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91.
Quantification of alpha-synuclein binding to lipid vesicles using fluorescence correlation spectroscopy 下载免费PDF全文
Alpha-synuclein (alphaS) is a soluble synaptic protein that is the major proteinaceous component of insoluble fibrillar Lewy body deposits that are the hallmark of Parkinson's disease. The interaction of alphaS with synaptic vesicles is thought to be critical both to its normal function as well as to its pathological role in Parkinson's disease. We demonstrate the use of fluorescence correlation spectroscopy as a tool for rapid and quantitative analysis of the binding of alphaS to large unilamellar vesicles of various lipid compositions. We find that alphaS binds preferentially to vesicles containing acidic lipids, and that this interaction can be blocked by increasing the concentration of NaCl in solution. Negative charge is not the only factor determining binding, as we clearly observe binding to vesicles composed entirely of zwitterionic lipids. Additionally, we find enhanced binding to lipids with less bulky headgroups. Quantification of the protein-to-lipid ratio required for binding to different lipid compositions, combined with other data in the literature, yields an upper bound estimate for the number of lipid molecules required to bind each individual molecule of alphaS. Our results demonstrate that fluorescence correlation spectroscopy provides a powerful tool for the quantitative characterization of alphaS-lipid interactions. 相似文献
92.
Jasmonates act as signal transduction intermediates when plants are subjected to environmental stresses such as UV radiation, osmotic shock and heat. In the past few years several groups have reported that jasmonates exhibit anti-cancer activity in vitro and in vivo and induce growth inhibition in cancer cells, while leaving the non-transformed cells intact. Recently, jasmonates were also discovered to have cytotoxic effects towards metastatic melanoma both in vitro and in vivo.Three mechanisms of action have been proposed to explain this anti-cancer activity. The bio-energetic mechanism – jasmonates induce severe ATP depletion in cancer cells via mitochondrial perturbation. Furthermore, methyl jasmonate (MJ) has the ability to detach hexokinase from the mitochondria. Second, jasmonates induce re-differentiation in human myeloid leukemia cells via mitogen-activated protein kinase (MAPK) activity and were found to act similar to the cytokinin isopentenyladenine (IPA). Third, jasmonates induce apoptosis in lung carcinoma cells via the generation of hydrogen peroxide, and pro-apoptotic proteins of the Bcl-2 family.Combination of MJ with the glycolysis inhibitor 2-deoxy-d-glucose (2DG) and with four conventional chemotherapeutic drugs resulted in super-additive cytotoxic effects on several types of cancer cells. Finally, jasmonates have the ability to induce death in spite of drug-resistance conferred by either p53 mutation or P-glycoprotein (P-gp) over-expression.In summary, the jasmonates are anti-cancer agents that exhibit selective cytotoxicity towards cancer cells, and thus present hope for the development of cancer therapeutics. 相似文献
93.
Carolina M. Avila Nelilma C. Romeiro Carlos M.R. Sant’Anna Eliezer J. Barreiro Carlos A.M. Fraga 《Bioorganic & medicinal chemistry letters》2009,19(24):6907-6910
This Letter describes the results of two combined approaches: homology modeling and molecular docking studies, in order to propose the molecular basis of IKKβ inhibition by staurosporine and quercetin as ATP-competitive inhibitors. The results provides a rationale and structural frameworks for designing potent ATP binding-site inhibitors of IKKβ, which is an attractive drug target for inflammatory diseases and has been found to be responsible for some of the already observed pharmacological effects for marketed drugs. 相似文献
94.
Menegatti R Silva GM Zapata-Sudo G Raimundo JM Sudo RT Barreiro EJ Fraga CA 《Bioorganic & medicinal chemistry》2006,14(3):632-640
The present study describes the synthesis and pharmacological profiles of four novel pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives 2-5, which were structurally designed by using the sedative and analgesic drug zolpidem 1 as lead compound. The heterotricyclic system present in the target compounds 2-5 was constructed in good yields, exploiting a regioselective hetero Diels-Alder reaction of the key azabutadiene derivative 7 and functionalized N-phenylmaleimides 9-12. Additionally, we identified that 1-methyl-7-(4-nitrophenyl)-3-phenyl-3,6,7,8-tetrahydropyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8-dione derivative (LASSBio-873, 5) presented not only the most potent ability to promote sedation, which was similar to that induced by the standard benzodiazepine drug midazolam, but also potent central antinociceptive effect. 相似文献
95.
Nailton M. Nascimento-Júnior Thaiana C.F. Mendes Daniella M. Leal Claudia Maria N. Corrêa Roberto T. Sudo Gisele Zapata-Sudo Eliezer J. Barreiro Carlos A.M. Fraga 《Bioorganic & medicinal chemistry letters》2010,20(1):74-77
We described herein the optimization of the synthetic methodology exploited to obtain the pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine sedative prototype 1a and novel analogues designed by successive molecular simplifications. By applying microwave irradiation during the hetero Diels-Alder key-step to obtain the heterotricyclic scaffold, under solvent-free conditions, we were able to obtain the desired compounds in drastically shorter times and better yields. Additionally, in vivo evaluation of the sedative effects of these heterocyclic derivatives showed that 1a and the novel structurally-related analogue 1e were the most efficient compounds to impair the locomotor activity in mice at the dose of 10 μmol/kg. 相似文献
96.
