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91.
Heterochromatin Protein 1 (HP1) is a structural component of silent chromatin at telomeres and centromeres. Euchromatic genes repositioned near heterochromatin by chromosomal rearrangements are typically silenced in an HP1-dependent manner. Silencing is thought to involve the spreading of heterochromatin proteins over the rearranged genes. HP1 associates with centric heterochromatin through an interaction with methylated lysine 9 of histone H3, a modification generated by SU(VAR)3-9. The current model for spreading of silent chromatin involves HP1-dependent recruitment of SU(VAR)3-9, resulting in the methylation of adjacent nucleosomes and association of HP1 along the chromatin fiber. To address mechanisms of silent chromatin formation and spreading, HP1 was fused to the DNA-binding domain of the E. coli lacI repressor and expressed in Drosophila melanogaster stocks carrying heat shock reporter genes positioned 1.9 and 3.7 kb downstream of lac operator repeats. Association of lacI-HP1 with the repeats resulted in silencing of both reporter genes and correlated with a closed chromatin structure consisting of regularly spaced nucleosomes, similar to that observed in centric heterochromatin. Chromatin immunoprecipitation experiments demonstrated that HP1 spread bi-directionally from the tethering site and associated with the silenced reporter transgenes. To examine mechanisms of spreading, the effects of a mutation in Su(var)3-9 were investigated. Silencing was minimally affected at 1.9 kb, but eliminated at 3.7 kb, suggesting that HP1-mediated silencing can operate in a SU(VAR)3-9-independent and -dependent manner. 相似文献
92.
Beta-oxidation (beta-ox) occurs exclusively in the peroxisomes of Saccharomyces cerevisiae and other yeasts, leading to the supposition that fungi lack mitochondrial beta-ox. Here we present unequivocal evidence that the filamentous fungus Aspergillus nidulans houses both peroxisomal and mitochondrial beta-ox. While growth of a peroxisomal beta-ox disruption mutant (DeltafoxA) was eliminated on a very long-chain fatty acid (C(22:1)), growth was only partially impeded on a long-chain fatty acid (C(18:1)) and was not affected at all on short chain (C4-C6) fatty acids. In contrast, growth of a putative enoyl-CoA hydratase mutant (DeltaechA) was abolished on short-chain and severely restricted on long- and very long-chain fatty acids. Furthermore fatty acids inhibited growth of the DeltaechA mutant but not the DeltafoxA mutant in the presence of an alternate carbon source (lactose). Disruption of echA led to a 28-fold reduction in 2-butenoyl-CoA hydratase activity in a preparation of organelles. EchA was also required for growth on isoleucine and valine. The subcellular localization of the FoxA and EchA proteins was confirmed through the use of red and green fluorescent protein fusions. 相似文献
93.
94.
Di Gregorio GB Hensley L Lu T Ranganathan G Kern PA 《American journal of physiology. Endocrinology and metabolism》2004,287(1):E182-E187
Obesity-related insulin resistance may be caused by adipokines such as IL-6, which is known to be elevated with the insulin resistance syndrome. A previous study reported that IL-6 knockout mice (IL-6(-/-)) developed maturity onset obesity, with disturbed carbohydrate and lipid metabolism, and increased leptin levels. Because IL-6 is associated with insulin resistance, one might have expected IL-6(-/-) mice to be more insulin sensitive. We examined body weights of growing and older IL-6(-/-) mice and found them to be similar to wild-type (IL-6(+/+)) mice. Dual-energy X-ray absorptiometry analysis at 3 and 14 mo revealed no differences in body composition. There were no differences in fasting blood insulin and glucose or in triglycerides. To further characterize these mice, we fed 11-mo-old IL-6(-/-) and IL-6(+/+) mice a high- (HF)- or low-fat diet for 14 wk, followed by insulin (ITT) and glucose tolerance tests (GTT). An ITT showed insulin resistance in the HF animals but no difference due to genotype. In the GTT, IL-6(-/-) mice demonstrated elevated postinjection glucose levels by 60% compared with IL-6(+/+) but only in the HF group. Although IL-6(-/-) mice gained weight and white adipose tissue (WAT) with the HF diet, they gained less weight than the IL-6(+/+) mice. Total lipoprotein lipase activity in WAT, muscle, and postheparin plasma was unchanged in the IL-6 (-/-) mice compared with IL-6(+/+) mice. There were no differences in plasma leptin or TNF-alpha due to genotype. Plasma adiponectin was approximately 53% higher (71.7 +/- 14.1 microg/ml) in IL-6(-/-) mice than in IL-6(+/+) mice but only in the HF group. Thus these data show that IL-6(-/-) mice do not demonstrate obesity, fasting hyperglycemia, or abnormal lipid metabolism, although HF IL-6(-/-) mice demonstrate elevated glucose after a GTT. 相似文献
95.
