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| 1 | The endosomal-lysosomal system: from acidification and cargo sorting to neurodegeneration显示文摘The endosomal-lysosomal system is made up of a set of intracellular membranous compartments that dynamically interconvert,which is comprised of early endosomes,recycling endosomes,late endosomes,and the lysosome.In addition,autophagosomes execute autophagy,which delivers intracellular contents to the lysosome.Maturation of endosomes and/or autophagosomes into a lysosome creates an unique acidic environment within the cell for proteolysis and recycling of unneeded cellular components into usable amino acids and other biomolecular building blocks.In the endocytic pathway,gradual maturation of endosomes into a lysosome and acidification of the late endosome are accompanied by vesicle trafficking,protein sorting and targeted degradation of some sorted cargo.Two opposing sorting systems are operating in these processes:the endosomal sorting complex required for transport(ESCRT)supports targeted degradation and the retromer supports retrograde retrieval of certain cargo.The endosomal-lysosomal system is emerging as a central player in a host of neurodegenerative diseases,demonstrating potential roles which are likely to be revealed in pathogenesis and for viable therapeutic strategies.Here we focus on the physiological process of endosomal-lysosomal maturation,acidification and sorting systems along the endocytic pathway,and further discuss relationships between abnormalities in the endosomal-lysosomal system and neurodegenerative diseases,especially Alzheimer’s disease(AD). | Yong-Bo Hu Eric B Dammer Ru-Jing Ren Gang Wang | 2015 | Translational Neurodegeneration2015，4，1： | 4 |
| 2 | δ-secretase in neurodegenerative diseases: mechanisms, regulators and therapeutic opportunities显示文摘Mammalian asparagine endopeptidase(AEP)is a cysteine protease that cleaves its protein substrates on the Cterminal side of asparagine residues.Converging lines of evidence indicate that AEP may be involved in the pathogenesis of several neurological diseases,including Alzheimer’s disease,Parkinson’s disease,and frontotemporal dementia.AEP is activated in the aging brain,cleaves amyloid precursor protein(APP)and promotes the production of amyloid-β(Aβ).We renamed AEP to δ-secretase to emphasize its role in APP fragmentation and Aβ production.AEP also cleaves other substrates,such as tau,α-synuclein,SET,and TAR DNA-binding protein 43,generating neurotoxic fragments and disturbing their physiological functions.The activity of δ-secretase is tightly regulated