吡格列酮对糖尿病大鼠肾脏的保护作用

目的　探讨吡格列酮对糖尿病大鼠肾脏的保护作用及其机制。方法　采用链脲佐菌素诱导制备糖尿病大鼠动物模型 ,给予吡格列酮3mg· kg- 1· d- 1和 9mg· kg- 1· d- 1治疗 ,共 1 2 w。结果　给予治疗 1 2 w后 ,糖尿病治疗组大鼠尿蛋白定量 ,肾小球肥大均较糖尿病组显著降低 ,并可降低肾小球内细胞总数和减少肾小球内增殖细胞的数量 ,抑制系膜基质的增生和减轻尿蛋白的排泄。结论　吡格列酮对糖尿病大鼠肾脏具有保护作用。其防治糖尿病肾病发生、发展的作用机制可能部分是通过抑制糖尿病大鼠肾脏 PCNA过度表达。     

吡格列酮对急性胰腺炎肝损伤的保护作用研究

目的:探讨吡格列酮对急性胰腺炎(AP)患者肝损伤的保护作用及其机制。方法:选取AP患者144例,使用数字表法随机分为观察组和对照组,每组72例。速率法检测血丙氨酸转氨酶(ALT)、天门冬氨酸氨基转移酶(AST),ELISA法检测外周血炎性因子:肿瘤坏死因子α(TNF-α)、白介素-6(IL-6)、白介素-10(IL-10)。结果:治疗前2组血TNF-α、IL-6和IL-10水平以及ALT和AST等肝功能指标差异无统计学意义(均P0.05),治疗后观察组TNF-α和IL-6水平及ALT和AST均显著低于对照组(均P0.05),观察组血IL-10显著高于对照组(P0.05)。治疗前2组空腹血糖差异无统计学意义(P0.05),治疗后观察组的空腹血糖显著低于对照组(P0.05)。对照组不良反应发生率为5.6%(4/72),观察组不良反应发生率为6.9%(5/72),2组比较无统计学差异(P0.05)。结论:吡格列酮可以升高AP患者血IL-10表达,抑制炎症反应,发挥肝损伤保护作用,临床使用安全。     

吡格列酮拮抗链脲佐菌素诱导培养皮层神经元损伤的保护作用

目的研究吡格列酮对链脲佐菌素(STZ)诱导原代培养大鼠皮层神经元损伤是否具有保护作用。方法采用新生1 d~3d的Wistar大鼠,常规原代皮层神经细胞培养的方法,培养到第7天时,加入吡格列酮(0.01μmol/L,0.1μmol/L,1μmol/L),24h后,再加入STZ(100μmol/L),36h后通过检测cck-8,乳酸脱氢酶(LDH)释放检测和calcein-AM染色情况观察细胞的损伤情况。结果 STZ(100μmol/L)处理后,原代培养大鼠皮层神经细胞产生明显的损伤作用,吡格列酮(0.01μmol/L,0.1μmol/L)对STZ诱导的培养皮层神经细胞损伤有保护作用,吡格列酮(1μmol/L)对STZ诱导培养皮层神经细胞损伤没有保护作用。结论一定剂量的吡格列酮对STZ诱导的培养皮层神经细胞损伤有保护作用。     

吡格列酮对L6肌细胞脂联素和葡萄糖转运蛋白4表达的影响及其机制研究

建立棕榈酸诱导的大鼠L6肌细胞胰岛素抵抗模型后,以吡格列酮、c-Jun氨基末端激酶(JNK)抑制剂SP600125、p38丝裂原活化蛋白激酶(p38MAPK)抑制剂SB203580进行干预.应用Western 印迹法检测脂联素、葡萄糖转运蛋白4(GLUT4)蛋白表达和JNK、p38MAPK磷酸化水平.结果显示,吡格列酮可显著增加胰岛素抵抗状态下L6细胞p38MAPK磷酸化、脂联素和GLUT4蛋白表达(P＜0.05或P＜0.01),降低JNK磷酸化水平(P＜0.01).阻断p38MAPK信号通路后,吡格列酮上调L6细胞GULT4蛋白表达的效应显著降低(P＜0.01),而阻断JNK信号通路却无显著影响(P＞0.05).     

