TRAIL受体及其对细胞凋亡的调控

TRAIL(TNF related apoptosis inducing ligand)是新发现的肿瘤坏 死因子家族（TNF）成员，能够诱导多种肿瘤细胞凋亡，其中受体决定着TRAIL的生物学功能 ，在TRAIL诱导的细胞凋亡中发挥着重要作用，随着研究的不断深入，发现其受体的结构组 成与功能比原先所认识的更为复杂，并且在组成结构与功能上存在不一致性，提示TRAIL受 体对TRAIL功能的调节具有系统性，尚有许多待认识和研究的地方，本文仅对TRAIL受体的研 究新进展进行综述。     

细胞凋亡与肿瘤

细胞凋亡是一种进化保守的细胞死亡形式，不仅在正常的生理状态具有重要作用，而且与多种疾病的发生发展密切相关。近年来研究认为，细胞凋亡异常可能与肿瘤发生有关。凋亡调控基因已被看作是一类新的肿瘤发生相关基因。肿瘤的发生．是由于细胞增殖与细胞凋亡之间的平衡失调的结果，细胞凋亡在肿瘤生长过程中起负调控作用，因此研究抑制多种肿瘤细胞增殖并诱导细胞凋亡而对正常细胞影响不大是肿瘤治疗的新思路。     

细胞凋亡的机制与肿瘤的治疗

在多细胞生物体内,细胞会发生编程性死亡（即细胞凋亡）,使得细胞数量得到精确调控。细胞凋亡调控的异常与癌症、自身免疫病、神经退行性疾病等疾病密切相关。本文综述了参与细胞凋亡调控的分子机制,及细胞凋亡调控的异常与肿瘤的关系。     

细胞凋亡初探

细胞凋亡是近年来人们较为关注的一个研究课题,了解细胞凋亡的发生机制和发生过程,以及控制和诱导细胞凋亡的相关基因及底物,对于治愈人体组织器官退化和癌症都有着极其重要的意义。     

放线菌酮D与缺失p35基因的苜蓿银纹夜蛾病毒诱导Bm细胞凋亡的分析

凋亡对于有机体平衡细胞的增殖和死亡也起到了很重要的作用。不规则的细胞增殖导致癌症的发生。将无限增生的细胞转入凋亡途径,就可以较好地抑制癌症的发生。所以将细胞凋亡的理念应用于疾病的治疗和药物的研发,是理想的可行方式。本研究初步分析了放线菌酮D与病毒诱导细胞凋亡的异同。     

细胞凋亡分子机制的研究进展

细胞凋亡（apoptosis）,又称程序性细胞死亡（programme d cell death）,是一种进化保守和遗传决定的细胞自杀,其性质为生理性。在多细胞动物 ,凋亡对正常机体的发育和自身稳定起着极其重要的作用。现已发现, 有许多疾病的发生和 发展与凋亡机制异常有关。细胞凋亡为生物医学领域中最热门的课题之一。在过去5年里对 细胞凋亡的分子机制的研究取得了突破性进展。现已证明,多种基因产物参与了细胞凋亡过 程,其中包括肿瘤坏死因子受体（TNFR）基因超家族的产物死亡受体(death receptors)、 连接蛋白(adapters)、天门冬氨酸特异性半胱氨酸蛋白酶(caspases)和Bcl2家族调节蛋白 （Bcl2 protein family regulators）等。目前对每组蛋白的成员的化学特性、基本功能 和它们的上游和下游的相互作用分子等均有了较清楚的了解。这些结果为发展以凋亡机制相 关蛋白为靶分子的治疗性细胞凋亡干预手段奠定了基础。     

