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Novel mechanism of drug resistance to proteasome inhibitors in multiple myeloma 预览
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作者 Jianbiao Zhou Wee-Joo Chng 《世界临床肿瘤学杂志(英文版)》 2019年第9期303-306,共4页
Multiple myeloma(MM) is a cancer caused by uncontrolled proliferation of antibody-secreting plasma cells in bone marrow, which represents the second most common hematological malignancy. MM is a highly heterogeneous d... Multiple myeloma(MM) is a cancer caused by uncontrolled proliferation of antibody-secreting plasma cells in bone marrow, which represents the second most common hematological malignancy. MM is a highly heterogeneous disease and can be classified into a spectrum of subgroups based on their molecular and cytogenetic abnormalities. In the past decade, novel therapies, especially, the first-in-class proteasome inhibitor bortezomib, have been revolutionary for the treatment of MM patients. Despite these remarkable achievements, myeloma remains incurable with a high frequency of patients suffering from a relapse, due to drug resistance. Mutation in the proteasome β5-subunit(PSMB5) was found in a bortezomib-resistant cell line generated via long-term coculture with increasing concentrations of bortezomib in 2008, but their actual implication in drug resistance in the clinic has not been reported until recently. A recent study discovered four resistance-inducing PSMB5 mutations from a relapsed MM patient receiving prolonged bortezomib treatment. Analysis of the dynamic clonal evolution revealed that two subclones existed at the onset of disease, while the other two subclones were induced. Protein structural modeling and functional assays demonstrated that all four mutations impaired the binding of bortezomib to the 20 S proteasome, conferring different degrees of resistance. The authors further demonstrated two potential approaches to overcome drug resistance by using combination therapy for targeting proteolysis machinery independent of the 20 S proteasome. 展开更多
关键词 Multiple MYELOMA PROTEASOME inhibitor BORTEZOMIB PROTEASOME β5-subunit Drug resistance CLONAL evolution Combination therapy
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Regulation of NLR stability in plant immunity
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作者 Tao WANG Jiaxin LI Qian-Hua SHEN 《农业科学与工程前沿:英文版》 2019年第2期97-104,共8页
Plant nucleotide binding domain and leucinerich repeat (NLR) receptors recognize pathogen effectors directly or indirectly and mediate innate immune responses. NLR-mediated immunity also has direct impacts on plant gr... Plant nucleotide binding domain and leucinerich repeat (NLR) receptors recognize pathogen effectors directly or indirectly and mediate innate immune responses. NLR-mediated immunity also has direct impacts on plant growth and development, as well as yield and survival. The levels of NLR proteins are therefore intricately controlled in plants to balance defense responses and other processes. In recent years, the ubiquitination-26S proteasome system and the HSP90 chaperones have emerged as having key functions in the regulation of NLR stability. The N-end rule pathway of protein degradation is also directly linked to NLR stability. Recent progress in the regulation of NLR stability and turnover is summarized here, focusing on the key components and pathways. 展开更多
关键词 E3 UBIQUITIN LIGASE degradation nucleotidebinding leucine-rich repeat receptor plant immunity PROTEASOME protein STABILITY UBIQUITINATION
