• 【[评价p53和可溶性Fas配体 (sFasL) 血清浓度作为良恶性原发性滤泡性甲状腺肿瘤患者血清凋亡的指标]。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Kołomecki K,Maciaszczyk P,Stepień H,Cywiński J,Cielecka J,Stepień T,Kuzdak K
    BACKGROUND & AIMS: INTRODUCTION:Apoptosis (programmed cell death) is the best described mode of physiological cell death. During embryonal development and morphogenesis, apoptosis may be induced by two pathways. The first is external protein signal originating from other cell--also named as "death signal". Another one is specific cell reaction for external stress factors. Blood concentration of proteins regulating both pathways of apoptosis may be useful in early diagnosis and staging of thyroid tumors. The aim of study was evaluation of p53 and sFasL blood concentration in patients with benign follicular adenoma and follicular thyroid cancer. MATERIALS AND METHODS:The study population was composed of 28 patients: 14 with thyroid carcinoma and 14 patients with follicular neoplasm (NF). All patients underwent surgical treatment. P53 and sFasL levels were evaluated before surgery and related to the histopathological diagnosis obtained post-surgery. RESULTS:The analysis revealed high sFasL blood concentration in patients with follicular thyroid cancer in comparison with the group with follicular adenoma. There was no statistically significant difference between levels of p53 in both groups. CONCLUSIONS:Evaluation of sFasL serum level concentration may be useful in preoperative diagnosis of follicular thyroid tumors.
    背景与目标:
  • 【雌二醇通过上调Fas和Fas配体的表达来增加人冠状动脉内皮细胞的凋亡。】 复制标题 收藏 收藏
    DOI:10.1210/jc.2006-1225 复制DOI
    作者列表:Seli E,Guzeloglu-Kayisli O,Cakmak H,Kayisli UA,Selam B,Arici A
    BACKGROUND & AIMS: CONTEXT:In animal models, estrogen inhibits atherogenesis by inhibiting many of the early steps of atherosclerotic plaque formation. However, the lack of cardioprotective effect by postmenopausal hormone replacement therapy and possible increase in cardiovascular events observed during the first year after the initiation of hormone replacement therapy may suggest that once the plaque is formed, estrogen may have additional effects that may counteract its beneficial outcomes. Indeed, the effect of estrogen on plaque stability has not been identified. OBJECTIVE:We hypothesized that 17beta-estradiol (E2) may cause increased apoptosis in human coronary artery endothelial cells (HCAECs). This effect would explain an adverse effect on plaque stability in vivo. INTERVENTION(S) AND MAIN OUTCOME MEASURE(S):The effect of E2 on apoptosis, cell proliferation, and expression of proapoptotic molecules Fas and Fas ligand (FasL) in cultured HCAECs was evaluated. RESULTS:HCAECs in culture treated with E2 showed an increase in DNA strand breaks and nuclear fragmentation indicative of apoptosis. E2 treatment also induced a significant concentration-dependent increase in Fas mRNA and protein expressions in HCAECs. Moreover, the expression of FasL mRNA and secretion of FasL protein by HCAECs were enhanced in response to E2 treatments. CONCLUSIONS:E2 increases the apoptosis in cultured HCAECs. Enhanced Fas and FasL expressions in response to E2 suggest that activation of the Fas/FasL pathway may be a mediator of the proapoptotic effects of E2 in these cells.
    背景与目标:
  • 【激素难治性乳腺癌的治疗: 植入小鼠的人类肿瘤的凋亡和消退。】 复制标题 收藏 收藏
    DOI:10.1158/1535-7163.MCT-06-0205 复制DOI
    作者列表:Aneja R,Zhou J,Zhou B,Chandra R,Joshi HC
    BACKGROUND & AIMS: :Following surgery, the hormone dependence of breast tumors is exploited for therapy using antagonists such as tamoxifen, although occasional hormone-resistant clones do appear. Another chemotherapeutic strategy uses microtubule inhibitors such as taxanes. Unfortunately, these agents elicit toxicities such as leukocytopenia, diarrhea, alopecia, and peripheral neuropathies and are also associated with the emergence of drug resistance. We have previously described a tubulin-binding, natural compound, noscapine, that was nontoxic and triggered apoptosis in many cancer types albeit at 10 mumol/L or higher concentrations depending on the cell type. We now show that a synthetic analogue of noscapine, 9-bromonoscapine, is approximately 10-fold to 15-fold more potent than noscapine in inhibiting cell proliferation and induces apoptosis following G2-M arrest in hormone-insensitive human breast cancers (MDA-MB-231). Furthermore, a clear loss of mitochondrial membrane potential, release of cytochrome c, activation of the terminal caspase-3, and the cleavage of its substrates such as poly(ADP-ribose) polymerase, suggest an intrinsic apoptotic mechanism. Taken together, these data point to a mitochondrially mediated apoptosis of hormone-insensitive breast cancer cells. Human tumor xenografts in nude mice showed significant tumor volume reduction and a surprising increase in longevity without signs of obvious toxicity. Thus, our data provide compelling evidence that 9-bromonoscapine can be useful for the therapy of hormone-refractory breast cancer.
