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991.
The three-dimensional NMR structures of seven octapeptide analogs of somatostatin (SRIF), based on octreotide, with the basic sequence H-Cpa/Phe2-c[DCys3-Xxx7-DTrp/DAph(Cbm)8-Lys9-Thr10-Cys14]-Yyy-NH2 (the numbering refers to the position in native SRIF), with Xxx7 being Aph(Cbm)/Tyr/Agl(NMe,benzoyl) and Yyy being Nal/DTyr/Thr, are presented here. Most of these analogs exhibit potent and highly selective binding to sst2 receptors, and all of the analogs are antagonists inhibiting receptor signaling. Based on their consensus 3D structure, the pharmacophore of the sst2-selective antagonist has been defined. The pharmacophore involves the side chains of Cpa2, DTrp/DAph(Cbm)8, and Lys9, with the backbone for most of the sst2-selective antagonists comprised a Type-II' beta-turn. Hence, the sst2-selective antagonist pharmacophore is very similar to the sst2-selective agonist pharmacophore previously described. 相似文献
992.
993.
Liu P Zhang S Yao Q Liu X Wang X Huang C Huang X Wang P Yuan M Liu JY Wang QK Liu M 《Human genetics》2008,124(5):507-513
Disseminated superficial actinic porokeratosis (DSAP) is a chronic autosomal dominant cutaneous disorder with high genetic
heterogeneity. Two genetic loci for DSAP were identified, but no specific genes were reported to date. The pathogenic mechanism
of this disorder remains to be elucidated. In this study, a large, five-generation Chinese family with DSAP was genetically
characterized. Two known DSAP loci, DSAP1 and DSAP2, two DSAP candidate genes (SART3 and SSH1), one DSP-linked locus and one PPPD-linked locus were first excluded in the family. The family was then characterized by
genome-wide linkage analysis and a new DSAP locus was identified on chromosome 1p31.3–p31.1 with a maximum two-point LOD score
of 5.09 with marker D1S2897 (θ = 0). Fine mapping showed that the disease gene was located within an 8.2 cM or 11.9 Mb region between markers D1S438 and D1S464. This is the third locus identified for DSAP (DSAP3). Eight candidate genes including GNG12, IL12RB2, ITGB3BP, DNAJ6, PIN1L, GADD45A, RPE65 and NEGR1 were sequenced, but found to be negative for functional sequence variants. Further mutational analysis of the candidate genes
in the region will identify the specific gene for DSAP, which will provide insights into the pathogenesis of DSAP. 相似文献
994.
Puthanveetil P Wang F Kewalramani G Kim MS Hosseini-Beheshti E Ng N Lau W Pulinilkunnil T Allard M Abrahani A Rodrigues B 《American journal of physiology. Heart and circulatory physiology》2008,295(4):H1753-H1762
Glycogen is an immediate source of glucose for cardiac tissue to maintain its metabolic homeostasis. However, its excess brings about cardiac structural and physiological impairments. Previously, we have demonstrated that in hearts from dexamethasone (Dex)-treated animals, glycogen accumulation was enhanced. We examined the influence of 5'-AMP-activated protein kinase (AMPK) on glucose entry and glycogen synthase as a means of regulating the accumulation of this stored polysaccharide. After Dex, cardiac tissue had a limited contribution toward the development of whole body insulin resistance. Measurement of glucose transporter 4 (GLUT4) at the plasma membrane revealed an excess presence of this transporter protein at this location. Interestingly, this was accompanied by an increase in GLUT4 in the intracellular membrane fraction, an effect that was well correlated with increased GLUT4 mRNA. Both total and phosphorylated AMPK increased after Dex. Immunoprecipitation of Akt substrate of 160 kDa (AS160) followed by Western blot analysis demonstrated no change in Akt phosphorylation at Ser(473) and Thr(308) in Dex-treated hearts. However, there was a significant increase in AMPK phosphorylation at Thr(172), which correlated well with AS160 phosphorylation. In Dex-treated hearts, there was a considerable reduction in the phosphorylation of glycogen synthase, whereas glycogen synthase kinase-3-beta phosphorylation was augmented. Our data suggest that AMPK-mediated glucose entry combined with the activation of glycogen synthase and a reduction in glucose oxidation (Qi et al., Diabetes 53: 1790-1797, 2004) act together to promote glycogen storage. Should these effects persist chronically in the heart, they may explain the increased morbidity and mortality observed with long-term excesses in endogenous or exogenous glucocorticoids. 相似文献
995.