Endoplasmic reticulum stress and proteasome pathway involvement in human podocyte injury with a truncated COL4A3 mutation
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作者 Hui-Di Zhang Jian-Ni Huang +3 位作者 Yun-Zi Liu Hong Ren Jing-Yuan Xie Nan Chen 《中华医学杂志:英文版》 SCIE CAS CSCD 2019年第15期1823-1832,共10页
Background:Collagen type Ⅳ(COL4)-related nephropathy includes a variety of kidney diseases that occur with or without extra-renal manifestations caused by COL4A3-5 mutations.Previous studies revealed several novel mu... Background:Collagen type Ⅳ(COL4)-related nephropathy includes a variety of kidney diseases that occur with or without extra-renal manifestations caused by COL4A3-5 mutations.Previous studies revealed several novel mutations,including three COL4A3 missense mutations (G619R,G801R,and C1616Y) and the COL4A3 chr:228172489delA c.4317delA p.Thr1440ProfsX87 frameshift mutation that resulted in a truncated NC1 domain (hereafter named COL4A3 c.4317delA);however,the mutation mechanisms that lead to podocyte injury remain unclear.This study aimed to further explore the mutation mechanisms that lead to podocyte injury.Methods:Wild-type (WT) and four mutant COL4A3 segments were constructed into a lentiviral plasmid,then stably transfected into human podocytes.Real-time polymerase chain reaction and Western blotting were applied to detect endoplasmic reticulum stress (ERS)-and apoptosis-related mRNA and protein levels.Then,human podocytes were treated with MG132 (a proteasome inhibitor) and brefeldin A (a transport protein inhibitor).The human podocyte findings were verified by the establishment of a mus-Col4a3 knockout mouse monoclonal podocyte using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Casg) technology.Results:Our data showed that COL4A3 mRNA was significantly overexpressed in the lentivirus stably transfected podocytes.Moreover,the COL4A3 protein level was significantly increased in all groups except the COL4A3 c.4317delA group.Compared to the other test groups,the COL4A3 c.4317delA group showed excessive ERS and apoptosis.Podocytes treated with MG 132 showed remarkably increased intra-cellular expression of the COL4A3 c.4317delA mutation.MG132 intervention improved higher ERS and apoptosis levels in the COL4A3 c.4317delA group.Mouse monoclonal podocytes with COL4A3 chr:82717932insA c.4852insA p.Arg1618ThrfsX4 were successfully acquired;this NC1-truncated mutation suggested a higher level of ERS and relatively remarkable level of apoptosis compared to that of the WT 展开更多
关键词 Collagen type Ⅳ-related NEPHROPATHY COL4A3 MUTATION PODOCYTE injury PROTEASOME pathway MG132 Endoplasmic reticulum stress
Silencing Huwe1 reduces apoptosis of cortical neurons exposed to oxygen-glucose deprivation and reperfusion 预览
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作者 Guo-Qian He Wen-Ming Xu +3 位作者 Hui-Juan Liao Chuan Jiang Chang-Qing Li Wei Zhang 《中国神经再生研究:英文版》 SCIE CAS CSCD 2019年第11期1977-1985,共9页
