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eEF2K沉默联合丹参酮ⅡA磺酸钠协同抑制人肺腺癌细胞系A549增殖
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作者 王布 袁胜芳 +4 位作者 张长洪 苑程 黄攀登 张志华 赵建清 《基础医学与临床》 2022年第1期106-113,共8页
目的探讨真核延伸因子2激酶(eEF2K)基因转染及丹参酮ⅡA磺酸钠(STS)对肺腺癌细胞系A549增殖、侵袭和迁移的影响及其机制。方法预实验筛选STS最佳作用浓度。将A549细胞分为siRNA-NC组(转染siRNA-NC)、siRNA-eEF2K组(转染siRNA-eEF2K)、si... 目的探讨真核延伸因子2激酶(eEF2K)基因转染及丹参酮ⅡA磺酸钠(STS)对肺腺癌细胞系A549增殖、侵袭和迁移的影响及其机制。方法预实验筛选STS最佳作用浓度。将A549细胞分为siRNA-NC组(转染siRNA-NC)、siRNA-eEF2K组(转染siRNA-eEF2K)、siRNA-NC+STS组(转染siRNA-NC+10μg/mL STS)和siRNA-eEF2K+STS组(转染siRNA-eEF2K+10μg/mL STS)。CCK-8法、克隆形成实验、Transwell小室法、划痕实验和流式细胞测量术检测细胞存活率、克隆形成率、穿膜细胞数、迁移率和凋亡率;免疫印迹法(Western blot)检测蛋白激酶B(AKT)、磷酸化(p)-AKT、Ki67、基质金属蛋白酶2(MMP-2)和B淋巴细胞瘤-2基因(Bcl-2)蛋白表达。结果与siRNA-NC组比较,siRNA-eEF2K组、siRNA-NC+STS组和siRNA-eEF2K+STS组细胞存活率、克隆形成率、穿膜细胞数、迁移率和p-AKT、Ki67、MMP-2、Bcl-2蛋白均明显降低,细胞凋亡率明显升高(P<0.05),且siRNA-eEF2K+STS组中上述指标变化幅度最大。结论eEF2K沉默联合STS可协同抑制A549细胞增殖,其作用机制可能与抑制p-AKT、Ki67、MMP-2、Bcl-2蛋白表达有关。 展开更多
关键词 肺腺癌 真核延伸因子激酶-2 丹参酮ⅡA磺酸钠 增殖 侵袭
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早期糖尿病视网膜病变中eEF2K活性变化的实验观察 被引量:1
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作者 廖怿 何卉 +3 位作者 张兆强 孟菊峰 叶立军 张越华 《临床眼科杂志》 2019年第1期84-87,共4页
目的观察早期糖尿病大鼠视网膜中真核生物延伸因子2激酶(e EF2K)的变化,探讨e EF2K活性变化在早期糖尿病视网膜病变(DR)中的意义。方法建立SD大鼠链脲佐菌素(STZ)糖尿病高血糖模型,造模成功后,设立糖尿病大鼠(DM)组和正常对照(NC)组。qR... 目的观察早期糖尿病大鼠视网膜中真核生物延伸因子2激酶(e EF2K)的变化,探讨e EF2K活性变化在早期糖尿病视网膜病变(DR)中的意义。方法建立SD大鼠链脲佐菌素(STZ)糖尿病高血糖模型,造模成功后,设立糖尿病大鼠(DM)组和正常对照(NC)组。qRT-PCR检测DM组和NC组4周和8周时大鼠神经视网膜中e EF2K的表达情况。免疫荧光法观察定位神经视网膜中e EF2K激活标志物-磷酸化真核生物延伸因子2(p-eEF2)和Müller细胞活化标志物胶质纤维酸性蛋白(GFAP)表达情况。结果 4周和8周时DM组大鼠神经视网膜中e EF2K的表达水平与NC组相比无明显变化。8周时DM组大鼠神经视网膜各层均出现e EF2K激活表现,即p-eEF2表达增强。神经节细胞层出现细胞凋亡样改变,凋亡样神经节细胞中e EF2的磷酸化水平增强最为明显。神经视网膜中Müller细胞活化,GFAP蛋白表达增强。结论 STZ诱导糖尿病大鼠早期视网膜病变中神经视网膜内e EF2K激活,在凋亡样神经节细胞中e EF2K活性上升最为显著。 展开更多
关键词 糖尿病视网膜病变 真核生物延伸因子2激酶 神经节细胞 凋亡 胶质纤维酸性蛋白
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Discovery of a novel eEF2K inhibitor (BL-EKI03) that induces ER stress, autophagy and apoptosis in breast cancer
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《中国药理学通报》 CAS CSCD 北大核心 2015年第B11期231-232,共2页
Aim Recent evidence has revealed that Eukaryotic elongation factor-2 kinase (eEF2K) activity may confer cancer cell adaptation to metabolic stress, and high expression of eEF2K is found in several types of cancer. T... Aim Recent evidence has revealed that Eukaryotic elongation factor-2 kinase (eEF2K) activity may confer cancer cell adaptation to metabolic stress, and high expression of eEF2K is found in several types of cancer. Therefore, eEF2K may contribute to carcinogenesis and represent a promising therapeutic target; however, inhibi- tion