    背景与目标: : 手术后,尽管偶尔会出现激素抗性克隆,但使用他莫昔芬等拮抗剂来治疗乳腺肿瘤的激素依赖性。另一种化疗策略使用微管抑制剂,如紫杉烷。不幸的是,这些药物会引起毒性,例如白细胞减少,腹泻,脱发和周围神经病变,并且还与耐药性的出现有关。我们先前已经描述了一种微管蛋白结合的天然化合物noscapine,它是无毒的,并在许多癌症类型中触发了凋亡,尽管浓度为10 mumol/L或更高,具体取决于细胞类型。我们现在显示,在激素不敏感的人类乳腺癌 (MDA-MB-231) 中,诺司卡平的合成类似物9-溴单司卡平在抑制细胞增殖和诱导G2-M停滞后的凋亡方面比诺司卡平有效约10倍至15倍。此外,线粒体膜电位的明显丧失,细胞色素c的释放,末端caspase-3的激活以及其底物 (例如聚 (ADP-核糖) 聚合酶) 的裂解提示了内在的凋亡机制。综合起来,这些数据指出了激素不敏感的乳腺癌细胞的线粒体介导的凋亡。裸鼠的人类肿瘤异种移植物显示出显着的肿瘤体积减少和寿命的惊人增加,而没有明显的毒性迹象。因此,我们的数据提供了令人信服的证据,证明9-溴单可用于激素难治性乳腺癌的治疗。
  • 【耐药细胞提取物中癌基因依赖性凋亡。】 复制标题 收藏 收藏
    DOI:10.1101/gad.11.10.1266 复制DOI
    作者列表:Fearnhead HO,McCurrach ME,O'Neill J,Zhang K,Lowe SW,Lazebnik YA
    BACKGROUND & AIMS: Many genotoxic agents kill tumor cells by inducing apoptosis; hence, mutations that suppress apoptosis produce resistance to chemotherapy. Although directly activating the apoptotic machinery may bypass these mutations, how to achieve this activation in cancer cells selectively is not clear. In this study, we show that the drug-resistant 293 cell line is unable to activate components of the apoptotic machinery-the ICE-like proteases (caspases)-following treatment with an anticancer drug. Remarkably, extracts from untreated cells spontaneously activate caspases and induce apoptosis in a cell-free system, indicating that drug-resistant cells have not only the apoptotic machinery but also its activator. Comparing extracts from cells with defined genetic differences, we show that this activator is generated by the adenovirus E1A oncogene and is absent from normal cells. We provide preliminary characterization of this oncogene generated activity (OGA) and show that partially purified OGA activates caspases when added to extracts from untransformed cells. We suggest that agents that link OGA to caspases in cells would kill tumor cells otherwise resistant to conventional cancer therapy. As this killing relies on an activity generated by an oncogene, the effect of these agents should be selective for transformed cells.

