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81.
Sofia Barluenga Dr. Jean‐Gonzague Fontaine Cuihua Wang Dr. Kais Aouadi Dr. Ruihong Chen Dr. Kristin Beebe Len Neckers Dr. Nicolas Winssinger Prof. Dr. 《Chembiochem : a European journal of chemical biology》2009,10(17):2753-2759
The pochoximes, based on the radicicol pharmacophore, are potent inhibitors of heat shock protein 90 (HSP90) that retain their activity in vivo. Herein we report an extended library that broadly explores the structure–activity relationship (SAR) of the pochoximes with four points of diversity. Several modifications were identified that afford improved cellular efficacy, new opportunities for conjugation, and further diversifications. Cocrystal structures of pochoximes A and B with HSP90 show that pochoximes bind to a different conformation of HSP90 than radicicol and provide a rationale for the enhanced affinity of the pochoximes relative to radicicol and the pochonins. 相似文献
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Site-specific cleavage of mRNA has been identified in vivo for the polycistronic colicin E7 operon (ColE7), which occurs between G and A nucleotides located at the Asp52 codon (GAT) of the immunity gene (ceiE7). In vitro, this specific cleavage occurs only in the presence of the ceiE7 gene product (ImmE7). The crystal structure of dimeric ImmE7 has been determined at 1.8 A resolution by X-ray crystallographic analysis. We found that several residues located at the interface of dimeric ImmE7 bear surprising resemblance to the active sites of some RNases. These results suggest that dimeric ImmE7 may possess a novel RNase activity that cleaves its own mRNA at a specific site and thus autoregulates translational expression of the downstream celE7 gene as well as degradation of the upstream ceaE7 mRNA. 相似文献
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William A House Ross M Welch Steven Beebe Z Cheng 《Journal of the science of food and agriculture》2002,82(13):1452-1457
A whole‐body radioassay procedure was used to assess the bioavailability to rats of zinc (Zn) in seeds of 18 genotypes of beans (Phaseolus vulgaris L) that were grown hydroponically. Dry beans that were labelled intrinsically with 65Zn were added to test meals fed to rats that were marginally Zn‐deficient. The amount of Zn in the seeds varied between genotypes and ranged from 26.7 to 62.4 µg g?1 (from 0.41 to 0.95 µmol g?1) dry weight (DW). Similarly, the amount of iron (Fe) in the beans varied nearly twofold (from 52.3 to 96.3 µg g?1 DW), and Zn and Fe concentrations were positively correlated. Concentrations of myo‐inositolhexaphosphate (IP6) plus myo‐inositolpentaphosphate (IP5) varied from 18.1 to 27.3 µmol g?1 DW. Cultivars with white‐coloured seeds contained relatively small amounts of tannins varying from 0.12 to 0.16 mg g?1 DW (determined as catechin equivalents) compared to those with coloured seed coats (up to 2.58 mg g?1 DW). All rats readily ate the test meals so that Zn intake varied directly with seed‐Zn concentration. As indicated by 65Zn absorption, the bioavailability to rats of Zn in the seeds varied between genotypes and ranged from about 78 to 95% of the total Zn in the seeds. The bioavailability of Zn to marginally Zn‐deficient rats was not affected markedly by either IP5 + IP6 or tannin in the dry beans. These results demonstrate that the concentration of Zn in dry beans can be increased through traditional plant‐breeding techniques and that this may result in significant increases in the amount of bioavailable Zn in the beans. Increasing the amount of Zn in beans may contribute significantly to improving the Zn status of individuals dependent on beans as a staple food. © 2002 Society of Chemical Industry 相似文献
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BACKGROUND: The benefits of intensive glycemic control in patients with type 2 diabetes are not well quantified. It is therefore not clear which patients will benefit most from aggressive glycemic control. OBJECTIVE: To evaluate the efficacy of glycemic control in type 2 diabetes. DESIGN: Markov decision model. PATIENTS: Diabetic patients at a health maintenance organization. MAIN OUTCOME MEASURES: Risks for developing blindness and end-stage renal disease; number of patients and patient-years needed to treat to prevent complications. RESULTS: For a patient in whom diabetes developed before 50 years of age, reducing hemoglobin A1c levels from 9% to 7% results in an estimated 2.3-percentage point decrease (from 2.6% to 0.3%) in lifetime risk for blindness due to retinopathy. The same change in a patient with diabetes onset at 65 years of age would be expected to decrease the risk for blindness by 0.5 percentage points (from 0.5% to < 0.1%). However, the Markov model predicts substantially greater benefit when moving from poor to moderate glycemic control than when moving from moderate to almost-normal glycemic control. Targeting less than 20% of the patients at one health maintenance organization for intensified therapy may prevent more than 80% of the preventable patient-time spent blind. The risks for end-stage renal disease and the risk reduction provided by improved glycemic control are lower than those for blindness. CONCLUSIONS: This probability model, based on extrapolation from the experience with type 1 diabetes, suggests that patients with early onset of type 2 diabetes will accrue substantial benefit from almost-normal glycemic control. In patients with later onset, moderate glycemic control prevents most end-stage complications caused by microvascular disease. These results have important implications for informing patients and allocating health care resources. 相似文献
