fā)育過(guò)程，包括腦的發(fā)育、肢體的分化和軀干的形成。研究者已經(jīng)對(duì)FGFS在促有絲分裂、細(xì)胞的保護(hù)和促血管生成方面的作用進(jìn)行了探索。最近，學(xué)者們發(fā)現(xiàn)了在膽汁酸、葡萄糖和磷酸鹽平衡過(guò)程中起內(nèi)分泌調(diào)節(jié)作用的FGF19亞家族所具有的重要功能，這一發(fā)現(xiàn)引起了人們對(duì)該家族在藥理學(xué)方面應(yīng)用潛力的巨大興趣。本綜述探討了使用重組FGFS和小分子成纖維細(xì)胞生長(zhǎng)因子受體激酶抑制劑治療癌癥和心血管疾病等傳統(tǒng)的應(yīng)用方法和新發(fā)現(xiàn)的FGFS在治療代謝綜合征及堿性磷酸酶過(guò)少癥等疾病方面所具有的潛力。前言前言根據(jù)不同的序列同源性和系統(tǒng)發(fā)育的規(guī)律可將哺乳動(dòng)物的18種成纖維細(xì)胞生長(zhǎng)因子（FGF1FGF10和FGF16，F(xiàn)GF23）分為6亞家族FGF1和FGF2；FGF3，F(xiàn)GF7，F(xiàn)GF10，F(xiàn)GF22；FGF4，F(xiàn)GF5和FGF6；FGF8，F(xiàn)GF17和FGF18；FGF9，F(xiàn)GF16和FGF20和FGF19，F(xiàn)GF21和FGF231。部分已編號(hào)的“FGFS”并未被分配到任意亞家族中，其中包括成纖維細(xì)胞生長(zhǎng)因子同源因子（以往被稱為FGF11－FGF14）。這些因子具有和FGF家族很高的序列同源性，但沒(méi)有激活成纖維細(xì)胞生長(zhǎng)因子受體（FGFRS）的能力，因此不被規(guī)類為成纖維細(xì)胞生長(zhǎng)因子家族中的成員2（纖維細(xì)胞生長(zhǎng)因子同源因子的詳細(xì)介紹請(qǐng)參見(jiàn)方框1）；FGF15是小鼠體內(nèi)的人類FGF19的同源蛋白（即人類FGF19＝小鼠FGF15）。FGFS被公認(rèn)為一種旁泌因子，在胚胎發(fā)育過(guò)程種的組織和器官形成中起重要作用前5各亞家族的FGF生長(zhǎng)因子屬于這一類。與此相對(duì)的，最近人們證明了FGF19，F(xiàn)GF21和FGF23亞家族起內(nèi)分泌激素的功能，如對(duì)膽汁酸，膽固醇，葡萄糖，維生素D和磷酸鹽內(nèi)穩(wěn)調(diào)節(jié)器的作用，這種作用的發(fā)生主要依賴于靶向組織中KLOTHO蛋白質(zhì)的存在。與成纖維細(xì)胞生長(zhǎng)因子信號(hào)異常相關(guān)的人類疾病早有報(bào)道。發(fā)揮異常調(diào)控作了連續(xù)的正電性表面區(qū)域。相對(duì)的，F(xiàn)GF19、FGF21和FGF23亞家族的HBS包含由Β1Β2折疊和Β10Β12區(qū)域形成的隆起，使HSGAG和FGFS核心骨干的親和力降低，并導(dǎo)致這個(gè)亞家族的獨(dú)特的內(nèi)分泌特點(diǎn)。FGFRSFGFRSFGF配體通過(guò)結(jié)合和激活酪氨酸激酶受體家族發(fā)揮作用，這一過(guò)程需要HSGAG的參與。FGFR家族有四種受體基因（FGFR1FGFR4）編碼受體，所編碼受體由三個(gè)免疫球蛋白樣區(qū)域（D1、D2和D3區(qū)）、單通過(guò)（SINGLEPASS）跨膜區(qū)和細(xì)胞內(nèi)的酪氨酸激酶域構(gòu)成。FGFRS存在一段富含酸性氨基酸和絲氨酸的序列，位于D1區(qū)和D2區(qū)之間，成為酸盒（ACIDBOX）。FGFRS細(xì)胞外功能區(qū)的D2區(qū)和D3區(qū)是FGF的結(jié)合區(qū)域，而D1區(qū)和酸盒可以發(fā)揮自動(dòng)抑制FGF和FGFR結(jié)合的作用（圖2A）。通過(guò)外顯子跳躍刪除FGFR1、FGFR3中的D1域和（或）酸盒，使FGFR形成不同的異構(gòu)體。在FGFR1–3的D3區(qū)后半部分的選擇性剪接產(chǎn)生B型（FGFR1B–3B）和C型（FGFR1C–3C）異構(gòu)體,這些異構(gòu)體具有特殊的FGF結(jié)合性質(zhì)，主要存在于上皮細(xì)胞和間充質(zhì)細(xì)胞。上皮細(xì)胞和間充質(zhì)細(xì)胞含有不用的FGFR異構(gòu)體。每種FGF都要結(jié)合上皮或間充質(zhì)細(xì)胞的FGFRS，而FGF1比較特殊，可同時(shí)作用兩種剪切異構(gòu)體。HSGAGS和受體配體二聚體結(jié)合后，激活FGFR的胞內(nèi)酪氨酸激酶區(qū)域，通過(guò)轉(zhuǎn)磷酸作用激活酪氨酸環(huán)路，環(huán)路的磷酸化在酪氨酸C末端磷酸化后形成，然后激酶插入到近膜區(qū)。主要的FGFR胞內(nèi)作用底物是磷脂酶C（PLA）FRS1和FRS2（FGFR作用底物2）。FGFR的C末端的固有酪氨酸（在FGFR1中，該酪氨酸為Y766）磷酸化，產(chǎn)生一個(gè)PLCΓ的SH2區(qū)結(jié)合位點(diǎn)，這一過(guò)程需要PLCΓ的磷酸化和激活。相對(duì)的，F(xiàn)RS2由FGFR的近膜區(qū)組成。FRS2的磷酸化是MAPK通路（RAS–MITOGENACTIVATEDPROTEINKINASE）和PHOSPHOINOSITIDE3KINASE–AKT通路激活必需的。FGFS也可通過(guò)FGFFGFR復(fù)合物激活的胞吞作用在細(xì)胞核和細(xì)胞液中，作為內(nèi)源性配體發(fā)揮作用。FGFFGFRFGFFGFR特異性特異性FGFFGFR結(jié)合的特殊性在于其受到18種FGFS和7種主要FGFRS（FGFR1B、FGFR1C、FGFR2B、FGFR2C,、FGFR3B、FGFR3C和FGFR4）基本序列的差異性的影響，F(xiàn)GFS、FGFRS和HSGAGS三者的復(fù)合物的空間關(guān)系只是短暫存在。FGFRS的剪切異構(gòu)體具有組織特異性FGFRB異構(gòu)體在上皮組織中表達(dá)，F(xiàn)GFRC異構(gòu)體在間充質(zhì)細(xì)胞組織中表達(dá)。FGF即可在上皮組織中表達(dá)也可在間充質(zhì)細(xì)胞組織中表達(dá)，通常選擇與之相反的組織的受體作用。一般來(lái)說(shuō)，上皮組織中表達(dá)的FGFS會(huì)激活間充質(zhì)細(xì)胞中的FGFR，反之亦然。FGF1比較特殊，與同一種FGFR的B、C異構(gòu)體都可結(jié)合。FGFS過(guò)量表達(dá)會(huì)引起結(jié)合特性的異常，從而產(chǎn)生生理學(xué)病癥，如在癌癥中FGFS過(guò)量表達(dá)。FGF1、FGF2、FGF8和FGF10及其同家族FGFRS的研究發(fā)現(xiàn)了FGF的N末端和Β1折疊長(zhǎng)度的差異（FIG1B），F(xiàn)GFR的D3區(qū)有兩種異構(gòu)體形