HECT, UBA and WWE domain-containing 1(Huwe1), an E3 ubiquitin ligase involved in the ubiquitin-proteasome system, is widely expressed in brain tissue. Huwe1 is involved in the turnover of numerous substrates, includin... HECT, UBA and WWE domain-containing 1(Huwe1), an E3 ubiquitin ligase involved in the ubiquitin-proteasome system, is widely expressed in brain tissue. Huwe1 is involved in the turnover of numerous substrates, including p53, Mcl-1, Cdc6 and N-myc, thereby playing a critical role in apoptosis and neurogenesis. However, the role of Huwe1 in brain ischemia and reperfusion injury remains unclear. Therefore, in this study, we investigated the role of Huwe1 in an in vitro model of ischemia and reperfusion injury. At 3 days in vitro, primary cortical neurons were transduced with a control or shRNA-Huwe1 lentiviral vector to silence expression of Huwe1. At 7 days in vitro, the cells were exposed to oxygen-glucose deprivation for 3 hours and reperfusion for 24 hours. To examine the role of the c-Jun N-terminal kinase(JNK)/p38 pathway, cortical neurons were pretreated with a JNK inhibitor(SP600125) or a p38 MAPK inhibitor(SB203508) for 30 minutes at 7 days in vitro, followed by ischemia and reperfusion. Neuronal apoptosis was assessed by TUNEL assay. Protein expression levels of JNK and p38 MAPK and of apoptosis-related proteins(p53, Gadd45 a, cleaved caspase-3, Bax and Bcl-2) were measured by western blot assay. Immunofluorescence labeling for cleaved caspase-3 was performed. We observed a significant increase in neuronal apoptosis and Huwe1 expression after ischemia and reperfusion. Treatment with the shRNA-Huwe1 lentiviral vector markedly decreased Huwe1 levels, and significantly decreased the number of TUNEL-positive cells after ischemia and reperfusion. The silencing vector also downregulated the pro-apoptotic proteins Bax and cleaved caspase-3, and upregulated the anti-apoptotic proteins Gadd45 a and Bcl-2. Silencing Huwe1 also significantly reduced p-JNK levels and increased p-p38 levels. Our findings show that downregulating Huwe1 affects the JNK and p38 MAPK signaling pathways as well as the expression of apoptosis-related genes to provide neuroprotection during ischemia and reperfusion. All animal experiments and 展开更多
关键词 nerve REGENERATION ischemic stroke oxygen-glucose DEPRIVATION and REPERFUSION ischemia/reperfusion cortical neuron ubiquitin proteasome system Huwe1 APOPTOSIS therapeutic targets CELL culture CELL death neural REGENERATION
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家蚕Prosβ1基因在蛾翅及早期发育中的作用
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作者 秦笙 张静 +3 位作者 印锦 孙霞 王学杨 李木旺 《蚕业科学》 CAS CSCD 北大核心 2019年第2期181-186,共6页
家蚕是鳞翅目的代表物种,研究其翅发育相关基因有助于理解影响昆虫翅发育的内在因素,为鳞翅目害虫的遗传防治提供理论基础和靶标。家蚕的蛋白酶体β亚基1(Bombyx mori proteasome subunitβtype-1,BmProsβ1)是家蚕蛋白酶体核心颗粒的... 家蚕是鳞翅目的代表物种,研究其翅发育相关基因有助于理解影响昆虫翅发育的内在因素,为鳞翅目害虫的遗传防治提供理论基础和靶标。家蚕的蛋白酶体β亚基1(Bombyx mori proteasome subunitβtype-1,BmProsβ1)是家蚕蛋白酶体核心颗粒的组件之一,负责水解折叠错误或细胞不需要的蛋白质,在细胞发育和器官形成过程中发挥重要作用。利用RNAi干扰技术,在家蚕体腔翅原基附近注射体外合成的针对BmProsβ1基因的小RNA,qRT-PCR检测试验组翅原基中BmProsβ1的表达水平得到有效抑制;对干扰后翅表型的统计结果显示,试验组中小翅个体的比率占52.38%,而对照组中未出现小翅个体。表明在BmProsβ1表达受到抑制的情况下,会严重影响家蚕翅的发育。进一步利用CRISPR/Cas9技术对BmProsβ1进行基因敲除实验,结果显示注射sgRNA与Cas9 mRNA的蚕卵孵化率极低并在幼虫期死亡,而对照组孵化率达到37.92%。这表明BmProsβ1基因在家蚕的早期发育过程中也起到重要作用,其功能缺失会导致家蚕胚胎和幼蚕致死。 展开更多
关键词 家蚕 发育 蛋白酶体 BmProsβ1基因
Organelle aging:Lessons from model organisms
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作者 Mark Bouska Kerui Huang +1 位作者 Ping Kang Hua Bai 《遗传学报:英文版》 SCIE CAS CSCD 2019年第4期171-185,共15页
