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《Molecular & cellular proteomics : MCP》2022,21(12):100433
Molecular changes in the brain of individuals afflicted with Alzheimer's disease (AD) are an intense area of study. Little is known about the role of protein abundance and posttranslational modifications in AD progression and treatment, in particular large-scale intact N-linked glycoproteomics analysis. To elucidate the N-glycoproteome landscape, we developed an approach based on multi-lectin affinity enrichment, hydrophilic interaction chromatography, and LC-MS–based glycoproteomics. We analyzed brain tissue from 10 persons with no cognitive impairment or AD, 10 with asymptomatic AD, and 10 with symptomatic AD, detecting over 300 glycoproteins and 1900 glycoforms across the samples. The majority of glycoproteins have N-glycans that are high-mannosidic or complex chains that are fucosylated and bisected. The Man5 N-glycan was found to occur most frequently at >20% of the total glycoforms. Unlike the glycoproteomes of other tissues, sialylation is a minor feature of the brain N-glycoproteome, occurring at <9% among the glycoforms. We observed AD-associated differences in the number of antennae, frequency of fucosylation, bisection, and other monosaccharides at individual glycosylation sites among samples from our three groups. Further analysis revealed glycosylation differences in subcellular compartments across disease stage, including glycoproteins in the lysosome frequently modified with paucimannosidic glycans. These results illustrate the N-glycoproteomics landscape across the spectrum of AD clinical and pathologic severity and will facilitate a deeper understanding of progression and treatment development. 相似文献
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Benjamin C. Blum Weiwei Lin Matthew L. Lawton Qian Liu Julian Kwan Isabella Turcinovic Ryan Hekman Pingzhao Hu Andrew Emili 《Molecular & cellular proteomics : MCP》2022,21(1):100189
Metabolism is recognized as an important driver of cancer progression and other complex diseases, but global metabolite profiling remains a challenge. Protein expression profiling is often a poor proxy since existing pathway enrichment models provide an incomplete mapping between the proteome and metabolism. To overcome these gaps, we introduce multiomic metabolic enrichment network analysis (MOMENTA), an integrative multiomic data analysis framework for more accurately deducing metabolic pathway changes from proteomics data alone in a gene set analysis context by leveraging protein interaction networks to extend annotated metabolic models. We apply MOMENTA to proteomic data from diverse cancer cell lines and human tumors to demonstrate its utility at revealing variation in metabolic pathway activity across cancer types, which we verify using independent metabolomics measurements. The novel metabolic networks we uncover in breast cancer and other tumors are linked to clinical outcomes, underscoring the pathophysiological relevance of the findings. 相似文献
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《Bioorganic & medicinal chemistry》2016,24(7):1419-1430
Parkinson’s disease (PD) is a common chronic degenerative disease of the central nervous system. Due to a rapidly aging society worldwide, PD morbidity is on the rise; however, the treatment of PD with conventional drugs carries serious adverse reactions and cannot fix the root cause of PD, the degeneration of dopaminergic neurons, which limits conventional drug usage in clinical practice. In recent years, research on the pathogenesis of PD and its clinical manifestations has led to the discovery of an increasing number of novel targets in PD, including several small molecule targeted compounds. In this paper, we analyze and summarize the most recently published PD literature and review several recently discovered novel targets in PD and their small molecule targeted pharmacologically active agents based on their mechanisms of action and pharmacodynamic profiles. 相似文献
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Background and aimAβ1−42 is an amyloidogenic peptide found within senile plaques extracted from those who died with a diagnosis of Alzheimer’s disease. The potent neurotoxicity of this peptide is related to its propensity to form aggregated conformations in vivo, a process that is influenced by the species and concentration of metal ions present within the local environment. This study examines the impact of different metals upon the early aggregatory behaviour and size of Aβ1−42 under simulated physiological conditions.MethodsThe size and aggregatory behaviour of Aβ1−42 in the presence and absence of metal ions was monitored during the initial 30 min of fibril formation in real-time using dynamic light scattering.ResultsIntensity scattering measurements showed a clear tendency towards aggregation with regards to Aβ1−42 only solutions (10 μM). Both equimolar Al3+ & Cu2+ lowered and stabilised the dimensions of Aβ1−42 aggregates; however, a diminutive but significant increase in size was still observed over a 30-min period. While excess Al3+ continued to supress the size of Aβ1−42, a 10-fold increase in the concentration of Cu2+ accelerated peptide aggregation relative to that observed for equimolar metal but not compared to Aβ1−42 alone.ConclusionThese results infer that Al3+ ions stabilise and aid in the maintenance of smaller, toxic intermediates while excess Cu2+ facilitates the formation of larger, more inert, amorphous species exceeding 1 μm in size. Furthermore, we propose that metal-induced toxicity of Aβ1−42 is reflective of their ability to preserve smaller oligomeric species in vitro. 相似文献
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《Bioorganic & medicinal chemistry letters》2019,29(15):1957-1961
In our efforts to further investigate the impact of the spacer and membrane anchor to the neuroprotective activities, a series of bivalent compounds that contain cholesterol and extended spacers were designed, synthesized and biologically characterized. Our results support previous studies that incorporation of a piperazine ring into the spacer significantly improved the protective potency of bivalent compounds in MC65 cell model. Spacer length beyond 21 atoms does not add further benefits with 21MO being the most potent one with an EC50 of 81.86 ± 11.91 nM. Our results also demonstrated that bivalent compound 21MO suppressed the production of mitochondria reactive oxygen species. Furthermore, our results confirmed that both of the spacer and membrane anchor moiety are essential to metal binding. Collectively, the results provide further evidence and information to guide optimization of such bivalent compounds as potential neuroprotectants for Alzheimer’s disease. 相似文献
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《Bioorganic & medicinal chemistry letters》2019,29(15):1968-1973
Aberrant activation of calpain has been observed in various pathophysiological disorders including neurodegenerative diseases such as Alzheimer’s Disease. Here we describe our efforts on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded to clinical phase I studies. 相似文献
19.
Ling Wang Yu Wang Yiguang Tian Jinling Shang Xiaoou Sun Hongzhuan Chen Hao Wang Wen Tan 《Bioorganic & medicinal chemistry》2017,25(1):360-371
A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC50 to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out. Furthermore, compound 3 blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells and shows the required druggability and low cytotoxicity, suggesting this hybrid is a promising multifunctional drug candidate for Alzheimer’s disease (AD) treatment. 相似文献
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