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| 1 | 肝纤维化中丹参素对TGFβ_1/Smads/ERK信号通路的影响及其相互关系显示文摘目的探讨肝纤维化过程中转化生长因子β1(transforming growth factorβ,TGFβ1)/Smads/细胞外信号调节激酶(extracellular signal-regulated kinase,ERK)通路的相互作用。方法体外分离培养大鼠肝星状细胞(hepatic stellatecell,HSC),MTT法筛选丹参素最适浓度;以最适浓度丹参素及ERK阻断剂(PD98059)作用于经TGFβ1处理的HSC,CCK-8法检测各组HSC增殖;免疫细胞化学染色法检测各组HSC内α-平滑肌肌动蛋白(α-smooth muscle sctin,α-SMA)及Ⅰ、Ⅲ型胶原表达;RT-PCR检测各组HSC的Smad2、Smad3、Smad7 mRNA表达量;Western blot法检测各组Smad2/3、ERK1/2蛋白磷酸化及Smad7蛋白水平。结果 0.062 5~0.25 mmol/L的丹参素可有效抑制HSC增殖,作为最适处理浓度;PD98059(100μmol/L)可抑制TGFβ1诱导的HSC增殖,丹参素剂量依赖性抑制TGFβ1诱导的HSC增殖(P<0.01);TGFβ1促进细胞内α-SMA及Ⅰ、Ⅲ型胶原表达,PD98059及丹参素降低TGFβ1诱导的α-SMA及Ⅰ、Ⅲ型胶原水平;PD98059可拮抗TGFβ1诱导的Smad2、Smad3、Smad7 mRNA的表达(P<0.05,P<0.01),丹参素下调Smad2、Smad3 mRNA水平,但上调Smad7 mRNA水平(P<0.01);PD98059及丹参素抑制TGFβ1诱导的Smad2/3、ERK1/2蛋白磷酸化(P<0.01),但对TGFβ1诱导的Smad7蛋白表达上调有不同效应(P<0.01)。结论 TGFβ1上调Smad2、Smad3 mRNA表达及蛋白磷酸化,进而诱导HSC增殖、活化及胶原合成,ERK通路可能参与HSC中TGFβ1诱导Smad基因表达及蛋白磷酸化过程。丹参素对TGFβ1/Smad/ERK信号通路具有抑制效应。 | 唐静 戴立里 呙琳琳 武鹏宇 | 2011 | 第三军医大学学报2011，33，11： | 29 |
| 2 | Xihuang Pill(西黄丸) Induces Mesenchymal-Epithelial Transition and Inhibits Loss of Apical-Basal Polarity in Colorectal Cancer Cell through Regulating ZEB1-SCRIB Loop显示文摘Objective:To investigate the antiproliferative and anti-metastasis effect of Xihuang Pill(西黄丸,XP) on human colorectal cancer cell and to explore the molecular mechanism by which it produces the effects.Methods:Highly metastatic human colorectal cancer cell line LoVo was treated with low-,medium-,and highdose XP-containing serum(XP-L,XP-M,XP-H) groups for 48 h,cells intervened with no drug rat serum and PD98059[extracellular signal-regulated kinase(ERK) inhibitor]as negative and positive controls(NC and PC)groups.Cell proliferation assay was made using cell counting kit-8(CCK8).The 8 μm pore-size transwell chamber and 4',6-diamidino-2-phenylindole(DAPI) staining were applied to examine the ability of invasion and migration of the cells.The protein expression of ERK1/2,zinc finger E-box-binding homeobox 1(ZEB1),Scrib and lethal giant larvae homolog 2(Lgl2) was detected by Western blotting while the relative mRNA quantity of E-cadherin,N-cadherin,Occludin and junctional adhesion molecule-1(JAM1) was measured by realtime fluorescent quantitative polymerase chain reaction(RT-qPCR).Results:XP induced a dose-dependent suppression on the proliferation of LoVo cells(P<0.05 or P<0.01),with the inhibition rates varied from 27.30%to31.08%.Transwell assay showed that when preprocessed with PD98059 and XP-containing serum,the number of cells that passed the filter decreased significantly compared with that of NC group(P<0.05 or P<0.01).Moreover,XP inhibited the protein expression of ERK1/2 and ZEB1(P<0.05);and up-regulated the protein expression of Scrib and Lgl2(P<0.05).The mRNA levels of E-cadherin,Occludin and JAM1 of the XP intervened groups and PC group markedly ascended(P<0.05) while that of N-cadherin showed a descending tendency(P>0.05).Conclusion:XP intervention suppressed the ability of proliferation,invasion and migration of the LoVo cells.Regulating ZEB1-SCRIB Loop so as to recover epithelial phenotype and apical junctional complex might be one of the mechanisms by which XP produces the anti-metastasis effect. | 王邈 孟静岩 何俗非 | 2014 | Chinese Journal of Integrative Medicine2014，20，10： | 20 |