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TP Whetzel TR Stevenson RB Sharman RC Carlsen 《Canadian Metallurgical Quarterly》1997,100(7):1767-1775
It has been well documented that ischemic preconditioning limits ischemic-reperfusion injury in cardiac muscle, but the ability of ischemic preconditioning to limit skeletal muscle injury is less clear. Previous reports have emphasized the beneficial effects of ischemic preconditioning on skeletal muscle structure and capillary perfusion but have not evaluated muscle function. We investigated the morphologic and functional consequences of ischemic preconditioning, followed by a 2-hour period of tourniquet ischemia on muscles in the rat hindlimb. The 2-hour ischemia was imposed without preconditioning, or was preceded by three brief (10 minutes on/10 minutes off) preischemic conditioning intervals. We compared muscle morphology, isometric contractile function, and muscle fatigue properties in predominantly fast-twitch, tibialis anterior muscles 3 (n = 8) and 7 (n = 8) days after ischemia-reperfusion. Two hours of ischemia, followed by reperfusion, results in a 20 percent reduction of muscle mass (p < 0.05) and a 33 percent reduction in tetanic tension (p < 0.05) when compared with controls (n = 8) at 3 days. The same protocol, when preceded by ischemic preconditioning, results in similar decreases in muscle mass and contractile function. Neuromuscular transmission was also impaired in both ischemic groups 7 days after ischemia. Nerve-evoked maximum tetanic tension was 69 percent of the tension produced by direct muscle stimulation in the ischemia group and 65 percent of direct tension in the ischemic preconditioning/ischemia group. In summary, ischemic preconditioning, using the same protocol reported to be effective in limiting infarct size in porcine muscle, had no significant benefit in limiting injury or improving recovery in the ischemic rat tibialis anterior. The value of ischemic preconditioning in reducing imposed ischemic-reperfusion-induced functional deficits in skeletal muscle remains to be demonstrated. 相似文献
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Cytoprotective effects of adrenomedullin in glomerular cell injury: central role of cAMP signaling pathway 总被引:1,自引:0,他引:1
EN Chini CC Chini C Bolliger M Jougasaki JP Grande JC Burnett TP Dousa 《Canadian Metallurgical Quarterly》1997,52(4):917-925
Activation of cAMP signaling pathway was shown to inhibit some pathobiologic processes in mesangial cells (MC). We investigated whether adrenomedullin (ADM), a potent agonist of adenylate cyclase, is synthesized in MC and whether it can, via cAMP, suppress the generation of reactive oxygen metabolites (ROM) and proliferation of cells in glomeruli. With the use of an immunohistologic technique ADM was detected in mesangial and microvascular areas of rat glomeruli. MC grown in primary culture synthesized ADM, and the synthesis was stimulated by TNF alpha and IL-1 beta but not by PDGF and EGF. ADM inhibited ROM generation in MC dose-dependently and caused in situ activation of protein kinase A (PKA). In macrophages (cell line J774) ROM generation was about four times higher than in MC and was inhibited by ADM in a similar way as in MC. The rate of MC proliferation, measured by [3H]-incorporation, and the activity of mitogen-activated protein kinase (MAPK) stimulated by PDGF and EGF were dose-dependently inhibited by ADM; the maximum inhibition (at 10 nM ADM) was about -80%. Mitogenesis of MC and MAPK activity when stimulated to a similar extent by endothelin (ET-1) was inhibited by ADM to a significantly (P < 0.01) lesser degree (-30%). Further, ADM inhibited PDF-stimulated mitogenesis and activation of MAPK in cultured vascular smooth muscle cells (VSMC). The inhibition of PDGF-activated MAPK by ADM in VSMC was reversed by the protein kinase A (PKA) inhibitor, H89. Taken together, results indicate the adrenomedullin (ADM) generated in mesangial cells (MC) can suppress, via activation of the cAMP-protein kinase A (PKA) signaling pathway, reactive oxygen metabolites (ROM) generation in MC and infiltrating macrophages as well as mitogen-activated protein kinase (MAPK)-mediated mitogenesis in MC and vascular smooth muscle cells (VSMC). We suggest that introglomerular ADM may serve as a cytoprotective autoacoid that suppresses pathobiologic processes evoked by immuno-inflammatory injury of glomeruli. 相似文献