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Selected AbstractsA novel, promoter-based, target-specific assay identifies 2-deoxy- d -glucose as an inhibitor of globotriaosylceramide biosynthesisFEBS JOURNAL, Issue 18 2009Tetsuya Okuda Abnormal biosynthesis of globotriaosylceramide (Gb3) is known to be associated with Gb3-related diseases, such as Fabry disease. The Gb3 synthase gene (Gb3S) codes for ,1,4-galactosyltransferase, which is a key enzyme involved in Gb3 biosynthesis in vivo. Transcriptional repression of Gb3S is a way to control Gb3 biosynthesis and may be a suitable target for the treatment of Gb3-related diseases. To find a transcriptional inhibitor for Gb3S, we developed a convenient cell-based chemical screening assay system by constructing a fusion gene construct of the human Gb3S promoter and a secreted luciferase as reporter. Using this assay, we identified 2-deoxy- d -glucose as a potent inhibitor for the Gb3S promoter. In cultured cells, 2-deoxy- d -glucose markedly reduced endogenous Gb3S mRNA levels, resulting in a reduction in cellular Gb3 content and a corresponding accumulation of the precursor lactosylceramide. Moreover, cytokine-induced expression of Gb3 on the cell surface of endothelial cells, which is closely related to the onset of hemolytic uremic syndrome in O157-infected patients, was also suppressed by 2-deoxy- d -glucose treatment. These results indicate that 2-deoxy- d -glucose can control Gb3 biosynthesis through the inhibition of Gb3S transcription. Furthermore, we demonstrated the general utility of our novel screening assay for the identification of new inhibitors of glycosphingolipid biosynthesis. [source] Insight Into the Kinetic of Amyloid , (1,42) Peptide Self-Aggregation: Elucidation of Inhibitors' Mechanism of ActionCHEMBIOCHEM, Issue 17 2007Manuela Bartolini Dr. Abstract The initial transition of amyloid , (1,42) (A,42) soluble monomers/small oligomers from unordered/,-helix to a ,-sheet-rich conformation represents a suitable target to design new potent inhibitors and to obtain effective therapeutics for Alzheimer's disease. Under optimized conditions, this reliable and reproducible CD kinetic study showed a three-step sigmoid profile that was characterized by a lag phase (prevailing unordered/,-helix conformation), an exponential growth phase (increasing ,-sheet secondary structure) and a plateau phase (prevailing ,-sheet secondary structure). This kinetic analysis brought insight into the inhibitors' mechanism of action. In fact, an increase in the duration of the lag phase can be related to the formation of an inhibitor,A, complex, in which the non-amyloidogenic conformation is stabilized. When the exponential rate is affected exclusively, such as in the case of Congo red and tetracycline, then the inhibitor affinity might be higher for the pleated ,-sheet structure. Finally, by adding the inhibitor at the end of the exponential phase, the soluble protofibrils can be disrupted and the A, amyloidogenic structure can revert into monomers/small oligomers. Congo red and tetracycline preferentially bind to amyloid in the ,-sheet conformation because both decreased the slope of the exponential growth, even if to a different extent, whereas no effect was observed for tacrine and galantamine. Some very preliminary indications can be derived about the structural requirements for binding to nonamyloidogenic or ,-sheet amyloid secondary structure for the development of potent antiaggregating agents. On these premises, memoquin, a multifunctional molecule that was designed to become a drug candidate for the treatment of Alzheimer's disease, was investigated under the reported circular dichroism assay and its anti-amyloidogenic mechanism of action was elucidated. [source] ORIGINAL ARTICLE: Characteristics of plasma NOx levels in severe sepsis: high interindividual variability and correlation with illness severity, but lack of correlation with cortisol levelsCLINICAL ENDOCRINOLOGY, Issue 3 2010J. T. Ho Summary Objectives, Nitric oxide (NO) concentrations are elevated in sepsis and their vasodilatory action may contribute to the development of hyperdynamic circulatory failure. Hydrocortisone infusion has been reported to reduce nitric oxide metabolite (NOx) concentrations and facilitate vasopressor withdrawal in septic shock. Our aim was to determine whether NOx concentrations relate to (i) protocol-driven vasopressor initiation and withdrawal and (ii) plasma cortisol concentrations, from endogenous and exogenous sources. Demonstration of a relation between NOx, cortisol and vasopressor requirement may provide an impetus towards the study of hydrocortisone-mediated NOx suppression as a tool in sepsis management. Design, A prospective study of 62 patients with severe sepsis admitted to the intensive care unit. Measurements, Plasma NOx, total and free cortisol, and corticosteroid-binding globulin (CBG) concentrations were measured and related to protocol-driven vasopressor use for 7 days following admission. Results, Patients who developed septic shock (n = 35) had higher plasma NOx, total and free cortisol, and lower CBG concentrations than the nonseptic shock group (n = 27). Cortisol, CBG and NOx concentrations correlated with illness severity. Free cortisol, and to a lesser extent total cortisol, but not NOx concentrations, predicted septic shock. NOx concentrations were higher in nonsurvivors, and the concentrations were characteristically stable within individuals but marked interindividual differences were only partly accounted for by illness severity or renal dysfunction. NOx concentrations