Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alzheimer's disease (AD) is a complex disorder associated with multiple genetic defects either mutational or of susceptibility. Information available on AD genetics does not explain in full the etiopathogenesis of AD, suggesting that environmental factors and/or epigenetic phenomena may also contribute to AD pathology and phenotypic expression of dementia. The genomics of AD is still in its infancy, but is helping to understand novel aspects of the disease including genetic epidemiology, multifactorial risk factors, pathogenic mechanisms associated with genetic networks and genetically-regulated metabolic cascades. AD genomics is also helping to develop new strategies in pharmacogenomic research and prevention. Functional genomics, proteomics, pharmacogenomics, high-throughput methods, combinatorial chemistry and modern bioinformatics will greatly contribute to accelerate drug development for AD and other complex disorders. Main genes involved in AD include mutational loci (APP, PS1, PS2, TAU) and multiple susceptibility loci (APOE, A2M, AACT, LRP1, IL1A, TNF, ACE, BACE, BCHE, CST3, MTHFR, GSK3B, NOS) distributed across the human genome. Genomic associations integrate bigenic, trigenic, tetragenic or polygenic matrix models to investigate the genomic organization of AD in comparison to the control population. Similar genetic models are used in pharmacogenomics to elucidate genotype-specific responses of AD patients to a particular drug or combination of drugs. Using APOE-related monogenic models it has been demonstrated that the therapeutic response to drugs in AD is genotype-specific. A multifactorial therapy combining 3 different drugs yielded positive results during the 6-12 months in approximately 60% of the patients. With this therapeutic strategy, APOE-4/4 carriers were the worst responders, and patients with the APOE-3/4 genotype were the best responders. In bigenic and trigenic models it was possible to differentiate the influencial effect of PS1 and PS2 polymorphic variants on mental performance in response to multifactorial therapy. The application of functional genomics to AD can be a suitable strategy for harmonization in molecular diagnosis and drug clinical trials. Furthermore, the pharmacogenomics of AD may contribute in the future to optimise drug development and therapeutics, increasing efficacy and safety, and reducing side-effects and unnecessary costs.
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PMID:Pharmacogenomics in Alzheimer's disease. 1236 58

The transport of arginine has been characterized in human airway Calu-3 cells. As assessed with RT-PCR, Calu-3 cells express the genes for several transporters, such as the system y+-related SLC7A1, SLC7A2, and SLC7A4; the system y+L-related SLC7A6, SLC7A7, and SLC3A2; and the system B0,+-related SLC6A14. In polarized Calu-3 cell monolayers, apical arginine influx has a leucine-sensitive, sodium-dependent component and a leucine- and lysine-resistant sodium-independent fraction. At the basolateral membrane, arginine transport was fully sodium-independent and partially inhibited by leucine provided that sodium was present in the extracellular medium. Moreover, extracellular leucine trans-stimulated arginine efflux from the basolateral membrane in the presence, but not in the absence, of sodium. The transepithelial, apical to basolateral, arginine transport strictly depended on the presence of sodium and was markedly inhibited by apical leucine, but significantly trans-stimulated by the neutral amino acid added at the basolateral side. When added at the apical side, the NOS-inhibitors NMMA and NIL, CAA analogs with a free carboxyl group, markedly inhibited the apical arginine influx and the transepithelial flux of the cationic amino acid. The same compounds trans-stimulated basolateral arginine efflux. None of these effects were observed in the presence of the methyl ester analog NAME. The basolateral medium of Calu-3 cell monolayers, obtained after incubation in the presence of the three inhibitors at the apical side, inhibited the production of NO by activated murine macrophages. The inhibitory effect of the Calu-3 cell conditioned medium was time-dependent and markedly higher with NMMA and NIL than with NAME. Moreover, the NOS-inhibitory effect of the medium was significantly enhanced if NMMA and NIL, at the apical side, and basolateral leucine were simultaneously present during the conditioning procedure. These results indicate that 1) human airway epithelial cells express a functional system y+L at the basolateral membrane; 2) in this model, transepithelial arginine transport involves apical influx through system B0,+ and basolateral efflux through system y+L, and 3) the same transporters also perform an efficient transepithelial transport of amino acid-like NOS inhibitors.
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PMID:The transport of cationic amino acids in human airway cells: expression of system y+L activity and transepithelial delivery of NOS inhibitors. 1574 85