Antidiabetic drugs restore abnormal transport of amyloid-b across the

合集下载

整合素α4在美洲大蠊提取物黏糖氨酸抗肝纤维化中的作用

!489:;4<:!整合素α４在美洲大蠊提取物黏糖氨酸抗肝纤维化中的作用鲁　杰，周义霞，刘　叶，高　雅，陈科璇，李顶春，陈一晖，刘怀鄂，王宏图，李　武昆明医科大学第一附属医院感染与肝病科，昆明６５００３２摘要：目的　本研究基于黏糖氨酸（ＳＳＡＡ）在大鼠中的抗肝纤维化作用，研究整合素α４（ＩＴＧＡ４）在肝纤维化中的作用机制。

方法　大鼠腹腔内注射ＣＣｌ４诱导肝纤维化模型，在此基础上使用秋水仙碱或ＳＳＡＡ低、中、高剂量进行干预，以空白对照组、ＳＳＡＡ组作为对照。

实验干预１２周后，收集大鼠血清、肝脏标本，检测大鼠血清ＡＬＴ、ＡＳＴ水平，ＨＥ染色、天蓝猩红染色观察肝组织病理情况；实时荧光定量ＰＣＲ检测肝组织ＩＴＧＡ４、整合素β１（ＩＴＧＢ１）、ＴＧＦβ１、α－ＳＭＡ、ＴＩＭＰ２的转录水平；ＷｅｓｔｅｒｎＢｌｏｔ检测ＩＴＧＡ４、ＩＴＧＢ１、ＴＧＦβ１、α－ＳＭＡ、ＭＭＰ２、ＴＩＭＰ１、ＴＩＭＰ２的相对蛋白表达；免疫组化观察ＴＧＦβ１、α－ＳＭＡ蛋白表达。

计量资料多组间比较采用单因素方差分析，进一步两两比较采用ＬＳＤ－ｔ检验。

结果　ＣＣｌ４模型组中ＡＳＴ、ＡＬＴ显著升高，秋水仙碱或ＳＳＡＡ低、中、高剂量干预后能降低ＡＳＴ、ＡＬＴ水平，各组与ＣＣｌ４模型组相比差异均有统计学意义（Ｐ值均＜０．０５）。

ＣＣｌ４模型组中的ＨＥ染色和天蓝猩红染色结果显示肝小叶结构紊乱、胶原纤维增多，秋水仙碱或ＳＳＡＡ低、中、高剂量干预后肝小叶结构得到改善。

ＣＣｌ４模型组中的ＩＴＧＡ４、ＴＧＦβ１、α－ＳＭＡ和ＴＩＭＰ２各指标转录水平均显著高于其余各组，秋水仙碱或ＳＳＡＡ干预后能降低各因子转录水平，与ＣＣｌ４模型组相比差异均有统计学意义（Ｐ值均＜０．０５）。

ＣＣｌ４模型组中的ＩＴＧＡ４、ＴＧＦβ１、α－ＳＭＡ、ＴＩＭＰ２和ＴＩＭＰ１蛋白表达高于其余各组，ＭＭＰ２蛋白表达低于其余各组，在秋水仙碱或ＳＳＡＡ干预后均能抑制ＩＴＧＡ４、ＴＧＦβ１、α－ＳＭＡ、ＴＩＭＰ２、ＴＩＭＰ１表达，促进ＭＭＰ２表达。