| 3 | 人参皂苷Rb1和Rg1对海马神经元的影响显示文摘目的探讨人参皂苷(ginsenoside)Rb1和Rg1(GRb1,GRg1)对海马神经元突起生长及神经保护作用及其机制。方法培养SD新生大鼠海马神经元,分为:正常组、Rb1组、Rg1组、Rb1+API-2(Akt抑制剂)、Rg1+API-2、Rb1+PD98059(MEK抑制剂)和Rg1+PD98059组,培养1 d,用免疫染色观察神经突起的生长。加入Aβ25-35制备海马神经元损伤模型,分为正常组、损伤组(Aβ3组)、Rb1组、Rg1组、Rb1+API-2、Rg1+API-2、Rb1+PD98059和Rg1+PD98059,培养48 h,用Hoechst33258染色观察活细胞与凋亡细胞。用Elisa观察培养上清液里神经营养因子的浓度(nerve growth factor,NGF;brain-derived neurotrophic factor,BDNF;neurotrophin-3,NT-3)。结果 Rb1和Rg1组神经突起生长高于对照组(P<0.05);API-2和PD98059显著抑制了Rb1和Rg1诱导的神经突起生长(P<0.01),API-2的抑制效果强于PD98059;Rg1+API-2组BDNF高于对照组和Rg1组(P<0.05),其余各组间差异无统计学意义(P>0.05);Rg1组NT-3的浓度高于对照组(P<0.05);Rb1+PD98059组的NGF高于Rb1组。Rb1和Rg1组海马神经元的凋亡率显著低于损伤组(P<0.01);PD98059和API-2阻断了Rb1和Rg1对神经元的保护作用(P<0.01);神经营养因子水平各组间差异无统计学意义。结论 Rb1和Rg1促进海马神经元突起生长及抵抗Aβ25-35损伤,促进神经元的存活。其机制与Akt和ERK1/2的信号通路激活有关,与增加神经营养因子的分泌无关。 | 刘娟 裘莹 何晶 文蕾 管晓菲 袁琼兰 | 2011 | 同济大学学报(医学版)2011，32，3： | 19 |
| 4 | Formaldehyde up-regulates TRPV1 through MAPK and PI3K signaling pathways in a rat model of bone cancer pain显示文摘Objective Our previous study showed that tumor tissue-derived formaldehyde at low concentrations plays an important role in bone cancer pain through activating transient receptor potential vanilloid subfamily member 1 (TRPV1). The present study further explored whether this tumor tissue-derived endogenous formaldehyde regulates TRPV1 expression in a rat model of bone cancer pain, and if so, what the possible signal pathways are during the development of this type of pain. Methods A rat model of bone cancer pain was established by injecting living MRMT-1 tumor cells into the tibia. The formaldehyde levels were determined by high performance liquid chromatography, and the expression of TRPV1 was examined with Western blot and RT-PCR. In primary cultured dorsal root ganglion (DRG) neurons, the expression of TRPV1 was assessed after treatment with 100 μmol/L formaldehyde with or without pre-addition of PD98059 [an inhibitor for extracellular signal-regulated kinase], SB203580 (a p38 inhibitor), SP600125 [an inhibitor for c-Jun N-terminal kinase], BIM [a protein kinase C (PKC) inhibitor] or LY294002 [a phosphatidylinositol 3-kinase (PI3K) inhibitor]. Results In the rat model of bone cancer pain, formaldehyde concentration increased in blood plasma, bone marrow and the spinal cord. TRPV1 protein expression was also increased in the DRG. In primary cultured DRG neurons, 100 μmol/L formaldehyde significantly increased the TRPV1 expression level. Pre-incubation with PD98059, SB203580, SP600125 or LY294002, but not BIM, inhibited the formaldehyde-induced increase of TRPV1 expression. Conclusion Formaldehyde at a very low concentration up-regulates TRPV1 expression through mitogen-activated protein kinase and PI3K, but not PKC, signaling pathways. These results further support our previous finding that TRPV1 in peripheral afferents plays a role in bone cancer pain. | Ying Han Yan Li Xlng Xlao Jia Liu Xiang-Ling Meng Feng-Yu Liu Guo-Gang Xing You Wan | 2012 | Neuroscience Bulletin2012，28，2： | 19 |