at both the transcriptional and posttranslational levels.Here,we review the recent advances in the role of δ-secretase in neurodegenerative diseases,with a focus on its biochemical properties and the transcriptional and posttranslational regulation of its activity,and discuss the clinical implications of δ-secretase as a diagnostic biomarker and therapeutic target for neurodegenerative diseases. | Zhentao Zhang Ye Tian Keqiang Ye | 2020 | Translational Neurodegeneration2020，9，1： | 1 |
| 3 | 天冬酰胺内肽酶与创伤性脑损伤相关的阿尔茨海默病显示文摘TBI在全球意外伤害的死亡和伤残原因中居首位,带来了诸多经济、医疗等社会问题。实际上,全世界每年有1000万人死亡和就医直接归因于TBI,大约有5700万人患有脑损伤相关疾病[1]。TBI的幸存者会出现有多种病理现象,例如神经功能缺损,短期和长期脑损伤,认知、行为和情感障碍,所有这些都取决于损伤的严重程度。从功能成像研究中可以明显看出,认知方面的神经系统缺陷是由于海马萎缩和白质束受损所致[2]。TBI可根据其严重程度和作用机制进行分类[3]。在动物模型中,通过复制轻、中、重度不同程度的TBI,观察导致其结果恶化的临床因素对于疾病病理和治疗的理解至关重要。 | 刘易 丁怡 刘蓉 王建枝 柯丹 王小川 | 2021 | 中国病理生理杂志2021，37，3： | 1 |
| 4 | 裂解酶LysGH15的CHAP片段与底物互作的关键位点显示文摘金黄色葡萄球菌噬菌体裂解酶LysGH15对金葡菌表现出广谱高效的抗菌活性,本课题组已深入研究其三维结构,其中CHAP片段是LysGH15起催化作用的关键活性片段。本试验进一步通过分子模拟和对接的方法预测出CHAP与底物多肽DGlnNH2-LLys-DAla-5Gly结合的'口袋'结构,该结构由D33、S35、F36、Y50、R71、T72及N75这些氨基酸位点组成。由于脂肪族非极性氨基酸丙氨酸侧链最短且不带电荷,因此将这些位点均突变为丙氨酸,逐一研究它们对CHAP片段催化活性的影响:圆二色谱试验结果说明突变体二级结构并未发生变化;酶谱试验结果定性的说明F36突变为丙氨酸后突变体蛋白F36A的活性完全丧失,而其他位点的氨基酸突变后蛋白活性并未发生明显改变;细菌浊度测定和菌落计数试验进一步证明突变体F36A活性完全丧失,而其他突变体活性不变;鉴于F36位于'口袋'结构的'口'的部位,36位氨基酸很可能参与到CHAP与底物多肽的结合。本试验鉴定了LysGH15的CHAP与底物多肽互作过程中起关键作用的氨基酸位点。 | 胡丽媛 程梦珺 张玉凤 张蕾 蔡若鹏 孙长江 冯新 雷连成 顾敬敏 王烨 韩文瑜 | 2017 | 中国兽医学报2017，37，3： | 0 |
| 5 | 基于AEP/PI3K/AKT信号通路探讨温肾散结方对人前列腺癌细胞的调控作用和分子机制显示文摘目的:基于天冬酰胺内肽酶(AEP)/磷酸酰肌醇3-激酶(PI3K)/蛋白激酶B(PKB/AKT),探讨温肾散结方(WSSJ方)对人前列腺癌细胞增殖和迁移能力的影响,并进一步探讨其潜在的分子机制。方法:制备WSSJ方冻干粉;体外培养人前列腺癌PC3、DU145和22RV1细胞,CCK-8法检测WSSJ方对前列腺癌细胞相对活力的影响并测定最佳给药浓度;集落形成实验检测WSSJ方对单细胞增殖能力的影响;划痕实验检测WSSJ方对前列腺癌细胞迁移能力的影响;RT-qPCR检测细胞内AEP mRNA、PI3K mRNA及AKT mRNA表达;Western blotting检测细胞内AEP、PI3K及AKT蛋白表达。结果:WSSJ方组前列腺癌细胞增殖活力随给药浓度升高逐渐降低;WSSJ方组细胞计数与细胞融合情况均低于对照组;WSSJ方低、中、高剂量组细胞集落形成数量均少于对照组;WSSJ方组细胞迁移率显著低于对照组(P<0.01);WSSJ方组PC3细胞AKT蛋白相对表达量低于对照组,DU145细胞、22RV1细胞AEP、PI3K蛋白相对表达量均低于对照组,差异均有统计学意义(P<0.05或P<0.01);WSSJ方组PC3细胞、DU145细胞、22RV1细胞AEP mRNA、PI3K mRNA及AKT mRNA表达均显著低于对照组(P<0.05或P<0.01)。结论:WSSJ方能有效抑制人前列腺癌细胞的增殖和迁移能力,并且其对肿瘤细胞的抑制呈现剂量依赖性,作用机制可能与下调AEP抑制PI3K/AKT信号通路有关。 | 王田田 朱文静 盛东亚 聂伟冬 杨凡 彭煜 | 2023 | 中医药导报2023，29，6： | 0 |
| 6 | Legumain在肿瘤微环境中的作用显示文摘肿瘤微环境是肿瘤发生发展过程中重要的决定因素,受到细胞内多种蛋白质表达量异常或结构改变的影响。LGMN(Legumain)是一种半胱氨酸蛋白酶,参与多种蛋白质的加工,在体内发挥一定的生物学功能。同时LGMN在多种实体瘤中高表达,与恶性肿瘤的侵袭、扩散和转移密切相关,其具体生物学作用机制涉及多种途径,包括影响肿瘤微环境中肿瘤相关巨噬细胞和新生血管内皮细胞等。该文将对LGMN在肿瘤形成和进展中的作用机制及其与肿瘤微环境的关系加以综述,从而为系统阐明LGMN在肿瘤微环境中的作用机理以及探索新型的肿瘤诊断标志物和治疗靶点提供科学依据。 | 康瑾 薛凯凯 范雅荣 张晓龙 张清 董丽 刘小春 | 2022 | 中国细胞生物学学报2022，44，9： | 0 |
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