癌症干细胞研究获得新突破 ——苏州大学陈坚教授

肿瘤干细胞(Tumor Stem Cells,TSCs)理论自其被提出以来,就一直是恶性肿瘤研究领域内的大热门.研究人员认为,肿瘤干细胞一方面可以自我复制保持"干性",另一方面也可以分化成肿瘤细胞而促进肿瘤的生长.这一理论为人们重新认识肿瘤的起源和本质,肿瘤的临床诊断、治疗以及新药研发提供了新的方向和视角.从2007年开始,苏州大学陈坚教授就通过小白鼠实验研究得出:有一群细胞对放化疗都耐受,是癌症复发转移的祸害,这群硬骨头可以看作肿瘤干细胞.每个肿瘤细胞都有自己的生存寿命,这些细胞都会面临凋亡,但癌症干细胞不会,如果我们能找出并杀死癌症干细胞,其他肿瘤细胞也会慢慢凋亡.     

大蒜素对肿瘤细胞作用的研究进展

大蒜素(Allicin,AL)是一种含硫的有机化合物,具有抗氧化、降血压、降血脂、提高免疫力等多种作用.研究表明,其在抗肿瘤方面也有良好表现,对肝癌、胃癌、肺癌、子宫内膜癌、乳腺癌、食管癌、胰腺癌、膀胱癌、直肠癌等肿瘤细胞凋亡都有作用.其作用机制可能是通过阻滞细胞周期、诱导细胞发生线粒体途径的凋亡、抑制肿瘤基因表达等途径来实现的,大蒜素对一些抗肿瘤药物也有促进作用.文章通过查阅国内外近十年的文献,对大蒜素对肿瘤细胞作用的相关研究进展进行简要的综述.     

小鼠肝癌树突状细胞融合瘤苗促进肿瘤凋亡的实验研究

目的探讨小鼠肝癌树突状细胞融合瘤苗抗肿瘤作用及其机制。方法用PEG法制备小鼠肝癌树突状细胞融合瘤苗;流式细胞仪检测融合细胞表型特征;RT-PCR法检测肿瘤组织中TNF-αmRNA、IFN-γmRNA表达:Western blot法检测肿瘤组织中Bcl-2、Bax、Caspase-3蛋白表达。结果小鼠肝癌树突状细胞融合瘤苗具备树突状细胞及肝癌细胞表型特征,能显著促进肿瘤组织中TNF-αmRNA、IFN-γm-RNA及Bcl-2、Bax、Caspase-3蛋白表达。结论小鼠肝癌树突状细胞融合瘤苗能有效地诱导抗肿瘤免疫反应,促进肿瘤细胞凋亡,在预防和治疗肝癌的复发及转移过程中有广阔的应用前景。     

靶向IL18-EGF融合蛋白的表达及其体外抗肿瘤活性研究

人白介素-18(human interleukin 18,hIL18)基因与表皮生长因子受体干扰序列(EGFloop C sequence,EGF)构建IL18-EGF融合基因,利pET32a/E.coli BL21(DE3)表达IL18-EGF融合基因,通过纯化获得有活性的靶向的IL18-EGF融合蛋白,并进行体外细胞试验评价IL18-EGF融合蛋白的抗肿瘤活性.结果表明IL18-EGF融合蛋白能促进人PBMNC的增殖,诱导KG-1细胞分泌IFN-γ、促进肿瘤抗原诱导的B细胞、NK及其CD4+T细胞的活化.     

Apoptosis in health and disease and modulation of apoptosis for therapy: An overview

Apoptosis a physiological mechanism that eliminates excessive, damaged or unwanted cells, is a highly regulated pathway important for maintaining homeostasis in multicellular organisms. It can be initiated through various signals via the extrinsic pathway which involves death receptors, or via the intrinsic pathway which is initiated by intracellular damage and involves the mitochondria and release of cytochrome c from it to further activate caspases. The Bcl-2 family of proteins is situated upstream to the irreversible damage of cellular constituents and is an important checkpoint in the fate of a cell. The pro-apoptotic members, BH3 only members include BID, BAD and BIM. They directly or indirectly activate multidomain BAX/BAK that constitute the requisite gateway to the intrinsic pathway which operates at the mitochondrial surface and endoplasmic reticulum. In contrast, antiapoptotic members such as Bcl-2, Bcl-XL bind and sequester activation. Downstream of mitochondria, the apoptosome involvement is seen to generate caspase activity. Post mitochondria regulation involves IAPs, and their inhibitors. The pathogenesis of several diseases such as cancer, neurodegenerative disorders, autoimmune disorders, heart disease, infectious diseases including AIDS is closely related to aberrant apoptosis. Consequently interest has emerged in employing various the rapeutic approaches such as gene therapy, antisense therapy, recombinant biologicals, organic and combinatorial chemistry, to specifically target apoptosis signaling pathways such as death receptors FAS/TRAIL, Bcl-2, p53, IAPs, SMAC and caspases, etc. and are now advancing from preclinical to clinical phase.     