| 5 | Jagged-1/Notch3 signaling transduction pathway is involved in apelin-13-induced vascular smooth muscle cells proliferation显示文摘apelin/apelin 受体(APJ, apelinangiotensin 像受体 1 ) 系统是一最新 deorphanized G 联合蛋白质的受体系统。是重要规章的因素的 apelin 和 APJ 在心血管的系统被表示。我们的以前的研究显著地表明了那 apelin-13 刺激脉管的光滑的肌肉房间(VSMC ) 增长。在这份报纸,我们的数据建议表明 transduction 小径的 Jagged-1/Notch3 被支持 Cyclin D1 的表示涉及 apelin-13-induced VSMC 增长。结果显示 apelin-13 在集中依赖者和时间依赖者礼貌刺激 VSMC 和 Jagged-1 和 Notch3 的表示的增长。apelin-13 导致的 Jagged-1 和 Notch3 的增加的表示能被细胞外的调整信号的蛋白质 kinase (英皇家空军之阶级最低之兵) 废除封锁。PD98059 (英皇家空军之阶级最低之兵禁止者) 能禁止 apelin-13 导致的 Jagged-1/Notch3 的激活。用小介入 RNA 的 Notch3 的下面规定禁止 Cyclin D1 的表示并且阻止 apelin-13-induced VSMC 增长。在结论, Jagged-1/Notch3 发信号 transduction 小径涉及 apelin-13 导致的 VSMC 增长。 | Lifang Li Lanfang Li Feng Xie Zidong Zhang Yu Guo Guotao Tang Deguan Lv Qixuan Lu Linxi Chen Jian Li | 2013 | Acta Biochimica et Biophysica Sinica2013，45，10： | 18 |
| 6 | Norcantharidin induces apoptosis in HeLa cells through caspase, MAPK, and mitochondrial pathways显示文摘AIM: To investigate the mechanism of norcantharidin (NCTD)-induced HeLa cell apoptosis. METHODS: HeLa cell growth inhibition was measured by MTT method. Apoptosis was detected by Hoechst 33258 staining and agarose gel electrophoresis. Caspase activities were assayed using caspase apoptosis detection kit. Western blot analysis was used to evaluate the level of ICAD, ERK/p-ERK, JNK/p-JNK, and Bcl-X.L/Bax expression. RESULTS: Norcantharidin inhibited HeLa cell growth in a time- and dose-dependent manner. HeLa cells treated with norcantharidin showed typical characteristics of apoptosis including the morphological changes and DNA fragmentation. Caspase family inhibitor (z-VAD-fmk), caspase-8, -9 inhibitor (z-IETD-fmk, Ac-LEHD-CHO, respectively) and caspase-3 inhibitor (z-DEVD-fmk) partially prevent norcantharidin-induced apoptosis, but initiator caspase-1 inhibitor (Ac-YVAD-fmk) did not. The activities of caspase-3, -8, and -9 were up-regulated after norcantharidin treatment. Furthermore, NCTD-induced activation of caspase-3 resulted in the degradation of the inhibitor of caspase-activated DNase (ICAD). Up-regulation of mitochondrial Bax expression and down-regulation of Bcl-xLexpression also participated in the apoptosis induced by NCTD. Although p38 MAPK inhibitor (SB203580) failed to block cell death, ERK MAPK inhibitor (PD98059) and JNK MAPK inhibitor (SP600125) had marked inhibitory effects on norcantharidin-induced apoptosis. Moreover, the phosphorylation of JNK were up-regulated followed by delayed ERK phosphorylation after treatment with NCTD, suggesting that ERK and JNK were both responsible for NCTD-induced apoptosis in HeLa cells and worked at different stages. CONCLUSION: The cytotoxic effect of NCTD on HeLa cells was mainly due to apoptosis. The anti-tumor mechanism of NCTD might involve caspses, mitochondrial, and MAPKs pathways. | Wei-weiAN Xian-fengGONG Min-weiWANG Shin-ichiTASHIRO SatoshiONODERA TakashiIKEJIMA | 2004 | Acta Pharmacologica Sinica2004，25，11： | 15 |