吡格列酮对SD大鼠非酒精性脂肪肝病形成的预防作用及其机制

目的:探讨吡格列酮(pioglitazone,PIO)对SD大鼠非酒精性脂肪肝病(non-alcoholic fatty liverdisease,NAFLD)形成的干预作用及机制.方法:♂SD大鼠72只,随机分为正常饮食组(NG)、高脂饮食组(HG)和PIO干预组(PIOG)各24只.PIOG喂饲高脂饲料,并同时予PIO药物灌胃8 wk.正糖高胰岛素钳夹实验检测IR水平,放免法和全自动生化仪检测血清生化指标,RT-PCR检测过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptorγ,PPARγ)mRNA表达,Western blot检测肝组织c-Jun氨基末端激酶(c-Jun amino-terminalkinase 1,JNK1)和PPARγ蛋白表达.结果:HG大鼠GIR水平降低和JNK1蛋白表达增高,均呈明显时间依赖性(均P<0.05);8 wk末HG大鼠肝细胞出现明显脂肪变性,与NG相比,体质量、肝指数,TG、ALT、AST、FFAs、FINS、TNF-α水平明显增高,IR加重,JNK1蛋白表达明显升高,肝组织PPARγ表达明显降低(TG:1.23±0.08 vs 0.62±0.12,ALT:92.80±7.09 vs 51.34±8.12;AST:153.22±20.65 vs 119.26±13.61;FFAs:511.94±24.88vs 335.31±15.71;FINS:41.23±1.84 vs 22.65±2.25;TNF-α:1.02±0.12 vs 0.34±0.07,均P<0.05);而PIOG大鼠,上述各项指标均得到明显改善,但仍不能完全达到NG大鼠水平(均P<0.05).结论:PIO对于由高脂饮食诱导的NAFLD的形成及其他IR相关疾病有预防作用.     

吡格列酮保护大鼠心肌缺血再灌注损伤机制的研究

目的探讨吡格列酮保护大鼠心肌缺血再灌注损伤的机制,观察细胞外信号调节激酶1/2(ERK1/2)、低氧诱导因子-1α(HIF-1α)表达的变化。方法将SD大鼠30只随机分为5组:假手术组,缺血再灌注组,吡格列酮5mg组,吡格列酮10mg组和吡格列酮20mg组,每组6只,利用体内结扎左前降支的方法建立缺血再灌注损伤模型,Western blot法检测心肌组织ERK1/2、磷酸化ERK1/2的变化,RT-PCR法检测HIF-1α mRNA的变化。结果缺血再灌注组心肌组织ERK1/2表达较假手术组无变化,吡格列酮各组对其表达无影响;缺血再灌注组磷酸化ERK1/2表达上调,吡格列酮各组表达进一步上调,与吡格列酮剂量相关;缺血再灌注组HIF-1α mRNA表达上调,吡格列酮各组促进其进一步上调,与剂量无关。结论心肌缺血再灌注损伤时,机体可调动内源性生存激酶表达上调,应对急性损伤,吡格列酮可进一步促进这些激酶上调,发挥抗心肌缺血再灌注损伤作用。     

吡格列酮对糖耐量异常患者的干预作用

目的 观察吡格列酮对糖耐量异常患者的治疗效果.方法 用随机双盲法比较119例老年糖耐量异常患者在饮食加运动控制的基础上给予口服吡格列酮和安慰剂干预治疗,经治疗1年后,检测空腹血糖(FPG)及葡萄糖耐量试验(OGTT)后2 h血糖(2hPG),总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、胰岛素抵抗指数、空腹胰岛素(FINS)和OGTT后2 h胰岛素(PINS)水平的变化.结果 吡格列酮组与安慰剂组相比FPG、2 hPG、TC、TG、LDL、FINS及PINS均明显下降,HDL升高,吡格列酮组糖尿病的发病率为3.3%,低于安慰剂组的发病率(8.5%).结论 吡格列酮能够降低IGT人群糖尿病的发病率,在调节血脂、减轻胰岛素抵抗的同时,可使糖耐量异常明显改善.     

