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71.
Caspase-3:治疗神经退行性疾病的新靶点 总被引:9,自引:0,他引:9
Caspase-3是caspases家族(一类天冬氨酸特异性酶切半胱氨酸蛋白酶)中的成员,是哺乳动物细胞凋亡的关键蛋白酶.随着研究的深入,发现caspase-3在神经退行性疾病的病理过程中起着很重要的角色.Caspase-3在这些疾病的病理过程中,不仅仅是起着凋亡的效应器作用,还能直接与老年性痴呆症、帕金森氏症、亨廷顿舞蹈病、脊椎小脑失调等疾病的致病蛋白质分子相互作用,参与致病机制.因此,caspase-3是治疗神经退行性疾病的新靶点,寻找caspase-3高效高选择性的抑制剂将为治疗神经退行性疾病提供新的途径. 相似文献
72.
Min Lu Bin Liu Hui Xiong Fang Wu Chunhong Hu Ping Liu 《Journal of cellular and molecular medicine》2019,23(4):2431-2441
Despite initial dramatic efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR‐TKIs) in EGFR‐mutant lung cancer patients, subsequent emergence of acquired resistance is almost inevitable. Resveratrol and its derivatives have been found to exert some effects on EGFR‐TKI resistance in non‐small cell lung cancer (NSCLC), but the underlying mechanisms remain unclear. We screened several NSCLC cell lines with gefitinib resistance by MTT assay and analysed the miR‐345/miR‐498 expression levels. NSCLC cells were pre‐treated with a resveratrol derivative, trans‐3,5,4‐trimethoxystilbene (TMS) and subsequently challenged with gefitinib treatment. The changes in apoptosis and miR‐345/miR‐498 expression were analysed by flow cytometry and q‐PCR respectively. The functions of miR‐345/miR‐498 were verified by CCK‐8 assay, cell cycle analysis, dual‐luciferase reporter gene assay and immunoblotting analysis. Our results showed that the expression of miR‐345 and miR‐498 significantly decreased in gefitinib resistant NSCLC cells. TMS pre‐treatment significantly upregulated the expression of miR‐345 and miR‐498 increasing the sensitivity of NSCLC cells to gefitinib and inducing apoptosis. MiR‐345 and miR‐498 were verified to inhibit proliferation by cell cycle arrest and regulate the MAPK/c‐Fos and AKT/Bcl‐2 signalling pathways by directly targeting MAPK1 and PIK3R1 respectively. The combination of TMS and gefitinib promoted apoptosis also by miR‐345 and miR‐498 targeting the MAPK/c‐Fos and AKT/Bcl‐2 signalling pathways. Our study demonstrated that TMS reduced gefitinib resistance in NSCLCs via suppression of the MAPK/Akt/Bcl‐2 pathway by upregulation of miR‐345/498. These findings would lay the theoretical basis for the future study of TMS for the treatment of EGFR‐TKI resistance in NSCLCs. 相似文献
73.
Hailan Yao Kechun Zhou Dong Yan† Mingtao Li‡ Yizheng Wang† 《Journal of neurochemistry》2009,108(4):909-919
Chronic loss of intracellular K+ can induce neuronal apoptosis in pathological conditions. However, the mechanism by which the K+ channels are regulated in this process remains largely unknown. Here, we report that the increased membrane expression of Kv2.1 proteins in cortical neurons deprived of serum, a condition known to induce K+ loss, promotes neuronal apoptosis. The increase in I K current density and apoptosis in the neurons deprived of serum were inhibited by a dominant negative form of Kv2.1 and MK801, an antagonist to NMDA receptors. The membrane level of Kv2.1 and its interaction with SNAP25 were increased, whereas the Kv2.1 phosphorylation was inhibited in the neurons deprived of serum. Botulinum neurotoxin, an agent known to prevent formation of soluble N -ethylmaleimide-sensitive factor attachment protein receptor complex, suppressed the increase in I K current density. Together, these results suggest that NMDA receptor-dependent Kv2.1 membrane translocation is regulated by a soluble N -ethylmaleimide-sensitive factor attachment protein receptor-dependent vesicular trafficking mechanism and is responsible for neuronal cell death induced by chronic loss of K+ . 相似文献
74.
