特发性肺纤维化的发病机制的研究进展

目前认为,特发性肺纤维化(IPF)是由于持续或反复的有害刺激,使肺泡上皮细胞损伤增加,正常肺泡结构再生修复发生障碍,成纤维细胞激活进行异常修复,最终导致纤维化.我们就此机制进行阐述. 一、上皮细胞的异常 1.肺泡上皮细胞凋亡:国际上普遍采用博莱霉素诱导的鼠类肺纤维化模型来研究特发性肺纤维化的发病机制.凋亡相关通路主要有Fas/FasL介导的死亡受体通路和线粒体通路.有研究[1]表明,博莱霉素诱导的肺泡上皮细胞凋亡依赖的活性氧激活的线粒体途径是一条非Fas/FasL依赖的途径.线粒体途径是通过Bc1-2蛋白家族的促凋亡蛋白和抗凋亡蛋白进行调节的,关键的调控步骤是Bcl-2家族蛋白通过在线粒体上形成离子通道改变线粒体膜的通透性,进而调控CytC释放.因此,线粒体途径也可被称为Bcl-2敏感的细胞凋亡途径.     

BCL-2抑制剂在慢性淋巴细胞白血病中的研究进展

细胞凋亡指为维持内环境稳定而进行的细胞程序性死亡,其中内源性细胞凋亡途径受B细胞淋巴瘤-2(B-cell lymphoma-2,BCL-2)家族蛋白的调控[1].BCL-2家族蛋白的表达失调阻断正常的凋亡途径,促进恶性肿瘤的发生发展及耐药性的产生.靶向该凋亡途径的小分子抑制剂维奈克拉(Venetoclax),在治疗血液...     

近3年线粒体介导细胞凋亡的研究进展

线粒体是细胞活动的"动力工厂",在调节细胞生存凋亡过程中发挥关键性的作用。在细胞凋亡过程中,线粒体膜通透性转换孔过度的开放会促使线粒体跨膜电位降低,导致一些相关的促凋亡因子,如细胞色素C凋亡诱导因子(apoptosis inducing factor,AIF)、B细胞淋巴瘤-2(Bcl-2)家族以及膜间隙中的Caspase前体蛋白(procaspase)等从线粒体中释放进入胞质,共同参与对细胞的调节。研究线粒体对细胞凋亡的机制,对于研究调控细胞凋亡具有极其重要的理论意义。本研究以线粒体对细胞凋亡作用近3年研究为基础,对线粒体介导细胞凋亡中的作用机制进行综述。     

急性肝功能衰竭大鼠中凋亡相关蛋白的表达

细胞凋亡为急、慢性肝病的主要特征之一.近来研究表明,Bcl-2家族蛋白在细胞凋亡的胞内信号转导途径中发挥重要作用[1-3].目前发现,Bcl-2家族蛋白有20余种,其中Bcl-2、Bcl-xL蛋白具有抗凋亡作用,而Bad、Bax和Bid等具有促凋亡作用[2-4].     

唯BH3域蛋白诱导的细胞凋亡与肿瘤化疗

凋亡对组织发育、维持内环境稳定有着极其重要的作用.细胞过度增殖或死亡减少会导致自身免疫性疾病或肿瘤形成.对小线虫(Celegans)凋亡调节基因的研究证实凋亡由遗传基因控制,基因突变引起凋亡抑制.哺乳动物内存在内源性线粒体通路和外源性死亡受体通路.线粒体死亡通路有bcl-2家族蛋白调控.bcl-2基因家族包括促进和抑制细胞凋亡两大类成员,它们具有不同的结构、功能和分布,通过增加线粒体外膜通透性引起凋亡.     

硫氧还蛋白、硫氧还蛋白相互作用蛋白与消化系疾病的关系

硫氧还蛋白系统是一类具有氧化还原活性的小分子蛋白系统,由硫氧还蛋白(TRX)、还原型辅酶Ⅱ(NADPH)和硫氧还蛋白还原酶(TRX-R)3部分组成,具有调节细胞氧化还原状态、对抗氧化应激、激活转录因子促进细胞生长以及抑制细胞凋亡等作用.硫氧还蛋白相互作用蛋白\硫氧还蛋白结合蛋白2\维生素D3上调蛋白1(TXNIP\TBP-2\VDUP-1)属于硫氧还蛋白结合蛋白的家族成员,通过抑制硫氧还蛋白系统的功能而发挥介导氧化应激、抑制细胞增殖及诱导细胞凋亡等作用,是TRX的负性调节因子.氧化应激与细胞凋亡参与了许多消化系疾病的发生发展.TRX与TXNIP作为氧化应激相关因子,可能在消化性疾病中发挥一定的作用.本文就TRX及TXNIP的结构特点、生物学功能以及与消化系疾病的关系等方面作一综述.     