of eEF2K for cancer drug discovery still remains in its infancy. This study aimed at developing a series of eEF2K inhibitor as candidate anti-tumor drugs in breast cancer and illustrating the possible mechanisms of its anti- tumor activity in vitro and in vivo. Methods In silico screening, structure modifications, MTT assay and molecular dynamics (MD) simulations were applied for the discovery of the novel eEF2K inhibitor (BL-EKI03). Observa- tions of cell morphology were executed through several methods including ER-traeker, MDC and Hoeehst 33258 staining and GFP-LC3 transfeetion. Flow eytometrie analyses of MDC and Annexin V/PI were used for quantifica- tion of autophagy and apoptosis ratio. Western blot and ITRAQ analysis were used to explore the detailed mecha- nisms of BL-EKI03-induced ER stress, autophagie death and apoptosis in breast cancer cells. Furthermore, an in vivo xenograft mouse model was established for validating the anti-tumor efficacy of BL-EKI03. Results Firstly, a novel eEF2K inhibitor (BL-EKI03) with a good affinity for eEF2K was eventually discovered after computational screening and synthesis of a series of candidate compounds targeting eEF2K. Subsequently, our results demonstra- ted that BL-EKI03 has remarkable anti-proliferative activities and induces endoplasmie retieulum (ER) stress, au- tophagy and apoptosis in MCF-7 and MDA-MB-436 cells. More importantly, the mechanism for BL-EKI03-indueed autophagie death involves eEF2K-mediated AMPK-mTOR-ULK complex pathways. The proteomies analyses and ex-perimental validation revealed that the BL-EKI03-induced mechanism was also involved BIRC6, BNIP1, SNAP29 and Bif-1, which might be regulated by eEF2K. Moreover, BL-EKI03 exerted its anti-tumor activities without re- markable toxicity, and it also induced autophagy and apoptosis by targeting eEF2K in fifo. Conclusion In this study, a novel eEF2K inhibitor (BL-EKI03) was discovered with remarkable anti-proliferative activities and in- duced endoplasmic reticulum (ER) stress, autophagy and apoptosis of breast cancer in vitro and in fifo. These findings highlight a new small-molecule eEF2K inhibitor (BL-EKI03) that has the potential to impact future breast cancer therapy. 展开更多
关键词 eukaryotic elongation factor-2 kinase (eEF2K)lure (ER) stress AUTOPHAGY APOPTOSIS Breast cancer. eEF2K INHIBITOR (BL-EKI03) endoplasmic reticu-
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真核延长因子Ⅱ激酶在肿瘤细胞中的作用 被引量:2
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作者 宋洪美 马建华 +3 位作者 祝鸿程 孙新臣 何田丽 马建新 《医学综述》 2016年第12期2342-2345,共4页
