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151.
Duplantier AJ Dombroski MA Subramanyam C Beaulieu AM Chang SP Gabel CA Jordan C Kalgutkar AS Kraus KG Labasi JM Mussari C Perregaux DG Shepard R Taylor TJ Trevena KA Whitney-Pickett C Yoon K 《Bioorganic & medicinal chemistry letters》2011,21(12):3708-3711
High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X7 receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X7R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis. 相似文献
152.
153.
Ramudu SK Korivi M Kesireddy N Lee LC Cheng IS Kuo CH Kesireddy SR 《The Chinese journal of physiology》2011,54(2):79-86
Diabetes is characterized by elevated blood glucose levels and disturbed homeostasis of metabolic enzymes in whole-body. This study aimed to investigate the effect of ginger administration on altered blood glucose levels, intra- and extra-mitochondrial enzymes and tissue injuries in streptozotocin (STZ)-induced diabetic rats. Wistar strain rats (n = 30) were equally divided into 5 groups: normal control (NC), ginger treated (Gt, 200 mg/kg b.w. orally/30 days), diabetic control (DC, 50 mg/kg b.w.), diabetic plus ginger treated (D + Gt) and diabetic plus glibenclamide treated (D + Gli) groups. We found highly elevated blood glucose levels in the diabetic group, and the glucose levels were significantly (P < 0.001) lowered by ginger administration. Activities of intra- and extra-mitochondrial enzymes such as glucose-6-phosphate dehydrogenase (G6PD), succinate dehydrogenase (SDH), malate dehydrogenase (MDH) and glutamate dehydrogenase (GDH) were significantly (P < 0.01) decreased in the kidneys of the diabetic rats, while this was significantly reversed by 30 days of ginger treatment. We also observed consistent renal tissue damages in the diabetic rats; however, these injuries recovered in the ginger-treated diabetic rats as shown in histopathological studies. In this study, we demonstrated that an ethanolic extract of ginger could lower the blood glucose levels as well as improve activities of intra- and extra-mitochondrial enzymes in diabetic rats. Our results suggest that ginger extracts could be used as a nephro-protective supplement particularly to reverse diabetic-induced complications. 相似文献
154.
The physiological function of Photosystem I (PSI) is a sunlight energy converter, catalyzing one of the initial steps in driving oxygenic photosynthesis in cyanobacteria, algae and higher plants. The Chlamydomonas reinhardtii PSI structure was not known since it contains a unique structure having additional light harvesting complex I (LHCI) subunits, which play a major role in the transfer of sunlight energy to the reaction center. Here, individual subunits of LHC and core subunits are built based on the PDB taken from RCSB Protein Data Bank. The model gives information about the geometrical existence of subunits following a flanking order of Lhca5, Lhca1, Lhca6, Lhca4, Lhca2, Lhca8, Lhca9, Lhca7, and Lhca3. The new subunit PsaO is located close to the PsaH, PsaI and PsaL subunits, thus it may be involved in the state transition mechanism and stabilization of PSI-LHCI supercomplexes. The modeled PSI-LHCI structure of C. reinhardtii shows a unique arrangement of PsaN, PsaO of PSI core subunits and Lhca5 to Lhca9 of LHCI subunits. There are many non-covalent interactions among the PSI and LHCI subunits, which suggest that C. reinhardtii PSI-LHCI supercomplexes are more complex than higher plants. These results strongly support the experimental data that, even with harsh treatment of the PSI-LHCI supercomplexes with detergent, the complexes do not dissociate due to strong interactions between the PSI core and LHCI. Thus, our 3D model may give valid structural information of the PSI-LHCI arrangement and its physiological role in C. reinhardtii. 相似文献
155.
156.