吡格列酮对大鼠非酒精性脂肪性肝病的预防作用

非酒精性脂肪性肝病（NAFLD）是临床常见肝病之一，随着生活方式及膳食结构的改变，NAFLD的发病率明显增高。其发病机制目前尚不明确，有研究认为胰岛素抵抗（IR）是导致NAFLD的重要病因之一。吡格列酮作为过氧化物酶体增殖物激活受体γ的高亲和力激动剂，能明显增强组织对胰岛素的敏感性。我们通过高脂饮食建立NAFLD的动物模型，用吡格列酮进行干预，探讨IR与NAFLD的关系，评估吡格列酮对NAFLD的预防作用。     

吡格列酮预处理对大鼠脑缺血再灌注损伤保护作用及机制

目的 研究吡格列酮预处理对缺血再灌注大鼠脑组织的保护作用与机制.方法 75只雄性SD大鼠随机分为假手术组、生理盐水预处理组和吡格列酮预处理组,采用线栓法制作大鼠局灶性脑缺血再灌注模型.缺血2 h再灌注22 h后观察大鼠神经功能评分,测量脑梗死体积,检测脑组织中IL-6、iNOS和NO含量,采用HE染色及Nissl染色观察脑组织病理改变.结果 与生理盐水预处理组比较,吡格列酮预处理组大鼠的神经功能评分明显降低、脑梗死体积缩小(P＜0.05或P＜0.01),脑组织中IL-6、iNOS和NO含量降低(均P＜0.01),病理学观察显示其脑组织神经细胞受损程度更小.结论 吡格列酮对大鼠局灶性脑缺血再灌注损伤有保护作用,其作用机制与其减轻脑组织炎症反应和NO神经毒性损伤有关.     

吡格列酮对成骨细胞Bax、Bcl-2蛋白表达的影响

目的 研究吡格列酮对成骨细胞增殖及凋亡的影响,并进一步了解其凋亡发生机制.方法 以MC3T3-E1成骨细胞株为实验对象,分别用0、5、10、20、30、40 μmol/L吡格列酮干预,观察细胞活性、细胞周期及凋亡率的变化,同时检测细胞Bcl-2,Bax蛋白表达.结果 随着浓度增加,成骨细胞的活性逐渐降低;与对照组相比,G0/G1,G2/M期细胞增多,S期细胞明显减少;凋亡率在5、10 μmol/L时低于对照组,30、40 μmol/L较对照组显著增高;Bax表达在10 μmol/L时明显减弱,20 μmol/L时回复到正常,30、40μmol/L较对照组显著增强;Bcl-2表达在浓度≤20 μmol/L时显著增强;对于Bax/Bcl-2相对表达强度与细胞凋亡率做相关性分析,两者呈显著性正相关(n=15,r=0.796,P＜0.01).结论 吡格列酮在低浓度抑制成骨细胞凋亡,对细胞起保护作用,较高浓度则促进细胞凋亡,Bax/Bcl-2参与其凋亡机制,并可能起关键调控作用.吡格列酮抑制成骨细胞DNA合成,抑制细胞增殖,导致细胞活性下降.