Akt/FoxO传导通路调节细胞凋亡作用的研究进展

Foxo转录因子是PKB／Akt的下游靶点。Akt调节细胞生存和增殖。Akt磷酸化Foxo抑制Fox0的转录功能,促进细胞生存、生长和增殖。在癌症中FoxO在不同的细胞信号通路中发挥重要作用。FoxO通过两个途径抑制凋亡信号,促进细胞生长,其包括线粒体靶点蛋白Bcll2家族的多种前凋亡成员的表达、死亡受体配体如Fas配体和肿瘤坏死因子相关凋亡诱导配体（TRAIL）的表达,或是增加各种细胞周期蛋白依赖性激酶抑制蛋白的水平。本文主要概括了Akt／FoxO调节细胞生长和生存的机制,以期为抗癌治疗提供新的可能。     

TNF-α诱导肝细胞凋亡机制的回顾与展望

在多种肝脏疾病中都涉及到TNF-α诱导的肝细胞凋亡.TNF-α在细胞凋亡过程中发挥多种效应,主要由TNF-R1介导.TNF-R1的激活导致了多种凋亡途径的激活,包括促凋亡的Bcl-2家族蛋白、活性氧、c-Jun NH2-末端激酶、组织蛋白酶B、酸性鞘磷脂酶及中性鞘磷脂酶.这些途径密切相关并主要作用于线粒体,线粒体释放致凋亡因子及其他物质,导致细胞凋亡.     

TNF-α诱导肝细胞凋亡机制的回顾与展望

在多种肝脏疾病中都涉及到TNF-α诱导的肝细胞凋亡.TNF-α在细胞凋亡过程中发挥多种效应,主要由TNF-R1介导.TNF-R1的激活导致了多种凋亡途径的激活,包括促凋亡的Bcl-2家族蛋白、活性氧、c-Jun NH2-末端激酶、组织蛋白酶B、酸性鞘磷脂酶及中性鞘磷脂酶.这些途径密切相关并主要作用于线粒体,线粒体释放致凋亡因子及其他物质,导致细胞凋亡.     

肺纤维化大鼠上皮细胞凋亡及Bcl-xl和Bid动态变化

目的 探讨肺纤维化大鼠中Bcl-2家族部分蛋白介导的线粒体途径引起上皮细胞凋亡的动态变化及相关关系.方法 选取SD大鼠48只,随机分为4组:空白对照组(24只)、模型7d组(8只)、模型14 d组(8只)、模型28 d组(8只).应用博莱霉素(5 mg/kg)气管内注入建立实验性大鼠肺纤维化模型,空白对照组注入等量生理盐水,各组动物于第7、14、28天随机处死8只,取肺组织采用HE染色观察病理变化,TUNEL法检测肺组织细胞凋亡,RT-PCR和免疫组化法分别检测肺组织Bid、Bcl-xl mRNA以及蛋白的表达.结果 实验性大鼠肺纤维化发病过程中,呈现典型的肺泡炎(7 d)、肺泡炎与纤维化并存(14 d)及稳定的肺纤维化(28 d)等表现;同时间段模型组肺组织细胞凋亡指数、Bid mRNA及蛋白表达均显著高于空白对照组(P＜0.01),Bcl- xl mRNA及蛋白表达显著低于空白对照组(P＜0.01);模型组细胞凋亡与Bid蛋白及mRNA从第7天开始逐步升高,第28天达最高峰,Bid mRNA与细胞凋亡指数呈正相关(r=0.8275,t =7.937 5,P＜0.01);模型组Bcl-xl蛋白与Bcl-xl mRNA表达在第7天开始下降,第28天达最低峰,Bcl-xl mRNA与细胞凋亡指数呈负相关(r=-0.633 8,t=-4.489,P＜0.01); Bcl-xl mRNA与Bid mRNA无明显相关性(r=-0.3869,t=-2.2986,P＞0.05).结论 细胞凋亡在肺纤维形成中起重要作用,肺纤维化细胞凋亡可能与Bcl-2家族蛋白的表达失衡有关.     