Most cellular processes descend into failure during aging. While a large collection of longevity pathways has been identified in the past decades, the mechanism for age-related decline of cellular homeostasis and orga... Most cellular processes descend into failure during aging. While a large collection of longevity pathways has been identified in the past decades, the mechanism for age-related decline of cellular homeostasis and organelle function remains largely unsolved. It is known that many organelles undergo structural and functional changes during normal aging, which significantly contributes to the decline of tissue function at old ages. Since recent studies have revealed an emerging role of organelles as regulatory hubs in maintaining cellular homeostasis, understanding of organelle aging will provide important insights into the cellular basis of organismal aging. Here we review current progress on the characterization of age-dependent structural and functional alterations in the more well-studied organelles, as well as the known mechanisms governing organelle aging in model organisms, with a special focus on the fruit fly Drosophila melanogaster. 展开更多
关键词 LONGEVITY Mitochondria Nucleus AUTOPHAGOSOME LYSOSOME PROTEASOME Cell membrane
PBS3 Protects EDS1 from Proteasome-Mediated Degradation in Plant Immunity
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作者 Ming Chang Jinping Zhao +8 位作者 Huan Chen Guangyong Li Jian Chen Min Li Ian A.Palmer Junqi Song James R.Alfano Fengquan Liu Zheng Qing Fu 《分子植物:英文版》 SCIE CAS CSCD 2019年第5期678-688,共11页
Plant immunity is controlled by both positive regulators such as PBS3 and EDS1 and negative regulators such as NPR3 and NPR4.However,the relationships among these important immune regulators remain elusive.In this stu... Plant immunity is controlled by both positive regulators such as PBS3 and EDS1 and negative regulators such as NPR3 and NPR4.However,the relationships among these important immune regulators remain elusive.In this study,we found that PBS3 interacts with EDS1 in both the cytoplasm and the nucleus,and is required for EDS1 protein accumulation?NPR3 and NPR4,which function as salicylic acid receptors and adaptors of Cullin3-based E3 ligase,interact with and mediate the degradation of EDS1 via the 26S proteasome.We further discovered that PBS3 inhibits the polyubiquitination and subsequent degradation of EDS1 by reducing the association of EDS1 with the Cullin3 adaptors NPR3 and NPR4.Furthermore,we showed that PBS3 and EDS1 also contribute to PAMP-triggered immunity in addition to effector-triggered immunity.Collectively,our study reveals a novel mechanism by which plants fine-tune defense resporises by inhibiting the degradation of a positive player in plant immunity. 展开更多
关键词 PBS3 EDS1 NPR3 NPR4 the 26S PROTEASOME PAMP-triggered IMMUNITY
Proteomic analysis reveals dysregulated cell sign aling in ejaculated spermatozoa from in fertile men
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作者 Luna Samanta Rakesh Sharma +1 位作者 Zhihong Cui Ashok Agarwal 《亚洲男性学杂志:英文版》 SCIE CAS CSCD 2019年第2期121-130,共10页
Dysfunctional sperm maturation is the primary reason for the poor sperm motility and morphology in infertile men.Spermatozoa from infertile men were fractioned on three-layer density gradient(80%,60%,and 40%).Fraction... Dysfunctional sperm maturation is the primary reason for the poor sperm motility and morphology in infertile men.Spermatozoa from infertile men were fractioned on three-layer density gradient(80%,60%,and 40%).Fraction 1(Fl)refers to the least mature stage having the lowest den sity,whereas the fraction 4(F4)in eludes the most dense and morphologically mature motile spermatozoa.Fraction 2(F2)and fraction 3(F3)represent the intermediate stages.Proteins were extracted and separated by dimensional gel.Bands were digested with trypsin and analyzed on a LTQ-Orbitrap Elite