    背景与目标: 许多遗传毒性药物通过诱导凋亡来杀死肿瘤细胞; 因此,抑制凋亡的突变会产生对化学疗法的抵抗力。尽管直接激活凋亡机制可能会绕过这些突变,但如何选择性地在癌细胞中实现这种激活尚不清楚。在这项研究中,我们表明抗药性293细胞系在用抗癌药物治疗后无法激活凋亡机制的成分-冰样蛋白酶 (caspases)。值得注意的是,来自未处理细胞的提取物会自发激活胱天蛋白酶并在无细胞系统中诱导凋亡,这表明耐药细胞不仅具有凋亡机制,而且具有其激活剂。比较具有确定的遗传差异的细胞提取物,我们表明该激活剂是由腺病毒E1A癌基因产生的,而正常细胞中不存在。我们提供了这种癌基因产生的活性 (OGA) 的初步表征,并表明当添加到未转化细胞的提取物中时,部分纯化的OGA会激活胱天蛋白酶。我们建议将OGA与细胞中的胱天蛋白酶联系起来的药物会杀死原本对常规癌症治疗具有抗性的肿瘤细胞。由于这种杀灭依赖于癌基因产生的活性,因此这些药物的作用应对转化细胞具有选择性。
  • 【功能性精子发生的发展需要早期大量的生发细胞凋亡。】 复制标题 收藏 收藏
    DOI:10.1093/emboj/16.9.2262 复制DOI
    作者列表:Rodriguez I,Ody C,Araki K,Garcia I,Vassalli P
    BACKGROUND & AIMS: Transgenic mice expressing high levels of the BclxL or Bcl2 proteins in the male germinal cells show a highly abnormal adult spermatogenesis accompanied by sterility. This appears to result from the prevention of an early and massive wave of apoptosis in the testis, which occurs among germinal cells during the first round of spermatogenesis. In contrast, sporadic apoptosis among spermatogonia, which occurs in normal adult testis, is not prevented in adult transgenic mice. The physiological early apoptotic wave in the testis is coincident, in timing and localization, with a temporary high expression of the apoptosis-promoting protein Bax, which disappears at sexual maturity. The critical role played by the intracellular balance, probably hormonally controlled, of the BclxL and Bax proteins (Bcl2 is apparently not expressed in normal mouse testis) in this early apoptotic wave is shown by the occurrence of a comparable testicular syndrome in mice defective in the bax gene. The apoptotic wave appears necessary for normal mature spermatogenesis to develop, probably because it maintains a critical cell number ratio between some germinal cell stages and Sertoli cells, whose normal functions and differentiation involve an elaborate network of communication.

    背景与目标: 在雄性生发细胞中表达高水平BclxL或Bcl2蛋白的转基因小鼠显示出高度异常的成年精子发生并伴有不育。这似乎是由于防止了睾丸中早期大量的凋亡波,而这种凋亡波在第一轮精子发生期间发生在生发细胞中。相反,在成年转基因小鼠中,不能阻止正常成年睾丸中发生的精原细胞间的零星凋亡。睾丸中的生理性早期凋亡波在时间和定位上是重合的,与促凋亡蛋白Bax的暂时高表达,该蛋白在性成熟时消失。BclxL和Bax蛋白 (Bcl2显然在正常小鼠睾丸中未表达) 的细胞内平衡 (可能受激素控制) 在这种早期凋亡波中起关键作用,这表现为在小鼠中出现类似的睾丸综合征。bax基因。凋亡波似乎是正常成熟精子发生发展所必需的,可能是因为它在某些生发细胞阶段和支持细胞之间保持了临界的细胞数比,支持细胞的正常功能和分化涉及复杂的通讯网络。
  • 【NLRX1通过控制线粒体活性抑制组织损伤中的氧化应激和凋亡。】 复制标题 收藏 收藏
    DOI:10.1084/jem.20161031 复制DOI
    作者列表:Stokman G,Kors L,Bakker PJ,Rampanelli E,Claessen N,Teske GJD,Butter L,van Andel H,van den Bergh Weerman MA,Larsen PWB,Dessing MC,Zuurbier CJ,Girardin SE,Florquin S,Leemans JC
    BACKGROUND & AIMS: :Mitochondrial dysfunction is the most prominent source of oxidative stress in acute and chronic kidney disease. NLRX1 is a receptor of the innate immune system that is ubiquitously expressed and localized in mitochondria. We investigated whether NLRX1 may act at the interface of metabolism and innate immunity in a model of oxidative stress. Using a chimeric mouse model for renal ischemia-reperfusion injury, we found that NLRX1 protects against mortality, mitochondrial damage, and epithelial cell apoptosis in an oxidative stress-dependent fashion. We found that NLRX1 regulates oxidative phosphorylation and cell integrity, whereas loss of NLRX1 results in increased oxygen consumption, oxidative stress, and subsequently apoptosis in epithelial cells during ischemia-reperfusion injury. In line, we found that NLRX1 expression in human kidneys decreased during acute renal ischemic injury and acute cellular rejection. Although first implicated in immune regulation, we propose that NLRX1 function extends to the control of mitochondrial activity and prevention of oxidative stress and apoptosis in tissue injury.
