Induction of Nur77-dependent apoptotic pathyway by Apaensin through activation of JNK and P38MAPK and high content screen model of nulear receptor modulators

第一章主要介绍香豆素类衍生物通过激活p38和JNK通路调控Nur77依赖的细胞凋亡。香豆素化合物是从植物中提取的天然产物，具有包括抗肿瘤效应在内的广泛药理学活性，但这类化合物的抗肿瘤活性作用机制还不太为人所知。在本文中，我们首次发现香豆素类化合物Apaensin可以诱导肿瘤细胞凋亡，这种凋亡效应是通过激活JNK和p38MAPK激酶调控Nur77-Bcl-2凋亡信号通路实现的。我们发现在用JNK和p38抑制剂抑制JNK和p38MAPK的表达后，Apaensin所诱导的肿瘤细胞凋亡效应有所减弱，且用siRNA技术抑制Nur77的表达后也可以削弱肿瘤细胞的凋亡。进一步研究表明，Apaensin激活的...Chapter one describes induction of Nur77-dependent apoptotic pathway by a coumarin derivative through activation of JNK and p38MAPK. Coumarins are nature products derived from plant, and it has a broad range of pharmacological activities including anticancer effects. However the anticancer molecular mechanisms of this compound remain largely unknown. In this paper, we first find that apaensin coul...学位：理学硕士院系专业：药学院_化学生物学学号：3232012115308

The regulation of TAK1 function by caspase

TAK1是NF-κB信号通路中的核心激酶蛋白。它参与先天性免疫、炎症反应、肿瘤形成等众多信号通路，其中在炎症反应和天然免疫通路中被深入研究。在TAK1激酶被激活后，它将磷酸化IKK和MAP2K等激酶，进而活化NF-κB和MAPK，从而使细胞的炎症因子表达来产生炎症反应。通过敲除小鼠的TAK1发现，小鼠细胞中与炎症和先天性免疫相关的效应因子如NF-κB、JNK和P38的激活均受到抑制，表明TAK1在相关信号通路的调控过程中处于核心地位。 细胞凋亡是一种细胞程序性坏死的方式，当细胞受到凋亡刺激后，细胞将走向凋亡。Caspase家族既可以作为细胞凋亡过程中的中间环节又可以作为凋亡的最终执行者。因此...TAK1 plays an important role in NF-κB signaling pathway, which involves in the process of innate immunity, inflammation and tumor formation. How TAK1 contributes to inflammation and innate immunity has been received depth study recently. It has been revealed that activation of TAK1 induces phosphorylation of IKK and MAP2K, which consequently stimulates the activation of NF-κB and MAPK and then exp...学位：理学硕士院系专业：生命科学学院_生物化学与分子生物学学号：2162013115260

Molecular mechanisms of cell death induced by matrine in human cholangiocarcinoma Cells

胆管癌是起源于胆管上皮的一种恶性肿瘤，在我国发病率和死亡率逐年上升。而胆管癌细胞抵抗凋亡是导致胆管癌化疗失败的重要原因，所以研发能够诱导胆管癌细胞以不发生凋亡的死亡新途径的化疗药显得十分重要。苦参碱具有多途径、多种机制的抗肿瘤活性，已经证实能够诱导多种肿瘤细胞死亡，但是在胆管癌中的生物学作用和潜在机制却鲜有报道。程序性坏死(necroptosis)是可被调控的程序性细胞死亡，在形态学上具有典型的坏死样形态改变，依赖于受体相互作用蛋白1和3，此外，可被程序性坏死的特异性抑制剂Nec-1所阻断。近年来发现诱导细胞程序性坏死在治疗肿瘤耐药方面具有巨大潜能。 本实验主要对苦参碱诱导胆管癌QBC939...Cholangiocarcinoma is a malignant tumor originated from biliary epithelial cells. The morbidity and mortality in China is increasing year by year. Resistance to apoptosis remains one of the most challenges in chemotherapy of cholangiocarcinoma. Searching for new agent inducing non-apoptotic cell death could be useful to treat cholangiocarcinoma. Matrine has multiple pathways and multiple mechanism...学位：理学硕士院系专业：医学院_微生物学学号：2452013115344

Study on the Function of the Neuron-Specific Protein TMEM59L in the Central Nervous System and in Oxidative Stress-Induced Cell Death

细胞凋亡是受基因严格调控的、自然发生的程序性细胞死亡过程，而细胞自噬是细胞组分自我降解的过程，二者在发育、组织稳态以及病原体防御中扮演着重要角色。细胞凋亡和细胞自噬发生异常会引发多种疾病包括癌症和神经系统疾病。神经元对于氧化应激十分敏感，并易于受到活性氧的攻击；当神经元长期暴露于包括过氧化氢在内的活性氧的攻击时会引发细胞死亡，导致各种神经系统疾病。因此，鉴定参与神经元死亡的新基因蛋白并揭示其作用机制，将有助于阐明神经系统疾病的致病机理。 TMEM59L为新发现的脑特异性高表达蛋白，其组织表达特异性预示着TMEM59L可能在神经系统中发挥重要作用。一项早期研究发现过表达TMEM59L可以引发细...Apoptosis is naturally occurring programmed cell death and autophagy is a process of self-degradation of cellular components,both of them are essential for normal development and tissue homeostasis. Dsregulation of apoptosis and autophagy can impair cellular functions and cause multiple diseases including cancers and neurological disorders. Neuronal cells are susceptible to oxidative insults. Chro...学位：理学博士院系专业：医学院_生理学学号：2452012015397

The protective effect of resveratrol on human lens epithelial cells against ultraviolet-induced apoptosis

AIM: To investigate the protective effect of resveratrol on human lens epithelial cells against ultraviolet-induced apoptosis. METHODS:Subcultured human lens epithelial cell line, ultraviolet induced cell apoptosis, 20μmol/L resveratrol pretreated cell, the indicators change was observed: rate of apoptosis was detected by flow cytometry and apoptosis-related factors of caspses-3 and caspase-9 were detected by colorimetric detection, ultrastructure changes were observed under transmission electron microscope. RESULTS: Flow cytometry instrument testing found that resveratrol can suppress the apoptosis induced by ultraviolet irradiation, caspses-3 and caspase-9 content in positive control group were significantly higher than that of the negative control group at the same time period, the difference was statistically significant(P<0.05); caspses-3 and caspase-9 content in experimental group were lower than that in the positive control group at the same time, the difference was statistically significant(P<0.05). In addition, the damage of human lens epithelial cells was alleviated with the incubation time of resveratrol elongated. CONCLUSION:Resveratrol may inhibit ultraviolet-induced apoptosis of human lens epithelial cells, it has preventive function against radioactive cataract, and it can provide reliable evidence for pursuing effective medicine to prevent and treat cataract