Abstract：

Objective To investigate the effects of pioglitazone on osteoblast proliferation and apoptosis.Methods MC3T3-E1 mouse osteoblastic cells were treated with 0, 5, 10, 20, 30, and 40 μmol/L pioglitazone for 24 h. Cell viability was measured by MTT, cell cycle and apoptosis were inspected with flow cytometry, the expressions of Bcl-2 and Bax proteins were examined via immuno-chemical staining. Results Survival of osteoblasts decreased in a dose-dependent manner. Compared with the control group, the cells in the G0/G1 and G2/M stages increased, while the cells in S stage decreased significantly. The percentage of apoptosis at 5 and 10 μmol/L were lower than that of the control group(P ＜ 0.05), While it was increased significantly at 30 and 40 μmol/L(P ＜0.01). Bax expression was attenuated at 10 μmol/L(P＜0. 01), returned to normal by 20 μmol/L, and was increased by 30 and 40 μmol/L(P ＜ 0. 01). Bcl-2 expression was enhanced at the dose ≤ 20 μmol/L(P ＜0.01). Positive correlation was found between the death rate and the expression intensity of Bax/Bcl-2(n = 15, r=0.796, P＜0.01). Conclusions Pioglitazone inhibits apoptosis of osteoblasts at low concentrations and protects the cells, but promotes their apoptosis at higher concentration, Bax/Bcl-2 may play an important role in mediating the piglitazone-induced apoptosis of osteoblasts. It inhibits DNA synthesis and cell proliferation.     

p38MAPK途径在淫羊藿甙促成骨细胞分化中的作用

观察淫羊藿甙对体外培养新生大鼠颅盖骨成骨细胞p38丝裂原活化蛋白激酶(MAPK)蛋白表达的影响,探讨淫羊藿甙防治骨质疏松症的信号转导机制.结果 显示淫羊藿甙可以在5 min内激活p38MAPK途径,并且可以上调Cbfa1蛋白表达和活性升高,加用p38MAPK途径的抑制剂SB203580后可以部分抑制淫羊藿甙对Cbfa1蛋白和活性的上调作用.

Abstract：

This paper was aimed to investigate the effects of icariin on the expression of p38 mitogen activated protein kinase(MAPK)protein in rat osteoblasts cultured in vitro, to elucidate the signal transduction of icariin in preventing and treating osteoporosis. The results showed that p38MAPK could be activated by icariin within 5min, and Cbfal could also be upregulated, and SB203580, an inhibitor of p38MAPK pathway, could partly inhibit Cbfal upregulation by icariin.     

盐酸羟考酮通过JNK/p38MAPK信号通路调控异丙肾上腺素诱导的心肌细胞凋亡的机制

目的探究盐酸羟考酮对异丙肾上腺素(ISO)诱导的心肌细胞凋亡的影响及其作用机制。方法体外培养心肌细胞H9c2,设置对照组、ISO组、盐酸羟考酮1μmol/L组、盐酸羟考酮5μmol/L组、盐酸羟考酮10μmol/L组、ISO+SB203580〔c-Jun氨基末端激酶/p38丝裂原活化蛋白激酶(JNK/p38MAPK)信号通路阻断剂〕组。噻唑蓝(MTT)法检测心肌细胞存活率;流式细胞学法检测各组心肌细胞的凋亡率;Western印迹检测心肌细胞的B淋巴细胞瘤(Bcl)-2、B淋巴细胞瘤-2相关蛋白(Bax)及JNK/p38MAPK信号通路相关蛋白的表达;测定培养细胞上清液乳脱氢酶(LDH)、肌酸激酶(CK)含量。结果与对照组比较,ISO组心肌细胞存活率降低,各给药组心肌细胞存活率明显升高(P<0.05);与对照组比较,ISO组心肌细胞的凋亡率明显升高(P<0.05),而盐酸羟考酮可显著降低细胞凋亡率(P<0.05);与ISO组比较,盐酸羟考酮10μmol/L组LDH、CK水平及Bax、磷酸化(p)-JNK、p-p38MAPK表达水平显著降低(P<0.05),Bcl-2表达水平显著升高(P<0.05);阻断JNK/p38MAPK信号通路可显著增加细胞存活率(P<0.05),降低细胞凋亡率(P<0.05),促进Bcl-2表达(P<0.05),而抑制Bax表达(P<0.05)。结论盐酸羟考酮对ISO诱导的心肌细胞损伤具有抗凋亡作用,其作用机制可能与抑制JNK/p38MAPK信号通路的活化有关。     

