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21.
A small molecule library of 1,3-dioxoisoindoline-5-carboxamides 4 was designed based on the pharmacophore model, synthesized and biologically evaluated as potential T-type calcium channel blockers. The most active compounds 4d and 4n show T-type calcium channel blocking activity with IC50 values of 0.93 and 0.96 microM, respectively.  相似文献   
22.
Virtual screening of the commercial databases was done by using a three dimensional pharmacophore previously developed for T-type calcium channel blockers using CATALYSTtrade mark program. Biological evaluation of 25 selected virtual hits resulted in the discovery of a highly potent compound VH04 with IC(50) value of 0.10 microM, eight times as potent as the known selective T-type calcium channel blocker, mibefradil. Search for similar compounds yielded several hits with micro-molar IC(50) values and high T-type calcium channel selectivity. Based on the structure of the virtual hits, small molecule libraries with novel scaffolds were designed, synthesis and biological evaluation of which are currently in progress. This result shows a successful example of ligand based drug discovery of potent T-type calcium channel blockers.  相似文献   
23.

Background

Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.

Methods

We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.

Results

We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P = 0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P = 0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P < 0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P = 0.09).

Conclusions

Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-015-0238-y) contains supplementary material, which is available to authorized users.  相似文献   
24.
Kim S  Rhim H 《Molecules and cells》2011,32(3):289-294
Overload of intracellular Ca2+ has been implicated in the pathogenesis of neuronal disorders, such as Alzheimer’s disease. Various mechanisms produce abnormalities in intracellular Ca2+ homeostasis systems. L-type Ca2+ channels have been known to be closely involved in the mechanisms underlying the neurodegenerative properties of amyloid-β (Aβ) peptides. However, most studies of L-type Ca2+ channels in Aβ-related mechanisms have been limited to CaV1.2, and surprisingly little is known about the involvement of CaV1.3 in Aβ-induced neuronal toxicity. In the present study, we examined the expression patterns of CaV1.3 after Aβ25–35 exposure for 24 h and compared them with the expression patterns of CaV1.2. The expression levels of CaV1.3 were not significantly changed by Aβ25–35 at both the mRNA levels and the total protein level in cultured hippocampal neurons. However, surface protein levels of CaV1.3 were significantly increased by Aβ25–35, but not by Aβ35–25. We next found that acute treatment with Aβ25–35 increased CaV1.3 channel activities in HEK293 cells using whole-cell patch-clamp recordings. Furthermore, using GTP pulldown and co-immunoprecipitation assays in HEK293 cell lysates, we found that amyloid precursor protein interacts with β3 subunits of Ca2+ channels instead of CaV1.2 or CaV1.3 α1 subunits. These results show that Aβ25–35 chronically or acutely upregulates CaV1.3 in the rat hippocampal and human kidney cells (HEK293). This suggests that CaV1.3 has a potential role along with CaV1.2 in the pathogenesis of Alzheimer’s disease.  相似文献   
25.
26.
We examined differences in bird communities in relation to characteristics of habitat structure in a pine forest, Samcheok, South Korea. An unburned stand, a stand burned 7 years earlier and then naturally restored, and a stand where Japanese red pine Pinus densiflora seedlings were planted after the fire were used for the survey. Habitat structure was dramatically changed by postfire silvicultural practices. Number of stand trees, shrubs, seedlings, snags, and vegetation coverage were significantly different among study stands. We made 1,421 detections of 46 bird species during 23 separate line transect surveys per stand between February 2007 and December 2008. The mean number of observed bird species and individuals, bird species diversity index (H′), and Simpson’s diversity index (D s) were highest in the unburned stand and lowest in the pine seedling stand. There were more species and individuals of forest-dwelling birds in the unburned stand than both burned stands. Canopy and cavity nesters, foliage searchers, bark gleaners, and timber drillers were significantly higher in the unburned stand. In the pine seedling stand, densities of birds that prefer open field and shrub cover were higher. Stand structure was simplified in the pine seedling stand by postfire practices. Because of differences in habitat structure and bird communities, postfire practices in the burned stand should be re-evaluated. Also, management strategies for pine forest after forest fires are needed based on results of long-term experiments.  