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131.
Chakraborty S Shah NH Fishbein JC Hosmane RS 《Bioorganic & medicinal chemistry letters》2011,21(2):756-759
Synthesis and biochemical inhibition studies of a novel transition state analog inhibitor of guanase bearing the ring structure of azepinomycin have been reported. The compound was synthesized in five-steps from a known compound and biochemically screened against the rabbit liver guanase. The compound exhibited competitive inhibition profile with a Ki of 16.7 ± 0.5 μM. 相似文献
132.
M. Henriksen S. Rosager J. Aaboe H. BliddalAuthor vitae 《Journal of electromyography and kinesiology》2011,21(5):746-753
Pain changes movement but most studies have focused on basic physiological adaptations during non-functional movement tasks. The existing studies on how pain affects lower extremity gross movement biomechanics have primarily involved movements in which the quadriceps is the primary muscle and little attention has been given to how pain in other muscles affects functional movement. The purpose of this study was to investigate the changes in the gait patterns of healthy subjects that occur during experimental muscle pain in the biceps femoris.In a cross-over study design, 14 healthy volunteers underwent EMG assisted 3D gait analyses before, during and after experimental biceps femoris pain induced by intramuscular injections of hypertonic saline. Isotonic saline injections were administered as a non-painful control.The experimental biceps femoris pain led to reductions in hip extensor moments, knee flexor and lateral rotator moments. No changes in lower extremity kinematics and EMG activity in any of the recorded muscles were observed.It is concluded that experimental muscle pain in the biceps femoris leads to changes in the gait pattern in agreement with unloading of the painful muscle. The changes are specific to the painful muscle. The present study provides support to the theory that musculoskeletal pain is a protective signal leading to changes in movement patterns that serve to unload the painful tissue. 相似文献
133.
The toxicities of 4 short-chain alcohols--namely methanol, ethanol, iso-propanol and iso-butanol--were compared in the nematode Caenorhabditis elegans using several different ecotoxicological endpoints. Range-finding tests were conducted using transgenic PC161 worms carrying a double reporter construct (GFP plus lacZ) linked to the stress-inducible hsp16-1 promoter. These tests showed little response from the GFP reporter, but gave good dose-response curves for the lacZ reporter--showing clear induction at 0.5% v/v ethanol in an overnight assay, but only at 4% in a shorter 6-h assay. Comparison of the short-term dose-response curves shows a confusing pattern of differences between the four alcohols tested, although dose-dependence is evident across at least part of the concentration range. Feeding inhibition assays are somewhat inconclusive with regard to alcohol type, although iso-butanol and iso-propanol appear more toxic than ethanol, while methanol is least toxic. To resolve some of the remaining ambiguities, we also used a fecundity assay to show that iso-propanol is more toxic than ethanol, and a lethality assay to show that iso-butanol is more toxic than iso-propanol. Most of the endpoints studied are consistent with the following order of toxicity: iso-butanol > iso-propanol > ethanol > or = methanol. 相似文献
134.
Okuda J Toyotome T Kataoka N Ohno M Abe H Shimura Y Seyedarabi A Pickersgill R Sasakawa C 《Biochemical and biophysical research communications》2005,333(2):531-539
Shigella effectors injected into the host cell via the type III secretion system are involved in various aspects of infection. Here, we show that one of the effectors, IpaH9.8, plays a role in modulating inflammatory responses to Shigella infection. In murine lung infection model, DeltaipaH9.8 mutant caused more severe inflammatory responses with increased pro-inflammatory cytokine production levels than did wild-type Shigella, which resulted in a 30-fold decrease in bacterial colonization. Binding assays revealed that IpaH9.8 has a specific affinity to U2AF(35), a mammalian splicing factor, which interferes with U2AF(35)-dependent splicing as assayed for IgM pre-mRNA. Reducing the U2AF(35) level in HeLa cells and infecting HeLa cells with wild-type caused a decrease in the expression of the il-8, RANTES, GM-CSF, and il-1beta genes as examined by RT-PCR. The results indicate that IpaH9.8 plays a role in Shigella infection to optimize the host inflammatory responses, thus facilitating bacterial colonization within the host epithelial cells. 相似文献
135.