鲁斯可皂苷元通过抑制p38MAPK途径及心肌细胞焦亡改善小鼠阿霉素心肌病

目的 观察和探索鲁斯可皂苷元(Rus)对小鼠阿霉素(DOX)心肌病的影响及可能机制,旨在为临床上DOX心脏毒性的预防和治疗提供参考依据.方法 通过单次腹腔注射DOX(15mg/kg)的方式构建急性DOX心肌病小鼠模型,采用随机数表法将32只雄性C57BL/6小鼠(8～10周)随机分为空白对照组(Sham组)、Rus组、...     

Activation of p38 MAPK induced by a multi-cycle ischaemic preconditioning protocol is associated with attenuated p38 MAPK activity during sustained ischaemia and reperfusion

The role of p38 mitogen-activated protein kinase (MAPK) in ischaemic preconditioning remains controversial. Since most previous studies focussed on events only during sustained ischaemia, the aim of this study was to establish the activation pattern of p38 MAPK during a multicycle preconditioning protocol, sustained ischaemia as well as reperfusion and to correlate these events with functional recovery of the isolated perfused rat heart. Isolated perfused rat hearts were preconditioned by 3x5 min global ischaemia followed by 25 min global ischaemia and 30 min reperfusion. Non-preconditioned hearts were subjected to 25 min global ischaemia and 30 min reperfusion. Hearts were freeze-clamped and p38 MAPK activation in tissue lysates was assessed by standard Western blotting techniques, using a dual phospho-p38 MAPK antibody as well as a non-radioactive IP-kinase assay. The results showed that transient dual phosphorylation and activation of p38 MAPK occurs during a 3x5 min preconditioning protocol: the activation was maximal during the first episode, becoming progressively lower during the second and third episodes. p38 MAPK activation was significantly less during both sustained ischaemia and reperfusion in preconditioned hearts, when compared with non-preconditioned hearts. Attenuation of p38 MAPK activity during sustained ischaemia and reperfusion was associated with improved functional recovery. The effect of inhibition of p38 MAPK activation on cardioprotection was further evaluated in adult, isolated cardiomyocytes. Administration of SB 203580 (1-10 microM) before and during the preconditioning protocol, had no effect on cell morphology and viability after 2 h hypoxia, compared to untreated preconditioned cardiomyocytes. When administered to non-preconditioned cells before the onset of 2 h hypoxia, it caused a significant improvement in both morphology and viability. In summary, the results suggest that attenuation of the kinase activity during sustained ischaemia and reperfusion may be an essential element of the preconditioning process.     

黑芥子苷通过p38/JNK MAPK信号通路对阿霉素心脏毒性的保护作用

目的:探讨黑芥子苷对阿霉素诱导的心脏毒性的作用及机制。方法:10周龄雄性C57/BL6小鼠随机分为对照组、黑芥子苷组、阿霉素组和黑芥子苷+阿霉素组。阿霉素组和黑芥子苷+阿霉素组给予单次腹腔注射阿霉素(15 mg/kg),对照组和黑芥子苷组给予单次腹腔注射生理盐水(15 mg/kg),黑芥子苷组和黑芥子苷+阿霉素组小鼠同时用黑芥子苷5 mg/kg灌胃,每2天1次,共3次。7 d后超声心动图检测心脏功能,Western blot检测心肌中凋亡相关蛋白和MAPK信号通路相关蛋白的表达水平。结果:黑芥子苷组与对照组小鼠超声心动图各指标、凋亡相关蛋白表达水平和MAPK相关蛋白表达水平的差异无统计学意义。与对照组相比,阿霉素组小鼠LVEDD、LVESD均明显增大,LVEF和LVFS均明显减小,Bax表达水平、p38和JNK的磷酸化水平明显升高,Bcl-2表达水平明显降低(P均<0.05)。与阿霉素组相比,黑芥子苷+阿霉素组小鼠LVEDD、LVESD均明显减小,LVEF和LVFS均明显增大,Bax表达水平、p38和JNK的磷酸化水平均明显降低,Bcl-2表达水平明显升高(P均<0.05)。结论:黑芥子苷通过p38/JNK MAPK信号通路减少心肌细胞凋亡,减轻阿毒素诱导的心脏毒性。     