Apolipoprotein A-I: A Molecule of Diverse Function

Apolipoprotein A-I (apo A-I) an indispensable component and a major structural protein of high-density lipoprotein (HDL), plays a vital role in reverse cholesterol transport and cellular cholesterol homeostasis since its identification. Its multifunctional role in immunity, inflammation, apoptosis, viral, bacterial infection etc. has crossed its boundary of its potential of protecting cardiovascular system and lowering cardiovascular disease risk, attributing HDL to be known as a protective fat removal particle. Its structural homology with prostacyclin stabilization factor has contributed to its anti-clotting and anti-aggregatory effect on platelet which has potentiated its cardio-protective role as well as its therapeutic efficacy against Alzheimer’s disease. The binding affinity and neutralising action against endotoxin lipopolysaccharide, reduces the toxic manifestations of septic shock. As a negative acute phase protein, it blocks T-cell signalling of macrophages. However the recently identified anti-tumor activity of apo A-I has been highlighted in various models of melanoma, lung cancer, ovarian cancer, lymphoblastic leukaemia, gastric as well as pancreatic cancers. These cancer fighting effects are directed towards regression of tumor size and distant metastasis by its immuno modulatory activity as well as its clearing effect on serum lysophospholipids. This lowering effect on lysophospholipid concentration is utilized by apo A-I mimetic peptides to be used in retarding tumor cell proliferation and as a potential cancer therapeutic agent. Not only that, it inhibits the tumor associated neo-angiogenesis as well as brings down the matrix degrading enzymes associated with tumor metastasis. However this efficient therapeutic potential of apo A-I as an anti tumor agent awaits further future experimental studies in humans.     

沙尔威辛抗肿瘤多药耐药分子机制及耐药特性研究

肿瘤多药耐药 (multidrugresistance ,MDR)是临床化疗成功最为严重的障碍 .首先阐明了新拓扑异构酶II抑制剂沙尔威辛对MDR肿瘤细胞直接的细胞毒性作用及下调mdr 1基因和P 糖蛋白的作用 .沙尔威辛能有效杀伤MDR细胞株 ,如K5 62 A0 2 ,KB VCR和MCF 7 ADR细胞 ,其杀伤能力与对相应亲本细胞相当 ,而明显强于几种临床常用的抗癌药物 .沙尔威辛下调mdr 1基因和P 糖蛋白的表达 ,但并不影响MRP和LRP基因 .其次 ,揭示了转录因子c jun的激活 ,在沙尔威辛下调K5 62 A0 2细胞内mdr 1基因表达及诱导凋亡过程中起着关键作用 .沙尔威辛增加K5 62 A0 2细胞的c jun表达明显早于其减少mdr 1基因的表达 ;c jun反义寡核苷酸消除沙尔威辛升高c jun蛋白、下调mdr 1基因表达的作用 .沙尔威辛还促进JNK和c jun磷酸化并增强转录因子AP1的DNA结合活性 .此外 ,c jun反义寡核苷酸还抑制沙尔威辛的凋亡诱导和细胞毒性作用 .最后 ,进一步研究发现沙尔威辛本身不引起MDR表型 .成功建立了对沙尔威辛具有 8 91倍耐药的A5 4 9 SAL细胞株 .该细胞株对抗代谢药产生 6.70倍的耐药 ,但对多种其他天然来源的抗肿瘤药物、烷化剂以及铂类化合物则缺乏交叉耐药性 .     