| 7 | Salvianolate Reduces Murine Myocardial Ischemia and Reperfusion Injury via ERK1/2 Signaling Pathways in vivo显示文摘Objective:To analyze the effects of salvianolate on myocardial infarction in a murine in vivo model of ischemia and reperfusion(l/R) injury.Methods:Myocardial l/R injury model was constructed in mice by 30 min of coronary occlusion followed by 24 h of reperfusion and pretreated with salvianolate 30 min before l/R(SAL group).The SAL group was compared with SHAM(no l/R and no salvianolate),l/R(no salvianolate),and ischemia preconditioning(IPC) groups.Furthermore,an ERK1/2 inhibitor PD98059(1 mg/kg),and a phosphatidylinositol-3-kinase(PI3-K) inhibitor,LY294002(7.5 mg/kg),were administered intraperitoneal injection(i.p) for 30 min prior to salvianolate,followed by l/R surgery in LY and PD groups.By using a double staining method,the ratio of the infarct size(IS) to left ventricle(LV) and of risk region(RR) to LV were compared among the groups.Correlations between IS and RR were analyzed.Western-blot was used to detect the extracellular signal-regulated kinase 1/2(ERK1/2) and protein kinase B(AKT) phosphorylation changes.Results:There were no significant differences between RR to LV ratio among the SHAM,l/R,IPC and SAL groups(P>0.05).The SAL and IPC groups had IS of 26.1%± 1.4%and 22.3%±2.9%of RR,respectively,both of which were significantly smaller than the l/R group(38.5%±2.9%of RR,P<0.05,P<0.01,respectively).Moreover,the phosphorylation of ERK1/2 was increased in SAL group(P<0.05),while AKT had no significant change.LY294002 further reduced IS,whereas the protective role of salvianolate could be attenuated by PD98059,which increased the IS.Additionally,the IS was not linearly related to the RR(r=0.23,0.45,0.62,0.17,and 0.52 in the SHAM,l/R,SAL,LY and PD groups,respectively).Conclusion:Salvianolate could reduce myocardial l/R injury in mice in vivo,which involves an ERK1/2 pathway,but not a PI3-K signaling pathway. | QI Jian-yong YU Juan HUANG Dong-hui GUO Li-heng WANG Lei HUANG Xin HUANG Hai-ding ZHOU Miao ZHANG Min-zhou Jiashin Wu | 2017 | Chinese Journal of Integrative Medicine2017，23，1： | 14 |
| 8 | Oxidized low-density lipoprotein activates adipophilin through ERK1/2 signal pathway in RAW264.7 cells显示文摘它被报导了那氧化低密度的脂蛋白(Ox-LDL ) 能增加 adipophilin 的表示。然而,详细机制充分没被理解。这研究的目的是在 adipophilin 表示和细胞内部的类脂化合物微滴累积上调查 Ox-LDL 的机制。一个鼠标像巨噬细胞的房间线, RAW264.7,全部被使用,并且 Ox-LDL 以一种剂量依赖者方式导致了 adipophilin 表示,这被发现。而且, Ox-LDL 导致了 peroxisome 激活 proliferator 的受体 --(PPAR ) 表示和 PPAR 特定的禁止者 T0070907 没废除 Ox-LDL-induced adipophilin 表示,而是特定的收缩筋 GW1929。而且, Ox-LDL 导致了 ERK1/2 的 phosphorylation,并且由 PD98059 的 ERK1/2-specific 抑制压制了 Ox-LDL-induced PPAR 和 adipophilin 表示。结果显示出那 ERK1/2 或 PPAR 特定的抑制减少了细胞内部的类脂化合物微滴的数量。同时, PPAR 特定的收缩筋增加了细胞内部的类脂化合物微滴。这些结果建议 Ox-LDL-induced 经由 ERK1/2 激活在 adipophilin 水平增加是在 RAW264.7 房间导致细胞内部的类脂化合物微滴的更大的数量的机制之一,它显示 adipophilin 涉及动脉粥样硬化患者前进。 | Qingnan Liu Zhibing Dai Zhiqiang Liu Xiaohui Liu Chaoke Tang Zuo Wang Guanghui Yi Lushan Liu Zhisheng Jiang Yongzong Yang Zhonghua Yuan | 2010 | Acta Biochimica et Biophysica Sinica2010，42，9： | 13 |
| 9 | 线粒体ATP敏感钾通道介导缺氧预处理期细胞外信号调节蛋白激酶活化的机制显示文摘目的 探讨线粒体ATP敏感钾通道 (mKATP)与细胞外信号调节蛋白激酶 (ERK1/2 )在缺氧预处理延迟保护机制中的相互关系。 方法 采用SD大鼠心肌细胞培养复制、缺氧 /复氧损伤模型及缺氧预处理模型 ,建立对照组、缺氧 /复氧组、缺氧预处理组、二氮嗪组、5 羟基癸酸 +二氮嗪组、5 羟基癸酸 +缺氧预处理组、二氮嗪 +MGP组、缺氧预处理 +2 巯基丙酰基甘氨酸 (MGP)组、二氮嗪 +PD980 5 9组 ,以细胞存活率等作为反映心肌细胞损伤的指标 ,并于预处理后不同时间点分别测定细胞内活性氧含量及ERK1/2 的活性。 结果 缺氧预处理组及二氮嗪组细胞存活率和细胞内超氧化物歧化酶活性〔(81 9± 11 4 ) %、(13 6± 3 7)U/L ,(79 2± 12 4 ) %、(16 5± 4 6 )U/L〕均显著高于缺氧 /复氧组〔(4 2 2± 7 3) %、(8 8± 2 8)U/L〕 ,缺氧预处理组及二氮嗪组乳酸脱氢酶释放〔(10 1 9± 18 9)U/L、(97 5± 17 7)U/L〕均显著低于缺氧 /复氧组〔(2 5 0 5± 4 3 6 )U/L ,均为P <0 0 1〕。缺氧预处理及二氮嗪均可快速诱导细胞内大量的活性氧生成并激活ERK1/2 ,但这些作用均可被mKATP阻滞剂 5 羟基癸酸及氧自由基清除剂MGP所阻断。二氮嗪的细胞保护作用还可被ERK1/2 阻滞剂PD980 5 9所抵消。 结论 mKATP可通过诱导活性? | 龚开政 张振刚 黄轶峰 卜平 董丰 柳健 | 2004 | 中华老年医学杂志2004，23，9： | 11 |
