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41.
Roychowdhury S Martinez L Salgado L Das S Rasenick MM 《Biochemical and biophysical research communications》2006,340(2):441-448
Heterotrimeric G proteins participate in signal transduction by transferring signals from cell surface receptors to intracellular effector molecules. Interestingly, recent results suggest that G proteins also interact with microtubules and participate in cell division and differentiation. It has been shown earlier that both alpha and betagamma subunits of G proteins modulate microtubule assembly in vitro. Since G protein activation and subsequent dissociation of alpha and betagamma subunits are necessary for G proteins to participate in signaling processes, here we asked if similar activation is required for modulation of microtubule assembly by G proteins. We reconstituted Galphabetagamma heterotrimer from myristoylated-Galpha and prenylated-Gbetagamma, and found that the heterotrimer blocks Gi1alpha activation of tubulin GTPase and inhibits the ability of Gbeta1gamma2 to promote in vitro microtubule assembly. Results suggest that G protein activation is required for functional coupling between Galpha/Gbetagamma and tubulin/microtubules, and supports the notion that regulation of microtubules is an integral component of G protein mediated signaling. 相似文献
42.
43.
Adenylyl cyclases are widely distributed across all kingdoms whereas guanylyl cyclases are generally thought to be restricted to eukaryotes. Here we report that the α-proteobacterium Rhodospirillum centenum secretes cGMP when developing cysts and that a guanylyl cyclase deletion strain fails to synthesize cGMP and is defective in cyst formation. The R. centenum cyclase was purified and shown to effectively synthesize cGMP from GTP in vitro, demonstrating that it is a functional guanylyl cyclase. A homologue of the Escherichia coli cAMP receptor protein (CRP) is linked to the guanylyl cyclase and when deleted is deficient in cyst development. Isothermal calorimetry (ITC) and differential scanning fluorimetry (DSF) analyses demonstrate that the recombinant CRP homologue preferentially binds to, and is stabilized by cGMP, but not cAMP. This study thus provides evidence that cGMP has a crucial role in regulating prokaryotic development. The involvement of cGMP in regulating bacterial development has broader implications as several plant-interacting bacteria contain a similar cyclase coupled by the observation that Azospirillum brasilense also synthesizes cGMP when inducing cysts. 相似文献
44.
Peter Lorenz Sanjoy Roychowdhury Mario Engelmann Gerald Wolf Thomas F W Horn 《Nitric oxide》2003,9(2):64-76
Hydroxystilbenes are naturally occurring polyphenols with protective effects against reactive oxygen and nitrogen species (ROS/RNS). Here, we investigated oxyresveratrol (OXY), which is contained in high amounts in mulberry wood, in comparison to the antioxidant resveratrol (RES). We found that OXY is a more effective scavenger for 2,2-diphenyl-1-picryl-hydrazyl (DPPH, 100 microM) used as a general free radical model, compared to RES or trans-4-hydroxystilbene (IC(50)=28.9, 38.5, and 39.6 microM, respectively). When primary glial cell cultures were loaded with the ROS/RNS-sensitive fluorochrome 2,7-dichlorodihydrofluorescein, the lowest rise in the fluorescence signal after H(2)O(2) exposure was seen when the cells were pretreated with OXY. Using 4,5-diaminofluorescein (DAF-2) to monitor free nitric oxide levels (7.7 microM NO) in a spectrofluorimetric cell-free assay, we found again that OXY (at 5 microM) is a more effective scavenger. Accordingly, cultures of the murine microglial cell line N9 and primary mixed glial cultures were used to test the drug effects of NO production upon expression of the inducible isoform of nitric oxide synthase (iNOS). We found that both compounds considerably diminished NO (nitrite) levels, RES more effectively than OXY (IC(50)=22.36 and 45.31 microM). RES but not OXY down-regulated the expression of iNOS protein, but both did not alter iNOS activity. Furthermore, OXY displayed a generally lower cytotoxicity than RES. The radical and ROS scavenging properties, as well as the lower cytotoxicity towards microglia and the known good water solubility suggest OXY as a potential protectant against ROS/RNS. 相似文献
45.
F Bennett HS Kezar V Girijavallabhan Y Huang R Huelgas R Rossman NY Shih JJ Piwinski M MacCoss CD Kwong JL Clark AT Fowler F Geng A Roychowdhury RC Reynolds JA Maddry S Ananthan JA Secrist C Li R Chase S Curry HC Huang X Tong F George Njoroge A Arasappan 《Bioorganic & medicinal chemistry letters》2012,22(15):5144-5149
Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC(50)) was low. 相似文献
46.