hybrid mass spectrometer system.Functional annotations of proteins were obtained using bioinformatics tools and pathway databases.A total of 1585 proteins were detected in the four fractions of spermatozoa.A dysregulated protein turnover and protein folding may lead to accumulation of defective proteins or proteins that otherwise would have been eliminated during the process of maturation,resulting in the impairment of sperm fun ction.Aberra nt chaper one expressi on may be a major con tributing factor to the defective sperm function.Androge n receptor was predicted as a transcription regulator in one of the networks and the affected pathways were chaperone-mediated stress response,proteosomal pathway,and sperm function.The down regulation of key pathways and protei ns which compromises the fertilizi ng potential of spermatozoa may provide in sight into the mecha nisms that lead to male infertility. 展开更多
关键词 androgen receptor CHAPERONE IMMATURE sperm INFERTILE MEN PROTEASOME SPERMATOZOA
Proteasomal deubiquitinase UCH37 inhibits degradation of β-catenin and promotes cell proliferation and motility
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作者 Zijian Li Luming Zhou +3 位作者 Tianxia Jiang Libin Fan Xiaoying Liu Xiaobo Qiu 《生物化学与生物物理学报:英文版》 SCIE CAS CSCD 2019年第3期277-284,共8页
The ubiquitin–proteasome system degrades most cellular proteins in eukaryotes.UCH37,also known as UCH-L5,is a deubiquitinase binding to Rpn13,a receptor for ubiquitinated substrates in the 26 S proteasome.But,it rema... The ubiquitin–proteasome system degrades most cellular proteins in eukaryotes.UCH37,also known as UCH-L5,is a deubiquitinase binding to Rpn13,a receptor for ubiquitinated substrates in the 26 S proteasome.But,it remains unclear how UCH37 influences the proteasomal degradation of the ubiquitinated substrates.Because deletion of UCH37 is embryonically lethal in mice,this study aims to investigate the role of UCH37 in proteasomal degradation by constructing the UCH37-deficient cell lines using CRISPR/Cas9 technology.Our results demonstrated that deletion of UCH37 decreased the levels of proteasomal Rpn13,implying that UCH37 might facilitate incorporation of Rpn13 into the proteasome.Meanwhile,deletion of UCH37 decreased the levels of β-catenin and the early endosomal protein Rab8.β-Catenin interacts with TCF/LEF to control transcription,and is involved in development,tissue homeostasis and tumorigenesis.We further found that deletion of UCH37 increased the levels of the ubiquitinated β-catenin and accelerated the hydrogen peroxide-stimulated degradation of β-catenin.Deletion of UCH37 also down-regulated the transcription of c-Myc,a downstream effector of β-catenin,and inhibited cell proliferation and motility.These results raise the possibility that UCH37 maintains the homeostasis of proteasomal degradation reciprocally by assisting the recruitment of the ubiquitin receptor Rpn13 into the proteasome and by reversing ubiquitination of certain critical substrates of the 26 S proteasome. 展开更多
关键词 UBIQUITIN PROTEASOME deubiquitinase β-catenin UCH37
家蚕BmRpt4基因在翅膀发育中的功能研究
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作者 孙霞 张静 +3 位作者 印锦 秦笙 张国政 李木旺 《应用昆虫学报》 CAS CSCD 北大核心 2019年第5期1048-1053,共6页