真核延长因子Ⅱ激酶(eE F2K)是一个在钙调蛋白通路中结构和功能上比较独特的蛋白激酶。eE F2K可以在蛋白质合成、细胞周期及在肿瘤细胞中诱导自噬和凋亡,且在蛋白质延伸过程中起一个关键作用。其下游基因真核延长因子Ⅱ(eE F2)属于GTP... 真核延长因子Ⅱ激酶(eE F2K)是一个在钙调蛋白通路中结构和功能上比较独特的蛋白激酶。eE F2K可以在蛋白质合成、细胞周期及在肿瘤细胞中诱导自噬和凋亡,且在蛋白质延伸过程中起一个关键作用。其下游基因真核延长因子Ⅱ(eE F2)属于GTP家族成员是蛋白质合成所必需的,eE F2K磷酸化eE F2,从而抑制eE F2的活性阻止蛋白质的正常合成。近年来,在脑胶质瘤、乳腺癌等多种肿瘤中报道eE F2K表达上调,促进肿瘤的发生、发展。因此,进一步探讨eE F2K在肿瘤细胞中的潜在分子机制,将有望成为肿瘤治疗中新的生物指标和药物靶点。 展开更多
关键词 真核延长因子Ⅱ激酶 真核延长因子Ⅱ 肿瘤
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Therapeutic Effect and Mechanism of New Maixian Powder on DSS-induced UC Rats 被引量:1
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作者 Minjun FU Rongzhen SHI +2 位作者 Jianjun SHEN Meixia YANG Hongbin ZHENG 《Medicinal Plant》 CAS 2018年第3期58-61,共4页
[Objectives] To study the therapeutic effect and mechanism of New Maixian Powder on ulcerative colitis( UC) rats through observing its regulatory effect on the protein kinase R-like endoplasmic reticulum kinase( PERK)... [Objectives] To study the therapeutic effect and mechanism of New Maixian Powder on ulcerative colitis( UC) rats through observing its regulatory effect on the protein kinase R-like endoplasmic reticulum kinase( PERK)/eukaryotic translation initiation factor-2α( e IF-2α)/nuclear transcription factor-kappa B( NF-κB) signaling pathway. [Methods]First,60 SD rats were randomly divided into normal group,model group,mesalazine group,and New Maixian Powder low,medium and high dose groups,10 rats each group. Then,dextran sulfate sodium( DSS) was used to induce UC rats. The mesalazine group was given 0. 42 g/( kg·d) of mesalazine sustained-release granule suspension,New Maixian Powder low,medium and high dose groups were given 1. 5,3,and 6 g/( kg·d) of New Maixian Powder suspension,respectively,and other groups were given an equal volume of physiological saline,continuous intragastric administration for 14 d. Next,the disease activity index( DAI) of UC rats was evaluated; the expression of NF-κB in serum was measured by enzyme-linked immunosorbent assay( ELISA); the expression of PERK and e IF-2α protein and m RNA in colon tissue was detected by Western blot and real-time quantitative polymerase chain reaction( RT q-PCR). [Results] Compared with the normal group,the DAI score and serum NF-κB level in the model group were significantly higher( P < 0. 05),and PERK and e IF-2α protein and m RNA levels in the colon tissue were increased( P < 0. 05); compared with the model group,the DAI score decreased and serum NF-κB level declined in the New Maixian Powder group,and the expression of PERK and e IF-2α protein and m RNA in New Maixian Powder medium dose and high dose groups declined( P < 0. 05). [Conclusions]New Maixian Powder has good therapeutic effect on UC rats,and its mechanism may be connected with the inhibition of the activation of PERK/e IF-2α/NF-κB signaling pathway. 展开更多