    背景与目标: : 线粒体功能障碍是急性和慢性肾脏疾病中氧化应激的最突出来源。NLRX1是先天免疫系统的受体,广泛表达并定位在线粒体中。我们研究了NLRX1是否可能在氧化应激模型中作用于代谢和先天免疫的界面。使用嵌合小鼠肾缺血再灌注损伤模型,我们发现NLRX1以氧化应激依赖性方式保护死亡率,线粒体损伤和上皮细胞凋亡。我们发现NLRX1调节氧化磷酸化和细胞完整性,而NLRX1的丢失会导致缺血再灌注损伤期间的耗氧量增加,氧化应激以及上皮细胞的凋亡。我们发现,在急性肾缺血损伤和急性细胞排斥反应期间,人肾脏中NLRX1的表达降低。尽管首先涉及免疫调节,但我们建议NLRX1功能扩展到控制线粒体活性以及预防组织损伤中的氧化应激和凋亡。
  • 【糖酵解代谢赋予HL60rho0细胞对全反式维甲酸和三氧化二砷联合诱导的凋亡的抵抗力。】 复制标题 收藏 收藏
    DOI:10.1016/j.leukres.2007.04.014 复制DOI
    作者列表:Herst PM,Hesketh EL,Ritchie DS,Berridge MV
    BACKGROUND & AIMS: :Glycolytic cancers are resistant to many forms of chemotherapy and some respond poorly to differentiation therapies. Here, we investigate the effects of exposure to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) on differentiation and cell survival in the human leukemia cell line, HL60 and its mitochondrial gene knockout mutant, HL60rho0. Glycolytic HL60rho0 cells exposed to single and combined treatments expressed less CD15, in most cases, but produced a stronger respiratory burst than parental HL60 cells. HL60rho0 cells were also significantly more resistant to apoptosis after combined ATO+ATRA treatment compared with HL60 cells, and this was associated with failure to upregulate Fas expression.
    背景与目标: : 糖酵解性癌症对多种形式的化学疗法具有抵抗力,有些对分化疗法的反应较差。在这里,我们研究了暴露于全反式维甲酸 (ATRA) 和三氧化二砷 (ATO) 对人白血病细胞系HL60及其线粒体基因敲除突变体HL60rho0的分化和细胞存活的影响。在大多数情况下,暴露于单一和联合治疗的糖酵解HL60rho0细胞表达较少的CD15,但比亲代HL60细胞产生更强的呼吸爆发。与HL60细胞相比,联合ATO ATRA处理后,HL60rho0细胞对凋亡的抵抗力也明显增强,这与Fas表达上调失败有关。
  • 【p53抑癌基因和Fas/Apo-1在诱导癌细胞凋亡和分化中的作用。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Takahashi R
    BACKGROUND & AIMS: :Recent studies have suggested that wild-type p53 blocks cell cycle progression near the G1-S boundary and is involved in both differentiation and apoptosis in many types of cells including cancer cells. p53 expression is enhanced upon DNA-damaging apoptotic stimuli while Fas/Apo-1, a member of the tumor necrosis factor receptor family expressed on cell surface, transduces a signal for apoptosis upon specific ligand or antibody engagement. We demonstrated that stable transfection of the wild-type p53 gene under the control of CMV promoter induced differentiation and apoptosis under restricted conditions in cancer cells, and often caused sensitization of p53-transfected cells to Fas/Apo-1 signal. To investigate the interaction between two major apoptotic pathways involving p53 and Fas/Apo-1 we have established a system that allows to induce wild-type p53 overexpression and apoptosis in cancer cells upon treatment with anti-Fas antibody. The system also allows to investigate other factors interacting with p53 and Fas/Apo-1, and should provide a clue to understanding the biological and biochemical aspects of apoptosis.
    背景与目标: : 最近的研究表明,野生型p53阻断G1-S边界附近的细胞周期进程,并参与包括癌细胞在内的许多类型细胞的分化和凋亡。p53表达在破坏DNA的凋亡刺激时增强,而Fas/Apo-1 (在细胞表面表达的肿瘤坏死因子受体家族的成员) 在特异性配体或抗体接合时转导凋亡信号。我们证明,在CMV启动子控制下,野生型p53基因的稳定转染可在限制条件下诱导癌细胞的分化和凋亡,并经常引起p53-transfected细胞对Fas/Apo-1信号的敏感性。为了研究涉及p53和Fas/Apo-1的两个主要凋亡途径之间的相互作用,我们建立了一个系统,该系统允许在用抗Fas抗体治疗后诱导野生型p53过表达和癌细胞凋亡。该系统还允许研究与p53和Fas/Apo-1相互作用的其他因素,并且应该为了解凋亡的生物学和生化方面提供线索。
  • 【细胞凋亡信号通路与淋巴细胞稳态。】 复制标题 收藏 收藏
    DOI:10.1038/cr.2007.52 复制DOI
    作者列表:Xu G,Shi Y
    BACKGROUND & AIMS: :It has been almost three decades since the term "apoptosis" was first coined to describe a unique form of cell death that involves orderly, gene-dependent cell disintegration. It is now well accepted that apoptosis is an essential life process for metazoan animals and is critical for the formation and function of tissues and organs. In the adult mammalian body, apoptosis is especially important for proper functioning of the immune system. In recent years, along with the rapid advancement of molecular and cellular biology, great progress has been made in understanding the mechanisms leading to apoptosis. It is generally accepted that there are two major pathways of apoptotic cell death induction: extrinsic signaling through death receptors that leads to the formation of the death-inducing signaling complex (DISC), and intrinsic signaling mainly through mitochondria which leads to the formation of the apoptosome. Formation of the DISC or apoptosome, respectively, activates initiator and common effector caspases that execute the apoptosis process. In the immune system, both pathways operate; however, it is not known whether they are sufficient to maintain lymphocyte homeostasis. Recently, new apoptotic mechanisms including caspase-independent pathways and granzyme-initiated pathways have been shown to exist in lymphocytes. This review will summarize our understanding of the mechanisms that control the homeostasis of various lymphocyte populations.