【目的】 研究分析编码蛋白酶体调控复合物亚基基因BmRpt4(Regulatory particle triple-A ATPase4,BGIBMGA010794)在家蚕翅膀发育过程中的功能。【方法】 利用CRISPR/Cas9基因组编辑技术,将BmRpt4的gRNAs和Cas9 mRNA直接注射到家蚕胚胎... 【目的】 研究分析编码蛋白酶体调控复合物亚基基因BmRpt4(Regulatory particle triple-A ATPase4,BGIBMGA010794)在家蚕翅膀发育过程中的功能。【方法】 利用CRISPR/Cas9基因组编辑技术,将BmRpt4的gRNAs和Cas9 mRNA直接注射到家蚕胚胎中,观察G0代家蚕个体雏翅率,并分析雏翅个体中BmRpt4基因突变情况。【结果】 经统计,对照组G0代家蚕个体均表现为正常翅,而实验组注射BmRpt4的gRNAs和Cas9 mRNA后,G0代约66.7%家蚕个体表现出小翅表型。在分子水平上对小翅表型个体进行检测,发现BmRpt4基因在两个gRNA及其之间位置均有不同长度片段的缺失或者插入,说明在这些突变个体中BmRpt4基因被不同程度的敲除,从而其功能缺失,导致出现小翅表型。【结论】 该研究结果表明编码蛋白酶体调控亚基的BmRpt4基因在家蚕翅膀发育中具有重要作用,为蛋白酶体在生物组织器官发育中调控作用研究提供重要实验依据。 展开更多
关键词 雏翅 蛋白酶体 CRISPR/Cas9技术 基因组编辑 家蚕
金诺芬衍生物的合成及抗肿瘤活性 预览
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作者 张培全 杨倩倩 +1 位作者 龙惠丹 陈鑫 《高等学校化学学报》 SCIE EI CAS CSCD 北大核心 2019年第10期2097-2103,共7页
设计合成了一类新型金诺芬衍生物,采用核磁共振波谱(NMR)和高分辨质谱(HRMS)确认了其结构.以目标化合物处理肿瘤细胞后,采用四氮唑蓝盐(MTS)法检测细胞增殖情况,用流式细胞仪检测细胞凋亡情况,采用蛋白质免疫印迹(Western blot)法检测... 设计合成了一类新型金诺芬衍生物,采用核磁共振波谱(NMR)和高分辨质谱(HRMS)确认了其结构.以目标化合物处理肿瘤细胞后,采用四氮唑蓝盐(MTS)法检测细胞增殖情况,用流式细胞仪检测细胞凋亡情况,采用蛋白质免疫印迹(Western blot)法检测总的泛素化蛋白(Ub-Prs)、K48位链接多聚泛素化蛋白以及蛋白酶体外源性特异性底物(GFPu)的表达情况.结果表明,金诺芬衍生物可通过抑制蛋白酶体功能来发挥抗肿瘤效果. 展开更多
关键词 金诺芬衍生物 蛋白酶体 抗肿瘤活性
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蛋白酶体相关自身炎症综合征研究进展
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作者 徐莉 唐雪梅 《中国实用儿科杂志》 CSCD 北大核心 2018年第1期33-36,共4页
随着对自身炎症性疾病研究的不断深入,近年来发现了由蛋白酶体基因突变所致的一系列临床综合征,包括中条-西村综合征、伴脂肪代谢障碍的日本炎症综合征、关节挛缩-肌萎缩-小细胞贫血-脂膜炎相关脂营养不良综合征以及慢性非典型中性粒... 随着对自身炎症性疾病研究的不断深入,近年来发现了由蛋白酶体基因突变所致的一系列临床综合征,包括中条-西村综合征、伴脂肪代谢障碍的日本炎症综合征、关节挛缩-肌萎缩-小细胞贫血-脂膜炎相关脂营养不良综合征以及慢性非典型中性粒细胞性皮炎伴脂营养不良和发热。这类疾病统称为蛋白酶体相关自身炎症综合征或蛋白酶体病。与目前已知的由白细胞介素(IL)-1介导的自身炎症性疾病相比,蛋白酶体相关自身炎症综合征的基因突变导致蛋白酶体功能障碍、Ⅰ型干扰素(IFN)持续产生,且对IL-1抑制剂的治疗无反应。针对IFN途径的JAK1/JAK2抑制剂可望为这类患者带来疗效。 展开更多
关键词 自身炎症综合征 蛋白酶体 Ⅰ型干扰素
针刺调控泛素-蛋白酶体途径对干预海洛因脑损伤的影响 被引量:2
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作者 张利达 曹江鹏 +5 位作者 蔡兴慧 吴生兵 侯晓蓉 高永龙 张荣军 宋小鸽 《针灸推拿医学:英文版》 CSCD 2018年第2期80-88,共9页
目的:观察针刺对泛素-蛋白酶体途径(UPP)的调控作用,探讨针刺干预海洛因脑损伤的作用.方法:将30只雄性Sprague-Dawley (SD)大鼠按随机数字表法分为对照组、模型组和针刺组.模型组和针刺组大鼠采用连续8d递增量肌肉注射海洛因,染... 目的:观察针刺对泛素-蛋白酶体途径(UPP)的调控作用,探讨针刺干预海洛因脑损伤的作用.方法:将30只雄性Sprague-Dawley (SD)大鼠按随机数字表法分为对照组、模型组和针刺组.模型组和针刺组大鼠采用连续8d递增量肌肉注射海洛因,染毒后停止肌肉注射海洛因5d,自然戒断.按染毒(成瘾)-脱毒的方法,反复3个阶段,建立海洛因复吸大鼠模型.对照组按照建立海洛因复吸大鼠模型的周期,在染毒期给予大鼠肌肉注射生理盐水,在脱毒期不给予任何治疗;模型组在染毒期给予大鼠连续递增量肌肉注射海洛因,在脱毒期不给予任何治疗;针刺组在染毒期处理与模型组相同,在脱毒期给予针刺百会和大椎治疗,每次留针30 min,每天1次,连续5d.于实验第39d取3组大鼠的海马、中脑腹侧被盖区(VTA)脑组织.运用脱氧核糖核苷酸末端转移酶介导的缺口末端标记法(TUNEL)检测脑神经细胞的凋亡情况.运用免疫组化法、定量实时PCR (RT-qPCR)法检测泛素(Ub)、泛素蛋白连接酶(E3)、26S mRNA和蛋白的表达.结果:与模型组相比,针刺组大鼠海马、VTA中TUNEL染色阳性细胞数显著减少(P<0.01),Ub、E3、26S mRNA和蛋白表达表达明显减少(P<0.01).结论:减少神经细胞凋亡,调节大鼠海马、VTA区的Ub、E3、26S mRNA和蛋白的表达,可能是针刺干预海洛因脑损伤的作用机制之一. 展开更多
关键词 针刺疗法 泛素 蛋白酶体 物质禁断综合征 海洛因依赖 脑损伤 大鼠
猪布鲁菌感染对巨噬细胞泛素蛋白酶体功能的影响 被引量:1
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作者 董炳梅 张春玲 +4 位作者 孙培娇 于智慧 王金良 苗立中 沈志强 《中国兽医学报》 CSCD 北大核心 2018年第2期332-335,363共5页
巨噬细胞(macrophage,Mφ)是布鲁菌的主要宿主细胞,为了探明布鲁菌感染与Mφ泛素-蛋白酶体功能之间的关系,本试验在应用蛋白酶体抑制剂Lactacystin与促进剂IFN-γ的基础上,对Mφ感染猪种布鲁菌S2株(Brucella suis,B.suis)后... 巨噬细胞(macrophage,Mφ)是布鲁菌的主要宿主细胞,为了探明布鲁菌感染与Mφ泛素-蛋白酶体功能之间的关系,本试验在应用蛋白酶体抑制剂Lactacystin与促进剂IFN-γ的基础上,对Mφ感染猪种布鲁菌S2株(Brucella suis,B.suis)后细胞上清中泛素、蛋白酶体及胞内B.suis数量进行了检测。结果显示,IFN-γ与Lactacystin对Mφ泛素的表达均有明显的促进作用,且IFN-γ效果显著优于Lactacystin;其次IFN-γ有效促进了M,p蛋白酶体的表达,而Lactacystin显著抑制了Mφ蛋白酶体的表达。在此基础上,将B.suis感染不同状态的MQ,在0.5~24h分别进行胞内B.suis计数,研究表明,一方面B.suis的感染促进了Mφ泛素及蛋白酶体的表达;另一方面,泛素蛋白酶体系统功能的增强,显著降低了B.suis的早期感染,但对于B.suis感染中后期作用不明显,而感染后期抑制Mφ蛋白酶体功能,却可显著降低B.suis的胞内增殖能力。 展开更多
关键词 布鲁菌 巨噬细胞 泛素 蛋白酶体
Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer's disease 预览
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作者 Isaac G. Onyango 《中国神经再生研究:英文版》 SCIE CAS CSCD 2018年第1期19-25,共7页
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广州管圆线虫蛋白酶体α5基因的克隆、表达及重组蛋白对人THP-1巨噬细胞凋亡的影响