簡(jiǎn)介：中文中文2700字出處出處BIOLOGIAPLANTARUM,2004,481129132八種野生郁金物種的體外植株再生和遺傳保護(hù)八種野生郁金物種的體外植株再生和遺傳保護(hù)INVITROPLANTREGENERATIONANDGENOTYPECONSERVATIONOFEIGHTWILDSPECIESOFCURCUMA組織培養(yǎng)和凍存組，國(guó)家局植物遺傳資源，新德里110012，印度ALBERTKATZCENTERFORDESERTAGROBIOLOGY,BENGURIONUNIVERSITYOFTHENEGEV,SEDEBOQUERCAMPUS,ISRAEL摘要摘要對(duì)八種郁金野生物種的體外植株再生和中期基因保存方法進(jìn)行了優(yōu)化。這兩種現(xiàn)象都存在基因型依賴性，所使用細(xì)胞分裂素的種類和濃度對(duì)其有著顯著的影響。在一般情況下，發(fā)現(xiàn)芐基腺嘌呤（BA）比測(cè)試的其他細(xì)胞分裂素有利于植株再生和異戊烯基腺嘌呤（2IP）則有利于基因型保護(hù)。每個(gè)發(fā)芽數(shù)介于13至72和貯存期由264至379天。在30天的培養(yǎng)后，CMALABARICA在MS114ΜMZEATIN（72個(gè)芽）中芽的再生頻率最高。郁金（未知的野生種）在MS246ΜM的2IP中可能存儲(chǔ)期最長(zhǎng)，最長(zhǎng)期限（379天）。其次是CAROMATICA在MS228ΜMZEATIN中（363天）。組織培養(yǎng)的植株同他們的母本形態(tài)相似。在體外培養(yǎng)保存的植物的組織可以快速繁殖及轉(zhuǎn)移到溫室土壤中產(chǎn)生正常的根莖。關(guān)鍵詞關(guān)鍵詞種質(zhì)資源，遺傳資源，微體繁殖，組織培養(yǎng)姜黃屬植物（姜科）由80余種根莖型多年生草本植物組成，廣泛分布于亞洲熱帶地區(qū)，亦分布于非洲和澳洲。體外技術(shù)可用于郁金種質(zhì)資源保護(hù)，馬鈴薯，木薯和山藥種質(zhì)資源的情況可以證明。在我們的實(shí)驗(yàn)室組織培養(yǎng)已成為無(wú)性繁殖和各種作物品種保護(hù)的有效方法。直接組織培養(yǎng)再生植株（不通過(guò)愈傷組織）是體外保存計(jì)劃成功的先決條件因?yàn)橥ㄟ^(guò)愈傷組織誘導(dǎo)再生植株可能導(dǎo)致體細(xì)胞無(wú)性系變異。NADGAUDA等（1978）和BALACHANDRAN等（1990年）報(bào)道了以CLONGA根莖上的芽作為外植體進(jìn)行體外增殖和通過(guò)葉片誘導(dǎo)的愈傷組織進(jìn)行增殖。然而，除了CAERUGINOSA，CCAESIA（BALACHANDRAN1990年）和CAROMATICANAYAK2000，這些關(guān)于野生物種的快繁報(bào)告是無(wú)法現(xiàn)成利用的。迄今用于野生郁金物種的保護(hù)的體外技術(shù)還沒(méi)有系統(tǒng)工作的報(bào)告。目前的研究對(duì)野生郁金的直接植株再生和有效保護(hù)的體外方法進(jìn)行了優(yōu)化。根莖的芽采自八種野生郁金物種的根狀莖的新芽，分別為CAERUGINOSAROXB表2四種細(xì)胞分裂素（在兩個(gè)濃度）對(duì)體外保存郁金野生物種（天數(shù)）的影響。在所有的物種測(cè)試中所有細(xì)胞分裂素都使用兩個(gè)濃度，外植體100來(lái)自于莖基部。然而，芽的形成量在各種不同的物種是不同的（表1）。培養(yǎng)3周后，新芽形成小芽（12CM）。在45個(gè)星期的培養(yǎng)中觀察芽數(shù)，沒(méi)有進(jìn)一步增加。芽的再生遵照每個(gè)物種的獨(dú)特模式。測(cè)試物種種類和細(xì)胞分裂素對(duì)芽的再生有著顯著的差異。所有的物種合計(jì)，每個(gè)培養(yǎng)管芽數(shù)平均為13至72（見(jiàn)表1）。CMALABARICA在MS114ΜMZEATIN中產(chǎn)生最多數(shù)目的芽（每個(gè)72個(gè)芽）。CAROMATICA，CBROG，CCAESIA，CRAKTAKANTA和CSP在MS111ΜMBA中能產(chǎn)生較多芽。BA有利于CLONGA和CAROMATICA（NAYAK2000年）快速繁殖已經(jīng)有文獻(xiàn)報(bào)導(dǎo)。2IP對(duì)CLONGA再生芽作用見(jiàn)于SALVI等的報(bào)道中，但在我們的研究中沒(méi)有發(fā)現(xiàn)野生物種芽數(shù)在2IP培養(yǎng)基中高于其他細(xì)胞分裂素的培養(yǎng)基。沒(méi)有數(shù)據(jù)表明在有各種分裂素的培養(yǎng)基中培養(yǎng)物發(fā)現(xiàn)較長(zhǎng)的芽。然而，CBROG在MS116ΜMKINETIN中有最高長(zhǎng)度的芽（56厘米），其次是CAROMATICA在MS111ΜMBA中的芽48CM。生根不影響芽發(fā)育成植株。觀察發(fā)現(xiàn)培養(yǎng)4周后在所有培養(yǎng)基上生根。不用嘗試去收集每個(gè)芽的根的確切個(gè)數(shù)，根是否來(lái)源于單獨(dú)的芽在培養(yǎng)中難以區(qū)別。然而，觀察轉(zhuǎn)移到土壤中的植物，每個(gè)芽有24個(gè)主根。。每個(gè)物種移植到泥土中存活的強(qiáng)壯的植物高達(dá)96100％的存活率跟SALVI的等人的意見(jiàn)一致。組織培養(yǎng)的植株同母本的形態(tài)相似。對(duì)再生植株的遺傳穩(wěn)定性進(jìn)行了研究使用8種同工酶和RAPD分析，并沒(méi)有發(fā)現(xiàn)體外保存植發(fā)生變異?；谶z傳穩(wěn)定性研究的詳細(xì)結(jié)果將進(jìn)行單獨(dú)的報(bào)告。