    背景与目标: : 自从 “细胞凋亡” 一词首次被创造用来描述一种独特的细胞死亡形式以来,已经过去了近三十年,这种死亡形式涉及有序的基因依赖性细胞崩解。现在,人们普遍认为细胞凋亡是后生动物的基本生命过程,对于组织和器官的形成和功能至关重要。在成年哺乳动物体内,细胞凋亡对于免疫系统的正常运作尤其重要。近年来,随着分子生物学和细胞生物学的快速发展,人们对细胞凋亡机制的认识取得了很大进展。人们普遍认为,凋亡细胞死亡诱导有两种主要途径: 通过死亡受体的外在信号传导导致死亡诱导信号复合物 (DISC) 的形成,以及主要通过线粒体的内在信号传导导致细胞凋亡的形成。椎间盘或凋亡小体的形成分别激活执行凋亡过程的引发剂和常见的效应半胱天蛋白酶。在免疫系统中,两种途径都起作用; 但是,尚不清楚它们是否足以维持淋巴细胞的稳态。最近,淋巴细胞中存在新的凋亡机制,包括caspase非依赖性途径和颗粒酶启动途径。这篇综述将总结我们对控制各种淋巴细胞群体稳态机制的理解。
  • 【精子凋亡信号与卵母细胞穿透能力的关系。】 复制标题 收藏 收藏
    DOI:10.1111/j.1365-2605.2007.00768.x 复制DOI
    作者列表:Grunewald S,Said TM,Paasch U,Glander HJ,Agarwal A
    BACKGROUND & AIMS: :Human sperm have been documented to display apoptosis-like features such as externalization of phosphatidylserine (EPS), disruption of the transmembrane mitochondrial potential (MMP) and activation of caspases. Our aim was to evaluate possible association between activation of the apoptosis cascade in human sperm and its oocyte penetration capacity using the zona free hamster oocyte penetration assay (SPA). Semen specimens from 76 unselected donors were subjected to double density gradient centrifugation followed by incubation under capacitating conditions for 3 h and SPA. Apoptosis signalling was monitored by assessment of EPS, disruption of MMP and activation of caspase-3 by flow cytometry. Semen samples with subnormal SPA values (<20% penetrated oocytes) contained significantly higher amounts of spermatozoa with EPS, disrupted MMP and activated caspase-3 compared with those samples with normal SPA values (>20% penetrated oocytes, p < 0.01). All three apoptosis markers showed a significantly negative correlation with the percentage of penetrated oocytes (p < 0.01). Apoptosis-related signalling appears to have a negative association with sperm-oocyte penetration. The exclusion of sperm presenting with those apoptosis-related features during assisted reproduction may improve success rates of procedures such as intrauterine insemination and in vitro fertilization.