Bcl-2-family proteins and hematologic malignancies: history and future prospects

BCL-2 was the first antideath gene discovered, a milestone that effectively launched a new era in cell death research. Since its discovery more than 2 decades ago, multiple members of the human Bcl-2 family of apoptosis-regulating proteins have been identified, including 6 antiapoptotic proteins, 3 structurally similar proapoptotic proteins, and several structurally diverse proapoptotic interacting proteins that operate as upstream agonists or antagonists. Bcl-2-family proteins regulate all major types of cell death, including apoptosis, necrosis, and autophagy. As such, they operate as nodal points at the convergence of multiple pathways with broad relevance to biology and medicine. Bcl-2 derives its name from its original discovery in the context of B-cell lymphomas, where chromosomal translocations commonly activate the BCL-2 protooncogene, endowing B cells with a selective survival advantage that promotes their neoplastic expansion. The concept that defective programmed cell death contributes to malignancy was established by studies of Bcl-2, representing a major step forward in current understanding of tumorigenesis. Experimental therapies targeting Bcl-2 family mRNAs or proteins are currently in clinical testing, raising hopes that a new class of anticancer drugs may be near.     

Apoptosis in mammary gland and cancer

Homeostasis in normal tissue is regulated by a balance between proliferative activity and cell loss by apoptosis. Apoptosis is a physiological mechanism of cell loss that depends on both pre-existing proteins and de novo protein synthesis, and the process of apoptosis is integral to normal mammary gland development and in many diseases, including breast cancer. The mammary gland is one of the few organ systems in mammals that completes its morphologic development postnatally during two discrete physiologic states, puberty and pregnancy. The susceptibility of the mammary gland to tumorigenesis is influenced by its normal development, particularly during stages of puberty and pregnancy that are characterized by marked alterations in breast cell proliferation and differentiation. Numerous epidemiologic studies have suggested that specific details in the development of the mammary gland play a critical role in breast cancer risk. Mammary gland development is characterized by dynamic changes in the expression profiles of Bcl-2 family members. The expression of Bcl-2 family proteins in breast cancer is also influenced by estradiol and by progestin. Since the ratio of proapoptotic to antiapoptotic proteins determines apoptosis or cell survival, hormone levels may have important implications in the therapeutic prevention of breast cancer.     

Cell death provoked by loss of interleukin-3 signaling is independent of Bad, Bim, and PI3 kinase, but depends in part on Puma

Growth and survival of hematopoietic cells is regulated by growth factors and cytokines, such as interleukin 3 (IL-3). When cytokine is removed, cells dependent on IL-3 kill themselves by a mechanism that is inhibited by overexpression of Bcl-2 and is likely to be mediated by proapoptotic Bcl-2 family members. Bad and Bim are 2 such BH3-only Bcl-2 family members that have been implicated as key initiators in apoptosis following growth factor withdrawal, particularly in IL-3-dependent cells. To test the role of Bad, Bim, and other proapoptotic Bcl-2 family members in IL-3 withdrawal-induced apoptosis, we generated IL-3-dependent cell lines from mice lacking the genes for Bad, Bim, Puma, both Bad and Bim, and both Bax and Bak. Surprisingly, Bad was not required for cell death following IL-3 withdrawal, suggesting changes to phosphorylation of Bad play only a minor role in apoptosis in this system. Deletion of Bim also had no effect, but cells lacking Puma survived and formed colonies when IL-3 was restored. Inhibition of the PI3 kinase pathway promoted apoptosis in the presence or absence of IL-3 and did not require Bad, Bim, or Puma, suggesting IL-3 receptor survival signals and PI3 kinase survival signals are independent.     

