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51.
Richard B. Silverman Graham R. Lawton Hantamalala Ralay Ranaivo Laura K. Chico Jiwon Seo D. Martin Watterson 《Bioorganic & medicinal chemistry》2009,17(21):7593-7605
Several prodrug approaches were taken to mask amino groups in two potent and selective neuronal nitric oxide synthase (nNOS) inhibitors containing either a primary or secondary amino group to lower the charge and improve blood–brain barrier (BBB) penetration. The primary amine was masked as an azide and the secondary amine as an amide or carbamate. The azide was not reduced to the amine under a variety of in vitro and ex vivo conditions. Despite the decrease in charge of the amino group as an amide and as carbamates, BBB penetration did not increase. It appears that the uses of azides as prodrugs for primary amines or amides and carbamates as prodrugs for secondary amines are not universally effective for CNS applications. 相似文献
52.
In the infarcted rat heart, the increase of NO occurs in the hypertrophied myocardium of non-infarcted areas and its antihypertrophic
efficacy has been well established. As another endogenous regulator and the reliable index of heart pathology, B-type natriuretic
peptide also exhibits the antihypertrophic properties in many tissues by elevating intracellular cGMP. Several studies indicate
that natriuretic peptides family may exert some actions in part via a nitric oxide pathway following receptor-mediated stimulation
of iNOS. Therefore, it raises our great interest to ask what role NO plays in the antihypertrophic actions of B-type natriuretic
peptide in cardiomyocytes. Incubation of cardiomyocytes under mild hypoxia for 12 h caused a significant increase in cellular
protein content, protein synthesis and cell surface sizes. This growth stimulation was suppressed by exogenous B-type natriuretic
peptide in a concentration dependent manner. Furthermore, the generation of intracellular cGMP, the upregulation of iNOS mRNA
expression, the increase of iNOS activity and subsequent nitrite generation in hypertrophic cardiomyocytes was also increased
by B-type natriuretic peptide. AG, a selective iNOS inhibitor, inhibited the upregulation of iNOS expression and the increase
of iNOS activity by the combination of B-type natriuretic peptide/mild hypoxia or by the combination of 8-bromo-cGMP/mild
hypoxia. Rp-8-br-cGMP, cGMP dependent protein kinase inhibitor, attenuated the actions of B-type natriuretic peptide and 8-bromo-cGMP
which increases intracellular cGMP independent of B-type natriuretic peptide. In conclusion, our present data suggest that
B-type natriuretic peptide exerted the antihypertrophic effects in cardiomyocytes, which was partially attributed to induction
of iNOS-derived NO by cGMP pathway. 相似文献
53.
Our understanding of the evolution of the insulin signaling pathway (ISP) is still incomplete. One intriguing unanswered question is the explanation of the emergence of the glucostatic role of insulin in mammals. To find out whether this is due to the development of new sets of signaling transduction elements in these organisms, or to the establishment of new interactions between pre-existing proteins, we rebuilt putative orthologous ISPs in 17 eukaryotic organisms. Then, we computed the conservation of orthologous ISPs at different levels, from sequence similarity of orthologous proteins to co-evolution of interacting domains. We found that the emergence of glucostatic role in mammals can neither be explained by the development of new sets of signaling elements, nor by the establishment of new interactions between pre-existing proteins. The comparison of orthologous IRS molecules indicates that only in mammals have they acquired their complete functionality as efficient recruiters of effector sub-pathways. 相似文献
54.
The beta1 subunit enhances oxidative regulation of large-conductance calcium-activated K+ channels 总被引:3,自引:0,他引:3
Oxidative stress may alter the functions of many proteins including the Slo1 large conductance calcium-activated potassium channel (BKCa). Previous results demonstrated that in the virtual absence of Ca2+, the oxidant chloramine-T (Ch-T), without the involvement of cysteine oxidation, increases the open probability and slows the deactivation of BKCa channels formed by human Slo1 (hSlo1) alpha subunits alone. Because native BKCa channel complexes may include the auxiliary subunit beta1, we investigated whether beta1 influences the oxidative regulation of hSlo1. Oxidation by Ch-T with beta1 present shifted the half-activation voltage much further in the hyperpolarizing direction (-75 mV) as compared with that with alpha alone (-30 mV). This shift was eliminated in the presence of high [Ca2+]i, but the increase in open probability in the virtual absence of Ca2+ remained significant at physiologically relevant voltages. Furthermore, the slowing of channel deactivation after oxidation was even more dramatic in the presence of beta1. Oxidation of cysteine and methionine residues within beta1 was not involved in these potentiated effects because expression of mutant beta1 subunits lacking cysteine or methionine residues produced results similar to those with wild-type beta1. Unlike the results with alpha alone, oxidation by Ch-T caused a significant acceleration of channel activation only when beta1 was present. The beta1 M177 mutation disrupted normal channel activation and prevented the Ch-T-induced acceleration of activation. Overall, the functional effects of oxidation of the hSlo1 pore-forming alpha subunit are greatly amplified by the presence of beta1, which leads to the additional increase in channel open probability and the slowing of deactivation. Furthermore, M177 within beta1 is a critical structural determinant of channel activation and oxidative sensitivity. Together, the oxidized BKCa channel complex with beta1 has a considerable chance of being open within the physiological voltage range even at low [Ca2+]i. 相似文献
55.