关键词 New Maixian Powder Ulcerative colitis(UC) Protein kinase R-like endoplasmic reticulum kinase(PERK) eukaryotic translation initiation factor-2α(eIF-2α) Nuclear transcription factor-kappa B(NF-κB)
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eEF2K与肿瘤 被引量:2
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作者 刘启梁 《生命的化学》 CAS CSCD 2016年第5期633-638,共6页
真核延伸因子激酶-2(eukaryotic elongation factor 2 kinase,e EF2K)属于特殊的蛋白激酶——α-激酶小家族,并且是该家族中唯一的Ca^(2+)/Ca M依赖性蛋白激酶。e EF2K催化真核延伸因子-2(eukaryotic elongation factor 2,e EF2)的Thr5... 真核延伸因子激酶-2(eukaryotic elongation factor 2 kinase,e EF2K)属于特殊的蛋白激酶——α-激酶小家族,并且是该家族中唯一的Ca^(2+)/Ca M依赖性蛋白激酶。e EF2K催化真核延伸因子-2(eukaryotic elongation factor 2,e EF2)的Thr56位点发生磷酸化并导致其失活,从而抑制肽链延伸过程。除了受Ca^(2+)/Ca M调控,e EF2K还受到营养、能量相关信号分子如AMPK、m TORC1等的调控。近年来研究表明,e EF2K在多种肿瘤组织及细胞中高表达,并参与肿瘤生长、细胞周期、自噬、凋亡、血管新生、侵袭转移等过程的调控。因此e EF2K可能是潜在的肿瘤治疗靶点。本文就e EF2K的结构、调控,以及与肿瘤的恶性进程、治疗及预后等关系进行综述。 展开更多
关键词 真核延伸因子激酶-2 肿瘤 自噬 肿瘤治疗
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真核延伸因子2激酶与肿瘤 被引量:4
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作者 王根柱 戚欣 李静 《药学学报》 CAS CSCD 北大核心 2015年第7期808-813,共6页
真核延伸因子2激酶(e EF2K)是一种Ca2+/Ca M依赖性蛋白激酶,e EF2是其已知的唯一底物。e EF2K催化e EF2的Thr56位点发生磷酸化,导致降低e EF2与核糖体的结合能力进而抑制肽链延伸。现已发现,e EF2K在多种肿瘤细胞中高表达或高度活化,参... 真核延伸因子2激酶(e EF2K)是一种Ca2+/Ca M依赖性蛋白激酶,e EF2是其已知的唯一底物。e EF2K催化e EF2的Thr56位点发生磷酸化,导致降低e EF2与核糖体的结合能力进而抑制肽链延伸。现已发现,e EF2K在多种肿瘤细胞中高表达或高度活化,参与肿瘤进程的调控,因此e EF2K可能是一个潜在的肿瘤治疗靶点。本文就e EF2K的结构、功能、与肿瘤的关系及其抑制剂的研究进展进行综述。 展开更多
关键词 真核延长因子2激酶 肿瘤 抑制剂
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癌症治疗的新靶点——eEF2K 被引量:4
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作者 肖婷 刘锐 王明伟 《生命的化学》 CAS CSCD 2016年第3期397-403,共7页
真核生物延伸因子2激酶(eukaryotic elongation factor 2 kinase,eEF2K)由人类基因组eEF2K基因编码,归属于"α-激酶"非典型蛋白激酶小家族。eEF2K的活性要依赖于钙离子和钙调蛋白。研究显示,eEF2K在一定的代谢压力下能磷酸化... 真核生物延伸因子2激酶(eukaryotic elongation factor 2 kinase,eEF2K)由人类基因组eEF2K基因编码,归属于"α-激酶"非典型蛋白激酶小家族。eEF2K的活性要依赖于钙离子和钙调蛋白。研究显示,eEF2K在一定的代谢压力下能磷酸化并抑制真核生物延伸因子2(eukaryotic elongation factor 2,eEF2),进而抑制蛋白质合成过程中多肽链的延伸,使细胞中能量和氨基酸的消耗减少,帮助细胞适应营养或能量缺乏的不利条件。越来越多的证据显示,eEF2K可成为治疗癌症等疾病药物的新靶点。本文结合近年来报道的eEF2K小分子抑制剂探讨其在癌症等疾病治疗中的潜在价值。 展开更多
关键词 真核生物延伸因子2激酶 多肽链延伸 真核生物延伸因子2激酶抑制剂 高通量药物筛选
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氟比洛芬酯联合艾司氯胺酮对髋关节置换术老年患者术后镇痛效果的临床研究 被引量:5
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作者 陈晓林 张沛重 +1 位作者 徐国亭 李海中 《中国临床药理学杂志》 CAS CSCD 北大核心 2023年第19期2766-2770,共5页