相似文献   
27.
We have synthesized 3,4-dihydroquinazoline derivatives for the potent and selective T-type Ca(2+) channel blockers and evaluated for their inhibitory activities against two subtypes T-type Ca(2+) channels and N-type Ca(2+) channels. Among them, 5b (KYS05044, IC(50)=0.56+/-0.10 microM) was identified as potent T-type Ca(2+) channel blocker with in vitro selectivity profile at meaningful level (T/N-type, SI=>100).  相似文献   
28.
This study was undertaken to investigate whether a physiologically compatible concentration of 7-ketocholesterol had any effect on human vascular smooth muscle cells (HVSMCs). We found that 7-ketocholesterol changed the viability of human aorta smooth muscle cells (HAoSMC) not by cytotoxicity but by activation of tumor necrosis factor-alpha receptor (TNFR)-mediated death. Whereas TNF-alpha did not affect the viability in the presence of 7alpha-hydroxycholesterol or cholesterol, the cytokine induced HAoSMC death in the presence of 7-ketocholesterol as detected by morphology, viability, and fragmentation of chromosomal DNA. The HAoSMC death was inhibited by a neutralizing anti-TNF receptor 1 (TNFR1) antibody and by the caspase inhibitors of z-VAD and z-DEVD. Activations of caspase-8 and -3 were detected from dying HAoSMCs. 7-Ketocholesterol inhibited translocation of the nuclear factor kappaB (NF-kappaB) subunits of p65 and p50 from the cytosol into the nucleus, increase of NF-kappaB activity, and expression of caspase-8 homolog Fas ligand interleukin-1-converting enzyme inhibitory protein by TNF-alpha. We also found that X-chromosome-linked inhibitor of apoptosis protein was degraded in dying HAoSMC. The present study proposes that 7-ketocholesterol would contribute to the disappearance of HVSMC in the atherosclerotic lesions by enhancing receptor-mediated death. This is the first report demonstrating induction of TNF-alpha-mediated death by oxysterol in cells.  相似文献   
29.
Bae Y  Choi D  Rhim H  Kang S 《FEBS letters》2010,584(22):4505-4510
Hip2, a ubiquitin conjugating enzyme, is involved in the suppression of cell death. The present study revealed that Hip2 regulates the stability of the apoptotic and cell cycle regulator cyclin B1. Hip2 was found to interact with cyclin B1 to promote its degradation through the ubiquitin proteasome pathway. As a result, Hip2 significantly blocked cell death induced by the cyclin B1 protein, suggesting that Hip2 is involved in the regulation of cyclin B1-mediated cell death.

Structured summary

MINT-8045218, MINT-8045231: Hip2 (uniprotkb:P61086) physically interacts (MI:0915) with cyclin-B1 (uniprotkb:P14635) by pull down (MI:0096)  相似文献   
30.
Accumulating evidence suggests that HtrA1 (high-temperature requirement A1) is involved in modulating crucial cellular processes and implicated in life-threatening diseases, such as cancer and neuropathological disorders; however, the exact functions of this protease in vivo remain unknown. Here, we show that loss of HtrA1 function increases fibroblast growth factor 8 (FGF8) mRNA levels and triggers activation of FGF signaling, resulting in dorsalization in zebrafish embryos. Notably, HtrA1 directly cleaves FGF8 in the extracellular region, and this cleavage results in decreased activation of FGF signaling, which is essential for many physiological processes. Therefore, HtrA1 is indispensable for dorsoventral patterning in early zebrafish embryogenesis and serves as a key upstream regulator of FGF signaling through the control of FGF levels. Furthermore, this study offers insight into new strategies to control human diseases associated with HtrA1 and FGF signaling.  相似文献   
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