    背景与目标: : 人类精子已被证明具有凋亡样特征,例如磷脂酰丝氨酸 (EPS) 的外部化,跨膜线粒体电位 (MMP) 的破坏和胱天蛋白酶的激活。我们的目的是使用无带仓鼠卵母细胞渗透试验 (SPA) 评估人类精子中凋亡级联的激活与其卵母细胞渗透能力之间的可能关联。对来自76个未选择的供体的精液标本进行双密度梯度离心,然后在容量条件下孵育3小时和SPA。通过流式细胞术评估EPS,MMP破坏和caspase-3激活来监测凋亡信号。与具有正常SPA值 (>20% 穿透卵母细胞,p <0.01) 的那些样品相比,具有低于正常SPA值 (<20% 穿透卵母细胞) 的精液样品含有显著更高量的具有EPS、破坏的MMP和活化caspase-3的精子。3种凋亡标记物均与穿透卵母细胞的百分比呈显著负相关 (p <0.01)。凋亡相关信号似乎与精子卵母细胞的渗透呈负相关。在辅助生殖过程中排除具有凋亡相关特征的精子可能会提高子宫内人工授精和体外受精等手术的成功率。
  • 【牛乳铁蛋白通过连续渗透细胞膜和靶向线粒体而导致Jurkat T-白血病细胞凋亡。】 复制标题 收藏 收藏
    DOI:10.1016/j.yexcr.2007.05.015 复制DOI
    作者列表:Mader JS,Richardson A,Salsman J,Top D,de Antueno R,Duncan R,Hoskin DW
    BACKGROUND & AIMS: :Bovine lactoferricin (LfcinB) is a cationic antimicrobial peptide that kills Jurkat T-leukemia cells by the mitochondrial pathway of apoptosis. However, the process by which LfcinB triggers mitochondria-dependent apoptosis is not well understood. Here, we show that LfcinB-induced apoptosis in Jurkat T-leukemia cells was preceded by LfcinB binding to, and progressive permeabilization of the cell membrane. Colloidal gold electron microscopy revealed that LfcinB entered the cytoplasm of Jurkat T-leukemia cells prior to the onset of mitochondrial depolarization. LfcinB was not internalized by endocytosis because endocytosis inhibitors did not prevent LfcinB-induced cytotoxicity. Furthermore, intracellular delivery of LfcinB via fusogenic liposomes caused the death of Jurkat T-leukemia cells, as well as normal human fibroblasts. Collectively, these findings suggest that LfcinB caused damage to the cell membrane that allowed LfcinB to enter the cytoplasm of Jurkat T-leukemia cells and mediate cytotoxicity. In addition, confocal microscopy showed that intracellular LfcinB co-localized with mitochondria in Jurkat T-leukemia cells, while flow cytometry and colloidal gold electron microscopy showed that LfcinB rapidly associated with purified mitochondria. Furthermore, purified mitochondria treated with LfcinB rapidly lost transmembrane potential and released cytochrome c. We conclude that LfcinB-induced apoptosis in Jurkat T-leukemia cells resulted from cell membrane damage and the subsequent disruption of mitochondrial membranes by internalized LfcinB.
    背景与目标: 牛乳铁蛋白 (LfcinB) 是一种阳离子抗菌肽,可通过线粒体凋亡途径杀死Jurkat T-白血病细胞。然而,LfcinB触发线粒体依赖性细胞凋亡的过程尚不清楚。在这里,我们显示LfcinB诱导的Jurkat T白血病细胞凋亡之前,LfcinB与细胞膜结合并逐渐通透。胶体金电子显微镜显示,在线粒体去极化开始之前,LfcinB进入了Jurkat T-白血病细胞的细胞质。由于内吞作用抑制剂不能阻止LfcinB诱导的细胞毒性,因此LfcinB不会被内吞作用内化。此外,通过融合脂质体在细胞内递送LfcinB会导致Jurkat T-白血病细胞以及正常人成纤维细胞死亡。总的来说,这些发现表明LfcinB对细胞膜造成了损害,使LfcinB进入Jurkat T-白血病细胞的细胞质并介导了细胞毒性。此外,共聚焦显微镜显示细胞内LfcinB与线粒体共定位于Jurkat T-白血病细胞,而流式细胞术和胶体金电子显微镜显示LfcinB与纯化的线粒体迅速相关。此外,用LfcinB处理的纯化线粒体迅速失去跨膜电位并释放细胞色素c。我们得出结论,LfcinB诱导的Jurkat T-白血病细胞凋亡是由细胞膜损伤和随后内在化的LfcinB破坏线粒体膜引起的。
  • 【作为载气混合物的一部分,氢气的共同给药可抑制小鼠新生儿暴露于七氟醚引起的神经元凋亡和随后的行为缺陷。】 复制标题 收藏 收藏
    DOI:10.1097/ALN.0b013e318275146d 复制DOI
    作者列表:Yonamine R,Satoh Y,Kodama M,Araki Y,Kazama T
    BACKGROUND & AIMS: BACKGROUND:In animal models, several anesthetics induce widespread increases in neuronal apoptosis in the developing brain with subsequent neurologic deficits. Although the mechanisms are largely unknown, the neurotoxicity may, at least in part, be due to elevated oxidative stress caused by mitochondrial dysfunction. In an investigation of potential therapies that could protect against this type of damage, we studied the effects of molecular hydrogen on anesthetic-induced neurotoxicity in the developing mouse brain. METHODS:Six-day-old C57BL/6 mice were exposed to 3% sevoflurane for 6 h with or without hydrogen (< 1.3%) as part of the carrier gas mixture. Apoptosis was evaluated by immunohistochemical staining for cleaved caspase-3 (n = 8-10/group). Western blot analysis for cleaved poly-(adenosine diphosphate-ribose) polymerase was also performed to examine apoptosis (n = 3-6/group). Oxidative stress was assessed by immunohistochemical staining for 4-hydroxy-2-nonenal (n = 8/group). Long-term memory and social behavior were examined using the fear conditioning test and the sociability test, respectively (n = 18-20/group). RESULTS:Western blot analysis showed that coadministration of 1.3% hydrogen gas significantly (P < 0.001) reduced the level of neuronal apoptosis to approximately 40% compared with sevoflurane exposure alone. Immunohistochemical analysis showed that hydrogen reduced oxidative stress induced by neonatal sevoflurane exposure. Although neonatal sevoflurane exposure caused impairment in long-term memory and abnormal social behaviors in adulthood, mice coadministered hydrogen gas with sevoflurane did not exhibit these deficits. CONCLUSIONS:Inhalation of hydrogen gas robustly decreased neuronal apoptosis and subsequent cognitive impairments caused by neonatal exposure to sevoflurane.