Defensin γ-thionin from Capsicum chinense improves butyrate cytotoxicity on human colon adenocarcinoma cell line Caco-2

BackgroundButyrate is a histone deacetylase inhibitor that induces apoptosis and inhibits cell proliferation of colorectal cancer cells. To improve its anticancer activity, butyrate has been evaluated mixed with drugs and different molecules. Plant antimicrobial peptides are attractive anticancer alternative molecules because they show selective cytotoxic activity against different cancer cell lines. In this work, we explore if the plant defensin γ-thionin (Capsicum chinense) can improve butyrate activity on Caco-2 cell line and we also determined the mechanism of death activated.ResultsThe combined treatment of γ-thionin (3.5 µM) and butyrate (50 mM) showed higher cytotoxicity on Caco-2 cells with respect to single treatments. Also, the combined treatment reduced cell proliferation and exhibited a higher rate of apoptosis than single treatments. Combined treatment induced caspases 8 and 9 activation to an extent comparable with that of butyrate while γ-thionin did not activate caspases. Additionally, reactive oxygen species generation preceded the onset of apoptosis, and superoxide anion production was higher in cells treated with the combined treatment.ConclusionsThe γ-thionin from Habanero chili pepper improved the butyrate cytotoxicity on Caco-2 cells. This effect occurred through apoptosis induction associated with reactive oxygen species production. Therefore, the combination of butyrate with cytotoxic antimicrobial peptides could be an attractive strategy for cancer therapy.How to cite: Velázquez-Hernández ME, Ochoa-Zarzosa A, López-Meza JE, Defensin γ-thionin from Capsicum chinense improves butyrate cytotoxicity on human colon adenocarcinoma cell line Caco-2. Electron J Biotechnol 2021;52. https://doi.org/10.1016/j.ejbt.2021.04.009     

PTEN--一种肿瘤抑制蛋白

PTEN（10号染色体缺失的磷酸酶及张力蛋白同源物）作为一个重要的抑癌蛋白,其生物学功能主要体现在调节与细胞生长、增殖、分化、迁移和凋亡有关的信号通路上。在细胞中,PTEN 功能受到H2O2的氧化调节。     

Cytotoxicity and Apoptosis Inducing Activities of 2-Amino-4H-chromene-3-carbonitrile Derivatives Loaded on Gold Nanoparticles Against Human Breast Cancer Cell Line T47D

Chemotherapy drugs, used for prevention of uncontrolled cell proliferation in certain tissues as well as inducing apoptosis in tumor cells, are important candidates for treatment of cancer. The synthesized 2-amino-4H-chromene-3-carbonitrile derivatives effective on cancerous cells resistant to other drugs such as Paclitaxel were used due to their ability in induction of apoptosis. The growth inhibitory and inducing apoptosis activities were determined. In order to make it target-oriented, the best compound was conjugated with gold nanoparticles (NPs) by aspartic acid with chemical reduction method. Cytotoxicity effect of 2-amino-4H-chromene-3-carbonitrile derivatives against the T47D breast cancer cell line was determined by MTT assay. The synthesis of gold NPs was confirmed by transmission electron microscopy, UV–Vis and dynamic light scattering. To assess the effects of compounds on the process of apoptosis, staining methods with acridine orange–ethidium bromide and Hoechst staining by fluorescence microscopy and DNA fragmentation by the diphenylamine method were used. The synthesized compounds containing two NH₂ groups on benzene rings, demonstrated more cytotoxicity effect. The effect of conjugation with gold NPs and the induction of apoptosis were studied with the best compound. The cytotoxicity effects of the synthesized 2-amino-4H-chromene-3-carbonitrile compounds were changed by replacement of NO₂ group on thiol ring with different chemical groups on the benzene ring. Analyses of treated cell lines by conjugated and non-conjugated forms of compounds verified their ability in inducing apoptosis while conjugated form demonstrated higher apoptosis.     

