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941.
Steven T. Staben Nicole Blaquiere Vickie Tsui Aleksandr Kolesnikov Steven Do Erin K. Bradley Jenna Dotson Richard Goldsmith Timothy P. Heffron John Lesnick Cristina Lewis Jeremy Murray Jim Nonomiya Alan G. Olivero Jodie Pang Lionel Rouge Laurent Salphati BinQing Wei Ping Wu 《Bioorganic & medicinal chemistry letters》2013,23(3):897-901
Substructural class effects surrounding replacement of a ‘cis’ N-methyl aniline amide within potent and selective thienobenzoxepin PI3-kinase inhibitors are disclosed. While a simple aryl to alkyl switch was not tolerated due to differences in preferred amide conformation, heterocyclic amide isosteres with maintained aryl substitution improved potency and metabolic stability at the cost of physical properties. These gains in potency allowed lipophilic deconstruction of the arene to simple branched alkyl substituents. As such, overall lipophilicity-neutral, MW decreases were realized relative to the aniline amide series. The improved properties for lead compound 21 resulted in high permeability, solubility and bioavailability. 相似文献
942.
Brian S. Safina Zachary K. Sweeney Jun Li Bryan K. Chan Angelina Bisconte Diane Carrera Georgette Castanedo Michael Flagella Robert Heald Cristina Lewis Jeremy M. Murray Jim Nonomiya Jodie Pang Steve Price Karin Reif Laurent Salphati Eileen M. Seward Binqing Wei Daniel P. Sutherlin 《Bioorganic & medicinal chemistry letters》2013,23(17):4953-4959
In an effort to identify potent and isoform selective inhibitors of PI3Kδ, GNE-293 (34) was identified. Inhibitor 2 was found to induce micronuclei formation in both the MNT and HCA in vitro assays. Compounds testing negative for genotoxicity were successfully identified through modifications of the 2-benzimidazole substituent and the methylene moiety to disrupt planarity. A variety of heteroatom linkers were explored to examine their effect on potency and isoform selectivity by restricting torsional angles to favor ligand interactions with PI3Kδ’s Trp760. These modifications also resulted in an improved in vivo pharmacokinetic profile. 相似文献
943.
Lung cancer is an significant cause of death worldwide, and non–small-cell lung cancer (NSCLC) is the most common type of lung cancer. MicroRNAs (miRNAs) have been identified to play key roles in NSCLC development. Recently, it has been reported that miR-605-5p is a cancer-related miRNA in several types of tumors. In this study, we study the role of miR-605-5p in NSCLC cells. We find that miR-605-5p is upregulated in NSCLC cells. Overexpression of miR-605-5p significantly promotes lung cancer invasion and migration in H460 and H1299 cells. Besides this, miR-605-5p also promotes lung cancer cell carcinoma proliferation and metastasis in vivo. However, downregulation of miR-605-5p inhibits cell invasion and migration by inhibiting lung cancer cell carcinoma proliferation and metastasis. In addition, the luciferase report assay identifies 3′-untranslated region tumor necrosis factor α-induced protein 3 (TNFAIP3) as a target of miR-605-5p. Silencing of TNFAIP3 promotes invasion and proliferation in lung cancer. In addition, the knockdown of TNFAIP3 restores the significant decrease in invasion and proliferation in miR-605-5p-inhibitor–transfected lung cancer cells. In conclusion, miR-605-5p promotes invasion and proliferation by targeting TNFAIP3 in NSCLC, and may provide possible biomarkers for NSCLC therapy. 相似文献
944.
为实现多个基因在同一菌株中均一可溶性表达,简化基因工程亚单位多联多价疫苗中抗原生产的工艺步骤,本研究选用Ⅰ群4型禽腺病毒(FAdV-4) Fiber-2蛋白、鸡传染性法氏囊病病毒(IBDV) VP2蛋白和减蛋综合征病毒(EDSV)Fiber蛋白3种来自不同禽病毒的抗原为研究对象,利用原核表达系统,通过密码子优化、载体启动子改造和基因串联顺序优化,获得单一载体/多重转录单元的共表达重组质粒。将共表达重组质粒转化大肠杆菌BL21(DE3)菌株,进行3个基因的共表达。纯化后的蛋白进行Western blotting和蛋白活性检测。结果表明,目的基因经过密码子优化、载体启动子改造和基因串联顺序的优化后,获得均一可溶性共表达的3种蛋白,纯化后蛋白纯度大于80%,Western blotting分析和琼脂扩散试验表明串联表达的3种蛋白具有免疫反应性和抗原活性。文中通过目的基因密码子优化、表达载体启动子改造和基因串联等关键技术的突破,首次实现了3种不同禽病毒抗原的高效、均一、可溶性串联表达和纯化,为基因工程亚单位多联多价疫苗的研制奠定了基础。 相似文献
945.