簡(jiǎn)介：中文中文4465字出處出處INTENSIVECAREMEDICINE,2007,33711621167譯文譯文亞胺培南與多粘菌素相比在治療呼吸機(jī)相關(guān)性肺炎的安全性和有效性一個(gè)匹配的病例對(duì)照研究HKALLEL,LHERGA,MBAHLOUL,AHAKIM,HDAMMAK,HCHELLY,CBENHAMIDA,,ACHAARINREKIK,MBOUAZIZ摘要要目的本研究的目的是為了確定多粘菌素在治療由泛耐藥性銅綠假單胞菌或鮑曼不動(dòng)桿菌引起的呼吸機(jī)相關(guān)性肺炎的有效性和安全性。設(shè)計(jì)兩兩匹配一對(duì)一的研究。背景結(jié)合HABIBBOURGUIBAUNIVERSITYHOSPITAL（SFAX,TUNISIA）醫(yī)藥，外科重癥監(jiān)護(hù)病房的要求?；颊吡煞耗退幮缘孽U曼不動(dòng)桿菌引起的VAP患者與肺炎克雷伯氏菌進(jìn)行匹配,用60控管與由鮑曼不動(dòng)桿菌引起的VAP對(duì)銅綠假單胞菌敏感的藥物亞胺培南進(jìn)行匹配。在抗生素的治療中，所有患者的腎功能正常。干預(yù)措施案例患者通過(guò)多粘菌素靜脈注射治療，控制患者通過(guò)亞胺培南靜脈注射治療。測(cè)量及結(jié)果多粘菌素和亞胺培南群體之間的基準(zhǔn)線相似?？股刂委煹钠骄掷m(xù)時(shí)間多粘菌素為95±38天（范圍58天），亞胺培南89±28天（范圍520天）（P值032）。抗生素治療VAP中較好的臨床方案，多粘菌素占45（75），亞胺培南占43（717）。在治療抗生素的起始階段，兩組傳染病的時(shí)間分辨率參數(shù)無(wú)統(tǒng)計(jì)學(xué)差異。在抗生素的治療過(guò)程中，沒(méi)有一組的患者發(fā)展成腎功能衰竭。結(jié)論我們認(rèn)為，多粘菌素在治療VAP引起的耐銅綠假單胞菌和鮑曼不動(dòng)桿菌是一種安全的有效的選擇。關(guān)鍵字關(guān)鍵字呼吸機(jī)相關(guān)性的肺炎；腎毒性；亞胺培南說(shuō)明革蘭陰性菌的耐藥性（PDR）是一個(gè)全球性的重要問(wèn)題，特別是在重癥監(jiān)護(hù)室（ICU）1，2中。多重耐藥性使經(jīng)驗(yàn)性選擇抗菌藥物出現(xiàn)困難，同時(shí)延遲了合適的抗菌藥物治療3。在近日出版的文獻(xiàn)中，抵抗抗菌藥物使用的兩個(gè)最廣泛的微生物是銅綠假單胞菌和鮑曼不動(dòng)桿菌4。由于這個(gè)原因，最近多粘菌素已被看作是治療這些微生物的最后選擇4。/FIO2，血清尿素氮和肌酐濃度。當(dāng)天使用多粘菌素或者亞胺培南，記錄一下數(shù)據(jù)，發(fā)熱，白細(xì)胞計(jì)數(shù)，胸部X光檢查，PAO2/FIO2，血清尿素氮和肌酐濃度。每天記錄患者的情況，直至治療結(jié)束。結(jié)果有利或不利的情況（發(fā)燒的程度，白細(xì)胞計(jì)數(shù)和胸部透視）。不良反應(yīng)，主要是急性腎衰竭（基于每日血清尿素氮和肌酐采樣）和肌無(wú)力。當(dāng)患者出院，記錄以下變量日期記錄，從醫(yī)院ICU到出院。肺炎的診斷是基于（1）溫度≤36℃或≥385℃，（2）白細(xì)胞計(jì)數(shù)≤1500或≥1000萬(wàn)，（3）新的或者漸進(jìn)滲透的胸部X光片，（4）是否存在或者至少有一種微生物的濃度存在于106個(gè)/毫升的進(jìn)樣管23。急性腎衰竭（ARF）是血清超過(guò)150摩爾/升肌酐濃度，且血液尿毒氮濃度超過(guò)10毫摩爾/升。每日進(jìn)行VAP評(píng)估。VAP中被認(rèn)為具有良好的成果，如能很好的緩解敗血癥的相關(guān)癥狀（發(fā)熱，白細(xì)胞增多），PAO2/FIO2大于187（25KPA）24和放射性分辨率（減少或消失呈現(xiàn)胸部透視X線表現(xiàn)）。VAP中被認(rèn)為是不利的結(jié)果，如果沒(méi)有減免敗血癥有關(guān)的癥狀和無(wú)放射性的分辨率。微生物測(cè)試所有病原微生物的檢測(cè)使用常規(guī)微生物檢測(cè)辦法。藥敏試驗(yàn)采用紙片擴(kuò)散法（斷點(diǎn)是由全國(guó)衛(wèi)生委員會(huì)確定的臨床實(shí)驗(yàn)室標(biāo)準(zhǔn)2526）。多粘菌素的藥敏性是使用10G多粘菌素紙片法。如果抑菌區(qū)域≥11毫米，菌株被認(rèn)為是敏感的。中間的隔離格蘭陰性菌對(duì)抗生素的敏感性被認(rèn)為是抵抗的。阻礙耐藥性的定義為分離到抗假單胞菌青霉素類，頭孢菌素類，碳?xì)涿瓜┝祟?，喹諾酮類和氨基糖苷類的程度。一個(gè)隔離的定義是，如果它抵抗所有的抗假單胞菌青霉素類除了多粘菌素。治療方案在多粘菌素組中，患者采用多粘菌素SULFOMETHATE鈉靜脈注射治療。劑量為600萬(wàn)單位（≈10萬(wàn)/公斤），每天分為三劑。在亞胺培南的患者組，采用亞胺培南（亞胺培南/西斯他丁；MSD）靜脈注射治療。劑量為每日2G，分為四個(gè)劑量。在這項(xiàng)研究中，初始使用抗菌素治療的所有情況下，在實(shí)驗(yàn)的基礎(chǔ)上使用多粘菌素或者亞胺培南。統(tǒng)計(jì)分析確定變量百分率和連續(xù)變量均值（SD）。百分率比較采用卡方檢驗(yàn)和T檢驗(yàn)手段。WILCOXON配對(duì)試驗(yàn)是用來(lái)比較匹配標(biāo)準(zhǔn)（年齡，SAPSII，與PAO2/FIO2）。應(yīng)用KAPLANMEIER曲線被用來(lái)評(píng)估多粘菌素和亞胺培南組之間的差異（1）抗生素治療后的感染參數(shù)（2）28天后多粘菌素或亞胺培南治療VAP的

簡(jiǎn)介：中文中文47254725字出處出處BIOCHEMICALPHARMACOLOGY,2008,761115901611譯文譯文姜黃素及其天然、合成的類似物的生物活性研究進(jìn)展姜黃素及其天然、合成的類似物的生物活性研究進(jìn)展ANANDP,THOMASSG,KUNNUMAKKARAAB摘要摘要姜黃素是存在于印度調(diào)味品姜黃中的一種黃色色素，研究發(fā)現(xiàn)它有抗炎、止血、抗腫瘤、治療糖尿病以及心血管、肺、神經(jīng)系統(tǒng)、皮膚和肝等疾病，同時(shí)也能緩解骨骼和肌肉的損傷、抑郁癥、長(zhǎng)期的疲勞和神經(jīng)性疼痛。但姜黃素的顏色、水溶性差、以及體內(nèi)生物利用度低限制了它的應(yīng)用?；诮S素多種治療活性，因此人們急于尋求沒(méi)有上述問(wèn)題的“性能好的姜黃素”。人們探索了多種方法來(lái)克服這些局限性，包括從姜黃植物中尋找天然的姜黃素類似物，在自然界中尋找天然的姜黃素類似物，合成姜黃素類似物以及用各種油脂和新陳代謝的禁制因素來(lái)改造姜黃素，研制姜黃素的脂質(zhì)體和微粒體劑型，姜黃素前藥的研究，以及聚乙二醇化姜黃素的修飾。