Arasappan A Bennett F Girijavallabhan V Huang Y Huelgas R Alvarez C Chen L Gavalas S Kim SH Kosinski A Pinto P Rizvi R Rossman R Shankar B Tong L Velazquez F Venkatraman S Verma VA Kozlowski J Shih NY Piwinski JJ MacCoss M Kwong CD Clark JL Fowler AT Geng F Kezar HS Roychowdhury A Reynolds RC Maddry JA Ananthan S Secrist JA Li C Chase R Curry S Huang HC Tong X Njoroge FG 《Bioorganic & medicinal chemistry letters》2012,22(9):3229-3234
Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C-H arylation protocol. 相似文献
47.
A major worldwide health problem is hip fracture due to sideways fall among the elderly population. The effects of sideways fall on the hip are required to be investigated thoroughly. The objectives of this study are to evaluate the responses to trochanteric soft tissue thickness (T) variations and hip impact velocity (V) variations during sideways fall based on a previously developed CT scan derived 3D non-linear and non-homogeneous finite element model of pelvis-femur-soft tissue complex with simplified biomechanical representation of the whole body. This study is also aimed at quantifying the effects [peak impact force (F(max)), time to F(max), acceleration and peak principal compressive strain (epsilon(max))] of these variations (T,V) on hip fracture. It was found that under constant impact energy, for 81% decrease in T (26-5mm), F(max) and epsilon(max) increased by 38% and 97%, respectively. Hence, decrease in T (as in slimmer persons) strongly correlated to risk for hip fracture (phi) and strain ratio (SR) by 0.972 and 0.988, respectively. Also under same T and body weight, for 75% decrease in V (4.79-1.2m/s), F(max) and epsilon(max) decreased by 70% and 86%, respectively. Hence, increase in V (as in taller persons) strongly correlated to phi and SR by 0.995 and 0.984, respectively. For both variations in T and V, inter-trochanteric fracture situations were well demonstrated by phi as well as by SR and strain contours, similar to clinically observed fractures. These quantifications would be helpful for effective design of person-specific hip protective devices. 相似文献
48.
Protection of primary glial cells by grape seed proanthocyanidin extract against nitrosative/oxidative stress. 总被引:4,自引:0,他引:4
Previous studies showed that proanthocyanidins provide potent protection against oxidative stress. Here we investigate the effects of grape seed proanthocyanidin extract (GSPE) as a novel natural antioxidant on the generation and fate of nitric oxide (NO) in rat primary glial cell cultures. GSPE treatment (50 mg/L) increased NO production (measured by NO(2-) assay) by stimulation of the inducible isoform of NOS. However, GSPE failed to affect the LPS/IFN-gamma-induced NO production or iNOS expression. Similar responses were found in the murine macrophage cell line RAW264.7. GSPE did not show any effect on dihydrodichlorofluorescein fluorescence (ROS marker with high sensitivity toward peroxynitrite) either in control or in LPS/IFN-gamma-induced glial cultures even in the presence of a superoxide generator (PMA). GSPE treatment alone had no effect on the basal glutathione (GSH) status in glial cultures. Whereas the microglial GSH level declined sharply after LPS/IFN-gamma treatment, the endogenous GSH pool was protected when such cultures were treated additionally with GSPE, although NO levels did not change. Glial cultures pretreated with GSPE showed higher tolerance toward application of hydrogen peroxide (H(2)O(2)) and tert-butylhydroperoxide. Furthermore, GSPE-pretreated glial cultures showed improved viability after H(2)O(2)-induced oxidative stress demonstrated by reduction in lactate dehydrogenase release or propidium iodide staining. We showed that, in addition to its antioxidative property, GSPE enhances low-level production of intracellular NO in primary rat astroglial cultures. Furthermore, GSPE pretreatment protects the microglial GSH pool during high output NO production and results in an elevation of the H(2)O(2) tolerance in astroglial cells. 相似文献
49.
A route is presented to append, in a single step, alkynyl thioesters to the 5-position of a pyrimidine ring of a nucleoside that is unprotected. These products should be useful to support in vitro selection experiments with functionalized DNA. 相似文献
50.