排序方式: 共有74条查询结果,搜索用时 15 毫秒
51.
Rubinsztein DC DiFiglia M Heintz N Nixon RA Qin ZH Ravikumar B Stefanis L Tolkovsky A 《Autophagy》2005,1(1):11-22
Increased numbers of autophagosomes/autophagic vacuoles are seen in a variety of physiological and pathological states in the nervous system. In many cases, it is unclear if this phenomenon is the result of increased autophagic activity or decreased autophagosome-lysosome fusion. The functional significance of autophagy and its relationship to cell death in the nervous system is also poorly understood. In this review, we have considered these issues in the context of acute neuronal injury and a range of chronic neurodegenerative conditions, including the Lurcher mouse, Alzheimer's, Parkinson's, Huntington's and prion diseases. While many issues remain unresolved, these conditions raise the possibility that autophagy can have either deleterious or protective effects depending on the specific situation and stage in the pathological process. 相似文献
52.
Alpha-Synuclein is degraded by both autophagy and the proteasome 总被引:19,自引:0,他引:19
Webb JL Ravikumar B Atkins J Skepper JN Rubinsztein DC 《The Journal of biological chemistry》2003,278(27):25009-25013
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of aggregates (Lewy bodies) in neurons. alpha-Synuclein is the major protein in Lewy bodies and rare mutations in alpha-synuclein cause early-onset PD. Consequently, alpha-synuclein is implicated in the pathogenesis of PD. Here, we have investigated the degradation pathways of alpha-synuclein, using a stable inducible PC12 cell model, where the expression of exogenous human wild-type, A30P, or A53T alpha-synuclein can be switched on and off. We have used a panel of inhibitors/stimulators of autophagy and proteasome function and followed alpha-synuclein degradation in these cells. We found that not only is alpha-synuclein degraded by the proteasome, but it is also degraded by autophagy. A role for autophagy was further supported by the presence of alpha-synuclein in organelles with the ultrastructural features of autophagic vesicles. Since rapamycin, a stimulator of autophagy, increased clearance of alpha-synuclein, it merits consideration as a potential therapeutic for Parkinsons disease, as it is designed for chronic use in humans. 相似文献
53.
Bryan Brinda Irum Khan Brian Parkin Heiko Konig 《Journal of cellular and molecular medicine》2018,22(3):1411-1427
Acute myeloid leukaemia (AML) is a malignant disorder of the myeloid blood lineage characterized by impaired differentiation and increased proliferation of hematopoietic precursor cells. Recent technological advances have led to an improved understanding of AML biology but also uncovered the enormous cytogenetic and molecular heterogeneity of the disease. Despite this heterogeneity, AML is mostly managed by a ‘one‐size‐fits‐all’ approach consisting of intensive, highly toxic induction and consolidation chemotherapy. These treatment protocols have remained largely unchanged for the past several decades and only lead to a cure in approximately 30–35% of cases. The advent of targeted therapies in chronic myeloid leukaemia and other malignancies has sparked hope to improve patient outcome in AML. However, the implementation of targeted agents in AML therapy has been unexpectedly cumbersome and remains a difficult task due to a variety of disease‐ and patient‐specific factors. In this review, we describe current standard and investigational therapeutic strategies with a focus on targeted agents and highlight potential tools that might facilitate the development of targeted therapies for this fatal disease. The classes of agents described in this review include constitutively activated signalling pathway inhibitors, surface receptor targets, epigenetic modifiers, drugs targeting the interaction of the hematopoietic progenitor cell with the stroma and drugs that target the apoptotic machinery. The clinical context and outcome with these agents will be examined to gain insight about their optimal utilization. 相似文献
54.
Binding isotherms can provide quantitive information regarding the stability of a molecular complex. Theorectical studies in recent years have been directed to systems in which a single ligand can exclude more than one polymer site (excluded-site effect). This system has minium of thre parameters to describe the binding data: the intrinsic binding constant, B; the remote-neighbor cooperative paramaters, σq and the number of excluded sites, q. It is suggested in the present communication that precise values for these three parameters can be obtained by utilizing the characteristics of two forms of data representation: θ vs ln m and θ/m vs θ, where θ is the degree of saturation (0?θ?1) and m is the molality of free ligand. The matrix generation method is used to obtain empirical equations relating the midpoint location and slope at the midpoint of the θ vs ln m plot to the three molecular parameters. A modified Scatchard theory is also presented for highly cooperative systems, which results in an expression relaing the maximum in the θ/m vs θ plot to the molecular parameters σq and q, thus providing the third equation for the three unknown parameters. The novel method f analysis is illustrated with the AMP-poly(L -arginine) and oligocytidylate–T7 DNA sstems. 相似文献
55.
Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension 总被引:1,自引:0,他引:1
56.