采用液体悬浮培养方法,研究胞外三磷酸腺苷(ATP)通过一氧化碳(NO)调节镉诱导对烟草(Nicotiana tabacum L.)悬浮细胞氧化压力和死亡水平的影响。结果显示,镉离子(Cd^2+)可以以剂量依赖的模式引起烟草悬浮细胞氧化压力和死亡水平的上升,而施加外源ATP可有效缓解Cd^2+诱导的氧化压力和细胞死亡。进一步研究发现,和外源ATP的缓解作用相似,NO的供体硝普钠(SNP)同样可以缓解Cd^2+诱导的氧化压力和细胞死亡水平的上升;且NO合成抑制剂(L-NAME)可部分解除外源ATP的缓解作用。研究结果表明外源ATP可通过NO调节镉诱导的氧化压力和细胞死亡。 相似文献
946.
Rana K Fam BC Clarke MV Pang TP Zajac JD MacLean HE 《American journal of physiology. Endocrinology and metabolism》2011,301(5):E767-E778
In men, as testosterone levels decrease, fat mass increases and muscle mass decreases. Increased fat mass in men, in particular central obesity, is a major risk factor for type 2 diabetes, cardiovascular disease, and all-cause mortality. Testosterone treatment has been shown to decrease fat mass and increase fat-free mass. We hypothesize that androgens act directly via the DNA binding-dependent actions of the androgen receptor (AR) to regulate genes controlling fat mass and metabolism. The aim of this study was to determine the effect of a global DNA binding-dependent (DBD) AR knockout (DBD-ARKO) on the metabolic phenotype in male mice by measuring body mass, fat mass, food intake, voluntary physical activity, resting energy expenditure, substrate oxidation rates, serum glucose, insulin, lipid, and hormone levels, and metabolic gene expression levels and second messenger protein levels. DBD-ARKO males have increased adiposity despite a decreased total body mass compared with wild-type (WT) males. DBD-ARKO males showed reduced voluntary activity, decreased food intake, increased serum leptin and adiponectin levels, an altered lipid metabolism gene profile, and increased phosphorylated CREB levels compared with WT males. This study demonstrates that androgens acting via the DNA binding-dependent actions of the AR regulate fat mass and metabolism in males and that the increased adiposity in DBD-ARKO male mice is associated with decreased voluntary activity, hyperleptinemia and hyperadiponectinemia and not with insulin resistance, increased food intake, or decreased resting energy expenditure. 相似文献
947.
Responses in the physiology and biochemistry of Korean pine (Pinus koraiensis) under supplementary UV-B radiation 总被引:1,自引:0,他引:1
The effect of supplementary UV-B radiation on Korean pine (Pinus koraiensis Sieb. et Zucc) was investigated. Compared with the control, the T1, T2, and T3 UV-B treatments increased by 1.40, 2.81, and 4.22 kJ m?2 d?1, respectively. Gas-exchange parameters, photosynthetic pigment concentrations, contents of secondary metabolites, epicuticular wax, free radical, malondialdehyde (MDA), and the activities of antioxidant enzymes were determined after 40 d of exposure. The concentrations of chlorophyll (Chl) a, Chl b, total Chl, carotenoid (Car), and the ratio Chl a/b in the pine needles were in the following order: T1 > T2 > T3. Compared with the control, the contents of flavonoids and epicuticular wax significantly decreased in all levels of supplementary UV-B radiations (p<0.05). Moreover, the contents of hydrogen peroxide (H2O2) and MDA significantly increased with the enhanced UV-B radiations (p<0.05). Korean pine can increase the catalase, ascorbate peroxidase, and superoxide dismutase activities to prevent oxidative stress by supplementary UV-B radiation. However, its defence mechanism is not efficient enough to prevent UV-Binduced damage. 相似文献
948.