| 10 | ERK1/2-HNF4α axis is involved in epigallocatechin-3-gallate inhibition of HBV replication显示文摘Epigallocatechin gallate(EGCG),a major polyphenol in green tea,exhibits diverse biological activities.Previous studies show that EGCG could effectively suppress HBV gene expression and replication,but the role of EGCG in HBV replication and its underlying mechanisms,especially the signaling pathways involved,remain unclear.In this study we investigated the mechanisms underlying EGCG inhibition on HBV replication with a focus on the signaling pathways.We showed that EGCG(12.5?50μM)dose-dependently inhibited HBV gene expression and replication in HepG2.2.15 cells.Similar results were observed in HBV mice receiving EGCG(25 mg·kg^?1·d^?1,ip)for 5 days.In HepG2.2.15 cells,we showed that EGCG(12.5?50μM)significantly activate ERK1/2 MAPK signaling,slightly activate p38 MAPK and JAK2/STAT3 signaling,while had no significant effect on the activation of JNK MAPK,PI3K/AKT/mTOR and NF-κB signaling.By using specific inhibitors of these signaling pathways,we demonstrated that ERK1/2 signaling pathway,but not other signaling pathways,was involved in EGCG-mediated inhibition of HBV transcription and replication.Furthermore,we showed that EGCG treatment dose-dependently decreased the expression of hepatocyte nuclear factor 4α(HNF4α)both at the mRNA and protein levels,which could be reversed by pretreatment with the ERK1/2 inhibitor PD98059(20μM).Moreover,we revealed that EGCG treatment dose-dependently inhibited the activity of HBV core promoter and the following HBV replication.In summary,our results demonstrate that EGCG inhibits HBV gene expression and replication,which involves ERK1/2-mediated downregulation of HNF4α.These data reveal a novel mechanism for EGCG to inhibit HBV gene expression and replication. | Zi-yu Wang Yu-qi Li Zhi-wei Guo Xing-hao Zhou Mu-dan Lu Tong-chun Xue Bo Gao | 2020 | Acta Pharmacologica Sinica2020，41，2： | 11 |
| 11 | PD98059对人骨髓间质干细胞分化为成骨细胞的影响显示文摘目的 :探讨胞外信号调节激酶 (ERK)信号传导途径对骨髓间质干细胞 (MSC)分化为成骨细胞的影响。方法 :采用Ficoll-Paque淋巴细胞分离液分离成人MSC ,体外扩增 ,应用地塞米松、β -甘油磷酸钠、vitaminC定向诱导MSC分化为成骨细胞。在成骨诱导液中加入不同剂量的PD980 59,观察其对成骨细胞形成的影响。结果 :MSC体外扩增 1 5代可获得 (3 - 4 )× 1 0 1 2 个细胞。在成骨诱导液作用下 ,MSC可在体外定向分化为成骨细胞。不同剂量的PD980 59均可抑制MSC分化为成骨细胞 ,并有剂量依赖关系 ;同时促使部分细胞转化为脂肪细胞。结论 | 张丽蓉 项鹏 夏文杰 陈振光 张秀明 李艳 李树浓 | 2002 | 中国病理生理杂志2002，18，8： | 10 |
| 12 | MAP kinase specifically mediates the ABA-induced H_2O_2 generation in guard cells of Vicia faba L.