泛素结合酶UbcH10与肿瘤（文献综述）

泛素结合酶UbcH10（Ubiquitin—conjugating enzymes,UbcH10）又称周期蛋白选择性泛素载体蛋白E2-C,属于泛素结合酶E2家族的成员,是肿瘤相关的泛素结合酶。在泛素介导的蛋白质降解途径中,E2蛋白的作用将来自E1活化酶的泛素转至具有E3连接酶活性的特异的底物蛋白的赖氨酸残基,泛素化的靶蛋白被26s蛋白酶体识别而降解”0。该泛素蛋白酶体系统（ubiquifin—proteasome system,UP—S）对调控蛋白质的动态平衡起关键作用而且对调控细胞进展（不论正常细胞还是肿瘤细胞）起决定性作用。特异性干涉UP—S的某一环节已被认为是一种很有前途的创新性抗肿瘤治疗方法。     

Proteasome inhibition-induces endoplasmic reticulum dysfunction and cell death of human cholangiocarcinoma cells

AIM： To determine if proteasome inhibition induces apoptosis in human cholangiocarcinoma cells, and if so, to elucidate the cellular mechanisms.
METHODS： Studies were performed in the human KMCH, KMBC, and Mz-ChA-1 cholangiocarcinoma, and normal rat cell lines. MG132, a peptide aldehyde, which inhibits the chymotrypsin-like activity of the proteaosome was employed for this study. Apoptosis was assessed morphologically by 4＇-6-Diamidino-2-phenylindole （DAPI） nuclear staining and fluorescence microscopy. Mitochondrial membrane potential was examined using a fluorescent unquenching assay. Ultrastructural changes during cell death were examined using transmission electron microscopy （TEM）. Caspase 3/7 activity was assessed using an enzymatic-based fluorescent assay. Cytosolic-free calcium concentrations were measured using Fura-2 and digitized fluorescent microscopy.
RESULTS： MG132, a proteasome inhibitor, induced apoptosis in all the cholangiocarcinoma cell lines examined. In contrast, minimal cytotoxicity was observed in normal rat cholangiocytes. Apoptosis was time- and -concentration-dependent. There was no change in the mitochondrial membrane potential between treated and untreated cells. Ultrastructural examination by transmission electron microscopy displayed the classic features of apoptosis, but in addition, there was also dramatic vacuolization of the endoplasmic reticulum （ER）. Unexpectedly, no increase in caspase 3/7 activity was observed in MG132 treated cells, nor did the pancaspase inhibitor, Q-VD-OPh prevent cell death. The protein synthesis inhibitor, cycloheximide, blocked apoptosis induced by proteosome inhibitor indicating that ER dysfunction was dependent upon the formation of new proteins.
CONCLUSION： Proteosome inhibition induces ER dysfunction and caspase-independent cell death selectively in human cholangiocarcinoma cells. Proteasome inhibitors warrant evaluation as anticancer agents for the treatment of human cholangiocarcinoma.     

姜黄素通过抑制α-突出核蛋白聚集保护鱼藤酮致多巴胺能细胞损伤的机制研究

,从而拮抗鱼藤酮诱导的PC12细胞的损伤.     

硼替佐米治疗套细胞淋巴瘤二例报告并文献复习

套细胞淋巴瘤是血液系统恶性肿瘤,是一种米源于滤泡外套cycIinD1(+)及CD5(+)的B细胞,常有t(11;14),占非霍奇金淋巴瘤(NHL)的3%～10%,其平均生存期为2～3年.该疾病目前尚不能完全治愈,传统的以CHOP方案为主化疗,虽然有较高的缓解率但也存在较高的复发率.硼替佐米是一种新型的蛋白酶体抑制剂,目前广泛的运用于治疗多发性骨髓瘤患者,并获得较为满意的临床疗效.硼替佐米用于治疗非霍奇金淋巴瘤国外近来也有少量研究,并显示出对套细胞淋巴痛的良好效果.     