姜黃素是一個(gè)同型二聚體包含一個(gè)甲氧基和一個(gè)羥基，一個(gè)含有兩個(gè)邁克爾受體的庚二烯以及一Α，Β二酮基。眾多研究小組修飾其同系物的結(jié)構(gòu)時(shí)已將這些集團(tuán)都考慮在內(nèi)。本文重點(diǎn)介紹用這些途徑產(chǎn)生活性更高的姜黃素類及其生物活性研究進(jìn)展。11介紹介紹姜黃素是一種從姜科植物姜黃的根莖中得到的不溶于水的多酚。由于其廣譜的藥理學(xué)活性，姜黃很早就被用于治療多種疾病，姜黃素是姜黃的主要活性成分。從化學(xué)的角度，姜黃素含有一個(gè)Α，Β不飽和基團(tuán)的Β二酮基，具有酮式烯酮式互變異構(gòu)現(xiàn)象。姜黃素已經(jīng)表現(xiàn)出抗氧化、抗炎、殺菌以及抗癌活性。它還能保肝、腎，抗凝血，預(yù)防心肌梗塞以及降血糖，抗風(fēng)濕的作用。而且已經(jīng)在很多動(dòng)物模型和人身上的試驗(yàn)表明姜黃素即使在很高的劑量下也是非常安全的。雖然姜黃素具有如此優(yōu)越功效和安全性，但迄今為止它并沒(méi)有被做為臨床藥物制劑。主要是因?yàn)樗乃苄圆?，生物利用度低，以及?qiáng)的染色能力，這些問(wèn)題已成了限制姜黃素臨床用藥的焦點(diǎn)，因此尋找活性相同或更高的姜黃素類似物成為國(guó)內(nèi)外科學(xué)家的研究熱點(diǎn)。本文介紹當(dāng)前在尋找活性更高的姜黃素類方面所做的素抗氧化活性的機(jī)制方面已被詳細(xì)系統(tǒng)研究，最近WRIGHT，SUNETAL，PRIYADARSINIETAL，LIGERETETAL，SUZUKIETAL，ANDCHENETAL的研究顯示酚羥基基團(tuán)對(duì)抗氧化活性非常重要，正如BARCLAYETAL早期所預(yù)測(cè)的那樣。SUGIYAMA在使用二甲基四氫化姜黃素探索了Β二酮基在抗氧化過(guò)程中潛在的作用，JOVANOVICETAL的工作進(jìn)一步支持了這一結(jié)論。鄰位烷氧基的存在加強(qiáng)了抗氧化活性，正如在二（34二羥基苯乙烯?；┘淄橹性黾右粋€(gè)羥基組分。羥基組分的位置效應(yīng)已在體內(nèi)條件下研究，似乎2位羥苯比4位羥基活性更好，如在二（2羥基苯乙烯?；┘淄楸?羥基苯組分在姜黃素中表現(xiàn)出更好的抗氧化活性。還原C7鏈上的CC鍵產(chǎn)生THC并沒(méi)有減少其抗氧化活性。構(gòu)效關(guān)系研究表明，雖然酚羥基在抗氧化中作用至關(guān)重要，羰基和Β二酮結(jié)構(gòu)對(duì)抗氧化活性也是有必要的。SARDIJIMANETAL研究了Β二酮基組分的重要性，應(yīng)用二（4羥基苯亞甲基）丙酮，2，6二苯亞甲基環(huán)己酮和環(huán)戊酮類似物等C5連接鏈的類似物。結(jié)果表明4羥基組分有助于提高抗氧化活性，當(dāng)羥基基團(tuán)鄰位1或2個(gè)甲氧基取代時(shí)活性加強(qiáng)。這些5碳鏈的二（4羥苯基）1，4戊二烯3酮表現(xiàn)出了比姜黃素更強(qiáng)的抗氧化活性。YOUSSEFETAL測(cè)試了2，6二苯亞甲基哌啶酮，環(huán)己酮和丙酮類似物，得到了相似的實(shí)驗(yàn)結(jié)果，他們發(fā)現(xiàn)結(jié)構(gòu)中含有3烷氧基4羥基基團(tuán)的類似物表現(xiàn)出更強(qiáng)的抗氧化活性。VENKATESWARLUETAL通過(guò)在姜黃素類化合物的苯環(huán)上添加羥基得到了大量多羥基類似物，測(cè)試結(jié)果表明其抗氧化活性也進(jìn)一步增強(qiáng)。姜黃素配合物的抗氧化能力也可通過(guò)另一方法研究。姜黃素的錳絡(luò)合物及其衍生物表現(xiàn)出姜黃素更強(qiáng)的SOD活性，羥基自由基清除活性和氮氧化物自由基清除活性。研究報(bào)道姜黃素的銅絡(luò)合物比姜黃素本身有更好的抗氧化，自由基清徐能?chē)?guó)和SOD酶活性。在以同等抗氧化能力分析的研究中發(fā)現(xiàn)姜黃素的釩、銦、鎵絡(luò)合物和姜黃素Ⅲ比它們各自的前體物活性更高?？傊寡趸钚运坪跻笥兄辽賰蓚€(gè)通過(guò)長(zhǎng)鏈連接的羥苯基結(jié)構(gòu)，并且增加含氧基團(tuán)其活性也隨之增加，尤其是同時(shí)具備這幾個(gè)因素時(shí)活性更強(qiáng)。到底長(zhǎng)鏈單位應(yīng)該是不飽和的還是含氧的至今還沒(méi)確定。232抗炎活性姜黃素C7連接鏈烯鍵的加氫以及羰基的還原都會(huì)使抗炎活性降低，它通過(guò)抑制IKB激酶的活性來(lái)阻止NFKB產(chǎn)生。早期研究指出羥基單位是提供抗炎活性的關(guān)鍵基團(tuán)，因?yàn)榉恿u基部位的?；饔煤屯榛饔脮?huì)大大降低其抗炎活性。

簡(jiǎn)介：中文中文3743字出處出處JOURNALOFTHESERBIANCHEMICALSOCIETY,2006,717733744譯文譯文一些席夫堿配合物的合成及抗菌活性研究一些席夫堿配合物的合成及抗菌活性研究SYNTHESISANDANTIBACTERIALACTIVITYOFSOMESCHIFFBASECOMPLEXESNAIRR,SHAHA,BALUJAS,CHANDAS摘要用2,4二羥基5乙基苯乙酮合成了兩個(gè)席夫堿A13硝基11,3二羥基4乙基6亞乙胺基苯；A32硝基11,3二羥基4乙基6亞乙胺基苯。然后，選擇金屬銅，鎳，鐵和鋅，形成其金屬配合物，合成8個(gè)金屬配合物。通過(guò)對(duì)抗一些臨床上重要的細(xì)菌，例如綠膿桿菌，變形桿菌，奇異變形桿菌，肺炎克雷伯菌和金黃色葡萄球菌，對(duì)其進(jìn)行抗菌活性的篩選。體外抗菌活性的測(cè)定采用瓊脂壟溝技術(shù)，以DMF（極性）和1,4二氧雜環(huán)己烷（非極性）作為溶劑。金屬配合物在不同溶劑中對(duì)細(xì)菌菌株影響的調(diào)查表明，抗菌活性由化合物的分子結(jié)構(gòu)、溶劑的使用和細(xì)菌菌株而定。在極性溶劑DMF中席夫堿A3對(duì)菌株表現(xiàn)出較好的抗菌活性。四種金屬配合物當(dāng)中，鋅配合物在1,4二氧雜環(huán)己烷溶劑中表現(xiàn)出最好的抗菌活性、其次是鐵；鎳配合物在DMF溶劑中表現(xiàn)出最好的抗菌活性、其次是鋅和鐵。關(guān)鍵詞席夫堿配合物；抗菌活性；DMF二甲基甲酰胺；二氧六環(huán)引言為了克服微生物對(duì)抗生素耐藥這個(gè)令人焦慮的問(wèn)題，迫切的需要發(fā)現(xiàn)對(duì)新目標(biāo)有活性的新型化合物。