显示文摘Mitogen-activated protein (MAP) kinase is involved in ABA- or H2O2-signaling, and H2O2 acts as inter-mediate in the downstream of ABA signal transduction pathway, which has recently emerged as a secondary mes-senger of ABA signaling. Using an epidermal strip bioassay and laser scanning confocal microscope, we provided the first evidence that MAP kinase plays an important role in H2O2 signal initial, amplification and specific targeting in response to stimuli in guard cells. ABA- or H2O2-induced Vicia faba stomatal closure was inhibited or reversed by the specific inhibitor PD98059 of MEK1/2; the guard cells were pre-incubated or -microinjected by 10 mmol·L-1 PD98059, ABA could not enhance the fluorescence intensity of H2O2 probe dichlorofluorescein (DCF). Meanwhile, after ABA induced the H2O2 accumulation in guard cells, the exogenous or intracellular PD98059 could reduce the DCF fluorescence intensity. Most interestingly, on the contrary to ABA, the DCF fluorescence intensity of guard cells treated by 100 mmol·L-1 salicylic acid (SA) was not down-regulated by PD98059, yet PD98059 did not regulate the stomatal move-ment being induced by light, dark or salicylic acid. These results suggest that MEK1/2 could mediate stomatal closure by abolishing the ABA-induced H2O2 generation/accumula- tion in the specific manner. | JIANG Jing1,2, AN Guoyong1, WANG Pengcheng1, WANG Pengtao1, HAN Jinfeng2, JIA Yanbin1 & SONG Chunpeng1 1. College of Life Sciences, Henan University, Kaifeng 475001, China 2. College of Agriculture Science, Henan Agriculture University, Zheng-zhou 450001, China Correspondence should be addressed to Song Chunpeng (e-mail: songcp @henu. edu.cn) | 2003 | Chinese Science Bulletin2003，48，18： | 10 |
| 13 | 不同水平干预对心肌细胞ERK核转位及c-fos表达的影响显示文摘目的观察血管紧张素(Ang)Ⅱ作用心肌细胞后细胞外信号调节激酶(ERK)活化、核转位情况、c-fos基因表达及在受体和信号ERK水平进行干预的影响.方法采用原代培养的心肌细胞,分别从细胞膜受体和细胞内信号ERK层面进行干预,用细胞免疫化学观察磷酸化ERK入核过程,RT-PCR测定c-fos基因表达量.结果 AngⅡ刺激心肌细胞可见胞核内出现磷酸化ERK染色,Valsartan(10-5 mol/L)、PD98059(5×10-5mol/L)可阻断AngⅡ引起的ERK活化、入核过程,而CGP42112A(10-5mol/L )则无阻断作用;AngⅡ可促进心肌细胞c-fos mRNA表达,在30~60 min达高峰,Valsartan 、PD98059均可抑制该作用,CGP42112A对该作用无明显影响.结论 AngⅡ可磷酸化胞质ERK,并使其发生转位入核,ERK的跨核转运可能是AngⅡ诱导c-fos原癌基因表达的前提. | 李爱萍 陈光辉 李天德 王友桂 李志敏 胡大一 | 2005 | 中华内科杂志2005，44，2： | 10 |
| 14 | 健骨颗粒促进成骨细胞增殖的分子机制显示文摘背景:ERK是依赖于Ras途径激活的一个蛋白激酶,在成骨细胞增殖和分化过程中发挥重要作用。而PD98059是MEK特异性抑制剂,它可通过抑制MEK的活性来抑制ERK的磷酸化,从而起到阻断ERK信号通路的作用。目前有关ERK在大鼠成骨细胞增殖和分化过程中的作用研究甚少。ERK在健骨颗粒促进大鼠成骨细胞增殖和分化过程中调控的作用更未被阐明。目的:观察ERK信号转导通路在健骨颗粒促成骨细胞增殖和分化过程中的作用。方法:取第3代SD大鼠头盖骨成骨细胞,空白组加入生理盐水血清;中药组加入最佳浓度的健骨颗粒含药血清;阻滞剂组添加PD98059阻断剂,中药加阻断剂组添加PD98059阻断剂与健骨颗粒含药血清。用MTT法测定细胞的增殖能力,比色法测碱性磷酸酶、羟脯氨酸水平。收集细胞实时荧光定量PCR-SYBRGREEN法检测Cbfa1、Ⅰ型胶原、OSXmRNA的表达,Westrenblot法检测成骨细胞ERK的表达情况。结果与结论:添加PD98059阻断剂后,阻滞剂组和中药加阻滞剂组中ERK的表达显著低于空白组和中药组。阻断剂组的成骨细胞内碱性磷酸酶、羟脯氨酸的表达以及Cbfa1、Ⅰ型胶原、OSXmRNA表达显著低于空白组和中药组。ERK在健骨颗粒促进大鼠成骨细胞增殖和分化过程中发挥重要作用,ERK信号通路可能是健骨颗粒促进成骨细胞增殖和分化的主要途径。 | 林煜 卢天祥 吴银生 黄云梅 林燕萍 | 2013 | 中国组织工程研究2013，17，15： | 10 |
| 15 | 高糖通过ERK_(1/2)途径调节足细胞产生明胶酶B显示文摘目的 探讨高糖持续刺激对足细胞培养上清液明胶酶活性、Ⅳ型胶原的影响及可能的信号途径。方法 小鼠足细胞系分为正常糖组、高糖组和甘露醇高渗对照组。应用明胶酶谱法观察三组细胞培养液上清明胶酶活性的动态变化,Western印迹分析法检测细胞培养液上清中Ⅳ型胶原α5链蛋白水平及足细胞ERK信号途径活化的变化。RT-PCR方法检测MMP-9 mRNA的表达。结果正常糖组和甘露醇高渗对照组培养液上清MMP-2和MMP-9活性在10天实验时间内无明显变化。高糖组细胞培养液上清MMP-2的活性没有明显变化;MMP-9活性于第2天开始升高,第3天达高峰为正常糖组的144.2±18.7%(P=0.006),第5天下降,第7天回到基础水平为正常糖组的76.6%±16.4%(P=0.218),直至第10天。足细胞培养上清中有较高基础水平的Ⅳ型胶原α5链蛋白;高糖组细胞培养上清Ⅳ型胶原α5链蛋白表达第2天开始下降,第3天达最低水平41.9%±25.5%(P=0.047),第5天回升到基础水平持续至第7天。上清MMP-9的活性与Ⅳ型胶原α5链蛋白的表达量呈负相关(r=-0.577,P=0.006)。正常糖组和甘露醇高渗对照组细胞培养上清Ⅳ型胶原α5链蛋白无变化。高糖刺激足细胞2天MMP-9 mRNA水平增加为正常糖组的199.8%±40.2%(P=0.003),刺激5天时为正常糖组的90.9±8.8%(P=0.411)。高糖刺激足细胞30 min可以活化ERK1/2,6 h达高峰,持续至24 h,48 h降至基础水平;在足细胞上未能检测到p38和JNK活化。ERK活化特异抑制剂PD98059预处理细胞后,能阻断高糖引起的MMP-9的活性和MMP-9 mRNA增加及Ⅳ型胶原α5链蛋白的下降。结论 ERK信号传导途径介导了高糖刺激足细胞MMP-9生成及相应的Ⅳ型胶原α5链蛋白动态反向改变。 | 白亚玲 黄海长 李惊子 赵玉庸 王海燕 | 2005 | 中华医学杂志2005，85，21： | 9 |