Brinda Somanadhan Weng-Keong Loke Meng-Kwoon Sim Mei-Lin Go 《Bioorganic & medicinal chemistry》2002,10(1):207-213
A series of quinuclidinone O-alkynyloximes (14-19) were synthesized and evaluated in radioligand displacement assays for binding affinities to M1-M3 muscarinic receptors. Radioligand displacement assays were carried out using [3H] oxotremorine-M and [3H] pirenzepine on rat cortical tissue and [3H] N-methylscopolamine on rat heart and submandibulary glands. Two alkynyloximes 15 and 18 had pirenzepine/oxotremorine M ratios which were indicative of muscarinic agonist and partial agonist activity, respectively. They were tested for their mnemonic effects in mice using the swimming escape task and found to attenuate scopolamine induced impairment of the task in mice at 2mg/kg. The results show that the O-alkynyloxime moiety linked to azacycles of appropriate size and rigidity (for example quinuclidine and tropane) is a potentially useful muscarinic pharmacophore that can be exploited for the design of muscarinic agonists. 相似文献
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58.
Susanne Cranz-Mileva Melissa C. Pamula Bipasha Barua Brinda Desai Yaejee Hannah Hong Jacquelyn Russell Richard Trent Jianqiu Wang Nancy C. Walworth Sarah E. Hitchcock-DeGregori 《PloS one》2013,8(10)
Tropomyosin, a coiled-coil protein that binds along the length of the actin filament, is a universal regulator of the actin cytoskeleton. We have taken a bioinformatics/proteomic approach to studying structure-function relationships in this protein. The presence of a single, essential tropomyosin gene, cdc8, in fission yeast, Schizosaccharomyces pombe, enables a systems-based approach to define the residues that are important for cellular functions. Using molecular evolution methodologies we identified the most conserved residues and related them to the coiled coil structure. Mutants in which one or more of 21 of the most conserved surface residues was mutated to Ala were tested for the ability to rescue growth of a temperature-sensitive cdc8 mutant when overexpressed at the restrictive temperature. Based on altered morphology of the septum and actin cytoskeleton, we selected three sets of mutations for construction of mutant cdc8 strains using marker reconstitution mutagenesis and analysis of recombinant protein in vitro: D16A.K30A, V114S.E117A.H118A and R121A.D131A.E138A. The mutations have sequence-specific effects on cellular morphology including cell length, organization of cytoskeletal structures (actin patches, actin cables and contractile rings), and in vitro actin affinity, lending credence to the proteomic approach introduced here. We propose that bioinformatics is a valid analysis tool for defining structure-function relationships in conserved proteins in this model organism. 相似文献
59.
Brinda Selvaraj Antonio J. Pierik Eckhard Bill Berta M. Martins 《Journal of biological inorganic chemistry》2013,18(6):633-643
4-Hydroxyphenylacetate decarboxylase (4Hpad) is an Fe/S cluster containing glycyl radical enzyme (GRE), which catalyses the last step of tyrosine fermentation in clostridia, generating the bacteriostatic p-cresol. The respective activating enzyme (4Hpad-AE) displays two cysteine-rich motifs in addition to the classical S-adenosylmethionine (SAM) binding cluster (RS cluster) motif. These additional motifs are also present in other glycyl radical activating enzymes (GR-AE) and it has been postulated that these orthologues may use an alternative SAM homolytic cleavage mechanism, generating a putative 3-amino-3-carboxypropyl radical and 5′-deoxy-5′-(methylthio)adenosine but not a 5′-deoxyadenosyl radical and methionine. 4Hpad-AE produced from a codon-optimized synthetic gene binds a maximum of two [4Fe–4S]2+/+ clusters as revealed by EPR and Mössbauer spectroscopy. The enzyme only catalyses the turnover of SAM under reducing conditions, and the reaction products were identified as 5′-deoxyadenosine (quenched form of 5′-deoxyadenosyl radical) and methionine. We demonstrate that the 5′-deoxyadenosyl radical is the activating agent for 4Hpad through p-cresol formation and correlation between the production of 5′-deoxyadenosine and the generation of glycyl radical in 4Hpad. Therefore, we conclude that 4Hpad-AE catalyses a classical SAM-dependent glycyl radical formation as reported for GR-AE without auxiliary clusters. Our observation casts doubt on the suggestion that GR-AE containing auxiliary clusters catalyse the alternative cleavage reaction detected for glycerol dehydratase activating enzyme. 相似文献
60.
Lei Bao Karen Messer Richard Schwab Olivier Harismendy Minya Pu Brian Crain Shawn Yost Kelly A. Frazer Brinda Rana Farnaz Hasteh Anne Wallace Barbara A. Parker 《PloS one》2015,10(11)