    背景与目标:
  • 【迷迭香酸通过抑制肝星状细胞活化/增殖和诱导凋亡来减弱肝纤维化。】 复制标题 收藏 收藏
    DOI:10.1016/j.apjtm.2017.05.012 复制DOI
    作者列表:El-Lakkany NM,El-Maadawy WH,Seif El-Din SH,Hammam OA,Mohamed SH,Ezzat SM,Safar MM,Saleh S
    BACKGROUND & AIMS: OBJECTIVE:To investigate the antifibrotic role of rosmarinic acid (RA), a natural polyphenolic compound, on HSCs activation/proliferation and apoptosis in vitro and in vivo. METHODS:The impact of RA on stellate cell line (HSC-T6) proliferation, activation and apoptosis was assessed along with its safety on primary hepatocytes. In vivo, rats were divided into: (i) normal; (ii) thioacetamide (TAA)-intoxicated rats for 12 weeks; (iii) TAA + silymarin or (iv) TAA + RA. At the end of experiment, liver functions, oxidative stress, inflammatory and profibrogenic markers, tissue inhibitor metalloproteinases type-1 (TIMP-1) and hydroxyproline (HP) levels were evaluated. Additionally, liver histopathology and immunohistochemical examinations of alpha-smooth muscle actin (α-SMA), caspase-3 and proliferation cellular nuclear antigen (PCNA) were determined. RESULTS:RA exhibited anti-proliferative effects on cultured HSCs in a time and concentration dependent manner showing an IC50 of 276 μg/mL and 171 μg/mL for 24 h and 48 h, respectively, with morphological reversion of activated stellate cell morphology to quiescent form. It significantly improved ALT, AST, oxidative stress markers and reduced TIMP-1, HP levels, inflammatory markers and fibrosis score (S1 vs S4). Furthermore, reduction in α-SMA plus elevation in caspase-3 expressions of HSCs in vitro and in vivo associated with an inhibition in proliferation of damaged hepatocytes were recorded. CONCLUSIONS:RA impeded the progression of liver fibrosis through inhibition of HSCs activation/proliferation and induction of apoptosis with preservation of hepatic architecture.
    背景与目标:
  • 【细胞外PAR-4介导的肿瘤细胞凋亡抵抗的新机制。】 复制标题 收藏 收藏
    DOI:10.1158/0008-5472.CAN-12-3212 复制DOI
    作者列表:Burikhanov R,Shrestha-Bhattarai T,Qiu S,Shukla N,Hebbar N,Lele SM,Horbinski C,Rangnekar VM
    BACKGROUND & AIMS: :Tumor suppressor PAR-4 acts in part by modulating sensitivity to apoptosis, but the basis for its activity is not fully understood. In this study, we describe a novel mechanism of antiapoptosis by NF-κB, revealing that it can block PAR-4-mediated apoptosis by downregulating trafficking of the PAR-4 receptor GRP78 from the endoplasmic reticulum to the cell surface. Mechanistic investigations revealed that NF-κB mediated this antiapoptotic mechanism by upregulating expression of UACA, a proinflammatory protein in certain disease settings. In clinical specimens of cancer, a strong correlation existed between NF-κB activity and UACA expression, relative to normal tissues. UACA bound to intracellular PAR-4 in diverse cancer cells, where it prevented translocation of GRP78 from the endoplasmic reticulum to the cell surface. This pathway of antiapoptosis could be inhibited by suppressing levels of NF-κB or UACA expression, which enhanced endoplasmic reticulum stress and restored GRP78 trafficking to the cell surface, thereby sensitizing cancer cells to apoptosis by extracellular PAR-4 or GRP78 agonistic antibody. In summary, our results identify a novel intracellular pathway of apoptosis mediated by NF-κB through UACA elevation, which by attenuating endoplasmic reticulum stress and GRP78 translocation to the cell surface can blunt the sensitivity of cancer cells to apoptosis.