Zhang HC Ye H Conway BR Derian CK Addo MF Kuo GH Hecker LR Croll DR Li J Westover L Xu JZ Look R Demarest KT Andrade-Gordon P Damiano BP Maryanoff BE 《Bioorganic & medicinal chemistry letters》2004,14(12):3245-3250
A novel series of acyclic 3-(7-azaindolyl)-4-(aryl/heteroaryl)maleimides was synthesized and evaluated for activity against GSK-3beta and selectivity versus PKC-betaII, as well as a broad panel of protein kinases. Compounds 14 and 17c potently inhibited GSK-3beta (IC(50)=7 and 26 nM, respectively) and exhibited excellent selectivity over PKC-betaII (325 and >385-fold, respectively). Compound 17c was also highly selective against 68 other protein kinases. In a cell-based functional assay, both 14 and 17c effectively increased glycogen synthase activity by inhibiting GSK-3beta. 相似文献
96.
Collins MA Hudak V Bender R Fensome A Zhang P Miller L Winneker RC Zhang Z Zhu Y Cohen J Unwalla RJ Wrobel J 《Bioorganic & medicinal chemistry letters》2004,14(9):2185-2189
A series of 1,4-dihydro-2H-[d][3,1]-benzoxazin-2-one and 1,3-dihydro-[3H]-indol-2-one containing 6- or 5-, respectively, appended substituted pyrrole moieties were synthesized and evaluated for their ability to modulate the activity of the progesterone receptor (PR). Key structural changes to the pyrrole moieties of these molecules were shown to have a predictive influence as to whether the compounds behaved as PR agonists or antagonists. Compounds with the 5(')-cyano-2(')-pyrrole moiety (e.g., 32, 33, and 38) were shown to be potent PR agonists (EC(50)'s of 1.1, 1.8, and 2.8 nM, respectively). Compounds with the 5(')-nitro-2(')-pyrrole moiety (e.g., 34 and 36) were shown to be PR antagonists (IC(50)'s of 180 and 36 nM, respectively). 相似文献
97.
Noe MC Snow SL Wolf-Gouveia LA Mitchell PG Lopresti-Morrow L Reeves LM Yocum SA Liras JL Vaughn M 《Bioorganic & medicinal chemistry letters》2004,14(18):4727-4730
N-Hydroxy-3-hydroxy-4-arylsulfonyltetrahydropyranyl-3-carboxamides were designed as novel inhibitors of MMP-13 and aggrecanase based on known endocyclic hydroxamate inhibitors of matrix metalloproteinases. These compounds offer favorable physicochemical properties and low metabolic clearance. Synthesis and structure-activity relationships are reported. 相似文献
98.
Showalter LA Weinman SA Østerlie M Lockwood SF 《Comparative biochemistry and physiology. Toxicology & pharmacology : CBP》2004,137(3):227-236
Oral bioavailability of natural and synthetic carotenoids is generally poor in rodents, and this has limited the ability to test these antioxidant compounds in well-defined rodent models of human disease. Various strategies have been employed, with variable success, to increase the percentage of the total oral dose absorbed by the rodent GI tract. In the current study, a novel carotenoid derivative (the disodium disuccinate diester of astaxanthin; Heptax) was administered by oral gavage in a lipophilic emulsion to C57BL/6 mice. Plasma appearance and tissue accumulation of non-esterified, free astaxanthin was studied by HPLC over 72 h after single- and multiple-dose regimens. One-time dosing of Heptax in emulsion at 500 mg/kg resulted in significant appearance of free astaxanthin in plasma (Cmax=0.2 mg/l; 381 nM) and accumulation in solid organs (e.g. liver Cmax=0.9 mg/l; 1735 nM), levels not previously reported after single carotenoid doses in rodents. At each point in the concentration/time curve (AUC), free astaxanthin levels in liver were greater than the corresponding concentration in plasma, suggesting concentrative uptake by the liver. As the ED50 as an antioxidant for non-esterified, free astaxanthin in model systems is approximately 200 nM, the current results suggest that hepatoprotection against oxidative insults may be achieved after a single dose of Heptax in these animals. In humans, where the bioavailability of oral carotenoids ranges from 40 to 60% of the total dose when given in lipophilic vehicle, much smaller oral doses may be utilized for therapeutic benefit in a particular clinical application. 相似文献
99.
100.
O'Neill DJ Shen L Prouty C Conway BR Westover L Xu JZ Zhang HC Maryanoff BE Murray WV Demarest KT Kuo GH 《Bioorganic & medicinal chemistry》2004,12(12):3167-3185
Two approaches were developed to synthesize the novel 7-azaindolyl-heteroarylmaleimides. The first approach was based upon the palladium-catalyzed Suzuki cross-coupling or Stille cross-coupling of 2-chloro-maleimide 5 with various arylboronic acids or arylstannanes. The second approach was based upon the condensation of ethyl 7-azaindolyl-3-glyoxylate 12 with various acetamides. The hydroxypropyl-substituted 7-azaindolylmaleimide template was first used to screen different heteroaryls attached to the maleimide. Replacement of hydroxypropyl with different chain lengths and different functional groups were studied next. Many compounds synthesized were demonstrated to have high potency at GSK-3beta, good GS activity in HEK293 cells and good to excellent metabolic stability in human liver microsomes. Three representative compounds (21, 33, and 34) were demonstrated to have good selectivity against a panel of 80 kinase assays. Among them, compound 33 exhibited very weak inhibitions at the other 79 kinase assays, and behaved as a highly selective GSK-3beta inhibitor. 相似文献