保护胰岛功能及促进胰岛再生临床治疗

李延兵许雯翁建平等 Diabetes Care 2004; 27:2597–2602
不同治疗方法对细胞体积的影响
细胞体积(%)
Diabetes 2003; 52: 102-110
胰岛素注射比口服降糖药及饮食控制对细胞体积和分泌胰岛素功能的保存更加有效!
胰岛素强化治疗对新诊断2型糖尿病患者β细胞功能和血糖控制的影响：多中心、随机、平行组研究
翁建平李延兵许雯时立新朱大龙周智广田浩明罗佐杰严励曾龙驿杨立勇等Lancet 2008
血糖达标率和达标时间差异
达标定义: FPG<6.1mmol/L，2hPG<8.0mmol/L
达标率（%）
达标时间（天）
10 9 8 7 6 5 4 3 2 1
97.1%
5.6
9.3
短期胰岛素强化治疗 β细胞K通道开放剂抗凋亡药物 Aminoguanidine Incretin mimetics and enhancers Thiazolidinediones 其他药物 ACEI/ARB 那格列奈/瑞格列奈
对T2DM的短期胰岛素强化治疗
2型糖尿病患者应快早使血糖达到理想控制水平,缓解高糖毒性和脂毒性,抑制炎症反应,使β细胞功能得到最大程度的恢复。胰岛素是作用最强的降糖药物,可使任何程度高血糖得到有效控制,最大程度解除糖毒性影响。
翁建平李延兵许雯时立新朱大龙周智广田浩明罗佐杰严励曾龙驿杨立勇等Lancet 2008
0
5
10
15
20
25
30
CSII
MDI
OHA
治疗前
治疗后
p<0.05
%
CSII改善胰岛素分泌质量优于OHA

齐墩果酸通过调节胆汁酸转运体和代谢酶改善ANIT诱导的肝内胆汁淤积

摘要背景：齐墩果酸（oleanolic acid，OA）是一种三萜类化合物，广泛存在于山楂、乌梅、女贞子等一些传统的中草药中，具有保肝、抗肿瘤和心血管系统保护等多种生物活性。

OA在保肝作用方面主要体现于对血清转氨酶的降低，故临床上用于肝炎的护肝治疗[1]，而对肝内胆汁淤积症的治疗还尚未有研究报道。

胆汁酸摄取转运体（NTCP）、外排转运体（Bsep、Mrp2 和Mrp3）、Ⅱ相代谢酶（UGT1A1、Sult2a1）以及核因子（FXR和Nrf2）参与了胆汁酸的转运和代谢，对缓解肝内胆汁淤积症具有重要意义。

实验目的：本文旨在探索OA对肝内胆汁淤积症的作用以及其作用机制，为OA在临床上应用于肝内胆汁淤积症提供理论依据。

实验方法：1、实验动物的分组和处理：将35只SPF级雄性大鼠（体重在180-220g），用标准饲料和水进行1周的喂养。

实验共有5组（n=7），具体如下所示：（1）正常组；（2）ANIT组（3）OA（50mg/kg）预干预组；（4）OA（100mg/kg）预干预组；（5）UDCA预干预组。

本实验中将预先给大鼠给药10天，在第10天对所有组别（除去空白组）的大鼠进行灌胃ANIT，ANIT单次急性造模要求大鼠给药前后都禁食12 h并在给药后48h进行取材。

2、实验检测项目：（1）利用各种生化检测试剂盒对大鼠血清中ALT、AST、ALP、TBIL、DBIL、TBA的含量进行检测；利用肝脏组织HE染色的来观察肝组织的形态和损伤程度。

（2）采用Rt-qPCR技术检测肝组织中钠离子-牛磺胆酸共转运蛋白（NTCP）、胆盐输出泵（Bsep）、多药耐药蛋白2（Mrp2）、多药耐药蛋白3（Mrp3）以及Ⅱ相代谢酶（UGT1A1、Sult2a1）的mRNA的表达水平。

（3）采用Western-blot技术检测肝脏钠离子-牛磺胆酸共转运蛋白（NTCP）、胆盐输出泵（Bsep）、多药耐药蛋白2（Mrp2）、多药耐药蛋白3（Mrp3）、Ⅱ相代谢酶（UGT1A1、Sult2a1）以及核因子（FXR、Nrf2）的蛋白表达水平。