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作者 闫兰竹 史晓萌 +4 位作者 祖雁文 陈茜茜 李星潘 闫宝龙 黄慧聪 《中国寄生虫学与寄生虫病杂志》 CSCD 北大核心 2018年第3期253-257,共5页
目的获得广州管圆线虫蛋白酶体α5基因(pas-5),构建其重组质粒,探讨PAS-5重组蛋白对人THP-1巨噬细胞凋亡的影响。方法以广州管圆线虫逆转录DNA为模板,PCR扩增pas-5基因,构建pcoldⅢ-pas-5重组质粒,转化至大肠埃希菌DH5α感受态细胞,... 目的获得广州管圆线虫蛋白酶体α5基因(pas-5),构建其重组质粒,探讨PAS-5重组蛋白对人THP-1巨噬细胞凋亡的影响。方法以广州管圆线虫逆转录DNA为模板,PCR扩增pas-5基因,构建pcoldⅢ-pas-5重组质粒,转化至大肠埃希菌DH5α感受态细胞,取菌液进行PCR、双酶切和测序鉴定。阳性质粒经0.1 mmol/L异丙基-β-D-硫代半乳糖苷诱导表达后,十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)和蛋白质印迹(Western blotting)分析重组蛋白表达情况,采用镍离子亲和层析法纯化重组蛋白。将用佛波酯诱导的人THP-1巨噬细胞经PAS-5(实验组)孵育18 h后,采用流式细胞术观察细胞凋亡情况,采用ELISA检测细胞培养上清中细胞因子白细胞介素-10(IL-10)水平,另设阴性对照组(牛血清白蛋白)和空白对照组(RPMI1640)。结果Pas-5基因PCR扩增产物约为800 bp,与预期大小相符。经菌液PCR、双酶切和测序鉴定获得pcoldⅢ-pas-5重组质粒。SDS-PAGE分析结果显示,PAS-5重组蛋白主要以包涵体形式存在,其相对分子质量约28 000。Western blotting分析结果显示,重组蛋白能与兔抗鼠His单克隆抗体特异性结合。镍离子亲和层析纯化重组蛋白后获得单一条带。流式细胞术分析结果显示,阴性对照组和实验组人THP-1巨噬细胞凋亡率分别为(0.380±0.194)%和(0.052±0.036)%,两者差异有统计学意义(P〈0.05)。ELISA检测结果显示,实验组细胞培养上清中IL-10水平为(77.606±1.766)pg/ml,高于阴性对照组的(45.652±5.975)pg/ml(P〈0.05)。结论获得了pas-5基因和重组质粒pcoldⅢ-pas-5,重组蛋白PAS-5可抑制人THP-1巨噬细胞凋亡,与IL-10水平提高有一定关系。 展开更多
关键词 广州管圆线虫 蛋白酶体 重组蛋白 人THP-1巨噬细胞 凋亡
Ubiquitin-proteasome system and oxidative stress in liver transplantation 预览
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作者 Norma Alva Arnau Panisello-Roselló +2 位作者 Marta Flores Joan Roselló-Catafau Teresa Carbonell 《世界胃肠病学杂志:英文版》 SCIE CAS 2018年第31期3521-3530,共10页
A major issue in organ transplantation is the development of a protocol that can preserve organs under optimal conditions.Damage to organs is commonly a consequence of flow deprivation and oxygen starvation following ... A major issue in organ transplantation is the development of a protocol that can preserve organs under optimal conditions.Damage to organs is commonly a consequence of flow deprivation and oxygen starvation following the restoration of blood flow and reoxygenation.This is known as ischemia-reperfusion injury(IRI):a complex multifactorial process that causes cell damage.While the oxygen deprivation due to ischemia depletes cell energy,subsequent tissue oxygenation due to reperfusion induces many cascades,from reactive oxygen species production to apoptosis initiation.Autophagy has also been identified in the pathogenesis of IRI,although such alterations and their subsequent functional significance are controversial.Moreover,proteasome activation may be a relevant pathophysiological mechanism.Different strategies have been adopted to limit IRI damage,including the supplementation of commercial preservation media with pharmacological agents or additives.In this review,we focus on novel strategies related to the ubiquitin proteasome system and oxidative stress inhibition,which have been used to minimize damage in liver transplantation. 展开更多
关键词 Liver TRANSPLANT ISCHEMIA-REPERFUSION injury OXIDATIVE stress PROTEASOME Redox regulation UBIQUITIN
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慢性阻塞性肺疾病患者蛋白酶体活性与日常体力活动的关系 预览
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作者 张霞 雍文穆 +4 位作者 李军委 侯亚儒 李艳红 仲健 郭秋野 《南昌大学学报:医学版》 CAS 2018年第3期45-48,共4页
目的探讨COPD患者蛋白酶体活性与日常体力活动的关系. 方法 选择174例慢性阻塞性肺疾病(COPD)住院患者为研究组,年龄55-74岁,平均(61.2±7.6)岁;选择同期健康体检的206名健康人群作为对照组.用六分钟步行试验(6MWT)明确2组研... 目的探讨COPD患者蛋白酶体活性与日常体力活动的关系. 方法 选择174例慢性阻塞性肺疾病(COPD)住院患者为研究组,年龄55-74岁,平均(61.2±7.6)岁;选择同期健康体检的206名健康人群作为对照组.用六分钟步行试验(6MWT)明确2组研究对象的体力活动水平(佩戴三轴运动加速度计),测量2组研究对象的体质量、身高、体脂含量(以去脂体块指数表示)、上臂围、小腿围.采用酶联免疫吸附试验检测血清蛋白酶体活性.采用Masterscreen-PET肺功能仪检测肺功能.用多因素Logistic回归分析COPD患者日常体力活动的影响因素. 结果 2组年龄、性别构成、BMI、上臂围、小腿围、去脂体块指数、高血压和糖尿病病史的比较,差异无统计学意义( P 〉0.05).研究组的吸烟率和饮酒率高于对照组( P 〈0.05, P 〈0.01),研究组肺功能指标(FEV1/FVC%)明显低于对照组( P 〈0.05),研究组的日常体力活动及6 MWT均明显少于对照组( P 〈0.05),研究组血清蛋白酶体活性明显高于对照组( P 〈0.05).多因素Logistic回归分析结果显示:高龄(≥60岁)、男性患者、吸烟、肺功能不良、蛋白酶体活性升高是影响COPD患者日常体力活动的独立危险因素. 结论 COPD患者血清蛋白酶体活性可能影响患者日常体力活动. 展开更多