周期性机械牵拉诱导A549细胞p38MAPK的表达

目的 探讨p38蛋白激酶(p38 MAPK)是否参与周期性机械牵拉刺激在人肺泡Ⅱ型上皮A549细胞的信号转导过程.方法 实验分对照组(刺激前)、机械牵拉(刺激后)5、15、30、60 min共5组,每组3皿细胞.建立离体的A549细胞机械牵拉模型:以大小为1000 μstrain的牵拉力刺激细胞,在刺激前和刺激后5、15、30、60 min时间点进行观察.结果 A549细胞经机械牵拉刺激后,磷酸化p38蛋白水平增加,以30 min时间点最为明显.随着机械牵拉时间的延长,在60 min时间点磷酸化p38蛋白水平下降至约基线水平.结论 机械牵拉刺激信号可激活A549细胞p38 MAPK,从而引起继发细胞信号转导及功能改变.     

辛伐他汀抑制人外周血单核巨噬细胞脂蛋白相关磷脂酶A2表达

目的 观察辛伐他汀对人外周血单核巨噬细胞脂蛋白相关磷脂酶A2(Lp-PLA2)表达的影响,并探讨其调控机制.方法 分离培养人外周血单核巨噬细胞,实验分为脂多糖(LPS)组、辛伐他汀组和丝裂原活化蛋白激酶(MAPK)干预组.LPS组:分别用不同浓度(0、1、10、102、103和104ng/ml)的LPS与细胞共同孵育6 h,观察不同浓度的辛伐他汀对LPS诱导的Lp-PLA2 mRNA和蛋白表达的影响;并用1μg/ml的LPS与细胞孵育不同时间(0、6、12、24和48 h),观察辛伐他汀作用不同时间对LPS诱导的Lp-PLA2 mRNA和蛋白表达的影响.辛伐他汀组:1 μg/ml的LPS+不同浓度的辛伐他汀(10-2～10-7mmol/L)与单核巨噬细胞共同孵育24 h,1 μg/ml LPS+10-3mmol/L的辛伐他汀与单核巨噬细胞孵育不同时间(0、6、24、24和48 h),观察辛伐他汀对LPS诱导的Lp-PLA2mRNA和蛋白表达及酶活性的影响.MAPK组:分别用10 μmol/L的p38抑制剂SB203580、20 μmol/L的ERK抑制剂U0126和20 μmol/L的JNK抑制剂SP600125预处理30 min后,将单核巨噬细胞与1μg/ml的LPS共同孵育24 h,观察MAPK信号通路在LPS介导的Lp-PLA2表达中的作用.逆转录-多聚酶链反应(RT-PCR)方法 检测Lp-PLA2 mRNA表达,比色法测定酶活性,Western blot方法 检测Lp-PLA2蛋白表达以及p38-MAPK蛋白及磷酸化水平.结果 (1)0.1μg/ml的LPS刺激6 h即可显著增加单核巨噬细胞Lp-PLA2 mRNA和蛋白的表达及其酶活性,并且随LPS浓度的增加和刺激时间的延长,该作用增强.(2)辛伐他汀可以明显抑制LPS诱导的Lp-PLA2的表达增加,并且降低酶活性,该作用呈浓度及时间依赖性.(3)辛伐他汀抑制LPS诱导的p38MAPK蛋白活化,p38MAPK的抑制剂SB203580可以完全阻断LPS介导的Lp-PLA2蛋白表达增加,与辛伐他汀作用相似.而MEK1/2的抑制剂U0126和JNK的抑制剂SP600125对LPS介导的Lp-PLA2蛋白表达的增加没有影响.结论 在培养的人外周血单核巨噬细胞中,辛伐他汀可以明显抑制LPS诱导的Lp-PLA2 mRNA和蛋白表达,降低Lp-PLA2酶活性,该作用至少部分由抑制p38MAPK信号转导通路介导.     