目的观察氟比洛芬酯联合艾司氯胺酮超前镇痛对髋关节置换术老年患者术后镇痛效果。方法将有髋关节置换术指征并接受手术治疗的老年患者随机分为氟比洛芬酯组、艾司氯胺酮组、联合镇痛组和对照组。所有患者于手术正式结束前30 min停止使... 目的观察氟比洛芬酯联合艾司氯胺酮超前镇痛对髋关节置换术老年患者术后镇痛效果。方法将有髋关节置换术指征并接受手术治疗的老年患者随机分为氟比洛芬酯组、艾司氯胺酮组、联合镇痛组和对照组。所有患者于手术正式结束前30 min停止使用维持麻醉药物,氟比洛芬酯组给予0.65 mg·kg^(-1)氟比洛芬酯;艾司氯胺酮组给予0.35 mg·kg^(-1)艾司氯胺酮;联合镇痛组给予0.35 mg·kg^(-1)氟比洛芬酯+0.25 mg·kg^(-1)艾司氯胺酮;对照组给予等量0.9%NaCl,各组执行超前麻醉方案30 min后立即更改为自控静脉镇痛(PCIA)模式。评估各组术前、术后24 h内数字等级评定量表(NRS)评分,用酶联免疫吸附试验法检测钙-钙调素依赖性蛋白激酶Ⅲ(CAMKⅢ)、白细胞介素-6(IL-6)、脑源性神经营养因子(BDNF)、5-羟色胺(5-HT)变化,统计术后慢性术后疼痛(CPSP)发生率。记录药物不良反应发生情况。结果本研究共入组107例患者,共脱落5例,总计纳入102人,其中氟比洛芬酯组25例、艾司氯胺酮组26例、联合镇痛组26例、对照组25例。术后第24 h,氟比洛芬酯组、艾司氯胺酮组、联合镇痛组和对照组NRS评分分别为(3.27±0.14)、(3.75±0.42)、(2.35±0.12)和(4.25±0.77)分,PCIA泵平均按压次数分别为(3.14±0.75)、(4.22±0.62)、(2.15±0.92)和(5.11±1.02)次,CAMKⅢ浓度分别为(41.21±7.16)、(48.24±9.45)、(30.66±8.21)和(59.77±23.49)pg·mL^(-1),IL-6浓度分别为(22.26±0.04)、(24.12±0.01)、(10.48±0.07)和(40.09±0.17)pg·mL^(-1),BDNF浓度分别为(0.99±0.24)、(0.80±0.33)、(1.23±0.14)和(0.55±0.38)ng·mL^(-1),5-HT浓度分别为(155.91±19.56)、(139.57±18.81)、(185.24±22.50)和(116.25±16.88)ng·mL^(-1);氟比洛芬酯组、艾司氯胺酮组、联合镇痛组的上述指标和对照组比较,氟比洛芬酯组的上述指标与艾司氯胺酮组比较,氟比洛芬酯组和艾司氯胺酮组的上述指标与联合镇痛组比较,差异均有统计学意义(均P<0.05)。氟比洛芬酯组、艾司氯胺酮组、联合镇痛组和对照组的CPSP总体发生率分别为11.54%、8.00%、3.85%和20.00%。氟比洛芬酯组、艾司氯胺酮组、联合镇痛组和对照组的药物不良反应发生率分别为19.23%、4.00%、7.69%和8.00%,差异均无统计学意义(均P>0.05)。结论氟比洛芬酯联合艾司氯胺酮超前镇痛模式可显著降低髋关节置换术老年患者术后24 h内疼痛程度,降低CPSP发生率,安全性较好。 展开更多
关键词 氟比洛芬酯 艾司氯胺酮 髋关节置换术 抑郁 真核延伸因子2激酶 白细胞介素6 脑源性神经营养因子 5-羟色胺
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GSK3β/eEF2K信号通过调控自噬参与肺成纤维细胞诱导分化
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作者 覃超群 黄斌 +5 位作者 阳芳 王昌明 肖影 黄汉灿 李丽英 高枫 《山东大学学报(医学版)》 CAS 北大核心 2022年第5期8-15,共8页
目的探讨糖原合成酶激酶3β(GSK3β)/真核延伸因子2激酶(eEF2K)在肺成纤维细胞转化为肌成纤维细胞过程中的表达,以及对细胞自噬和纤维化的影响。方法将L-929细胞(对照组)于适宜条件下培养48 h,加入5 ng/mL TGF-β1诱导其表型转化为肌成... 目的探讨糖原合成酶激酶3β(GSK3β)/真核延伸因子2激酶(eEF2K)在肺成纤维细胞转化为肌成纤维细胞过程中的表达,以及对细胞自噬和纤维化的影响。方法将L-929细胞(对照组)于适宜条件下培养48 h,加入5 ng/mL TGF-β1诱导其表型转化为肌成纤维细胞(TGF-β1组)。将空质粒、si-eEF2K及si-GSK3β转染肌成纤维细胞,培养48 h后采用免疫荧光染色法检测p-eEF2K和α-SMA蛋白表达情况,蛋白质印迹法检测各组eEF2K、p-eEF2K、GSK3β、P62及LC3-Ⅱ/Ⅰ蛋白表达情况。结果与对照组相比,TGF-β1组细胞p-eEF2K、GSK3β蛋白和α-SMA蛋白表达显著增加(P<0.05);转染si-eEF2K及si-GSK3β后,L-929细胞p-eEF2K/eEF2K表达下降(P<0.05),P62和LC3-Ⅱ/Ⅰ表达水平增加(P<0.05),α-SMA蛋白表达降低(P<0.05)。结论GSK3β/eEF2K信号可能通过降低自噬活性促进肺成纤维细胞向肌纤维细胞的表型转化,促进细胞纤维化进程。 展开更多
关键词 L-929细胞 成纤维细胞 肌纤维细胞 糖原合成酶激酶3β/真核延伸因子2激酶 SIRNA转染
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Integrative proteomics reveals the role of E3 ubiquitin ligase SYVN1 in hepatocellular carcinoma metastasis
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作者 Feiyang Ji Menghao Zhou +6 位作者 Zeyu Sun Zhengyi Jiang Huihui Zhu Zhongyang Xie Xiaoxi Ouyang Lingjian Zhang Lanjuan Li 《Cancer Communications》 SCIE 2021年第10期1007-1023,共17页