目的 观察不同浓度氟化钠对睾丸间质细胞增殖和细胞凋亡的影响,为氟中毒的机制研究提供依据.方法 取体外培养的睾丸间质细胞,胰酶消化后制成单细胞悬液,常规培养,待细胞融合率达80%,且未出现细胞分化时,将细胞分4组,加入不同浓度的氟化钠染毒(0,5,10,20 mg/L)睾丸间质细胞,分别干预0,24,48,72,96,1... 相似文献
75.
Yanhua Yang Hanhan Tang Yuanyuan Zhang Feifei Zhu Peng Lü Qin Yao Keping Chen 《Physiological Entomology》2018,43(3):159-168
The silkworm Bombyx mori L., representing an important economic insect and one of the best models for studying insect immunity, possesses an efficient and sophisticated innate immune system against invasive microorganisms. The innate immune system basically includes humoural immunity and cellular immunity. The humoural immunity, which functions via molecules including humoural factors, lysozymes, phenoloxidase, hemolin, lectins and, in particular, antimicrobial peptides, plays a central role in eliminating the invading pathogens. The cellular immunity is primarily carried out and mediated by plasmatocytes and granular cells of haemocytes in the haemolymph, usually followed by melanization. Additionally, apoptosis, a primary viral defence for insects lacking adaptive immunity, comprises an important part of the silkworm immune system. Currently, there is still the lack of a comprehensive and systematic understanding of the molecular mechanisms of silkworm immunity. We review the latest research progress on silkworm immune mechanisms, including phenoloxidase‐dependent melanization and apoptosis, which is conducive to improving our understanding of the silkworm immune mechanism, clarifying the relationship of various immune mechanisms, and also providing a theoretical basis and reference for the future research of insect immunity. 相似文献
76.
Maria Alice Mello Rocky S. Tuan 《In vitro cellular & developmental biology. Animal》1999,35(5):262-269
Summary To study the mechanisms regulating endochondral skeletal development, we examined the characteristics of long-term, high density
micromass cultures of embryonic chicken limb bud mesenchymal cells. By culture Day 3, these cells underwent distinct chondrogenesis,
evidenced by cellular condensation to form large nodules exhibiting cartilage-like morphology and extracellular matrix. By
Day 14, extensive cellular hypertrophy was seen in the core of the nodules, accompanied by increased alkaline phosphatase
activity, and the limitation of cellular proliferation to the periphery of the nodules and to internodular areas. By Day 14,
matrix calcification was detected by alizarin red staining, and calcium incorporation increased as a function of culture time
up to 2 to 3 wk and then decreased. X-ray probe elemental analysis detected the presence of hydroxyapatite. Analogous to growth
cartilage developing in vivo, these cultures also exhibited time-dependent apoptosis, on the basis of DNA fragmentation detected
in situ by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL), ultrastructural
nuclear morphology, and the appearance of internucleosomal DNA degradation. These findings showed that cellular differentiation,
maturation, hypertrophy, calcification, and apoptosis occurred sequentially in the embryonic limb mesenchyme micromass cultures
and indicate their utility as a convenient in vitro model to investigate the regulatory mechanisms of endochondral ossification. 相似文献
77.
K Machaca M M Compton 《Biology of the cell / under the auspices of the European Cell Biology Organization》1992,76(1):15-22
In the current study the internucleosomal DNA cleavage activity associated with apoptosis was investigated in avian thymocytes. Thymocyte nuclear proteins from glucocorticoid-treated chickens were incubated with chicken red blood cell (cRBC) nuclei, and DNA degradation was analyzed by agarose gel electrophoresis and fluorescence-activated flow cytometry. The thymocyte nuclear extract contained an endonuclease activity that degraded cRBC chromatin at internucleosomal sites as detected by agarose gel electrophoresis. Flow cytometry analysis of cRBC nuclei that were treated with thymocyte nuclear proteins demonstrated a loss of cellular DNA as a function of the amount of added nuclease activity. Furthermore, it was demonstrated that the thymocyte nuclear extract contained a nuclease activity that was capable of degrading radiolabelled naked 32P-DNA into acid soluble DNA fragments. All three assay methods demonstrate that the thymocyte nuclease activity can be inhibited by EDTA, zinc ions and the nuclease inhibitor aurintricarboxylic acid. Based on the analysis of cofactor requirement of this nuclease activity and its susceptibility to inhibitors, the endonuclease activity present in avian apoptotic thymocytes appears to be identical to the mammalian counterpart. 相似文献
78.