Renal Cell Carcinoma: Molecular Aspects

Renal cell carcinoma is the most common form of the kidney cancer accounting for more than 85% of the cases of which clear cell renal cell carcinoma (ccRCC) is the major histological subtype. The central molecular signature for ccRCC pathogenesis is the biallelic inactivation of VHL gene due to the presence of mutations/hyper-methylation/complete gene loss, which results in the downstream HIF activation. These events lead to increased tyrosine kinase receptor signalling pathways (RAS/MEK/ERK pathway, PI3K/AKT/mTOR pathway and NF-κB pathway), which through their downstream effector proteins causes the cell to proliferate and migrate. Recent studies have shown that VHL inactivation alone is not sufficient to induce the tumor. Mutations in numerous other genes that codes for chromatin modifiers (PBRM1, SETD2 and BAP1) and signalling proteins (PTEN and mTOR) have been identified along with activation of alternate signalling pathways like STAT and Sonic Hedgehog (SHH) pathway. It has also been shown that STAT pathway also works cooperatively with HIF to enhance the tumor progression. However, SHH pathway reactivation resulted in tumor regardless of the VHL status, indicating the complex nature of the tumor at the molecular level. Therefore, understanding the complete aetiology of ccRCC is important for future therapeutics.     

Role of oxidative stress in ethanol induced germ cell apoptosis — An experimental study in rats

The study was undertaken to evaluate the possible involvement of oxidative stress in the pathogenesis of ethanol induced testicular atrophy in rats. Adult male rats were orally administered ethanol at a dose of 1.6 g/kg body weight/day for four weeks. Twenty-four hours after the last treatment the rats were sacrificed using anesthetic ether. Testes were removed and weighed. Apoptosis was studied by using the Feulgen reaction on 5 μ thin paraffin sections of testis. Testicular homogenate was prepared and centrifuged. The supernatant was used for the estimation of extent of lipid peroxidation and antioxidant defense status. There was significant reduction in body weight: and in testicular weight and diameter in ethanol treated rats. Extent of germ cell apoptosis was significantly high in ethanol treated rats. Ethanol treated rats showed significantly high tissue TBARS level and glutathione S-transferase activity; and low tissue ascorbic acid, reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities. Chronic ethanol administration resulted in high oxidative stress in the testes either due to increased extent of lipid peroxidation or due to decreased antioxidant defenses, and thereby induces germ cell apoptosis leading to testicular atrophy.     

3,3′-Diindolylmethane Encapsulated Chitosan Nanoparticles Accelerates Inflammatory Markers,ER/PR,Glycoprotein and Mast Cells Population During Chemical Carcinogen Induced Mammary Cancer in Rats

The present study aimed to investigate the effect of 3,3′-diindolylmethane (DIM) on inflammatory markers, estrogen receptors (ER), progesterone receptors (PR), level of glycoprotein and the mast cell population in 7,12-dimethylbenz (a) anthracene (DMBA) 25 mg/kg b.wt. induced rat mammary carcinogenesis. After 8 weeks of tumor formation, rats had access to an oral administrated with DIM 10 mg/kg b.wt. and DIM@CS-NP 0.5 mg/kg body weight respectively for 8 weeks. The oral administration of DIM@CS-NP 0.5 mg/kg b.wt. suppressed the Cox-2, NF-κB and TNF-α protein expression on DMBA induced rats compared to DIM 10 mg/kg b.wt. The ER/PR levels were increased on DMBA induced rats, treated with DIM@CS-NP 0.5 mg/kg b.wt. reduced ER/PR level as well as glycoprotein and mast cell population than DIM 10 mg/kg b.wt. The result shows that, DIM@CS-NP 0.5 mg/kg b.wt. has the potentially inhibit abnormal levels of inflammatory markers, ER, PR, levels of glycoprotein and mast cell population compared to DIM 10 mg/kg b.wt.