Proapoptotic Bid is required for pulmonary fibrosis

The molecular mechanisms of pulmonary fibrosis are poorly understood. Previous reports indicate that activation of TGF-beta1 is essential for the development of pulmonary fibrosis. Here, we report that the proapoptotic Bcl-2 family member Bid is required for the development of pulmonary fibrosis after the intratracheal instillation of bleomycin. Mice lacking Bid exhibited significantly less pulmonary fibrosis in response to bleomycin compared with WT mice. The attenuation in pulmonary fibrosis was observed despite similar levels of inflammation, lung injury, and active TGF-beta1 in bronchoalveolar lavage fluid 5 days after the administration of bleomycin in mice lacking Bid and in WT controls. Bleomycin induced similar levels cell death in vitro in alveolar epithelial cells isolated from WT and bid(-/-) mice. By contrast, alveolar epithelial cells from bid(-/-) mice were resistant to TGF-beta1-induced cell death. These results indicate that Bcl-2 family members are critical regulators for the development of pulmonary fibrosis downstream of TGF-beta1 activation.     

Biological functions of melanoma-associated antigens

To date, dozens of melanoma-associated antigens (MAGEs) have been identified and classified into 2 subgroups, I andⅡ. Subgroup I consists of antigens which expression is generally restricted to tumor or germ cells, also named as cancer/testis (CT) antigen. Proteins and peptides derived from some of these antigens have been utilized in promising dinical trials of immunotherapies for gastrointestinal carcinoma,esophageal carcinoma, pulmonary carcinoma and so on. Various MAGE family members play important physiological and pathological roles during embryogenesis, germ cell genesis,apoptosis, etc. However, little is known regarding the role of MAGE family members in cell activities. It is reasonable to speculate that the genes for subgroup IMAGEs, which play important roles during embryogenesis, could be later deactivated by a genetic mechanism such as methylation.In the case of tumor formation, these genes are reactivated and the resultant proteins may be recognized and attacked by the immune system. Thus, the subgroup IMAGEs may play important roles in the immune surveillance of certain tumor types. Here, we review the classifications of MAGE family genes and what is known of their biological functions.     

Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis

Elevated expression of members of the BCL-2 pro-survival family of proteins can confer resistance to apoptosis in cancer cells. Small molecule obatoclax (GX15-070), which is predicted to occupy a hydrophobic pocket within the BH3 binding groove of BCL-2, antagonizes these members and induces apoptosis, dependent on BAX and BAK. Reconstitution in yeast confirmed that obatoclax acts on the pathway and overcomes BCL-2-, BCL-XL-, BCL-w-, and MCL-1-mediated resistance to BAX or BAK. The compound potently interfered with the direct interaction between MCL-1 and BAK in intact mitochondrial outer membrane and inhibited the association between MCL-1 and BAK in intact cells. MCL-1 has been shown to confer resistance to the BCL-2/BCL-XL/BCL-w-selective antagonist ABT-737 and to the proteasome inhibitor bortezomib. In both cases, this resistance was overcome by obatoclax. These findings support a rational clinical development opportunity for the compound in cancer indications or treatments where MCL-1 contributes to resistance to cell killing.     

线粒体DNA在肺纤维化发病机制中的作用

线粒体DNA是体内重要的遗传物质之一,参与编码13种蛋白质,易被活性氧所损伤。近年的研究发现,线粒体DNA损伤可导致线粒体功能障碍,与肺上皮细胞凋亡和肺纤维化的发病关系密切。维持线粒体DNA的完整性可能为治疗肺纤维化提供新的靶点。本文现对线粒体DNA在肺纤维化中的作用及其损伤修复机制的研究进展作简要概述,旨在为临床提供参考。     

Bryostatin analogue-induced apoptosis in mantle cell lymphoma cell lines

The anti-cancer effects of bryostatin-1, a potent diacylglycerol analogue, have traditionally been attributed to its action on protein kinase C. However, we previously documented apoptosis in a B non-Hodgkin lymphoma cell line involving diacylglycerol analogue stimulation of Ras guanyl-releasing protein, a Ras activator, and Bim, a proapoptotic Bcl-2 family protein. To further explore the role of Bim, we examined several Bim-deficient B non-Hodgkin lymphoma cells for their responses to pico, a synthetic bryostatin-1-like compound. The Bim(-) mantle cell lymphoma cell lines Jeko-1, Mino, Sp53, UPN1, and Z138 and the Bim(+) cell line Rec-1, as well as the Burkitt lymphoma cells lines BL2 (Bim(-)) and Daudi (Bim(+)), were examined for their response to pico using assays for proliferation and apoptosis as well as biochemical methods for Ras guanyl-releasing proteins and Bcl-2 family members. With the exception of UPN1, mantle cell lymphoma cell lines underwent pico-induced apoptosis, as did BL2. In some cases, hallmarks of apoptosis were substantially diminished in the presence of mitogen-activated protein kinase kinase inhibitors. Pico treatment generally led to increased expression of proapoptotic Bik, although the absolute levels of Bik varied considerably between cell lines. A pico-resistant variant of Z138 exhibited decreased Bik induction compared to parental Z138 cells. Pico also generally decreased expression of anti-apoptotic Bcl-XL and Mcl1. Although, these changes in Bcl-2 family members seem unlikely to fully account for the differential behavior of the cell lines, our demonstration of a potent apoptotic process in most cell lines derived from mantle cell lymphoma encourages a re-examination of diacylglycerol analogues in the treatment of this subset of B non-Hodgkin lymphoma cases.     