Background:Tumor metastasis is a major factor for poor prognosis of hepatocellular carcinoma(HCC),but the relationship between ubiquitination and metastasis need to be studiedmore systematically.We analyzed the ubiqui... Background:Tumor metastasis is a major factor for poor prognosis of hepatocellular carcinoma(HCC),but the relationship between ubiquitination and metastasis need to be studiedmore systematically.We analyzed the ubiquitinome of HCC in this study to have a more comprehensive insight into human HCC metastasis.Methods:The protein ubiquitination levels in 15 HCC specimens with vascular invasion and 15 without vascular invasion were detected by ubiquitinome.Proteins with significantly different ubiquitination levels between HCCs with and without vascular invasion were used to predict E3 ubiquitin ligases associated with tumor metastasis.The topological network of protein substrates and corresponding E3 ubiquitin ligaseswas constructed to identify the key E3 ubiquitin ligase.Besides,the growth,migration and invasion ability of LM3 and HUH7 hepatoma cell lines with andwithout SYVN1 expression interferencewere measured by cell proliferation assay,subcutaneous tumor assay,umphal vein endothelium tube formation assay,transwell migration and invasion assays.Finally,the interacting proteins of SYVN1 were screened and verified by protein interaction omics,immunofluorescence,and immunoprecipitation.Ubiquitin levels of related protein substrates in LM3 and HUH7 cells were compared in negative control,SYVN1 knockdown,and SYVN1 overexpression groups.Results:In this study,our whole-cell proteomic dataset and ubiquitinomic dataset contained approximately 5600 proteins and 12,000 ubiquitinated sites.We discovered increased ubiquitinated sites with shorter ubiquitin chains during the progression ofHCC metastasis.In addition,proteomic and ubiquitinomic analyses revealed that high expression of E3 ubiquitin-protein ligase SYVN1 is related with tumor metastasis.Furthermore,we found that SYVN1 interacted with heat shock protein 90(HSP90)and impacted the ubiquitination of eukaryotic elongation factor 2 kinase(EEF2K).Conclusions:The ubiquitination profiles of HCC with and without vascular invasion were significantly different.SYVN1 was the most important E3 ubiquitin-protein ligase responsible for this phenomenon,and itwas related with tumormetastasis and growth.Therefore,SYVN1might be a potential therapeutic target for HCC. 展开更多
关键词 cancer E3 ubiquitin-protein ligase eukaryotic elongation factor 2 kinase heat shock protein 90 hepatocellular carcinoma liver METASTASIS PROTEOMICS synoviolin UBIQUITIN
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