Complement inhibition reduces injury in the type 2 diabetic heart following ischemia and reperfusion
La Bonte LR Davis-Gorman G Stahl GL McDonagh PF 《American journal of physiology. Heart and circulatory physiology》2008,294(3):H1282-H1290
Chronic inflammation exacerbates the cardiovascular complications of diabetes. Complement activation plays an important role in the inflammatory response and is known to be involved in ischemia-reperfusion (I/R) injury in the nondiabetic heart. The purpose of this study was to determine if increased complement deposition explains, in part, the increased severity of neutrophil-mediated I/R injury in the type 2 diabetic heart. Nondiabetic Zucker lean control (ZLC) and Zucker diabetic fatty (ZDF) rats underwent 30 min of coronary artery occlusion followed by 120 min of reperfusion. Another group of ZDF rats was treated with the complement inhibitor FUT-175 before reperfusion. Left ventricular (LV) tissue samples were stained for complement deposition and neutrophil accumulation following reperfusion. We found significantly more complement deposition in the ZDF LV compared with the ZLC (P < 0.05), and complement deposition was associated with significantly greater neutrophil accumulation. In whole blood samples taken preischemia and at 120 min reperfusion, neutrophils exhibited significantly more CD11b expression in the ZDF group compared with the ZLC group (P < 0.05). Furthermore, intracellular adhesion molecule (ICAM)-1 expression following I/R was increased significantly in ZDF hearts compared with ZLC hearts (P < 0.001). These results indicate that, in the ZDF heart, increased ICAM-1 and polymorphonuclear neutrophil (PMN) CD11b expression play a role in increasing PMN accumulation following I/R. The infarct size of the ZDF was significantly greater than ZLC (P < 0.05), and treatment with FUT-175 significantly decreased infarct size, complement deposition, and PMN accumulation in the diabetic heart. These findings indicate an exacerbated inflammatory response in the type 2 diabetic heart that contributes to the increased tissue injury observed following ischemia and reperfusion. 相似文献
996.
997.
Dingle T Wee S Mulvey GL Greco A Kitova EN Sun J Lin S Klassen JS Palcic MM Ng KK Armstrong GD 《Glycobiology》2008,18(9):698-706
The biological and ligand-binding properties of recombinant C-terminal cell-binding domains (CBDs) and subdomains of the two large exotoxins, Toxin A (TcdA) and Toxin B (TcdB) expressed by Clostridium difficile were examined in the hemagglutination and Verocytotoxicity neutralization assays and by qualitative affinity chromatography using Sepharose-linked alpha Gal(1,3)betaGal(1,4)beta Glc as well as the direct electrospray ionization mass spectrometry (ES-MS) assay. These studies revealed that, whereas the full-length TcdA CBD agglutinated rabbit erythrocytes, neutralized TcdA-mediated Vero cell death and bound to alpha Gal(1,3)betaGal(1,4)beta Glc-derivatized Sepharose, the TcdB CBD was inactive in these functional assays. Moreover, retention by alpha Gal(1,3)betaGal(1,4)beta Glc-derivatized Sepharose corresponded to the number of available TcdA subdomain ligand-binding sites. By contrast, the ES-MS assays revealed that both the TcdA and TcdB CBD bind to 8-methoxycarbonyloctyl-alpha Gal(1,3)betaGal(1,4)beta Glc sequences with similar avidities. Additional ES-MS experiments using chemically altered alpha Gal(1,3)betaGal(1,4)beta Glc sequences also revealed that the TcdA and TcdB CBD will tolerate a fair amount of structural variation in their complementary glycan ligands. Although the studies are consistent with the known ligand-binding properties of the TcdA and TcdB holotoxins, they also revealed subtle heretofore unrecognized functional differences in their receptor recognition properties. 相似文献
998.
Lucia Acebey Amira Apaza Rosy de Michel Stephan Beck Valérie Jullian Grace Ruiz Alberto Gimenez Séverine Chevalley Michel Sauvain 《Biodiversity and Conservation》2008,17(8):1853-1859
Developing countries with a rich biodiversity want to control the use of this natural patrimony, especially in the research
of natural compounds of pharmaceutical interest. Here we present the organization of six permanent plots in a mountain tropical
forest on the east side of the Andean Cordillera in Bolivia, and their role in the discovery of plants with antiplasmodial
or antileishmanial activities. Permanent plots are widely used in ecological survey, but rarely in bioprospecting. This set-up
allows Bolivian authorities to control the bioprospecting, and facilitates further chemical studies on the bioactive plants.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Lucia Acebey and Amira Apaza have contributed equally to this work. 相似文献
999.
Simultaneous ammonium-nitrogen (NH(4)(+)-N) and copper removal, and copper recovery in synthetic wastewater using nitrifying biofilm from an ultra-compact biofilm reactor (UCBR) was demonstrated in batch studies, which consisted of three phases: Phase 1 for NH(4)(+)-N and copper removals, Phase 2 for copper recovery, and Phase 3 for NH(4)(+)-N removal. The results showed that more than 96.3% of copper was removed within 60min, while 60.1% of the adsorbed copper was recovered through rinsing the biofilms with 0.1mM of ethylenediaminetetraacetic acid (EDTA). The nitrifying biofilm was able to adsorb 0.245mg of copper/g of biofilms. After recovery treatment, 29.4% of copper remained bound within the nitrifying biofilms. No significant inhibitory effects towards NH(4)(+)-N removal in the presence of 0.92mg copper/L was noted in Phase 1 compared with the control test. However, lower initial pH condition in the recovery process and the accumulation of copper on the biofilm led to 50% inhibition on NH(4)(+)-N removal efficiency in the subsequent phase. 相似文献
1000.