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171.
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Debbie C. Crans Samantha Schoeberl Ernestas Gaidamauskas Bharat Baruah Deborah A. Roess 《Journal of biological inorganic chemistry》2011,16(6):961-972
The interactions of metabolites of the antidiabetic vanadium-containing drug bis(maltolato)oxovanadium(IV) (BMOV) with lipid
interface model systems were investigated and the results were used to describe a potentially novel mechanism by which these
compounds initiate membrane-receptor-mediated signal transduction. Specifically, spectroscopic studies probed the BMOV oxidation
and hydrolysis product interaction with interfaces created from cetyltrimethylammonium bromide (CTAB) which mimics the positively
charged head group on phosphatidylcholine. 1H and 51V NMR spectroscopies were used to determine the location of the dioxobis(maltolato)oxovanadate(V) and the maltol ligand in
micelles and reverse micelles by measuring changes in the chemical shift, signal linewidth, and species distribution. Both
micelles and reverse micelles interacted similarly with the complex and the ligand, suggesting that interaction is strong
as anticipated by Coulombic attraction between the positively charged lipid head group and the negatively charged complex
and deprotonated ligand. The nature of the model system was confirmed using dynamic light scattering studies and conductivity
measurements. Interactions of the complex/ligand above and below the critical micelle concentration of micelle formation were
different, with much stronger interactions when CTAB was in the form of a micelle. Both the complex and the ligand penetrated
the lipid interface and were located near the charged head group. These studies demonstrate that a lipid-like interface affects
the stability of the complex and raise the possibility that ligand exchange at the interface may be important for the mode
of action for these systems. Combined, these studies support recently reported in vivo observations of BMOV penetration into
3T3-L1 adipocyte membranes and increased translocation of a glucose transporter to the plasma membrane. 相似文献
173.
Wagner D Hanwell HE Schnabl K Yazdanpanah M Kimball S Fu L Sidhom G Rousseau D Cole DE Vieth R 《The Journal of steroid biochemistry and molecular biology》2011,126(3-5):72-77
24,25-Dihydroxyvitamin D (24,25VD) is a major catabolite of 25-hydroxyvitamin D (25VD) metabolism, and may be physiologically active. Our objectives were to: (1) characterize the response of serum 24,25VD(3) to vitamin D(3) (VD(3)) supplementation; (2) test the hypothesis that a higher 24,25VD(3) to 25VD(3) ratio (24,25:25VD(3)) predicts 25VD(3) response. Serum samples (n=160) from wk 2 and wk 6 of a placebo-controlled, randomized clinical trial of VD(3) (28,000IU/wk) were analyzed for serum 24,25VD(3) and 25VD(3) by mass spectrometry. Serum 24,25VD(3) was highly correlated with 25VD(3) in placebo- and VD(3)-treated subjects at each time point (p<0.0001). At wk 2, the 24,25:25VD(3) ratio was lower with VD(3) than with placebo (p=0.035). From wk 2 to wk 6, the 24,25:25VD(3) ratio increased with the VD(3) supplement (p<0.001) but not with placebo, such that at wk 6 this ratio did not significantly differ between groups. After correcting for potential confounders, we found that 24,25:25VD(3) at wk 2 was inversely correlated to the 25VD(3) increment by wk 6 in the supplemented group (r=-0.32, p=0.02) but not the controls. There is a strong correlation between 24,25VD(3) and 25VD(3) that is only modestly affected by VD(3) supplementation. This indicates that the catabolism of 25VD(3) to 24,25VD(3) rises with increasing 25VD(3). Furthermore, the initial ratio of serum 24,25VD(3) to 25VD(3) predicted the increase in 25VD(3). The 24,25:25VD(3) ratio may therefore have clinical utility as a marker for VD(3) catabolism and a predictor of serum 25VD(3) response to VD(3) supplementation. 相似文献
174.
Gemma S Butini S Campiani G Brindisi M Zanoli S Romano MP Tripaldi P Savini L Fiorini I Borrelli G Novellino E Maga G 《Bioorganic & medicinal chemistry letters》2011,21(9):2776-2779
Among the enzymes involved in the life cycle of HCV, the non-structural protein NS3, with its double function of protease and NTPase/helicase, is essential for the virus replication. Exploiting our previous knowledge in the development of nucleotide-mimicking NS3 helicase (NS3h) inhibitors endowed with key structural and electronic features necessary for an optimal ligand-enzyme interaction, we developed the tetrahydroacridinyl derivative 3a as the most potent NS3h competitive inhibitor reported to date (HCV NS3h K(i)=20 nM). 相似文献
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177.