p38MAPK对轻度热应激大鼠脾脏巨噬细胞免疫功能的影响

目的: 探讨p38MAPK在Bip蛋白介导的体外轻度热应激大鼠巨噬细胞功能改变中的信号作用.方法: p38MAPK抑制剂预处理大鼠脾脏巨噬细胞,将细胞置于41℃恒温箱中,使细胞轻度热应激,1 h后恢复到37℃(抑制组),以未应激(对照组)和41℃热应激1 h后60 min巨噬细胞(应激组)为对照,分别检测3组巨噬细胞吞噬、杀伤、趋化功能,同时检测p38MAPK蛋白和Bip蛋白的表达.结果: p38MAPK抑制剂预处理大鼠脾脏巨噬细胞,与应激组比较,轻度热应激后巨噬细胞吞噬、趋化和杀伤活性明显降低(0.17±0.01 vs 0.74±0.03,33.32±3.55 vs 82.07±5.17,24.20%±2.39% vs 60.80%±4.02%,均P<0.01);应激组p38MAPK蛋白表达明显上调,p38MAPK抑制剂预处理后,抑制组p38 MAPK蛋白表达受到抑制,与应激组比较差异有显著性(p38/β-actin: 2.863±0.794 vs 4.752±1.386,P<0.01);Bip蛋白的表达(Bip/β-act in)也因p38MAPK抑制剂预处理而由应激组的1.270±0.535降至抑制组的1.028±1.061( P<0.05).结论: p38MAPK抑制剂可显著抑制轻度热应激大鼠巨噬细胞吞噬、趋化和杀伤功能以及p38MAPK和Bip蛋白的表达.     

Estrogen facilitates neurite extension via apolipoprotein E in cultured adult mouse cortical neurons

Literature review suggests a close relationship between estrogen and apolipoprotein E (ApoE) in the central nervous system. Epidemiology studies show that estrogen replacement therapy (ERT) decreases the morbidity from several chronic neurological diseases. Alleles of ApoE modify the risk for and progression of the same diseases. ApoE levels in the rodent brain vary during the estrous cycle and increase after 17beta-estradiol administration. Both estradiol and ApoE3, the most common isoform of human ApoE, increase the extent of neurite outgrowth in culture. Combined, these observations suggest a common mechanism whereby estrogen may increase ApoE levels to facilitate neurite growth. We tested this hypothesis by characterizing the effects of estradiol and ApoE isoforms on neurite outgrowth in cultured adult mouse cortical neurons. Estradiol increased ApoE levels and neurite outgrowth. ApoE2 increased neurite length more so than ApoE3 in the presence of estradiol. Estradiol had no effect on neurite outgrowth from mice lacking the ApoE gene or when only ApoE4, the isoform of ApoE that is associated with increased risk of neurological disease, was exogenously supplied. Cultures from mice transgenic for human ApoE3 or ApoE4 showed the same isoform-specific effect. Neuronal internalization of recombinant human ApoE3 was greater than ApoE4, and ApoE3 was more effective than ApoE4 in facilitating neuronal uptake of a fatty acid. We conclude that estradiol facilitates neurite growth through an ApoE-dependent mechanism. The effects of ERT on chronic neurological diseases may vary with ApoE genotype. The clinical use of ERT may require ApoE genotyping for optimal efficacy.