超星医学英语试题及答案

超星医学英语试题及答案一、选择题（每题1分，共10分）1. Which of the following is not a type of cancer?A. MelanomaB. LeukemiaC. DiabetesD. Lymphoma2. The term "cardiology" refers to the study of:A. Heart diseasesB. Lung diseasesC. Kidney diseasesD. Brain diseases3. What is the medical term for a condition where the stomach contents flow back into the esophagus?A. GastritisB. GastroenteritisC. Esophageal refluxD. Duodenal ulcer4. The abbreviation "MRI" stands for:A. Magnetic Resonance ImagingB. Medical Research InstituteC. Multiple Respiratory InfectionD. Musculoskeletal Rehabilitation Institute5. Which of the following is a common symptom of the flu?A. Dry coughB. Acute abdominal painC. HeadacheD. All of the above6. The process of identifying the cause of a disease is known as:A. DiagnosisB. PrognosisC. TherapyD. Etiology7. What does "HIV" stand for?A. Hepatitis Influenza VirusB. Human Immunodeficiency VirusC. High Intensity VirusD. Heart Infection Virus8. The medical specialty dealing with the female reproductive system is:A. GynecologyB. ObstetricsC. DermatologyD. Cardiology9. Aspirin is commonly used as:A. AntibioticB. AntisepticC. AnalgesicD. Antihypertensive10. Which of the following is a method of preventing the spread of infectious diseases?A. VaccinationB. AmputationC. SurgeryD. Radiation therapy二、填空题（每空1分，共10分）1. The medical term for a break in the bone is a __________.2. The organ responsible for filtering the blood and removing waste is the __________.3. The process of treating a disease with drugs is known as __________.4. A person who specializes in the diagnosis and treatment of mental disorders is called a __________.5. The abbreviation for the common cold is __________.6. The medical term for a surgical cut is an __________.7. The study of the structure of the body is called__________.8. A condition where the body cannot properly regulate blood sugar levels is known as __________.9. The organ that pumps blood throughout the body is the__________.10. The medical term for a skin rash is __________.三、简答题（每题5分，共20分）1. Explain the difference between a virus and a bacterium.2. Describe the function of the thyroid gland.3. What are the stages of the typical cold sore cycle?4. Discuss the importance of a balanced diet in maintaining good health.四、阅读理解题（每题2分，共10分）Read the following passage and answer the questions.Passage:The human body is a complex system with various organsworking together to maintain life. The heart, for instance,is a vital organ that pumps blood throughout the body. Oxygen and nutrients are carried by the blood to different parts of the body, ensuring that cells receive the energy they need to function. The lungs are responsible for the exchange of gases, taking in oxygen and expelling carbon dioxide. The kidneysfilter the blood and remove waste products, which are then excreted from the body.Questions:1. What is the primary function of the heart?2. Which organ is responsible for gas exchange in the human body?3. What do the kidneys do in terms of blood filtration?4. What carries oxygen and nutrients to the cells of the body?5. What is expelled from the body by the lungs?五、翻译题（每题5分，共20分）1. 将下列句子从中文翻译成英文：请将您的手臂放在桌子上。