| 16 | 白头翁汤通过抑制TLR4-ERK1/2信号通路缓解LPS诱导的微血管内皮细胞炎性反应显示文摘近年来,中药复方抗炎机制的研究不断深入,白头翁汤复方(Pulsatilla decoction,PD)作为经典的清热解毒中药方剂常用于预防和治疗细菌性腹泻。然而其抗炎机制和靶细胞研究仍然不明确,本课题以大鼠肠黏膜微血管内皮细胞(RIMVECs)为模式细胞,旨在研究白头翁汤对LPS诱导的RIMVECs炎症反应的调控作用。利用LPS刺激RIMVECs,通过荧光定量PCR(RT-PCR)、蛋白免疫印迹(Western blot)的方法检测白头翁汤对LPS刺激后RIMVECs的炎性信号通路TLR4-ERK1/2信号通路关键蛋白TLR4、TRAF6、ERK的mRNA及蛋白表达。进一步采用酶联免疫吸附方法(ELISA)检测白头翁汤对LPS刺激后的炎性因子IL-6、IL-8、IL^(-1)β、TNF-α的分泌情况。结果表明:白头翁汤可以显著降低LPS诱导的TLR4、TRAF6、ERK的mRNA水平及蛋白表达并降低了LPS诱导的细胞下游炎性因子的分泌。白头翁汤通过抑制TLR4-ERK1/2信号通路缓解LPS所诱导的RIMVECs炎性反应,发挥抗炎作用。 | 贺尚文 王月明 张慧 侯思鲁 刘晓晔 董虹 | 2021 | 畜牧兽医学报2021，52，8： | 9 |
| 17 | TRAIL-induced apoptosis of hepatocellular carcinoma cells is augmented by targeted therapies显示文摘AIM:To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors,in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand(TRAIL),on overcoming TRAIL resistance in hepatocellular carcinoma(HCC)and to study the efficacy of agonistic TRAIL antibodies,as well as the commitment of antiapoptotic BCL-2 proteins, in TRAIL-induced apoptosis. METHODS:Surface expression of TRAIL receptors (TRAIL-R1-4)and expression levels of the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL were analyzed by flow cytometry and Western blotting,respectively. Knock-down of MCL-1 and BCL-xL was performed by transfecting specific small interfering RNAs.HCC cellswere treated with kinase inhibitors and chemotherapeutic drugs.Apoptosis induction and cell viability were analyzed via flow cytometry and 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS:TRAIL-R1 and-R2 were profoundly expressed on the HCC cell lines Huh7 and Hep-G2. However,treatment of Huh7 and Hep-G2 with TRAIL and agonistic antibodies only induced minor apoptosis rates.Apoptosis resistance towards TRAIL could be considerably reduced by adding the chemotherapeutic drugs 5-fluorouracil and doxorubicin as well as the kinase inhibitors LY294002[inhibition of phosphoinositol- 3-kinase(PI3K)],AG1478(epidermal growth factor receptor kinase),PD98059(MEK1),rapamycin(mam- malian target of rapamycin)and the multi-kinase inhibitor Sorafenib.Furthermore,the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL play a major role in TRAIL resistance:knock-down by RNA interference increased TRAIL-induced apoptosis of HCC cells.Additionally, knock-down of MCL-1 and BCL-xL led to a significant sensitization of HCC cells towards inhibition of both c-Jun N-terminal kinase and PI3K.CONCLUSION:Our data identify the blockage of survival kinases,combination with chemotherapeutic drugs and targeting of antiapoptotic BCL-2 proteins as promising ways to overcome TRAIL resistance in HCC. | Bruno Christian Koehler Toni Urbanik Binje Vick Regina Johanna Boger Steffen Heeger Peter R Galle Marcus Schuchmann Henning Schulze-Bergkamen | 2009 | World Journal of Gastroenterology2009，15，47： | 9 |