Versatility of BCR/ABL-expressing leukemic cells in circumventing proapoptotic BAD effects

BAD, the proapoptotic member of the "BH3-only" subfamily of BCL-2 proteins, is inactivated by phosphorylation at serines 112 and 136 and by sequestration in the cytoplasm where it interacts with members of the 14-3-3 family. In BCR/ABL-expressing cells, BAD is constitutively phosphorylated and mainly cytoplasmic, whereas in cells expressing BCR/ABL mutants unable to protect from apoptosis, BAD is nonphosphorylated. We show here that both the wild-type (WT) and the S112A/ S136A double mutant (DM) BAD are more potent inducers of apoptosis in parental than in BCR/ABL-expressing 32D myeloid precursor cells. Stable lines of parental cells expressing DM BAD could not be established and most clones from WT BAD retrovirus-infected parental cells lost BAD expression. On IL-3 withdrawal from parental 32D cells, BAD was rapidly dephosphorylated by the serine-threonine phosphatase 1 alpha, and localized in the mitochondria, whereas it remained phosphorylated and did not localize to the mitochondria in the cohort of BCR/ABL-expressing cells escaping apoptosis induced by WT BAD. Moreover, these cells showed high levels of BCL-2 and BCL-X(L) expression. The cohort of BCR/ABL-expressing cells resistant to apoptosis induced by DM BAD showed only high levels of BCL-2 and BCL-X(L). These findings suggest that BCR/ABL-expressing cells are more versatile than normal hematopoietic progenitors in counteracting the apoptotic potential of BAD, and raise the possibility that tumor cells activate multiple antiapoptotic pathways for survival in the face of death-inducing stimuli. (Blood. 2000;96:676-684)     

Visfatin inhibits apoptosis of pancreatic β-cell line, MIN6, via the mitogen-activated protein kinase/phosphoinositide 3-kinase pathway

Visfatin is an adipocytokine that plays an important role in attenuating insulin resistance by binding to insulin receptor. It has been suggested that visfatin plays a role in the regulation of cell apoptosis and inflammation by an as yet unidentified mechanism. This study investigated the protective effects of visfatin on palmitate-induced islet β-cell apoptosis in the clonal mouse pancreatic β-cell line MIN6. The cells were treated with palmitate and/or recombinant visfatin. An 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan assay was used to detect cell proliferation, V-FITC/propidium iodide staining was used to measure cell apoptosis and necrosis, and western blot analysis was used to detect the expression of proapoptotic proteins. The incubation of the cells with visfatin led to a concentration-dependent increase of cell proliferation (1.55-fold at 10(-7) M and 24 h compared with control, P<0.05). Visfatin significantly reduced the cell apoptosis induced by palmitate and caused a significant change in the expression of several proapoptotic proteins, including upregulation of Bcl-2 and a marked downregulation of cytochrome c and caspase 3. Visfatin also activated the ERK1/2 and the phosphoinositide 3-kinase (PI3K)/AKT signaling pathways in a time- and concentration-dependent manner, and the effect of visfatin on apoptosis was blocked by the specific ERK1/2 and PI3K/AKT inhibitors, PD098059 and LY294002. We conclude that visfatin can increase β-cell proliferation and prevent apoptosis, activate intracellular signaling, and regulate the expression of proapoptotic proteins. The antiapoptotic action of visfatin is mediated by activation of mitogen-activated protein kinase-dependent and PI3K-dependent signaling pathways.