Three cytokines use the IL-12p40 cytokine subunit namely: IL-12p70 (IL-12-comprised of IL-12p40 and IL-12p35), IL-23 (comprised of the IL-12p40 and IL-23p19 subunits) and homodimeric IL-12p40 (IL-12(p40)(2)). Following activation, immature dendritic cells (DCs) upregulate the chemokine receptor Chemokine-C-Receptor 7 (CCR7), and migrate in response to homeostatic chemokines such as chemokine (C-C motif) ligand 19 (CCL19). Induction of the cytokine IL-12p40 in response to pathogen-exposure, likely in its homodimeric form, is one of the primary events that mediates migration of DCs in response to CCL19. Here we show that following exposure to Francisella tularensis Live Vaccine Strain (LVS), DCs produce IL-12p40 and promote the migration of DCs to the chemokine CCL19 in an IL-12Rβ1- and IL-12p(40)(2)-dependent manner. Induction of IL-12p40 and resulting chemokine responsiveness in DCs is TLR2-dependent and coincides with the uptake of F. tularensis LVS and activation of DCs. Importantly, we show that IL-12Rβ1 signaling is required for DC migration from the lung to the draining lymph node following F. tularensis LVS exposure and coincides with accumulation of IL-12p40 expressing DCs in the draining lymph nodes. Together, these findings illustrate that IL-12p40 is induced rapidly in response to F. tularensis LVS and is required for DC migration through an IL-12Rβ1-IL-12(p40)(2) dependent mechanism. 相似文献
178.
Chaudhary S Pak JE Pedersen BP Bang LJ Zhang LB Ngaw SM Green RG Sharma V Stroud RM 《Methods (San Diego, Calif.)》2011,55(4):273-280
It is often an immense challenge to overexpress human membrane proteins at levels sufficient for structural studies. The use of Human Embryonic Kidney 293 (HEK 293) cells to express full-length human membrane proteins is becoming increasingly common, since these cells provide a near-native protein folding and lipid environment. Nevertheless, the labor intensiveness and low yields of HEK 293 cells and other mammalian cell expression systems necessitate the screening for suitable expression as early as possible. Here we present our methodology used to generate constructs of human membrane proteins and to rapidly assess their suitability for overexpression using transiently transfected, glycosylation-deficient GnT I-HEK 293 cells (HEK 293S). Constructs, in the presence or absence of a C-terminal enhanced green fluorescence protein (EGFP) molecule, are made in a modular manner, allowing for the rapid generation of several combinations of fusion tags and gene paralogues/orthologues. Solubilization of HEK 293S cells, using a range of detergents, followed by Western blotting is performed to assess relative expression levels and to detect possible degradation products. Fluorescence-detection size exclusion chromatography (FSEC) is employed to assess expression levels and overall homogeneity of the membrane proteins, to rank different constructs for further downstream expression trials. Constructs identified as having high expression are instantly suitable for further downstream large scale transient expression trials and stable cell line generation. The method described is accessible to all laboratory scales and can be completed in approximately 3 weeks. 相似文献
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180.
Russell RC Sufan RI Zhou B Heir P Bunda S Sybingco SS Greer SN Roche O Heathcote SA Chow VW Boba LM Richmond TD Hickey MM Barber DL Cheresh DA Simon MC Irwin MS Kim WY Ohh M 《Nature medicine》2011,17(7):845-853
Chuvash polycythemia is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the VHL (von Hippel-Lindau) gene, whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark abnormalities of Chuvash polycythemia, such as hypersensitivity to erythropoietin, are unclear. Here we show that VHL directly binds suppressor of cytokine signaling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction. In contrast, Chuvash polycythemia-associated VHL mutants have altered affinity for SOCS1 and do not engage with and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reversed the disease phenotype in Vhl(R200W/R200W) knock-in mice, an experimental model that recapitulates human Chuvash polycythemia. These results show that VHL is a SOCS1-cooperative negative regulator of JAK2 and provide biochemical and preclinical support for JAK2-targeted therapy in individuals with Chuvash polycythemia. 相似文献