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81.
5-azacytidine, a chemotherapeutic drug, induces TRAIL-mediated apoptosis in mouse thymocytes in vivo
Tomoaki TochitaniHiroyuki Kanemitsu Hirofumi YamauchiKazuyuki Uchida Hiroyuki Nakayama 《Experimental and toxicologic pathology》2011,63(3):237-242
5-azacytidine (5AzC) is a cytidine analogue with two main effects on cellular conditions; DNA damage, resulting in apoptosis, and DNA hypomethylation, restoring normal growth control and differentiation. However, the molecular mechanism of 5AzC-induced apoptosis is not fully understood. The aim of the present study is to clarify this mechanism in mouse thymocytes in vivo. Ten-week-old, male C57BL/6J mice were injected with 5AzC (100 mg/kg) intraperitoneally, and thymuses were examined for apoptotic changes. In the 5AzC-treated thymus, increases of TUNEL-positive thymocytes and cleaved caspase-3 protein, both biochemical features of apoptosis, were detected. 5AzC-induced apoptosis was observed even in the thymuses of mice deficient in p53, a critical factor in the intrinsic apoptotic pathway, and mice with mutated Fas, a death receptor. Furthermore, levels of p53 and Fas proteins were unchanged in the thymus following 5AzC-treatment in wild-type mice. In the 5AzC-treated thymus, the level of cleaved caspase-8 protein, an initiator of the extrinsic apoptotic pathway, increased with the cleavage of its target protein, Bid. Moreover, the level of TRAIL protein, which induces apoptosis through the cleavage of caspase-8, robustly increased in the thymus treated with 5AzC. In conclusion, the 5AzC-induced apoptosis of thymocytes in vivo is implemented through the extrinsic pathway with the activation of TRAIL. 相似文献
82.
多重调控病毒.基因载体的构建及其体外抗肿瘤活性 总被引:1,自引:1,他引:0
目的 构建一种新型的病毒.基因治疗载体.方法 通过克隆技术将人肿瘤坏死因子相关凋亡诱导配体(TRAIL)基因插入质粒载体pBHGE3的E3区,得到由主要晚期启动子(MLP)调控的腺病毒质粒pPE3-hTRAIL,再通过与质粒pSGS00在293细胞中进行位点特异性重组得到E1A、E1B基因分别受hTERT启动子与HRE启动子双重调控的重组增殖型腺病毒,用TCID50方法测定病毒滴度.通过增殖实验观察重组病毒的选择性增殖能力.利用酶联免疫吸附试验(ELISA)检测人TRAIL基因的表达.并进行噻唑蓝(MTT)比色法实验检测其杀伤肿瘤细胞的能力.结果 CNHK500-hTRAIL的病毒滴度为2.39×1010pfu/ml,增殖实验结果证实CNHK500-hTRAIL可以选择性地在端粒酶阳性的人肺癌细胞A549中增殖,其所携带的人TRAIL基因在A549中的表达量(183.12μg/L)明显高于携带该基因的非增殖型腺病毒载体Ad-hTRAIL(24.53μg/L,P<0.01).MTr显示CNHK500-hTRAIL对A549的杀伤能力明显高于携带该基因的非增殖型腺病毒载体Ad-hTRAIL,其半数抑制MOI值分别为17.825、0.197(P<0.01).结论 CNHKS00一hTRAIL是一种具备治疗肺癌潜力的新型病毒-基因治疗系统. 相似文献
83.
肿瘤坏死因子相关凋亡诱导配体(TRAIL)因其选择性诱导肿瘤细胞凋亡的特点而受到关注。目前,TRAIL及其受体已被广泛运用于妇科肿瘤的治疗研究中,不同的妇科肿瘤细胞株对TRAIL诱导的凋亡敏感性不同,某些细胞株对TRAIL耐药。克服肿瘤细胞对TRAIL的耐药,同时保护正常细胞免受伤害, 相似文献
84.