did not correlate with cortisol, did not relate to vasopressor requirement and did not fall after standard dose hydrocortisone, given for clinical indications. Conclusions, Nitric oxide production increased with sepsis severity but did not correlate with plasma cortisol or vasopressor requirement. NOx levels were not suppressed reproducibly by hydrocortisone. High interindividual variability of NOx levels suggests that absolute NOx levels may not be a suitable target for individualized hydrocortisone therapy. [source] Cecidophagy in adults of Demotina fasciculata (Coleoptera: Chrysomelidae) and its effect on the survival of Andricus moriokae (Hymenoptera: Cynipidae) inhabiting leaf galls on Quercus serrata (Fagaceae)ENTOMOLOGICAL SCIENCE, Issue 1 2010Takayoshi KATSUDA Abstract Females of Demotina fasciculata (Coleoptera: Chrysomelidae) were found to prefer to feed on galls induced by Andricus moriokae (Hymenoptera: Cynipidae) rather than on leaves of its host plant, Quercus serrata (Fagaceae). This is the first record of cecidophagy by adult chrysomelid beetles. Demotina fasciculata did not infest healthy galls induced by another unidentified cynipid species on the same host trees, but did feed on galls inhabited by an inquiline species Synergus quercicola (Hymenoptera: Cynipidae), presumably because such galls remained on the host trees longer than healthy galls. Galls of A. moriokae were infested more severely than cynipid galls inhabited by the inquiline. Therefore, higher density and thicker gall wall in A. moriokae galls seem to make them more suitable targets for D. fasciculata to attack. Larval chambers of A. moriokae galls were stripped by the infestation of gall walls and readily dropped to the ground, resulting in 100% death of cynipid larvae due to desiccation, while 62.5% of pupae survived when they had developed to the late stadium before the fall of larval chambers. [source] Hyperglycaemia and cardiovascular diseaseJOURNAL OF INTERNAL MEDICINE, Issue 2 2007M. Bartnik Abstract. Coronary artery disease and type 2 diabetes are chronic diseases of substantial and growing prevalence. Their coincidence is common, markedly enhancing mortality and morbidity. The risk for cardiovascular disease increases along a spectrum of blood glucose concentrations already apparent at levels regarded as normal. Accordingly, strategies for the early detection of glucometabolic disturbances are needed to find ways to prevent the occurrence of cardiovascular complications or to treat them already at an early stage. More specifically, abnormal glucose tolerance is almost twice as common amongst patients with a myocardial infarction as in population-based controls and a normal glucose regulation is indeed less common than abnormal glucose metabolism also amongst patients with stable coronary artery disease. Already an abnormal glucose tolerance is a strong risk factor for future cardiovascular events after an acute myocardial infarction. An oral glucose tolerance test should, therefore, be a part of the evaluation of total risk in all patients with coronary artery disease. As glucose disturbances are common and easy to detect, they may be suitable targets for novel secondary preventive efforts. [source] Cutting Balloon Angioplasty for Ostial Lesions of the Left Anterior Descending ArteryJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 1 2000TERUO INOUE M.D. We evaluated the effectiveness of Cutting Balloon angioplasty for ostial lesions of the left anterior descending artery compared with conventional balloon angioplasty. Cutting Balloon angioplasty (n = 7) produced larger acute gain (1.70 ± 0.37 vs 0.48 ± 0.25 mm, P < 0.001) and smaller late loss index (0.54 ± 0.55 vs 1.32 ± 0.81, P < 0.05) than conventional balloon angioplasty (n = 7). As a result, late restenosis was seen in only two patients undergoing Cutting Balloon angioplasty, but in all seven patients undergoing conventional balloon angioplasty. Ostial lesions of the left anterior descending artery may be one of the suitable targets of Cutting Balloon angioplasty. (J Interven Cardiol 2000;13:7,14) [source] The importance of starch and sucrose digestion in nutritive biology of synanthropic acaridid mites: ,-Amylases and ,-glucosidases are suitable targets for inhibitor-based strategies of mite control,ARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY (ELECTRONIC), Issue 3 2009Tomas Erban Abstract The adaptation of nine species of mites that infest stored products for starch utilization was tested by (1) enzymatic analysis using feces and whole mite extracts, (2) biotests, and (3) inhibition experiments. Acarus siro, Aleuroglyphus ovatus, and Tyroborus lini were associated with the starch-type substrates and maltose, with higher enzymatic activities observed in whole mite extracts. Lepidoglyphus destructor was associated with the same substrates but had higher activities in feces. Dermatophagoides farinae, Chortoglyphus arcuatus, and Caloglyphus redickorzevi were associated with sucrose. Tyrophagus putrescentiae and Carpoglyphus lactis had low or intermediate enzymatic activity on the tested substrates. Biotests on starch additive diets showed accelerated growth of species associated with the starch-type substrates. The inhibitor acarbose suppressed starch hydrolysis and growth of the mites. We suggest that the species with higher starch hydrolytic activity in feces were more tolerant to acarbose, and ,-amylase and ,-glucosidase of synanthropic mites are suitable targets for inhibitor-based strategies of mite control. © 2009 Wiley Periodicals, Inc. [source] | |||||||||||||