Wangping Yue Xingtang Fang Chunlei Zhang Yonghong Pang Haixia Xu Chuanwen Gu Ruying Shao Chuzhao Lei Hong Chen 《Molecular biology reports》2011,38(5):2927-2932
The ATP-binding cassette transporter ABCG2 (also known as breast cancer resistance protein, BCRP) belongs to the ATP-binding cassette (ABC) family of transmembrane drug transporters, playing a crucial role in the protection
of various cells and tissues against xenotoxins and/or endotoxins. Recently, several studies have proposed it as the potential
gene underlying the QTL on bovine chromosome 6. Hence, in this study, the PCR-SSCP method was applied to detect two polymorphisms
(A → C and A → G) in the target sequence coding nucleotide-binding domain (NBD) region of ABCG2 and evaluate its associations with milk production traits and mastitis-related traits among Chinese Holsteins. In the analyzed
population, the allelic frequencies for the A and B alleles were 0.5990 and 0.4010, respectively and the genotypic frequencies
were in Hardy–Weinberg disequilibrium (P < 0.01). Moreover, significant statistical relationships between the polymorphisms of ABCG2 gene and following traits, including milk yields, milk protein percentage and somatic cell scores (SCS), were found (P < 0.05). When compared with AA genotype, BB genotype was associated with higher milk yields during 1st and 2nd lactations,
as well as lower milk protein percentage and SCS. Thus, BB genotype is suggested to be a molecular marker for superior milk
performance. 相似文献
949.
Abiramy Krishnan Siti Aisyah Alias Clemente Michael Vui Ling Wong Ka-Lai Pang Peter Convey 《Polar Biology》2011,34(10):1535-1542
Various microbial groups are well known to produce a range of extracellular enzymes and other secondary metabolites. However,
the occurrence and importance of investment in such activities have received relatively limited attention in studies of Antarctic
soil microbiota. In order to examine extracellular enzyme production in this chronically low-temperature environment, fungi
were isolated from ornithogenic, pristine and human-impacted soils collected from the Fildes Peninsula, King George Island,
Antarctica during the austral summer in February 2007. Twenty-eight isolates of psychrophilic and psychrotolerant fungi were
obtained and screened at a culture temperature of 4°C for activity of extracellular hydrolase enzymes (amylase, cellulase,
protease), using R2A agar plates supplemented with (a) starch for amylase activity, (b) carboxymethyl cellulose and trypan
blue for cellulase activity or (c) skim milk for protease activity. Sixteen isolates showed activity for amylase, 23 for cellulase
and 21 for protease. One isolate showed significant activity across all three enzyme types, and a further 10 isolates showed
significant activity for at least two of the enzymes. No clear associations were apparent between the fungal taxa isolated
and the type of source soil, or in the balance of production of different extracellular enzymes between the different soil
habitats sampled. Investment in extracellular enzyme production is clearly an important element of the survival strategy of
these fungi in maritime Antarctic soils. 相似文献
950.
Chiu Tsai-Hsin Pang Jen-Chieh Chen Ming-Hui Tsen Hau-Yang 《World journal of microbiology & biotechnology》2011,27(2):465-469
Salmonella enterica serovar Choleraesuis (S.
Choleraesuis) can cause salmonellosis in pigs and humans. Currently, the most common method used for the subtyping of this Salmonella serovar is pulsed field gel electrophoresis (PFGE) using XbaI as a DNA digestion enzyme. In this study, we compared and combined PFGE with the randomly amplified polymorphic DNA method,
for the typing of 95 S. Choloraesuis strains isolated from diseased pigs. Using PFGE with XbaI, with AvrII, and with SpeI digested DNA, 29, 74, and 40 patterns, respectively, were obtained. Also, 53, 15, and 35 strains, respectively, belong to
the major patterns X1, A1, and S1. When these three digestion patterns were combined, 83 PFGE pattern combinations were obtained.
On the other hand, using RAPD with selected primer alone generated 76 patterns, and 11 strains which fell within a single
X1A1S1 PFGE combination pattern were discriminated into 10 patterns. Thus, for S. Choloraesuis, PFGE with AvrII allowed higher discrimination than PFGE with XbaI, and some of the PFGE groupings obtained by combining the XbaI, AvrII and SpeI digestion patterns were further subdivided by the RAPD method. 相似文献