药学考研英语试题及答案

药学考研英语试题及答案一、阅读理解（共20分，每题4分）阅读下列短文，从每题所给的四个选项（A、B、C和D）中，选出最佳选项。

Passage 1Drug resistance is a significant challenge in the treatment of infectious diseases. The emergence of drug-resistant strains of bacteria, viruses, and parasites has complicated the management of common and life-threatening infections. This phenomenon is driven by several factors, including the overuse and misuse of antimicrobial agents, inadequate infection control practices, and genetic mutations that confer resistance to drugs.36. What is the main cause of drug resistance?A. Genetic mutationsB. Inadequate infection control practicesC. Overuse and misuse of antimicrobial agentsD. All of the above37. Which of the following is NOT mentioned as a factor contributing to drug resistance?A. Genetic mutationsB. Inadequate infection control practicesC. Overuse and misuse of antimicrobial agentsD. Lack of public awareness38. What is the impact of drug resistance on the treatment of infectious diseases?A. It makes the management of infections more complicated.B. It reduces the effectiveness of antimicrobial agents.C. It leads to an increase in the number of infections.D. It results in a decrease in the cost of treatment.39. What can be inferred from the passage about the future of drug resistance?A. It will become less of a problem with better infection control.B. It will continue to be a significant challenge if current practices continue.C. It will be eradicated with the development of new drugs.D. It will have no effect on the treatment of life-threatening infections.Passage 1 答案36. D. All of the above37. D. Lack of public awareness38. A. It makes the management of infections more complicated.39. B. It will continue to be a significant challenge if current practices continue.二、词汇与语法（共20分，每题2分）40. The new drug is expected to be on the market by the _______ of next year.A. beginningB. endC. middleD. top41. Despite the high cost of the treatment, the patient’s condition showed _______ improvement.A. noB. noneC. anyD. some42. The research team is working on a project aimed at _______ the side effects of the medication.A. reducingB. increasingC. eliminatingD. enhancing43. The doctor prescribed a _______ dosage of the antibiotic for the patient.A. normalB. regularC. standardD. typical44. The study found that the drug was _______ effective in treating the symptoms.A. highlyB. slightlyC. notD. barely45. The patient was advised to take the medication _______ with food to reduce stomach irritation.A. separatelyB. togetherC. concurrentlyD. simultaneously词汇与语法答案40. B. end41. D. some42. A. reducing43. C. standard44. A. highly45. B. together三、完形填空（共20分，每题2分）阅读下面的短文，掌握其大意，然后从46-55各题所给的四个选项（A、B、C和D）中，选出最佳选项。

恩格列净诱导的线粒体稳态显著减轻小鼠心脏微血管缺血

Empagliflozin alleviates cardiac microvascular ischemia/reperfusion injury bymaintaining myocardial mitochondrial homeostasisSONG Chenfang,HUANG Zhenhe,CHEN Wei,WANG Fang,CAI Liangling,ZHAO Fei,ZHAO YueDepartment of Geriatrics,Xiehe Shenzhen Hospital,Huazhong University of Science and Technology,Shenzhen 518000,China摘要：目的探究恩格列净（EMPA ）在缓解心脏缺血再灌注（I/R ）损伤期间的微血管和内皮损伤的作用。

方法将小鼠随机分为3组，每组5只，一组小鼠按照每只10mg·kg -1·d -1EMPA 辅以饲料和蒸馏水连续喂养7d ，作为I/R+EMPA 组备用。

其余两组（I/R 组和sham 组）以普通饲料和蒸馏水连续喂养7d 后进行造模。

I/R 组和I/R+EMPA 组小鼠开胸手术以暴露心脏，并用丝线结扎左前降支冠状动脉45min 以诱导缺血，随后松开再灌注2h ；假手术（Sham ）组小鼠仅开胸后将线穿过前降支、不结扎。

在体外诱导sI/R 损伤前12h ，将10µmol/L 的EMPA 添加到HCAEC 中作为sI/R+EMPA 组备用，然后将sI/R 组和sI/R+EMPA 组细胞置于缺氧孵箱中孵育45min ，随后在正常培养条件下恢复2h ，以模拟缺氧后复氧的培养环境改变。

对照组HCAECs 在正常条件下进行培养。

通过电子显微镜检测心脏微血管的结构改变，蛋白质印迹和免疫荧光检测微血管中的纤维蛋白积累和内皮细胞相应蛋白表达情况、实时荧光定量聚合酶链式反应（qPCR ）检测促炎细胞因子等方法，检测EMPA 是否可以减轻心脏I/R 损伤期间的微血管损伤和内皮损伤。

