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931.
Bin Ma Kevin M. Guckian Edward Yin-Shiang Lin Wen-Cherng Lee Daniel Scott Gnanasambandam Kumaravel Timothy L. Macdonald Kevin R. Lynch Cheryl Black Sowmya Chollate Kyungmin Hahm Gregg Hetu Ping Jin Yi Luo Ellen Rohde Anthony Rossomando Robert Scannevin Joy Wang Chunhua Yang 《Bioorganic & medicinal chemistry letters》2010,20(7):2264-2269
Modifying FTY720, an immunosuppressant modulator, led to a new series of well phosphorylated tetralin analogs as potent S1P1 receptor agonists. The stereochemistry effect of tetralin ring was probed, and (?)-(R)-2-amino-2-((S)-6-octyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability. 相似文献
932.
Lin He Fan He Huichang Bi Jiankang Li Su Zeng Hai-Bin Luo Min Huang 《Bioorganic & medicinal chemistry letters》2010,20(20):6008-6012
Our kinetics studies demonstrated that the nature product chrysin exhibited a high inhibitory affinity of 54 nM towards human cytochrome P450 1A2 and was comparable to α-naphthoflavone (49 nM), whereas it represented a moderate affinity of 5225 nM against human cytochrome P450 2C9. However, it remains unclear how this inhibitor selectively binds 1A2. To better understand the isoform selectivity of chrysin, molecular docking and molecular dynamics simulations were performed. Chrysin formed a strong H-bond with Asp313 of 1A2. The stacking interactions with Phe226 also contributed to its tight binding to 1A2. The larger and much more open active site architectures of 2C9 may explain the weaker inhibitory affinity of chrysin towards 2C9. The predicted binding free energies suggest that chrysin preferred 1A2 (ΔGbind, pred = ?23.11 kcal/mol) to 2C9 (?20.41 kcal/mol). Additionally, the present work revealed that 7-hydroxy-flavone bound to 1A2 in a similar pattern as chrysin and represented a slightly less negative predicted binding free energy, which was further validated by our kinetics analysis (IC50 = 240 nM). Results of the study can provide insight for designing novel isoform-selective 1A2 inhibitors. 相似文献
933.
一种定量检测人血清高敏C反应蛋白的化学发光免疫方法 总被引:2,自引:0,他引:2
旨在建立一种可定量检测人血清高敏CRP的化学发光检测方法 (High-sensitivity C-reactive protein quantifiable chemiluminescent immunoassay,hs-CRP CLIA)。首先利用亲和层析和离子交换层析技术从肝硬化病人腹水中纯化出高纯度的天然CRP作为免疫原制备了22株CRP单克隆抗体 (单抗),其中13株单抗在磷酸胆碱配体捕获ELISA中呈阳性,然后利用方正滴定法筛选出单抗10C5和10C11建立了hs-CRP CLIA。试剂盒评估结果显示:该方法对血清中干扰物质IgG、血红蛋白、甘油三酯等无非特异性反应;该方法检测灵敏度高,在0.04~20.38 mg/L范围内定量检测人血清CRP标准品呈良好线性关系 (R2>0.993);该方法准确性高、可重复性好,平均回收率为99%,批内差为4.2%~5.8%,批间差为9.0%~11.5%;该方法与进口商品化高敏CRP ELISA试剂盒平行比较检测90份血清标本,结果显示两者有良好的可比性 (r=0.968)。综上,建立的hs-CRP CLIA是一种准确、可靠、可定量的高灵敏C反应蛋白检测方法,该方法的临床应用,有利于改善我国心脏病风险评估及肠炎性疾病预后判断。 相似文献
934.
SHP2是一种非受体型蛋白酪氨酸磷酸酶,其介导的信号转导异常与多种疾病包括肿瘤的发生和发展密切相关,对SHP2的深入研究有助于对其作用机制的阐明以及潜在药物学靶点的发现。本文简要介绍了SHP2的结构、功能及其介导的Ras/ERK信号通路,并着重阐述了SHP2与乳腺癌发展的关系。 相似文献
935.
936.
Although great progress in genome-wide association studies (GWAS) has been made,
the significant SNP associations identified by GWAS account for only a few
percent of the genetic variance, leading many to question where and how we can
find the missing heritability. There is increasing interest in genome-wide
interaction analysis as a possible source of finding heritability unexplained by
current GWAS. However, the existing statistics for testing interaction have low
power for genome-wide interaction analysis. To meet challenges raised by
genome-wide interactional analysis, we have developed a novel statistic for
testing interaction between two loci (either linked or unlinked). The null
distribution and the type I error rates of the new statistic for testing
interaction are validated using simulations. Extensive power studies show that
the developed statistic has much higher power to detect interaction than
classical logistic regression. The results identified 44 and 211 pairs of SNPs
showing significant evidence of interactions with FDR<0.001 and
0.001<FDR<0.003, respectively, which were seen in two independent studies
of psoriasis. These included five interacting pairs of SNPs in genes LST1/NCR3,
CXCR5/BCL9L, and GLS2, some of which were located in the target sites of
miR-324-3p, miR-433, and miR-382, as well as 15 pairs of interacting SNPs that
had nonsynonymous substitutions. Our results demonstrated that genome-wide
interaction analysis is a valuable tool for finding remaining missing
heritability unexplained by the current GWAS, and the developed novel statistic
is able to search significant interaction between SNPs across the genome. Real
data analysis showed that the results of genome-wide interaction analysis can be
replicated in two independent studies. 相似文献
937.