关键词 慢性阻塞性肺疾病 蛋白酶体 日常体力活动 多因素分析
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泛素-蛋白酶体途径与肝脏疾病的研究进展
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作者 吕莹 胡勇 《医学分子生物学杂志》 CAS 2018年第2期120-124,共5页
泛素-蛋白酶体途径(ubiquitin-proteasome pathway,UPP)是存在于真核细胞中精确调控细胞质和细胞核内蛋白质有序降解的途径,由泛素(Ub)、泛素激活酶(E1)、泛素结合酶(E2)、泛素连接酶(E3)、26S蛋白酶体和去泛素化酶(DUBs... 泛素-蛋白酶体途径(ubiquitin-proteasome pathway,UPP)是存在于真核细胞中精确调控细胞质和细胞核内蛋白质有序降解的途径,由泛素(Ub)、泛素激活酶(E1)、泛素结合酶(E2)、泛素连接酶(E3)、26S蛋白酶体和去泛素化酶(DUBs)组成。UPP存在于真核细胞整个生命过程中,参与并调节该细胞的各种生命活动,包括细胞周期调控、细胞信号转导、蛋白质降解、DNA修复及基因表达等,其异常表达与多种疾病的发生密切相关。文章在介绍了泛素.蛋白酶体系统的组成、功能的基础上,阐述了其对肝脏疾病影响的研究进展。 展开更多
关键词 泛素 蛋白酶体 肝脏疾病
Effect of -Lipoic Acid on Proteasomal Induction: Protection against Oxidative Damage in Human Skin Fibroblasts Cell Line NHDF 预览
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作者 Sohely Sikdar Maria Papadopoulou Jacques Dubois 《药理与制药(英文)》 2017年第9期292-305,共14页
As human skin is daily exposed to oxidative stress causing various unesthetical abnormalities, the road to effective anti-aging substances is being widely investigated. 20S proteasome is a key pathway in the breakdown... As human skin is daily exposed to oxidative stress causing various unesthetical abnormalities, the road to effective anti-aging substances is being widely investigated. 20S proteasome is a key pathway in the breakdown of oxidized proteins. But its activity declines dramatically in aging cells. Nrf2 inducers -lipoic acid (LA) and sulforaphane (SFN) have been described in the dietary industries for their antioxidant effects on various cell lines. However, since little is yet known about LA’s capacity to protect skin cells from premature and extrinsic aging;our aim was to demonstrate the beneficial effect of LA on the cellular detoxification systems. On this purpose, we evaluated its effects against injuries induced by H2O2 in NHDF and its likely positive effect on the chymotrypsin-like (CT-like) activity of 20S proteasome, using SFN as a reference. The cellular content in proteins was measured, as well as the production of Reactive Oxygen Species (ROS). Also, the induction of the proteasomal protein expression was investigated. The results show that after 48 h treatment, LA significantly decreased the percentage of ROS positive cells. Also, LA decreased the level of H2O2-induced carbonylated proteins and increased the proteasomal activity. Furthermore, LA upregulated the expression of the 20S proteasome &#223;-subunit responsible for the CT-like activity (PSMB5). Overall, both molecules enhanced cell proliferation over 8 days. So, our investigation found evidence of the higher capacity of LA to induce 20S proteasome activity with less toxicity in human fibroblasts compared to reference molecule SFN. These results tend to demonstrate that the induction of the proteasomal activity might be a part of the antioxidant potential of LA. To our knowledge, this is the first study to elucidate the capacity of LA to activate detoxification systems in human cell lines through the induction of 20S proteasome. 展开更多
关键词 Lipoic Acid PROTEASOME SKIN FIBROBLASTS OXIDATIVE Stress
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