口服4-氨基吡啶可用于区分创伤性周围神经损伤类型和促进功能恢复

口服4-氨基吡啶可用于区分创伤性周围神经损伤类型和促进功能恢复4-氨基吡啶（4-AP）是一种广谱钾通道阻滞剂，是FDA批准的用于对症治疗多发性硬化症的药物。

已有研究显示4-氨基吡啶可改善患有多种脱髓鞘疾病患者的神经肌肉功能。

口服制剂是最常用的药物形式，并且可以使用缓释制剂来延长作用时间。

但是，尚不知道人体等效剂量的4-氨基吡啶口服剂量是否对创伤性周围神经损伤有作用。

4-氨基吡啶对肌肉质量和力量的有益影响是否取决于神经的连续性以及受损神经中基因表达的变化方式，这一点也仍然未知。

美国赫尔歇医疗中心的John C. Elfar等开展了一项动物实验，旨在检测人体等效剂量4-氨基吡啶口服对有或没有神经连续性的创伤性周围神经损伤的作用。

该研究给予坐骨神经挤压或横断伤小鼠灌胃或腹腔注射4-氨基吡啶（10 µg）或其溶剂，并检测4-氨基吡啶药代动力学，小鼠运动功能、肌肉质量、固有肌力、神经形态和基因表达谱。

线性药代动力学结果显示，最大血浆4-氨基吡啶浓度与4-氨基吡啶剂量成正比。

急性单剂量口服4-氨基吡啶给药可导致运动功能快速短暂改善，这在有或没有神经连续性创伤性周围神经损伤间有所不同；慢性每日口服4-氨基吡啶治疗可显着增强挤压伤后的运动功能恢复，且这种作用与相关髓鞘形成，肌肉质量和离体肌肉力量的改善有关。

挤压伤神经的PCR阵列分析显示，涉及轴突炎症和再生的基因发生了显著变化。

以上结果表明，4-氨基吡啶有潜力在临床上以急性单剂量给药形式用于区分具有或不具有连续性的创伤性周围神经损伤患者，并长期治疗利于具有神经连续性的创伤性周围神经损伤患者功能恢复。

上述研究结果发表于《中国神经再生研究（英文版）》杂志2020年第10期。

文章摘要：4-氨基吡啶是FDA批准的用于多发性硬化症治疗的药物，可改善患者的神经肌肉功能。

我们最近的研究证明，4-氨基吡啶的局部、透皮或注射形式可改善小鼠创伤性周围神经损伤后的髓鞘形成、神经传导速度、肌肉萎缩和运动功能。

1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。

Antidiabeticdrugsrestoreabnormaltransportofamyloid-bacrossthebloodebrainbarrierandmemoryimpairmentindb/dbmice

FangChen,RongRongDong,KaiLongZhong,ArijitGhosh,SuSuTang,YanLong,MeiHu,MingXingMiao,JianMinLiao,HongBingSun,LingYiKong,HaoHong*

DepartmentofPharmacology,andJiangsuKeyLaboratoryofDrugDiscoveryforMetabolicDiseases,ChinaPharmaceuticalUniversity,Nanjing210009,China

articleinfoArticlehistory:Received21January2015Receivedinrevisedform19July2015Accepted21July2015Availableonline26July2015Keywords:AntidiabeticdrugsAmyloid-bBloodebrainbarrierAdvancedglycationendproductsLow-densitylipoproteinreceptorrelatedprotein1HippocampalsynapticplasticityabstractPreviousstudieshaveshownsigniﬁcantchangesinamyloid-b(Ab)transportacrossthebloodebrainbarrier(BBB)underdiabeticconditionswithhypoinsulinemia,whichisinvolvedindiabetes-associatedcognitiveimpairment.Presentstudyemployeddb/dbmicewithhyperinsulinemiatoinvestigatechangesinAbtransportacrosstheBBB,hippocampalsynapticplasticity,andrestorativeeffectsofantidiabeticdrugs.Ourresultsshowedthatdb/dbmiceexhibitedsimilarchangesinAbtransportacrosstheBBBtothatofinsulin-deﬁcientmice.Chronictreatmentofdb/dbmicewithantidiabeticdrugssuchasmetfor-min,glibenclamideandinsulinglarginesigniﬁcantlydecreasedAbinﬂuxacrosstheBBBdeterminedbyintra-arterialinfusionof125I-Ab1-40,andexpressionofthereceptorforadvancedglycationendproducts(RAGE)participatinginAbinﬂux.Insulinglargine,butnot,metforminorglibenclamideincreasedAb