Zhengdong Zhang Luo Wang Sheng Wei Zhensheng Liu Li-E. Wang Erich M. Sturgis Qingyi Wei 《DNA Repair》2010,9(5):558-566
Methylating agents are involved in carcinogenesis, and the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) removes methyl group from O6-methylguanine. Genetic variation in DNA repair genes has been shown to contribute to susceptibility to squamous cell carcinoma of the head and neck (SCCHN). We hypothesize that MGMT polymorphisms are associated with risk of SCCHN. In a hospital-based case–control study of 721 patients with SCCHN and 1234 cancer-free controls frequency-matched by age, sex and ethnicity, we genotyped four MGMT polymorphisms, two in exon 3, 16195C > T and 16286C > T and two in the promoter region, 45996G > T and 46346C > A. We found that none of these polymorphisms alone had a significant effect on risk of SCCHN. However, when these four polymorphisms were evaluated together by the number of putative risk genotypes (i.e. 16195CC, 16286CC, 45996GT + TT, and 46346CA + AA), a statistically significantly increased risk of SCCHN was associated with the combined genotypes with three to four risk genotypes, compared with those with zero to two risk genotypes (adjusted odds ratio (OR) = 1.27; 95% confidence interval (CI) = 1.05–1.53). This increased risk was also more pronounced among young subjects (OR = 1.81; 95% CI = 1.11–2.96), men (OR = 1.24; 95% CI = 1.00–1.55), ever smokers (OR = 1.25; 95% = 1.01–1.56), ever drinkers (OR = 1.29; 95% CI = 1.04–1.60), patients with oropharyngeal cancer (OR = 1.45; 95% CI = 1.12–1.87), and oropharyngeal cancer with regional lymph node metastasis (OR = 1.52; 95% CI = 1.16–1.89). In conclusion, our results suggest that any one of MGMT variants may not have a substantial effect on SCCHN risk, but a joint effect of several MGMT variants may contribute to risk and progression of SCCHN, particularly for oropharyngeal cancer, in non-Hispanic whites. 相似文献
938.
Insulin-like peptide 3 (INSL3) is an insulin superfamily peptide hormone, primarily expressed in the testes and playing a
key role in the fetus testes descent and suppression of male germ cell apoptosis. Insulin-degrading enzyme (IDE) is a zinc-metalloprotease,
responsible for in vivo degradation of insulin, Aβ, and other peptide hormones. IDE has high expression level in the testes,
implying it might be involved in INSL3 turnover in vivo. In present work, we studied in vitro degradation of INSL3 by IDE.
Recombinant human IDE degraded human INSL3, but its degradation rate for INSL3 is more than a magnitude lower than that for
insulin. However, IDE bound INSL3 and insulin with almost same affinity. IDE cleaved the peptide bond between B26R and B27W
of INSL3, and released a pentapeptide, WSTEA, from the C-terminal of B-chain. Our present work suggested that IDE might play
a role in INSL3 degradation in vivo. 相似文献
939.
Reentrant loops are an important structural motif in alpha-helical transmembrane proteins. A reentrant loop is a structural
motif that goes only halfway through the membrane and then turns back to the side from which it originates. The question of
what causes the reentrant loops to form such a unique topology is still unanswered. In this study, we try to answer this question
by analyzing the hydrophobicity distribution on the amino acid sequences of the reentrant loops. Our results show that reentrant
loops have very low hydrophobicity around the deepest point buried in the membrane and relative high hydrophobicity close
to the membrane surfaces. We speculate that this hydrophobicity distribution is a major force that stabilizes the unique reentrant
loop structure. Our results also show that this hydrophobicity distribution results in special patterns on protein sequences,
which can be captured using profile hidden Markov models (HMMs). The resulting profile HMMs can detect reentrant loops on
protein sequences with high sensitivity and perfect specificity. 相似文献
940.
Three new compounds, 1 – 3 , and 20 known compounds were isolated from the AcOEt and BuOH extract of edible Opuntia Milpa Alta. The petroleum ether extract was examined by GC and MS. A total of 26 compounds were identified, representing 95.6% of the total extract, phytosterol (36.03%) being the most abundant component, and polyunsaturated fatty acids (18.57%) represented the second largest group, followed by phytol (12.28%), palmitic acid, palmitate (13.54%), vitamin E (4.51%), and other compounds (7.47%). The effects of various extracts from edible Opuntia Milpa Alta (petroleum ether extract, AcOEt extract, BuOH extract, aqueous extract, H2O parts) and the positive control (received dimethylbiguanide) were tested on streptozotocin (STZ)‐induced diabetic mice. The results indicated that all the treatment groups could significantly decrease blood glucose levels in STZ‐induced diabetic mice compared to the model control group (P<0.01), except the aqueous extract group (P<0.05). Especially, the petroleum ether extract group and the positive control group showed remarkable decrease of blood glucose levels. Taken together, the results indicate that the petroleum ether extract is the major hypoglycemic part in edible Opuntia Milpa Alta, which may be developed to a potential natural hypoglycemic functional ingredient. 相似文献