56.
Hydrogen sulfide (H2S) is an important gaseous molecule in various plant developmental processes and plant stress responses. In this study, the transgenic Arabidopsis thaliana plants with modulated exp... 相似文献
57.
Janssen Dick B. op den Camp Huub J. M. Leenen Pieter J. M. van der Drift Chris 《Archives of microbiology》1980,124(2-3):197-203
Glutamine synthetase from Pseudomonas aeruginosa is regulated by repression/derepression of enzyme synthesis and by adenylylation/deadenylylation control. High levels of deadenylylated biosynthetically active glutamine synthetase were observed in cultures growing with limiting amounts of nitrogen while synthesis of the enzyme was repressed and that present was adenylylated in cultures with excess nitrogen.NADP-and NAD-dependent glutamate dehydrogenase could be separated by column chromatography and showed molecular weights of 110,000 and 220,000, respectively. Synthesis of the NADP-dependent glutamate dehydrogenase is repressed under nitrogen limitation and by growth on glutamate. In contrast, NAD-dependent glutamate dehydrogenase is derepressed by glutamate. Glutamate synthase is repressed by glutamate but not by excess nitrogen. 相似文献
58.
GSK-3在阿尔茨海默病样细胞骨架蛋白过度磷酸化中的作用(英) 总被引:3,自引:0,他引:3
神经原纤维缠结是阿尔茨海默病(Alzheimer disease, AD)的特征性病理改变.蛋白激酶和蛋白磷酸酯酶失衡可导致骨架蛋白的异常过度磷酸化,而异常过度磷酸化的tau 和神经丝 (neurofilament, NF) 是神经原纤维缠结的组成部分.在众多激酶中,糖原合酶激酶-3(glycogen synthase kinase-3,GSK-3)可能是AD神经退行性变起重要作用.为深入探讨GSK-3在AD样神经退行性变中的作用,以磷酯酰肌醇三磷酸激酶(phosphatidylinositol 3-kinase,PI3K)的特异性抑制剂渥曼青霉素(wortmannin,WT)处理野生型鼠成神经瘤细胞株(wild type mouse neuroblastoma cell lines, N2a wt),系统观察WT处理N2a wt不同时间点(1 h、3 h、6 h)细胞代谢率、细胞形态、细胞骨架蛋白tau和NF的磷酸化状态改变以及细胞的命运,并分析了GSK-3活性与上述参数改变之间的相关性.结果发现:1 μmol/L WT处理细胞1 h,GSK-3活性与未经WT处理的对照组相比明显增高,并伴有Ser9磷酸化的GSK-3水平的降低; NF磷酸化程度增强,tau在Ser198/Ser199/Ser202位点的磷酸化增强. 1 μmol/L WT处理细胞3 h,GSK-3活性与对照组和处理1 h 组相比明显下降,NF磷酸化程度较1 h降低,但仍高于正常水平.1 μmol/L WT处理细胞6 h,细胞形态、GSK-3活性、Ser9磷酸化形式的GSK-3β的表达、NF磷酸化程度与对照组相比均无明显改变.WT呈剂量依赖性降低细胞代谢率.1 μmol/L WT处理细胞1 h和3 h导致细胞变圆,突起变短甚至消失.1 μmol/L WT处理细胞1 h,用TUNEL法和电子显微镜技术未观察到细胞凋亡.研究结果提示:在N2a细胞中过度激活GSK-3可导致神经细丝和tau蛋白的AD样过度磷酸化,从而引起神经细胞的AD样退行性变. 相似文献
59.
Wei Choon Alvin Koh Eun Sang Choe Dong Kun Lee Seung-Cheol Chang Yoon-Bo Shim 《Biosensors & bioelectronics》2009,25(1):211-217
An all solid state potentiometric immunosensor (ASPI) has been developed to study the activation process of neuronal nitric oxide synthase (nNOS), the enzyme involved in the synthesis of nitric oxide generated under physiological conditions. At first, an all solid state H+-selective ISE was fabricated with the carboxylated poly(vinyl chloride) (PVC-COOH) film containing H+ ionophore, antibody was then immobilized on the polymer layer. The immunocomplex formation was detected by monitoring pH change due to interaction between urease labeled secondary antibody and antigen. Experimental parameters such as the amount of phosphorylated nNOS immobilized on the electrode surface and pH responses due to the antibody–antigen reaction were studied in detail. The calibration plot of the potentiometric potential vs. phosphorylated nNOS concentration exhibited a linear relationship in the range of 3.4–340.0 μg/ml. The calibration sensitivity of the phosphorylated nNOS immunosensor was −0.073 ± 0.002 mV/μg ml−1. The detection limit of nNOS was determined to be 0.2 μg/ml based on five-time measurements (95% confidence level, k = 3, n = 5). The reliability of the immunosensor was examined with rat brain tissues as well as neuronal cells, and the results shown were good, implying a promising approach for a novel electrochemical immunosensor platform with potential applications to clinical diagnosis. 相似文献
60.
Lipid peroxidation in cotton: Xanthomonas interactions and the role of lipoxygenases during the hypersensitive reaction 总被引:12,自引:0,他引:12