efﬂuxacrosstheBBBdeterminedbystereotaxicintra-cerebralinfusionof125I-Ab1-40,andexpressionofthelow-densitylipoproteinreceptorrelatedprotein1(LRP1)participatinginAbefﬂux.Moreover,treatmentwiththesedrugssigniﬁcantlydecreasedhippocampalAb1-40orAb1-42andinhibitedneuronalapoptosis.Thedrugsalsoamelioratedmemoryimpairmentconﬁrmedbyimprovedperformanceonbehavioraltasks.However,insulinglargineorglibenclamide,butnotmetformin,restoredhippocampalsynapticplasticitycharacterizedbyenhancinginvivolong-termpotentiation(LTP).FurtherstudyfoundthatthesethreedrugssigniﬁcantlyrestrainedNF-kB,butonlyinsulinglargineenhancedperoxisomeproliferator-activatedreceptorg(PPARg)activityattheBBBindb/dbmice.OurdataindicatethattheantidiabeticdrugscanpartiallyrestoreabnormalAbtransportacrosstheBBBandmemoryimpairmentunderdiabeticcontext.©2015ElsevierLtd.Allrightsreserved.

1.IntroductionAgrowingbodyofevidencesupportsanintriguingclinical/epidemiologicalconnectionbetweentype2diabetes(T2D)andAlzheimerdisease(AD)(StewartandLiolitsa,1999;Arvanitakisetal.,2004;Sanzetal.,2012).T2DsharesmanycommonfeatureswithAD,suchasdisruptedglucosemetabolism,insulinresistance,andcognitiveimpairment(Arvanitakisetal.,2004;Liuetal.,2011).Itisthereforesuggestedthatthereisaconvergentpointbetweenthesetwodiseases.EvidenceexiststosupportthatdefectivebraininsulinsignalingcontributestotheoccurrenceofAD(HoyerandNitsch,1989).Recentstudiessuggestthatdiabetesaffectsthebloodebrainbarrier(BBB)transportfunction,whichmightbean

initiativefactorincognitiveimpairmentorAD(Maengetal.,2007;Hongetal.,2009;Huber,2008;Liuetal.,2009).TheBBBisamonolayerofcellswithtightjunctionsthatcomprisesendothelialandependymalcellswithlimitedspacesorgapsbetweenthecells.Theendothelialbarrierissupplementedwithcapillarypericytesthatsharethebasementmembranewiththeendothelialcells.Moreover,perivascularend-feetoftheastrocytealmosttotallycovertheabluminalsurfaceofthemicrovascularbasementmem-brane.Itiscriticalformaintainingbrainfunctionthroughregu-latingthetransportofmaterialsbetweentheperipheralcirculationandthecentralnervoussystem.DysfunctionoftheBBBwithefﬂuxandinﬂuxtransportersmaycontributetothepathogenesisofsomedegenerativeneuronaldisorders(Uenoetal.,2010).RAGEandLRP1aretwomajorproteinsinvolvedinreceptor-mediatedamyloidb(Ab)trafﬁckingacrosstheBBB(Deaneetal.,

2004a,b;ZhangandLee,2011).RAGE,existingattheluminaof*Correspondingauthor.E-mailaddress:honghao@cpu.edu.cn(H.Hong).