藥物制劑來(lái)源于許多粗藥材，還來(lái)自日益增長(zhǎng)的野生物質(zhì)。然而，以植物為基礎(chǔ)的藥物受到物料的來(lái)源壽命的限制。因此，需要通過(guò)不斷尋求更有效和更便宜的原材料來(lái)延續(xù)這個(gè)行業(yè)。化合物解離后產(chǎn)生的不是單純的離子，而是復(fù)雜離子被稱作配位化合物。配位化合物表現(xiàn)出不同的特征屬性，這依賴于金屬離子對(duì)它們的約束、金屬的性質(zhì)以及配體的類型等。金屬配合物廣泛應(yīng)用于人類利益的各個(gè)領(lǐng)域。一個(gè)配金屬離子的溶液，水浴中回流45小時(shí)。得到深褐色沉淀，將沉淀物干燥。鎳配合物的合成01MOL的配體和氯化鎳分別在1,4二氧雜環(huán)己烷溶液和蒸餾水中制備。向配體溶液中滴加金屬離子溶液。加入氫氧化銨使溶液PH值保持在10105。水浴回流45小時(shí)，得到黃色沉淀，過(guò)濾、分別用1,4二氧雜環(huán)己烷溶液和熱水洗滌，除去多余的配體和金屬離子。將沉淀物干燥。鐵配合物的合成將溶有01MOL配體的1,4二氧雜環(huán)己烷溶液滴入一個(gè)含有01MOL硫酸亞鐵銨的緩沖溶液氫氧化銨醋酸中，維持PH值在775?；亓?6個(gè)小時(shí)，得到黃棕色沉淀，過(guò)濾、分別用1,4二氧雜環(huán)己烷溶液和熱水除去多余的配體和金屬離子。將沉淀物干燥。鋅配合物的合成01MOL配位的1,4二氧雜環(huán)己烷溶液滴加至含有01MOL的鋅和氫氧化銨存在的溶液中，保持PH值在1011之間。水浴回流45小時(shí)，得到褐色沉淀。過(guò)濾、分別用1,4二氧雜環(huán)己烷溶液和熱水除去多余的配體和金屬離子。將沉淀物干燥?？咕钚钥咕钚詼y(cè)定方法采用瓊脂壟溝技術(shù)。被研究的微生物有綠膿桿菌，變形桿菌，奇異變形桿菌，肺炎克雷伯菌和金黃色葡萄球菌。將化合物溶解在溶劑1,4二氧雜環(huán)己烷或DMF二者之一中，調(diào)配成最終濃度為1MG/01ML的溶液。循環(huán)中給一個(gè)測(cè)試菌株接種于25ML的氮液營(yíng)養(yǎng)液，在37℃的培養(yǎng)箱中培養(yǎng)24小時(shí)，來(lái)激活細(xì)菌。在一個(gè)100ML直徑的陪氏板中加入2830ML營(yíng)養(yǎng)瓊脂培養(yǎng)基。當(dāng)它達(dá)到4045℃時(shí)，取02ML的活性菌株用倒板接種技術(shù)接種到陪氏板上。在陪氏板完成準(zhǔn)備的過(guò)程中，維持層流氣流來(lái)保持嚴(yán)格消毒和無(wú)菌條件。使培養(yǎng)基凝固。在凝固后的培養(yǎng)基板上打一個(gè)小洞085厘米，用來(lái)填充測(cè)試樣品。每個(gè)菌株和各種溶劑用純?nèi)軇┙臃N作對(duì)照組。培養(yǎng)板在37℃培養(yǎng)24小時(shí)。通過(guò)這些化合物對(duì)特定的測(cè)試菌株形成的抑菌圈來(lái)確定合成化合物的抗菌活性。用三次單獨(dú)重復(fù)實(shí)驗(yàn)獲得的平均值來(lái)計(jì)算每個(gè)樣品的抑菌圈。結(jié)果與討論金屬離子通過(guò)合作酶系統(tǒng)在大量不同的的生物過(guò)程中發(fā)揮了重要的作用。這些離子通過(guò)相互螯合作用使化合物具有生物活性，但是，對(duì)金屬配合如何影響它們的活性卻知之甚少。八種金屬配合物及各自的控制對(duì)供試菌株生成不同程度的抑制作用區(qū)域。配合物的抗菌活性A1和A3和其金屬配合物在DMF和1,4二氧雜環(huán)己烷相反。

簡(jiǎn)介：SILVERSTAININGDNAINPOLYACRYLAMIDEGELSBRANTJBASSAM1DOI101038/NPROT2007330THISPROTOCOLDESCRIBESASIMPLESILVERSTAININGMETHODUSEDTOVISUALIZEDNAFRAGMENTSANDOTHERORGANICMOLECULESWITHUNSURPASSEDDETAILFOLLOWINGTRADITIONALPOLYACRYLAMIDEGELELECTROPHORESISPAGESENSITIVITYRIVALSRADIOISOTOPICMETHODSANDDNAINTHEPICOGRAMRANGECANBERELIABLYDETECTEDTHEDESCRIBEDPROTOCOLISFASTB1HANDISIMPLEMENTEDUSINGREADILYAVAILABLECHEMICALSANDMATERIALSTOACHIEVETHESENSITIVITYANDVISUALCLARITYEXPECTED,QUALITYREAGENTSANDCLEANHANDLINGAREIMPORTANTTHEUPDATEDPROTOCOLDESCRIBEDHEREISBASEDONTHEWIDELYUSEDMETHODOFBASSAMETAL1991,BUTPROVIDESIMPROVEDIMAGECONTRASTANDLESSRISKOFSTAININGARTEFACTSINTRODUCTIONTHESEPARATIONOFCOMPLEXDNASAMPLESANDOTHERBIOLOGICALMOLECULESWITHHIGHRESOLUTIONBYPOLYACRYLAMIDEGELELECTROPHORESISPAGEHASBROADAPPLICATIONHOWEVER,TOREALIZETHEPOTENTIALOFPAGE,AVISUALIZATIONMETHODOFFERINGSUPERIORCLARITYANDSENSITIVITYISALSOREQUIREDTHESILVERSTAININGMETHODDESCRIBEDHEREHASPROVENVERYEFFECTIVEINTHISREGARDASAMETHOD,SILVERSTAININGWASORIGINALLYDEVELOPEDTODETECTPROTEINSSEPARATEDBYPAGE1–3ITWASFURTHEROPTIMIZEDANDAPPLIEDTOVISUALIZEOTHERBIOLOGICALMOLECULES,FOREXAMPLE,NUCLEICACIDS4,5,LIPOPOLYSACCHARIDES6,GLYCOPROTEINSANDPOLYSACCHARIDES7THESEEARLIERPROTOCOLSWERE,HOWEVER,COMPARATIVELYTEDIOUSANDOFFEREDLIMITEDSENSITIVITYTHEDEVELOPMENTOFDNAAMPLIFICATIONFINGERPRINTINGDAFBYCAETANOANOLLE′SETAL8REQUIREDASUPERIORPROTOCOLTOADEQUATELYRESOLVEANDVISUALIZECOMPLEXDNAPROFILESTHESEREQUIREMENTSLEDDIRECTLYTOTHECODEVELOPMENTOFASUCCESSFULCOMBINATIONOFPOLYESTERBACKEDPAGEGELSANDDNASILVERSTAININGTHESILVERSTAINPROTOCOLDEVELOPEDFORDAFWASDESCRIBEDSEPARATELYBYBASSAMETAL,9ANDHASSINCEGAINEDWIDEACCEPTANCEINCLUDINGCOMMERCIALIZATIONEG,INTHEGENEPRINTSTRSYSTEMSANDSILVERSEQUENCEPRODUCTSFROMPROMEGACORPORATION,USASILVERSTAININGOFDNAANDOTHERBIOLOGICALSAMPLESHASSEVERALADVANTAGES?IMAGEDEVELOPMENTANDVISUALIZATIONISDONEUNDERNORMALAMBIENTLIGHTTHUS,THEPROCEDURECANBEPERFORMEDENTIRELYATTHELABORATORYBENCHWITHOUTTHENEEDFORDARKROOMORUVILLUMINATIONFACILITIES?THEIMAGEISRESOLVEDWITHTHEBESTPOSSIBLESENSITIVITYANDDETAIL,BECAUSESILVERISDEPOSITEDDIRECTLYONTHEMOLECULESWITHINTHETRANSPARENTGELMATRIXTHUSVISUALIZATIONISFROMTHEPRIMARYSOURCEANDDOESNOTSUFFERANYDEGRADATIONORBLURRINGTHATCANACCOMPANYSECONDARYIMAGINGDEVICESWHICHINVOLVEFLUORESCENCE,AUTORADIOGRAPHY,FOCUSINGLENSES,FILMDEVELOPMENTORDIGITALIMAGEPROCESSING?SILVERSTAININGOFFERSSIMILARSENSITIVITYTOAUTORADIOGRAPHY,BUTAVOIDSRADIOACTIVEHANDLING,DELAYSFROMDEVELOPMENTTIMESANDWASTEDISPOSALISSUES?ASAPREFERREDOPTION,GELSCANBEDRIEDONTOASEMIRIGIDPLASTICBACKINGFILMSUCHASGELBONDPAGFILM,CREATINGAPERMANENTRECORDOFTHEORIGINALMATERIAL8SEEREF10FORAREVISEDPROTOCOLAIRDRIEDGELSARERESILIENT,PRESERVINGACONCENTRATEDANDCONTRASTINTENSIFIEDIMAGETHEYCANALSOBESTOREDINDEFINITELYWITHOUTDISTORTION,OBVIATINGTHENEEDANDADDEDEXPENSEOFPHOTOGRAPHYANDPRINTINGINADDITION,THEPRESERVEDGELISA‘MOLECULARARCHIVE’,ASSTAINEDDNABANDSARE‘REAL’DNATHATCANBEEXTRACTED,AMPLIFIED,CLONEDANDDNASEQUENCEDWHILETHEPROTOCOLDESCRIBEDHEREFOCUSESONTHEVISUALIZATIONOFDNABYPAGE,THEMETHODCANBEUSEDWITHOUTMODIFICATIONTOVISUALIZEAWIDERANGEOFBIOLOGICALMOLECULESINCLUDINGRNA,POLYSACCHARIDES,LIPOPOLYSACCHARIDES,PROTEINSANDPOLYPEPTIDESINPOLYACRYLAMIDEGELSDATANOTSHOWNALTHOUGHTHISISANADVANTAGEINTERMSOFSCOPE,ITNEVERTHELESSMEANSTHATTHEPROTOCOLMUSTBEAPPLIEDWITHDUECARESTRAYHUMANFINGERPRINTSONTHEGELSURFACESTAINWITHPERFECTDETAILASWILLALMOSTANYOTHERBIOLOGICALIMPURITYINCORPORATEDINTOORONTOTHEGELMATRIXITISTHUSIMPORTANTTOUSEDUSTFREEREAGENTSOFTHEBESTANALYTICALGRADE,INCLUDINGTHEPURESTWATERAVAILABLEMATERIALSREAGENTSACETICACID,GLACIAL,ARSELECTACSCH3COOHEG,MALLINCKRODT,CATNOV193MCRITICALFORBESTRESULTS,MUSTBEOFHIGHPURITYSILVERNITRATECRYSTAL,ARACSAGNO3EG,MALINCKRODT,CATNO2169SEEREAGENTSETUPMCRITICALFORBESTRESULTS,MUSTBEOFHIGHPURITYFORMALDEHYDESOLUTION,ARACSHCHOEG,MALINCKRODT,CATNO5016SEEREAGENTSETUPMCRITICALFORBESTRESULTS,MUSTBEOFHIGHPURITYSODIUMTHIOSULFATENA2S2O3EG,SIGMA,CATNOS7026SEEREAGENTSETUPMCRITICALFORBESTRESULTS,MUSTBEOFHIGHPURITYSODIUMCARBONATEPOWDER,Z995,ACSREAGENTNA2CO3EG,SIGMAALDRICH,CATNO223530MCRITICALFORBESTRESULTS,MUSTBEOFHIGHPURITYETHANOLPOLYACRYLAMIDEGELFIXERSOLUTIONSEEREAGENTSETUPDEVELOPERSOLUTIONSEEREAGENTSETUPDEVELOPERSTOPSOLUTIONSEEREAGENTSETUPEQUIPMENTPLASTICSTORAGECARBOYSWITHSPIGOTFROMANYGENERALLABORATORYSUPPLIERPUORGGNIHSILBUPERUTAN7002?NATUREPROTOCOLS/MOCERUTANWWW//PTTHNATUREPROTOCOLS|VOL2NO11|2007|2649PROTOCOL11|TOWASHTHEGEL,POURSUFFICIENTDEIONIZEDWATERINTOTHESTAININGTRAYTOCOVERTHEGELTOADEPTHOFB5MM12|ROCKTHESTAININGTRAYCONTINUOUSLYONAPLATFORMROCKERFOR2MINLONGERTIMESMAYBENEEDEDIFGELSTHICKERTHANB1MMAREUSEDIFTHEGELISWASHEDFORTOOLONGOVERB20MIN,THENSTAININGMAYBECOMPROMISED,ANDFAINTERBANDSWILLRESULT13|ATTHEENDOFTHEWASH,CAREFULLYDECANTTHEWASHSOLUTIONASDESCRIBEDINSTEP1014|REPEATTHEWASHSTEPSTWOTIMESMOREFORATOTALOFTHREEWASHESINDEIONIZEDWATERMCRITICALSTEPWASHINGTHEGELISIMPORTANTITREMOVESACIDANDOTHERTRACESUBSTANCESTHATINTERFEREWITHSTAINING,ANDPROVIDESACLEAR,BLEMISHFREEBACKGROUNDTOTHEFINALSTAINFORMALDEHYDEPRETREATMENT15|ADDSUFFICIENTFORMALDEHYDESOLU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簡(jiǎn)介：BIODRUGS20082213744NOVELTHERAPEUTICSTRATEGIES11738804/08/00010037/4800/0?2008ADISDATAINFORMATIONBVALLRIGHTSRESERVEDFIBROBLASTGROWTHFACTOR21ASATHERAPEUTICAGENTFORMETABOLICDISEASESALEXEIKHARITONENKOVANDARMENBSHANAFELTBIOTECHOLOGYDISCOVERYRESEARCH,LILLYRESEARCHLABORATORIES,LILLYCORPORATECENTER,INDIANAPOLIS,INDIANA,USACONTENTSABSTRACT371THEROLEOFFIBROBLASTGROWTHFACTORSFGFSINTHEREGULATIONOFMETABOLICPROCESSES372OVERVIEWOFFGF21ANDITSINVITROEFFECTS383FGF21INVIVOPHARMACOLOGY394INSIGHTSINTOFGF21MECHANISMOFACTION405CONCLUSION43FIBROBLASTGROWTHFACTORFGF21ISAUNIQUEMEMBEROFTHEFGFFAMILY,WITHSEVERALMOLECULARCHARACTERISABSTRACTTICSTHATDIFFERFROMCLASSICALFGFSANDEXHIBITINGAPHARMACOLOGICPROFILETHATINCLUDESAVARIETYOFMETABOLICRESPONSESINVITROANDWHENTESTEDINVIVOINANIMALMODELSFGF21REPRESENTSANOVELANDATTRACTIVETHERAPEUTICAGENTFORTYPE2DIABETESMELLITUS,BECAUSEOFITSABILITYTOMODULATEDISEASEPHENOTYPEINPRECLINICALSETTINGSWITHOUTINDUCINGANYAPPARENTADVERSEEFFECTSALTHOUGHFGF21WASDISCOVEREDRELATIVELYRECENTLY,THEUNDERSTANDINGOFITSBIOLOGYANDTHERAPEUTICUTILITYISRAPIDLYEVOLVINGANUMBEROFKEYMETABOLICALLYLINKEDMOLECULESANDPATHWAYSHAVEBEENSUGGESTEDTOBEINVOLVEDINTHEMECHANISMOFACTIONOFFGF21,DEPENDINGONTHESPECIFICTARGETTISSUE/ORGANFURTHERRESEARCHINTOTHESEMECHANISMSSHOULDLEADTOIMPORTANTADVANCESINTHEUNDERSTANDINGOFFGF21BIOLOGYANDPAVETHEWAYFORNOVELTHERAPEUTICSTRATEGIESTHESPECIFICSOFFGF21ACTIVITIESBOTHINCELLCULTUREANDINVIVO,ITSPOTENTIALASATARGETFORDIABETES,ANDINSIGHTSINTOTHEMOLECULARMECHANISMSOFFGF21METABOLICACTIONSWILLBEDISCUSSEDINTHISREVIEW1THEROLEOFFIBROBLASTGROWTHFACTORSFGFSINRODENTS,RESPECTIVELY8,9WHENTESTEDINMICE,FGF19PROVIDESTHEREGULATIONOFMETABOLICPROCESSESRESISTANCETOOBESITYANDINSULINDESENSITIZATION10,11ANOTHERMEMBEROFTHEFGFFAMILY,FGF23,ISAKEYPLAYERINTHEREGULAFIBROBLASTGROWTHFACTORSFGFSANDTHEIRCORRESPONDINGRETIONOFPHOSPHATEANDCALCIUMMETABOLISM12,13LIKEWISE,THECEPTORSFGFRSHAVEBEENPRIMARILYASSOCIATEDWITHTHEPROCESSESOFDEVELOPMENT,TRANSFORMATION,ANDANGIOGENESIS14HOWOVEREXPRESSIONOFADOMINANTNEGATIVEFORMOFFGFR1INPANCREEVER,OVERTHELASTDECADE,NEWDATAHAVEEMERGEDSHOWINGTHATATICΒCELLSLEADSTODIABETESMELLITUSINMICE14FGFR2APPEARSTOFGF/FGFRMEDIATEDPATHWAYSMAYPLAYIMPORTANTROLESINDEFINBEAKEYMOLECULEINTHEPROCESSOFPANCREATICDEVELOPMENT1517INGANDREGULATINGFUNCTIONSOFENDOCRINERELEVANTTISSUESANDFGFR3ISACRITICALPLAYERINBONE,18WHEREASFGFR4HASBEENORGANS,ASWELLASMODULATINGVARIOUSMETABOLICPROCESSESFORIMPLICATEDINCHOLESTEROLMETABOLISMANDBILEACIDSYNTHESIS19EXAMPLE,FGF10ANDFGF16PLAYIMPORTANTROLESINADIPOCYTEANDTHEMETABOLICROLESOFFGF/FGFRARESTILLNOTPRECISELYDEFINEDPANCREATICBIOLOGY,57ANDFGF19ANDITSMOUSEORTHOLOGFGF15,REGULATECHOLESTEROLANDBILEACIDMETABOLISMINHUMANSANDANDARECURRENTLYUNDERINTENSEINVESTIGATIONFGF21ANDMETABOLICDISEASES39INDUCESUPREGULATIONOFPPARΓPROTEINALTHOUGHITISCURRENTLYINCIDENCEOFHEPATOCELLULARCARCINOMASINFGF21TRANSGENICMICEUNCLEARWHATPARTICULARIMPACTEACHOFTHESEEFFECTSHASONGLUCOSEAT12MONTHSOFAGEWASSIMILARTOTHATINCONTROLANIMALSTHUS,IFTRANSPORT,THESEDATAREVEALPOTENTIALSYNERGYINTHEACTIONSBEFGF21NEGATIVELYREGULATESCHEMICALLYINDUCEDHEPATOCARCITWEENTHESETWOREGULATORSOFGLUCOSEHOMEOSTASIS,FGF21ANDNOGENESIS,ITISLIKELYTOINTERFEREWITHDISEASEPROGRESSIONATITSPPARΓ31EARLYSTAGES24RECENTLY,ANOTHERLINEOFFGF21TRANSGENICMICEONAC57BL/6JBACKGROUNDHASBEENDESCRIBED26THESEANIMALSHAD50–1503FGF21INVIVOPHARMACOLOGYTIMESHIGHERLEVELSOFFGF21MRNAINTHELIVERTHANCONTROLANIMALS,ANDHADLOWEREDLEVELSOFSERUMCHOLESTEROL,TRITHEINVIVOBIOACTIVITYOFFGF21HASBEENOBSERVEDUSINGGLYCERIDES,GLUCOSEANDINSULININDICATIVEOFTHEIMPROVEDLIPIDNUMEROUSBIOMARKERSTHATILLUSTRATETHEEFFECTSOFFGF21ACTIONSANDGLYCEMICMETABOLISM,ANDAMELIORATEDINSULINRESISTANCE,INABROADRANGEOFANIMALSTUDIESCOVERINGAVARIETYOFDISEASECONSISTENTWITHPREVIOUSLYPUBLISHEDDATA20FGF21TRANSGENICMODELS20,2326,35MICEWEREALSOFOUNDTOHAVEELEVATEDSERUMLEVELSOFΒHYDROXYTHECONSEQUENCESOFENFORCEDEXPRESSIONOFHUMAN20ANDBUTYRATE,SUGGESTINGTHEINDUCTIONOFKETOGENESIS,ASWELLASHAVMOUSEFGF2123,26HAVEBEENEVALUATEDINTRANSGENICMICE20,24,26INGADIPOCYTESOFSMALLERSIZE,INCREASEDLIPASEEXPRESSIONINWHITEFGF21TRANSGENICANIMALSAPPEARVIABLE,NORMALATBIRTH,ANDADIPOSETISSUEANDELEVATEDSERUMLEVELSOFFREEFATTYACIDS,ALLESSENTIALLYINDISTINGUISHABLEFROMTHEIRWILDTYPELITTERMATESNOEVOCATIVEOFTHEINDUCTIONOFLYPOLYSIS26IMPORTANTLY,ASURINETICEABLY,THEYDONOTPOSSESSSIGNSOFNEOPLASIA,TUMORS,ORANYCONCENTRATIONSOFADRENALINEANDNORADRENALINEWEREREDUCEDINOTHEROVERTABNORMALITIESTHROUGHOUTTHEIRLIFESPAN,ASDEMONSTRAFGF21TRANSGENICANIMALS,FGF21DOESNOTAPPEARTOSTIMULATETEDBYEXTENSIVEMORPHOLOGICANDHISTOLOGICANALYSES20,23THUS,LIPOLYSISTHROUGHASYSTEMICINCREASEINCATECHOLAMINES26SURPROLONGEDEXPOSUREOFMICETOFGF21DOESNOTLEADTOCARCINOGENPRISINGLY,THESEFGF21TRANSGENICMICEWEREALSOREPORTEDTOHAVEICEVENTSNEVERTHELESS,ASPECIFICPHENOTYPEOFFGF21TRANSGENIC1–2oCLOWERCOREBODYTEMPERATURES,REDUCEDLOCOMOTORACTIVITY,MICEWASREVEALEDUPONAVARIETYOFCHALLENGESANDENHANCEDTORPORDURING24HOURFASTINGCOMPAREDWITHTHEIRC57BL/6MICEOVEREXPRESSINGHUMANFGF21FROMTHELIVERCONTROLLITTERMATES26ALTHOUGHINTRIGUING,THELATTEROBSERVATIONSCIRCULATINGLEVELSOF70–150N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