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Caspases, effectors of apoptosis, are key mediators of neuronal death in several neurodegenerative diseases. Caspase-8 and caspase-6 have been implicated in the pathogenesis of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease (AD). ß-Amyloid precursor protein (APP) is cleaved at Asp664 in its intracellular domain by caspase-8. We and other laboratories recently showed that obliteration of the caspase cleavage site on APP alleviates functional AD-like deficits in a mouse model. Therefore, caspase cleavage of APP constitutes a potential novel target for therapeutic intervention. To identify chemical inhibitors of caspase-8 cleavage, we screened a subset of the chemical library at the Harvard NeuroDiscovery Center’s Laboratory for Drug Discovery in Neurodegeneration. We show that caspase-8, but not caspase-1, -3, or -9, cleaves a biotinylated peptide derived from APP at Asp664, and we report the development of a sensitive high-throughput assay for caspase-8 cleavage of APP and the use of that assay for the identification of specific small molecule “hit” compounds that potently inhibit Asp664 cleavage of APP. Furthermore, we demonstrate that one of these compounds (LDN-0021835) inhibits the cleavage of APP at Asp664 in cell-based assays. 相似文献
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Jain MR Li Q Liu T Rinaggio J Ketkar A Tournier V Madura K Elkabes S Li H 《Journal of proteome research》2012,11(3):1791-1803
Clinically relevant formalin-fixed and paraffin-embedded (FFPE) tissues have not been widely used in neuroproteomic studies because many proteins are presumed to be degraded during tissue preservation. Recent improvements in proteomics technologies, from the 2D gel analysis of intact proteins to the "shotgun" quantification of peptides and the use of isobaric tags for absolute and relative quantification (iTRAQ) method, have made the analysis of FFPE tissues possible. In recent years, iTRAQ has been one of the main methods of choice for high throughput quantitative proteomics analysis, which enables simultaneous comparison of up to eight samples in one experiment. Our objective was to assess the relative merits of iTRAQ analysis of fresh frozen versus FFPE nervous tissues by comparing experimental autoimmune encephalomyelitis (EAE)-induced proteomic changes in FFPE rat spinal cords and frozen tissues. EAE-induced proteomic changes in FFPE tissues were positively correlated with those found in the frozen tissues, albeit with ~50% less proteome coverage. Subsequent validation of the enrichment of immunoproteasome (IP) activator 1 in EAE spinal cords led us to evaluate other proteasome and IP-specific proteins. We discovered that many IP-specific (as opposed to constitutive) proteasomal proteins were enriched in EAE rat spinal cords, and EAE-induced IP accumulation also occurred in the spinal cords of an independent mouse EAE model in a disability score-dependent manner. Therefore, we conclude that it is feasible to generate useful information from iTRAQ-based neuroproteomics analysis of archived FFPE tissues for studying neurological disease tissues. 相似文献
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Adkar BV Tripathi A Sahoo A Bajaj K Goswami D Chakrabarti P Swarnkar MK Gokhale RS Varadarajan R 《Structure (London, England : 1993)》2012,20(2):371-381
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Negative charges at protein kinase C sites of troponin I stabilize the inactive state of actin
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Alterations in the troponin complex can lead to increases or decreases in contractile activity. Most mutations of troponin that cause hypertrophic cardiomyopathy increase the activity of cardiac muscle fibers. In at least some cases these mutants stabilize the active state of regulated actin. In contrast, phosphorylation of troponin I at residues 43, 45, and 144 inhibits muscle contractility. To determine if alterations of troponin I that reduce activity do stabilize the inactive state of actin, we introduced negative charges at residues 43, 45, and 144 of troponin I to mimic a constitutively phosphorylated state. At saturating calcium, all mutants decreased ATPase rates relative to wild-type actin-tropomyosin-troponin. Reduced activation of ATPase activity was seen with a single mutation at S45E and was not further altered by mutating the other two sites. In the presence of low concentrations of NEM-S1, wild-type troponin was more active than the mutants. At high NEM-S1, the rates of wild-type and mutants approached the same limiting value. Changes in Ca2+ affinity also support the idea that the equilibrium between states of actin-tropomyosin-troponin was shifted to the inactive state by mutations that mimic troponin I phosphorylation. 相似文献
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Although the amino acid glutamate is used as an intercellular signaling molecule for normal bone homeostasis, little is known regarding its possible role in the metabolic disruption characteristic of bone metastasis. We have previously shown in vitro that cancer cell lines relevant to bone metastasis release glutamate into the extracellular environment. This study demonstrates the expression of multiple glutamate transporters in cancer cell lines of non-central nervous system origin. Furthermore, we identify the molecular mechanism responsible for glutamate export and show that this system can be inhibited pharmacologically. By highlighting that glutamate secretion is a common biological feature of cancer cells, this study suggests that tumor-derived glutamate could interfere with glutamate-dependent intercellular signaling in normal bone. Pharmacological interference with cancer cell glutamate release may be a viable option for limiting host bone response to invading tumor cells in bone metastasis. 相似文献
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Exosomes secreted by hypoxic cardiosphere‐derived cells enhance tube formation and increase pro‐angiogenic miRNA
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