Gassler N Roth W Funke B Schneider A Herzog F Tischendorf JJ Grund K Penzel R Bravo IG Mariadason J Ehemann V Sykora J Haas TL Walczak H Ganten T Zentgraf H Erb P Alonso A Autschbach F Schirmacher P Knüchel R Kopitz J 《Gastroenterology》2007,133(2):587-598
BACKGROUND AND AIMS: The constant renewal of enterocytes along the crypt-villus axis (CVA) of human small intestine is due to cell-inherent changes resulting in the apoptotic cell death of senescent enterocytes. The aim of the present study was to examine underlying molecular mechanisms of the cell death at the villus tip. METHODS: Characterization of human acyl-coenzyme A (CoA) synthetase 5 (ACSL5) was performed by cloning, recombinant protein expression, biochemical approaches, and several functional and in situ analyses. RESULTS: Our data show that different amounts of acyl-CoA synthetase 5-full length (ACSL5-fl) and a so far unknown splice variant lacking exon 20 (ACSL5-Delta 20) are found in human enterocytes. In contrast with the splice variant ACSL5-Delta 20, recombinant and purified ACSL5-fl protein is active at a highly alkaline pH. Over expression of ACSL5-fl protein is associated with a decrease of the anti-apoptotic FLIP protein in a ceramide-dependent manner and an increased cell-surface expression of the death receptor TRAIL-R1. Expression analyses revealed that the ACSL5-fl/ACSL5-Delta 20 ratio increases along the CVA, thereby sensitizing ACSL5-fl-dominated cells at the villus tip to the death ligand TRAIL, which is corroborated by functional studies with human small intestinal mucosal samples and an immortalized human small intestinal cell line. CONCLUSIONS: Our results suggest an ACSL5-dependent regulatory mechanism that contributes to the cellular renewal along the CVA in human small intestine. Deregulation of the ACSL5-fl/ACSL5-Delta 20 homeostasis in the maturation and shedding of cells along the CVA might also be of relevance for the development of intestinal neoplasia. 相似文献
85.
Insulin-dependent diabetes mellitus (IDDM) is an organ-specific autoimmune disorder triggered by autoreactive T cells directed
to pancreas beta-cell antigens. In this disorder, more than 90% of beta cells are destroyed. Cell death may be mediated via
soluble or membrane-bound cell death ligands. One of these ligands may be tumour necrosis factor (TNF)-related apoptosis-inducing
ligand (TRAIL), a member of the TNF-α superfamily. In the present study, we examined whether TRAIL had cytotoxic effects on
adult rat pancreas beta cell cultures and INS1-E rat insulinoma cell line cultures or not. In this study, cell destruction
models were built with TRAIL concentrations of 10, 100 and 1000 ng. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) test was used for evaluating cell viability. It was detected that cell cultures with TRAIL added showed no differences
statistically when compared with control cultures containing no toxic additions. These results showed that TRAIL did not have
significant cytotoxic effects on pancreas beta cell culture and INS-1E rat insulinoma cell line cultures. Detection of the
expression of TRAIL receptors and natural apoptosis inhibitor proteins will be favourable to investigate the resistance mechanisms
to TRAIL-induced cell death in this cell culture system. 相似文献
86.
Olaf Hoffmann Frauke Zipp Joerg R. Weber 《Journal of molecular medicine (Berlin, Germany)》2009,87(8):753-763
In a wide variety of acute and chronic central nervous system (CNS) disorders, inflammatory processes contribute to the damage
of brain cells and progression of the disease. Along with other regulatory cytokines, tumour necrosis factor-related apoptosis-inducing
ligand (TRAIL) is involved in the pathology of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis
(EAE), bacterial meningitis (BM), HIV encephalitis (HIVE), stroke and Alzheimer's disease (AD). In these conditions, TRAIL
is released within the brain mainly by activated microglia and leukocytes infiltrating from the blood stream. TRAIL promotes
apoptosis of parenchymal cells in MS/EAE, HIVE, AD and stroke through interaction with TRAIL death receptors expressed on
these cells. Frequently, cells in the diseased brain display increased susceptibility to apoptosis induction by TRAIL due
to upregulation of death receptors and downregulation of decoy receptors. On the other hand, TRAIL inhibits the proliferation
of encephalitogenic T cells in EAE, and it is involved in the clearance of infected brain macrophages in HIVE and of activated
neutrophils in BM by interaction with their death receptors. Especially in BM, the ability of TRAIL to limit an acute granulocyte-driven
inflammation carries significant neuroprotective potential. Given the diversity of beneficial and harmful effects in the immune
and nervous system, TRAIL is a double-edged sword in diseases involving CNS inflammation. 相似文献
87.