Manoli DS Subramanyam D Carey C Sudin E Van Westerhuyzen JA Bales KL Blelloch R Shah NM 《PloS one》2012,7(5):e38119
The vast majority of animals mate more or less promiscuously. A few mammals, including humans, utilize more restrained mating strategies that entail a longer term affiliation with a single mating partner. Such pair bonding mating strategies have been resistant to genetic analysis because of a lack of suitable model organisms. Prairie voles are small mouse-like rodents that form enduring pair bonds in the wild as well as in the laboratory, and consequently they have been used widely to study social bonding behavior. The lack of targeted genetic approaches in this species however has restricted the study of the molecular and neural circuit basis of pair bonds. As a first step in rendering the prairie vole amenable to reverse genetics, we have generated induced pluripotent stem cell (IPSC) lines from prairie vole fibroblasts using retroviral transduction of reprogramming factors. These IPSC lines display the cellular and molecular hallmarks of IPSC cells from other organisms, including mice and humans. Moreover, the prairie vole IPSC lines have pluripotent differentiation potential since they can give rise to all three germ layers in tissue culture and in vivo. These IPSC lines can now be used to develop conditions that facilitate homologous recombination and eventually the generation of prairie voles bearing targeted genetic modifications to study the molecular and neural basis of pair bond formation. 相似文献
157.
Nossaman BD Pankey EA Badejo AR Casey DB Uppu S Murthy SN Kadowitz PJ 《Nitric oxide》2012,26(4):223-228
Responses to glyceryl trinitrate/nitroglycerin (GTN), S-nitrosoglutathione (GSNO), and sodium nitrite were compared in the intact chest rat. The iv injections of GTN, sodium nitrite, and GSNO produced dose-dependent decreases in pulmonary and systemic arterial pressures. In as much as cardiac output was not reduced, the decreases in pulmonary and systemic arterial pressures indicate that GTN, sodium nitrite, and GSNO have significant vasodilator activity in the pulmonary and systemic vascular beds in the rat. Responses to GTN were attenuated by cyanamide, but not allopurinol, whereas responses to nitrite formed by the metabolism of GTN were attenuated by allopurinol and cyanamide. The results with allopurinol and cyanamide suggest that only mitochondrial aldehyde dehydrogenase is involved in the bioactivation of GTN, sodium nitrite, and GSNO, whereas both pathways are involved in the bioactivation of nitrite anion in the intact rat. The comparison of vasodilator activity indicates that GSNO and GTN are more than 1000-fold more potent than sodium nitrite in decreasing pulmonary and systemic arterial pressures in the rat. Following administration of 1H-[1,2,4]-oxadizaolo[4,3-]quinoxaline-1-one (ODQ), responses to GTN were significantly attenuated, indicating that responses are mediated by the activation of soluble guanylyl cyclase. These data suggest that the reduction of nitrite to nitric oxide formed from the metabolism of GTN, cannot account for the vasodilator activity of GTN in the intact rat and that another mechanism; perhaps the formation of an S-NO, may mediate the vasodilator response to GTN in this species. 相似文献
158.
Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol. 总被引:1,自引:0,他引:1
B Subramanyam S M Pond D W Eyles H A Whiteford H G Fouda N Castagnoli 《Biochemical and biophysical research communications》1991,181(2):573-578
Evidence that the parkinsonian inducing agent MPTP is biotransformed to a pyridinium species that selectively destroys nigrostriatal neurons in humans and subhuman primates has prompted studies to evaluate the metabolic fate of the structurally related neuroleptic agent haloperidol. With the aid of a highly sophisticated atmospheric pressure ionspray HPLC/MS/MS assay, unambiguous evidence has been obtained for the presence of the haloperidol pyridinium species in extracts of urine obtained from haloperidol-treated patients and in extracts of NADPH-supplemented human liver microsomal incubation mixtures containing haloperidol. The potential significance of the formation of this putative neurotoxic pyridinium species is considered. 相似文献
159.
160.
Syntrophism (cross-feeding) could be demonstrated between mutants of Mycobacterium fortuitum and Mycobacterium smegmatis, and previously characterized mutants of Bacillus subtilis, auxotrophic for arginine, histidine, lysine or phenylalanine. Based on this cross-feeding data, the possible site of blockage in the biosynthetic pathways of the mutants could be inferred. 相似文献