运动诱导机体对氧应激系统性适应的分子机制

机体运动时伴随ATP需求增加、有氧和无氧代谢增强,其结果是ROS生成增加, 但研究证明规律运动可降低一些与ROS有关的疾病发生率,运动对这些疾病的预防作用一定程度是由于机体对氧化应激产生了适应.其分子机制是体内抗氧化物和一些基本的氧化损伤修复酶活性的增加,对氧化攻击抵抗能力的增强,并且这一变化是系统性的、全身性的.骨骼肌、肝脏和脑这些器官虽然在运动过程中的代谢特点和功能完全不同,但它们的适应反应却非常相似:由于氧化还原稳态的改变,体内抗氧化酶、DNA修复酶和蛋白酶体复合物的活性增加,使氧化损伤水平降低、对氧化应激的抵抗力增强等.因而,运动促进健康的作用其机制可能就是运动可使机体具有较高的抵抗ROS的水平.     

蛋白酶体抑制剂Bortezomib及其在多发性骨髓瘤中的研究进展

 蛋蛋白酶体抑制剂Bortezomib通过抑制蛋白酶体及NF-κB使骨髓瘤细胞凋亡,从Borte-zomib作用分子机制、药理作用、临床前研究、临床疗效评价、耐药及联合用药等方面进行了阐述。     

小分子蛋白酶体激动剂的研究进展

蛋白酶体控制着与生命活动密切相关蛋白的降解,对生物体内蛋白内稳态的维持起到了关键作用。随着衰老,体内蛋白酶体活性降低,导致一些受损蛋白的产生大于消耗,这些蛋白的堆积导致各种疾病的产生,如各种神经退行性疾病。因此,促进毒性蛋白降解被认为是治疗这类疾病的潜在方案,而提高蛋白酶体活性则是一种重要策略。但目前蛋白酶体激动剂的研究还处于初级阶段,本文将讨论目前各类小分子蛋白酶体激动剂的研究进展,包括研究方法、药理作用、构效关系和存在的问题等。     

泛素—蛋白酶体通路在凋亡调控中的作用

泛素－蛋白酶体通路是生物体内进行蛋白质选择性降解的重要途径之一，它参与细胞内许多重要的生理生化过程（如DNA修复，细胞周期的运转，信号传递、抗在的提呈，蛋白的跨膜定位等）。近年来，其在细胞凋亡中的作用越来越受到重视，与之相关的调控机制也被广泛研究，蛋白酶体抑制剂在体外可诱导多种肿瘤细胞的凋亡，为人类开发新的抗肿瘤药物提供了新的思路。本文主要就泛素－蛋白酶体通路中各成分与凋亡的相关性，其可能的调控机制以及相关的体内实验做一综述。     

ITI推出UPS药物发现靶的项目

ITI Life Sciences公司已上马一项930万美元的开发项目，以泛素蛋白酶体系统（ubiquitin proteasome system，UPS）作为新一代药物发现的靶的，这可带来癌症、炎症性及感染性疾病新药的发现。     

泛素羧基末端水解酶-1抑制剂对多巴胺能神经元的神经毒性作用

Objective To investigate the neurotoxic effects ofLDN-57444, a specific ubiquitin C-termiual hydrolase L1 (UCH-L1) inhibitor, on dopaminergic neurons and the possible mechanism. Methods The viability of SK-N-SH cells exposed to 5, 10, 25, 50, 75 or 100 μmol/L LDN-57444 for 24 h was assessed using MTT assay, and the cell apoptosis was detected with Hoechst staining. Western blot was performed to identify the expressions of UCH-L1 protein, ubiquitin monomer and polyubiquitinated proteins, and the activity of the ubiquitin-proteasome system (UPS) was evaluated with fluorometry. Results After exposure to UCH-LI inhibitor for 24 h, the cell process-like structures of SK-N-SH cells diminished, and the cell body shrank and became spherical. Exposure to LDN-57444 resulted in concentration-dependent reduction of the cell viability, and the reduction became statistically significant following the exposure to 50 μmol/L LDN-57444, as compared with that in the control group (P<0.05). The exposure also resulted in obvious cell apoptosis as shown by nuclear fragmentation and presence of the apoptotie bodies. Western blot detected no obvious changes in UCH-L1 protein expression but identified reduced ubiquitin monomer and increased polyubiquitinated protein expression in the cells. Fluorometry showed reduced activity of UPS in the exposed cells. Conclusion UCH-L1 inhibitor produces neurotoxicity to dopaminergie neurons and induces cell apoptosis possibly as the result of impaired UPS activity and intracellular accumulation of polyubiquitinated proteins following the exposure.