Elena Riboldi Roberta Daniele Marco A. Cassatella Silvano Sozzani Daniela Bosisio 《Immunobiology》2009,214(9-10):868
Plasmacytoid dendritic cells (PDC) are a functionally distinct lineage of dendritic cells characterized by the release of large amounts of type I interferon (IFN I). IFN I release is efficiently triggered by viral infection and modulates several aspects of immune reactions including the activation of cytotoxic mechanisms finalized to the elimination of infected cells. In this study, we report that TLR7 and TLR9 ligands can induce the secretion of biologically active TNF-related apoptosis-inducing ligand (TRAIL) by PDC. Accordingly, PDC supernatant is endowed with TRAIL-mediated cytotoxic activity when tested on a TRAIL-sensitive Jurkat cell line. TRAIL production is only partially dependent on the autocrine production of IFN I as documented by the use of a blocking anti-IFNRA antibody and the stimulation with exogenous IFN I. Importantly, both TRAIL secretion and cytotoxic activity of PDC supernatants are completely abolished by BDCA2 ligation. These results provide further insights into the biological role of BDCA-2 and document a negative regulatory pathway of PDC cytotoxic activity that may be relevant in pathological situations such as tumors and autoimmune diseases. 相似文献
88.
TRAIL参与氧合血红蛋白诱导的脑血管内皮细胞凋亡 总被引:1,自引:1,他引:0
目的目前对自发性蛛网膜下腔出血(SAH)后脑血管痉挛(CVS)的机制尚不十分清楚,研究认为脑血管内皮细胞的凋亡发挥了重要作用。本实验探讨了肿瘤坏死因子相关凋亡诱导配体(TRAIL)及caspase3在血管内皮细胞凋亡中作用。方法在离体培养的脑血管内皮细胞中,观察给予氧合血红蛋白(OxyHb)处理以及给予caspase3拮抗剂或TRAIL后,运用实时荧光定量聚合酶链反应(PCR)和Western blot检测两者在mRNA和蛋白水平表达的改变。结果和生理盐水阴性对照相比,单纯OxyHb处理以及OxyHb+TRAIL处理后,血管内皮caspase3表达均显著升高(P〈0.05)。TRAIL能够上调OxyHb刺激诱导的caspase3表达(P〈0.05)。和生理盐水对照组相比,OxyHb处理后,血管内皮TRAIL表达显著上调(P〈0.05)。但是,和OxyHb处理相比,caspase3拮抗剂Ac—DEVD—CHO(ADC)不能明显改变OxyHb刺激诱导的TRAIL蛋白的表达上调(P〉0.05)。结论TRAIL能够促进SAH后OxyHb刺激导致的内皮细胞凋亡。在凋亡的级联反应过程中,TRAIL能够活化下游caspase3,从而启动凋亡过程。因此,TRAIL及其受体在SAH后CVS的发生、发展过程中可能有着重要作用。 相似文献
89.
David Capper Timo Gaiser Christian Hartmann Antje Habel Wolf Mueller Christel Herold-Mende Andreas von Deimling Markus David Siegelin 《Acta neuropathologica》2009,117(4):445-456
Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising cancer drug. However, many tumours
are resistant to TRAIL-based therapies. Glioma cells with stem cell features (SCG), such as CD133 expression and neurosphere
formation, have been recently identified to be more resistant to cytotoxic drugs than glioma cells lacking stem-cell-like
features (NSCGs). Here we report that SCGs are completely resistant to 100–2,000 ng/ml TRAIL, whereas NSCGs revealed a moderate
sensitivity to TRAIL. We found that SCGs exhibited only low levels of caspase-8 mRNA and protein, known to be indispensable
for TRAIL-induced apoptosis. In addition, we detected hypermethylation of CASP8 promoter in SCGs, whereas NSCGs exhibited a non-methylated CASP8 promoter. Reexpression of caspase-8 by 5-Aza-2′-deoxycytidine was not sufficient to restore TRAIL sensitivity in SCGs cells,
suggesting that additional factors cause TRAIL resistance in SCGs. Our data suggest that therapy with TRAIL, either as monotherapy
or in combination with demethylating agents, is not effective in treating glioblastoma because SCGs are not targeted by such
treatment. 相似文献
90.