| 18 | Ginsenoside Rg1 protects against neurodegeneration by inducing neurite outgrowth in cultured hippocampal neurons显示文摘Ginsenoside Rg1(Rg1) has anti-aging and anti-neurodegenerative effects. However, the mechanisms underlying these actions remain unclear. The aim of the present study was to determine whether Rg1 affects hippocampal survival and neurite outgrowth in vitro after exposure to amyloid-beta peptide fragment 25–35(Aβ_(25–35)), and to explore whether the extracellular signal-regulated kinase(ERK) and Akt signaling pathways are involved in these biological processes. We cultured hippocampal neurons from newborn rats for 24 hours, then added Rg1 to the medium for another 24 hours, with or without pharmacological inhibitors of the mitogen-activated protein kinase(MAPK) family or Akt signaling pathways for a further 24 hours. We then immunostained the neurons for growth associated protein-43, and measured neurite length. In a separate experiment, we exposed cultured hippocampal neurons to Aβ_(25–35) for 30 minutes, before adding Rg1 for 48 hours, with or without Akt or MAPK inhibitors, and assessed neuronal survival using Hoechst 33258 staining, and phosphorylation of ERK1/2 and Akt by western blot analysis. Rg1 induced neurite outgrowth, and this effect was blocked by API-2(Akt inhibitor) and PD98059(MAPK/ERK kinase inhibitor), but not by SP600125 or SB203580(inhibitors of c-Jun N-terminal kinase and p38 MAPK, respectively). Consistent with this effect, Rg1 upregulated the phosphorylation of Akt and ERK1/2; these effects were reversed by API-2 and PD98059, respectively. In addition, Rg1 significantly reversed Aβ_(25–35)-induced apoptosis; this effect was blocked by API-2 and PD98059, but not by SP600125 or SB203580. Finally, Rg1 significantly reversed the Aβ_(25–35)-induced decrease in Akt and ERK1/2 phosphorylation, but API-2 prevented this reversal. Our results indicate that Rg1 enhances neurite outgrowth and protects against Aβ_(25–35)-induced damage, and that its mechanism may involve the activation of Akt and ERK1/2 signaling. | Liang Huang Li-feng Liu Juan Liu Ling Dou Ge-ying Wang Xiao-qing Liu Qiong-lan Yuan | 2016 | Neural Regeneration Research2016，11，2： | 9 |
| 19 | PD98059抑制MAPK/ERK信号通路对胃癌细胞生物学功能的影响显示文摘目的:研究MAPK/ERK信号通路中关键信号分子MEK和ERK在胃癌SGC-7901细胞中的表达及PD98059抑制MAPK/ERK通路对胃癌细胞生物学功能的影响。方法:体外培养胃癌细胞株SGC-7901,不同浓度(0、25、50、100、200、300和400 mmol/L)PD98059处理24 h后CCK-8法检测细胞增殖率变化;再用0、25、50和100μmol/L PD98059处理24 h后采用实时荧光定量PCR(qPCR)检测MEK和ERK m RNA的表达量;Western blot检测MEK和ERK蛋白的表达;流式细胞术检测细胞周期和凋亡变化。同时设正常胃黏膜上皮GES-1细胞为对照。结果:与正常胃黏膜上皮GES-1细胞相比,胃癌SGC-7901细胞中MEK和ERK mRNA的表达升高,差异具有统计学意义(P<0.05);p-MEK、p-ERK蛋白的表达亦显著升高,差异具有统计学意义(P<0.05)。0~200μmol/L PD98059处理SGC-7901细胞后,细胞增殖率随着抑制剂浓度的升高而降低(P<0.05)。当PD98059浓度处于200~400μmol/L时抑制作用逐渐趋于平稳。0~100μmol/L PD98059作用后MEK、ERK m RNA的表达量低于对照组(P<0.05),随着PD98059浓度升高,ERK mRNA表达量逐渐降低(P<0.05)。Western blot检测结果显示50和100μmol/L PD98059作用后p-MEK1/2、p-ERK1/2蛋白表达降低(P<0.05)。且抑制剂PD98059使胃癌SGC-7901细胞发生G0/G1期阻滞,可诱导细胞凋亡。结论:MAPK/ERK信号通路在胃癌细胞中激活,PD98059通过抑制MAPK/ERK信号通路的活性可影响胃癌细胞的生物学功能。 | 刘梦琪 张文文 陈晓伟 沈孝兵 | 2019 | 癌变.畸变.突变2019，31，1： | 7 |
| 20 | PD98059对肝癌细胞Ras-MAPK信号转导的作用显示文摘目的:探讨PD98059对肝癌细胞信号转导的作用及其作用机制。方法:将PD98059加入肝癌细胞系SMMC-7721细胞中,通过细胞活力、DNA合成、MAPK活性和MAPK含量的变化,观察PD98059对肝癌细胞信号转导的作用。结果:PD98059可明显抑制SMMC-7721细胞活力、DNA合成、MAPK活性和MAPK含量(与对照组比较,P<0.05),其抑制作用具有浓度依赖性。结论:PD98059可通过阻断Ras-MAPK信号通路而发挥其抑制作用;Ras-MAPK通路极有可能成为肝癌治疗的新靶点。 | 宋霆婷 姜玉华 李妙玉 王瑾 | 2005 | 实用医学杂志2005，21，5： | 7 |
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