    背景与目标: : 肿瘤抑制因子PAR-4部分通过调节对凋亡的敏感性起作用,但其活性的基础尚不完全清楚。在这项研究中,我们描述了NF-κ b抗凋亡的新机制,揭示了它可以通过下调PAR-4受体GRP78从内质网到细胞表面的运输来阻断PAR-4介导的凋亡。机理研究表明,NF-κ b通过上调UACA (在某些疾病环境中是一种促炎蛋白) 的表达来介导这种抗凋亡机制。在癌症的临床标本中,相对于正常组织,NF-κ b活性与UACA表达之间存在很强的相关性。UACA与多种癌细胞中的细胞内PAR-4结合,阻止了GRP78从内质网转移到细胞表面。抑制NF-κ b或UACA表达的水平可以抑制这种抗凋亡途径,从而增强内质网应激并恢复GRP78向细胞表面的运输,从而使癌细胞对细胞外PAR-4或GRP78激动抗体的凋亡敏感。总之,我们的结果确定了由NF-κ b通过UACA升高介导的新的细胞内凋亡途径,该途径通过减弱内质网应激和GRP78易位到细胞表面可以减弱癌细胞对凋亡的敏感性。
  • 【泼尼松龙通过内在途径诱导角膜上皮细胞凋亡。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-017-04509-8 复制DOI
    作者列表:Ryu JS,Ko JH,Kim MK,Wee WR,Oh JY
    BACKGROUND & AIMS: :Glucocorticoid eye drops are one of the most widely used medications in ophthalmology. However, little is known about the effects of glucocorticoids on corneal epithelial cells that are directly exposed to topically-administered glucocorticoids. Here we investigated the effects of prednisolone, a synthetic glucocorticoid analogue frequently used in the clinic, on corneal epithelial cells. Results showed that prednisolone decreased survival of corneal epithelial cells by inhibiting proliferation and inducing apoptosis in a dose-dependent manner. The levels of mitochondrial reactive oxygen species (mtROS), cleaved caspase-3, and -9 were increased by prednisolone. The effects of prednisolone on apoptosis and mtROS were blocked 1) by the glucocorticoid receptor (GR) antagonist RU-38486, 2) in cells with GR siRNA knockdown, and 3) by treatment with N-acetylcysteine. Transcript levels of pro-inflammatory cytokines were increased in corneal epithelial cells upon hyperosmolar stress, but repressed by prednisolone. In NOD.B10.H2b mice, topical administration of 1% prednisolone increased apoptotic cells in the corneal epithelium. Together, data indicate that prednisolone induces apoptosis in corneal epithelial cells through GR and the intrinsic pathway involving mtROS, caspase-9, and -3. The pro-apoptotic effects of glucocorticoids along with their anti-inflammatory effects should be considered when glucocorticoid eye drops are used in patients with ocular surface disease.
    背景与目标: : 糖皮质激素滴眼液是眼科使用最广泛的药物之一。然而,关于糖皮质激素对直接暴露于局部施用糖皮质激素的角膜上皮细胞的影响知之甚少。在这里,我们研究了泼尼松龙 (一种临床上经常使用的合成糖皮质激素类似物) 对角膜上皮细胞的影响。结果表明,泼尼松龙通过抑制增殖和诱导凋亡以剂量依赖性方式降低了角膜上皮细胞的存活率。泼尼松龙增加了线粒体活性氧 (mtROS),裂解caspase-3和-9的水平。泼尼松龙对细胞凋亡和mtROS的影响被1) 糖皮质激素受体 (GR) 拮抗剂RU-38486阻断,2) 用GR siRNA敲低的细胞中,以及3) 用N-乙酰半胱氨酸处理。高渗应激时,角膜上皮细胞中促炎细胞因子的转录水平增加,但被泼尼松龙抑制。在NOD.B10.H2b小鼠中,局部施用1% 泼尼松龙增加了角膜上皮中的凋亡细胞。总之,数据表明泼尼松龙通过GR和涉及mtROS,caspase-9和-3的内在途径诱导角膜上皮细胞凋亡。当糖皮质激素滴眼液用于眼表疾病患者时,应考虑糖皮质激素的促凋亡作用及其抗炎作用。

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