ContentslistsavailableatScienceDirectNeuropharmacology

journalhomepage:www.elsevier.com/locate/neuropharm

Neuropharmacology101(2016)123e136theendothelialcytoplasm,isthoughttotransportperipheralAbintothebrain,whileLRP1,locatedatbothluminaandabluminaoftheendothelialcytoplasm,transportsAboutofthebrain(Shibataetal.,2000;Deaneetal.,2003);thesetransportersattheBBBarecriticalforregulationofAbhomeostasisinthebrain.OurpreviousstudiesshowedsigniﬁcantincreaseinRAGE-dependentAbinﬂuxandremarkabledecreaseinLRP1-dependentAbefﬂuxacrosstheBBB,accompaniedbycerebralAbaccumulationandmemoryimpairmentinstreptozotocin(STZ)-induceddiabeticmicewithhypoinsulinemia(Hongetal.,2009;Liuetal.,2009,2013).ThusrestorationofabnormaltransportofAbacrosstheBBBisanimportantstrategyforprotectionagainstmemoryimpairmentcausedbyintracerebralAbaccumulationindiabeticcondition.Herein,weuseddb/dbmice,amousemodelofspontaneousdia-beteswithhyperinsulinemia,toinvestigatechangesinAbtransportacrosstheBBBandrestorativeeffectsofsomecommonly-usedantidiabeticdrugssuchasmetformin,glibenclamideandinsulinglargineonabnormaltransportofAbacrosstheBBB.2.Materialsandmethods2.1.AnimalsType2diabeticmaledb/db(BKS.Cg-mþ/þLeprdb/J)mice(approx.6weeksold,weighing30e40g)andtheirleanwild-typecontrols(C57BLKS/Jdb/þ)wereobtainedfromModelAnimalResearchCenterofNanjingUniversity(Nanjing,China).AllanimalprocedureswereperformedinaccordancewiththeguidelinesoftheInstitutionalAnimalCareandUseCommitteeofChina.Micewerehousedunderstandardconditions(12-hlight/12-hdarkcyclestartingat8:30am;23±2󰀂C;55±10%humid-ity)insolid-bottomedcagesonwoodchipbeddingwithfreeaccesstowaterandstandardlaboratorychow.2.2.MaterialsInsulinglarginewaspurchasedfromSanoﬁ-AventisCo.,Ltd(Paris,France).MetforminwaspurchasedfromBeijingJingfengPharmaceuticalCo.,Ltd(Beijing,China).Glibenclamidewaspur-chasedfromShanghaiSineCo.,Ltd(Shanghai,China).Antibodieswerepurchasedfromdifferentcompanies:rabbitanti-mouseAb1e40,Ab1e42andRAGEfromAbcamTechnologyCo.,Ltd.(HongKong,China);rabbitanti-mousepro-orcleavedcaspase-3,Bcl-2,Bax,NF-kBp65andPPARgfromCellSignalingTechnology,Inc.(Boston,MA,USA);rabbitanti-mouseLRP1fromSantaCruzBiotechnology,Inc.(Heidelberg,Germany);rabbitanti-mouseHis-toneH3,b-actinandgoatanti-rabbitsecondaryantibodiesfromBioworldTechnologyCo.,Ltd.(Minneapolis,MN,USA).Streptavidin-biotincomplex(SABC)immunohistochemistrykitwaspurchasedfromBosterBiotechnologyCo.,Ltd(Wuhan,China).Mouseinsulin(INS),mouseAb1e40,mouseAb1e42,advancedglycationendproducts(AGEs)ELISAkitswerepurchasedfromCusabioBiotechCo.,Ltd.(Wilmington,DE,USA).Coomassie(Bradford)proteinassaykitandGlucoseOxidaseKitwerepurchasedfromNanjingJianchengBiotechInstitute(Nanjing,China).Nucleoproteinextractionkitwaspur-chasedfromSangonBiotechCo.,Ltd.(Shanghai,China).HumanAb1e40proteinfragmentwaspurchasedfromSigmaeAldrich(USA).Na125Iand14CwerepurchasedfromChengduGaotongIsotopeCo.,Ltd.(Chengdu,China)andAmericanRadiolabeledChemicals,Inc.(USA)respectively.Human125I-Ab1e40and14C-inulinweresynthe-sizedatJiangnanInstituteofNuclearMedicine(Wuxi,China)andXenoBioticLaboratories,Inc.(Nanjing,China)respectively.AliquotsofradiolabeledAb1-40werekeptatÀ20󰀂Cforamaximumof4weeksbeforeuse.HPLCanalysisconﬁrmedthatmorethan99%of125I-Ab1e40(4330Da;70mCi/mg)radioactivitywaspresentintheformofnonoxidizedmonomericpeptide.14C-inulin(5000Da,1.5mCi/mg)wasusedasareferencemolecule.Alltheotherchemicalswereofanalyticalgradeandcommerciallyavailable.