Franziska Todt Zeynep Cakir Frank Reichenbach Frederic Emschermann Joachim Lauterwasser Andrea Kaiser Gabriel Ichim Stephen WG Tait Stephan Frank Harald F Langer Frank Edlich 《The EMBO journal》2015,34(1):67-80
The Bcl-2 proteins Bax and Bak can permeabilize the outer mitochondrial membrane and commit cells to apoptosis. Pro-survival Bcl-2 proteins control Bax by constant retrotranslocation into the cytosol of healthy cells. The stabilization of cytosolic Bax raises the question whether the functionally redundant but largely mitochondrial Bak shares this level of regulation. Here we report that Bak is retrotranslocated from the mitochondria by pro-survival Bcl-2 proteins. Bak is present in the cytosol of human cells and tissues, but low shuttling rates cause predominant mitochondrial Bak localization. Interchanging the membrane anchors of Bax and Bak reverses their subcellular localization compared to the wild-type proteins. Strikingly, the reduction of Bax shuttling to the level of Bak retrotranslocation results in full Bax toxicity even in absence of apoptosis induction. Thus, fast Bax retrotranslocation is required to protect cells from commitment to programmed death. 相似文献
79.
Expression level of c-FLIP versus Fas determines susceptibility to Fas ligand-induced cell death in murine thymoma EL-4 cells 总被引:4,自引:0,他引:4
The caspase-8 inhibitor c-FLIP blocks death receptor-mediated cell death and plays an essential role in the regulation of lymphocyte homeostasis and the immune escape of tumors. The murine thymoma cell line EL-4 was resistant to Fas ligand (FasL)-induced apoptosis by constitutive expression of FLIP (L). Cycloheximide downregulated the expression of FLIP (L) and markedly sensitized EL-4 cells to FasL-induced apoptosis. In contrast, DNA-damaging agents sensitized EL-4 cells to FasL-induced cell death via an increase of cell-surface Fas without any influence on FLIP (L) expression. Enforced expression of transfected Fas rendered EL-4 cells highly susceptible to FasL-induced cell death. These findings demonstrate that susceptibility to FasL-induced cell death mainly depends on the expression level of c-FLIP versus cell-surface Fas. 相似文献
80.
苜蓿丫纹夜蛾核多角体病毒 (Autographacalifornicamulticapsidnucleopolyhedrovirus,AcMNPV)感染可诱导斜纹夜蛾 (Spodopteralitura)离体细胞Sl zsu 1发生典型的细胞凋亡。通过细胞松弛素 (cytochalasinD)和NH4Cl的抑制实验 ,分别排除病毒粒子结合细胞受体蛋白 ,和病毒在核内体运输过程启动细胞凋亡信号发生的可能性。RT PCR实验证实 ,病毒基因组进入了细胞核 ,极早期基因ie 1开始了转录 ;而DNA聚合酶抑制剂 (芽栖菌素 )的存在对病毒诱导的细胞凋亡程度与进程均没有明显的影响。这说明细胞凋亡的信号是先于病毒晚期复制事件启动的。单独转染AcMNPV极早期基因ie 1可诱导斜纹夜蛾离体细胞系Sl zsu 1细胞发生部分凋亡 ,转染 2 4h后出现凋亡小体 ,4 8h达到高峰。提取转染细胞的总DNA电泳 ,可检测到典型的DNA梯形条带 (DNAladder)。另外 ,AcMNPV的ie 1基因温度敏感突变株tsB82 1在非受纳温度感染细胞时 ,细胞不发生凋亡。这些结果暗示 ,在AcMNPV感染诱导的Sl zsu 1细胞凋亡中 ,ie 1基因是一个凋亡信号的直接或间接诱导因子。 相似文献