Price DL Rockenstein E Ubhi K Phung V MacLean-Lewis N Askay D Cartier A Spencer B Patrick C Desplats P Ellisman MH Masliah E 《PloS one》2010,5(11):e14020
Dementia with Lewy bodies (DLB) and Parkinson's Disease (PD) are neurodegenerative disorders of the aging population characterized by the abnormal accumulation of alpha-synuclein (alpha-syn). Previous studies have suggested that excitotoxicity may contribute to neurodegeneration in these disorders, however the underlying mechanisms and their relationship to alpha-syn remain unclear. For this study we proposed that accumulation of alpha-syn might result in alterations in metabotropic glutamate receptors (mGluR), particularly mGluR5 which has been linked to deficits in murine models of PD. In this context, levels of mGluR5 were analyzed in the brains of PD and DLB human cases and alpha-syn transgenic (tg) mice and compared to age-matched, unimpaired controls, we report a 40% increase in the levels of mGluR5 and beta-arrestin immunoreactivity in the frontal cortex, hippocampus and putamen in DLB cases and in the putamen in PD cases. In the hippocampus, mGluR5 was more abundant in the CA3 region and co-localized with alpha-syn aggregates. Similarly, in the hippocampus and basal ganglia of alpha-syn tg mice, levels of mGluR5 were increased and mGluR5 and alpha-syn were co-localized and co-immunoprecipitated, suggesting that alpha-syn interferes with mGluR5 trafficking. The increased levels of mGluR5 were accompanied by a concomitant increase in the activation of downstream signaling components including ERK, Elk-1 and CREB. Consistent with the increased accumulation of alpha-syn and alterations in mGluR5 in cognitive- and motor-associated brain regions, these mice displayed impaired performance in the water maze and pole test, these behavioral alterations were reversed with the mGluR5 antagonist, MPEP. Taken together the results from study suggest that mGluR5 may directly interact with alpha-syn resulting in its over activation and that this over activation may contribute to excitotoxic cell death in select neuronal regions. These results highlight the therapeutic importance of mGluR5 antagonists in alpha-synucleinopathies. 相似文献
97.
98.
Yao Li C Shi JX Weiss D Goldschmidt EE 《Biochemical and biophysical research communications》2003,306(2):402-407
We report the isolation and characterization of two sucrose transporter cDNAs (CitSUT1 and CitSUT2) from citrus. CitSUT1 and CitSUT2 encode putative proteins (CitSUT1 and CitSUT2) of 528 and 607 amino acids, respectively. CitSUT1 and CitSUT2 share high similarities with sucrose transporters isolated from other plants. The expression of CitSUT1 in mature leaf discs is repressed by exogenous sucrose, glucose, mannose, and the glucose analog 2-deoxyglucose but not by another glucose analog 3-O-methylglucose, indicating a hexokinase (HXK)-mediated signaling pathway. CitSUT2 expression is not affected by exogenous sugars. Whereas CitSUT1 expresses strongly in source, sugar exporting organs, CitSUT2 expresses more strongly in sink, sugar importing organs, suggesting different physiological roles for these sucrose transporters. 相似文献
99.
100.
Hsp70 Reduces alpha-Synuclein Aggregation and Toxicity 总被引:5,自引:0,他引:5
Klucken J Shin Y Masliah E Hyman BT McLean PJ 《The Journal of biological chemistry》2004,279(24):25497-25502
Aggregation and cytotoxicity of misfolded alpha-synuclein is postulated to be crucial in the disease process of neurodegenerative disorders such as Parkinson's disease and DLB (dementia with Lewy bodies). In this study, we detected misfolded and aggregated alpha-synuclein in a Triton X-100 insoluble fraction as well as a high molecular weight product by gel electrophoresis of temporal neocortex from DLB patients but not from controls. We also found similar Triton X-100 insoluble forms of alpha-synuclein in an alpha-synuclein transgenic mouse model and in an in vitro model of alpha-synuclein aggregation. Introducing the molecular chaperone Hsp70 into the in vivo model by breeding alpha-synuclein transgenic mice with Hsp70-overexpressing mice led to a significant reduction in both the high molecular weight and detergent-insoluble alpha-synuclein species. Concomitantly, we found that Hsp70 overexpression in vitro similarly reduced detergent-insoluble alpha-synuclein species and protected cells from alpha-synuclein-induced cellular toxicity. Taken together, these data demonstrate that the molecular chaperone Hsp70 can reduce the amount of misfolded, aggregated alpha-synuclein species in vivo and in vitro and protect it from alpha-synuclein-dependent toxicity. 相似文献