Vivas L Easton A Kendrick H Cameron A Lavandera JL Barros D de las Heras FG Brady RL Croft SL 《Experimental parasitology》2005,111(2):105-114
Plasmodium falciparum lactate dehydrogenase (PfLDH) is essential for ATP generation. Based on structural differences within the active site between P. falciparum and human LDH, we have identified a series of heterocyclic azole-based inhibitors that selectively bind within the PfLDH but not the human LDH (hLDH) active site and showed anti-malarial activity in vitro and in vivo. Here we expand on an azole, OXD1, from this series and found that the anti-P. falciparum activity was retained against a panel of strains independently of their anti-malarial drug sensitivity profile. Trophozoites had relatively higher PfLDH enzyme activity and PfLDH-RNA expression levels than rings and were the most susceptible stages to OXD1 exposure. This is probably linked to their increased energy requirements and consistent with glycolysis being an essential metabolic pathway for parasite survival within the erythrocyte. Further structural elaboration of these azoles could lead to the identification of compounds that target P. falciparum through such a novel mechanism and with more potent anti-malarial activity. 相似文献
136.
Colin?M.?BeierEmail author Jonathan?L.?Horton John?F.?Walker Barton?D.?Clinton Erik?T.?Nilsen 《Plant Ecology》2005,176(1):131-142
Inhibition of canopy tree recruitment beneath thickets of the evergreen shrubs Rhododendron maximum L. and Kalmia latifolia L. has long been observed in Southern Appalachian forests, yet the mechanisms of this process remain unresolved. We present a first-year account of suppression of oak seedlings in relation to Rhododendron and Kalmia basal area, light and resource availability, seedling performance and the rates of seedling damage (i.e., herbivory). We found no evidence of first-year seedling suppression or significant resource deficiencies beneath thickets of K. latifolia in mature mixed hardwood stands. Suppression beneath R. maximum was apparent during the first growing season. We found that seedling biomass, light availability prior to canopy closure, and seedling tissue C:N ratios were negatively correlated with R. maximum basal area. Basal area of R. maximum was positively correlated with seedling mortality rates, soil [Al], and early-growing season leaf herbivory rates. Seedling growth was positively correlated with light and tissue C:N, while negatively correlated with soil [Al]. Overall, our results support the inhibition model of shade-mediated carbon limitation beneath dense understory shrubs and indicate the potential importance of herbivory and aluminum toxicity as components of a suppression mechanism beneath R. maximum thickets. We present a causal model of first year inhibition beneath R. maximum in the context of our findings and the results of prior studies. 相似文献
137.
Erythrocyte acetylcholinesterase (AChE) is bound to the membrane by a complex glycosylphosphatidylinositol anchor, so the effect of alcohol on AChE activity may reflect direct and/or membrane-mediated effects. The indication of a direct interaction between n-butanol and AChE molecules is the activation/inhibition of AChE by occupation of the enzyme's active and/or regulatory sites by alcohol. The activation of AChE can occur only at low concentrations of alcohols, while at high concentrations AChE is inhibited. In this work the mechanism of inhibition of erythrocyte AChE by n-butanol at high concentrations was studied. The values of activity, calculated assuming parabolic competitive inhibition, which implies that one or two molecules of inhibitor bind to the enzyme, fit well to the experimental values. From the values of the inhibition constants it was concluded that at high n-butanol concentrations two alcohol molecules usually interact with AChE. 相似文献
138.
Kalliri E Grzyska PK Hausinger RP 《Biochemical and biophysical research communications》2005,338(1):191-197
Co(II), Ni(II), and N-oxalylglycine (NOG) are well-known inhibitors of Fe(II)/alpha-ketoglutarate (alphaKG)-dependent hydroxylases, but few studies describe their kinetics and no spectroscopic investigations have been reported. Using taurine/alphaKG dioxygenase (TauD) as a paradigm for this enzyme family, time-dependent inhibition assays showed that Co(II) and Ni(II) follow slow-binding inhibition kinetics. Whereas Ni(II)-substituted TauD was non-chromophoric, spectroscopic studies of the Co(II)-substituted enzyme revealed a six-coordinate site (protein alone or with alphaKG) that became five-coordinate upon taurine addition. The Co(II) spectrum was not perturbed by a series of anions or oxidants, suggesting the Co(II) is inaccessible and could be used to stabilize the protein. NOG competed weakly (Ki approximately 290 microM) with alphaKG for binding to TauD, with the increased electron density of NOG yielding electronic transitions for NOG-Fe(II)-TauD and taurine-NOG-Fe(II)-TauD at 380 nm (epsilon380 90-105 M(-1) cm(-1)). The spectra of the NOG-bound TauD species did not change significantly upon oxygen exposure, arguing against the formation of an oxygen-bound state mimicking an early intermediate in catalysis. 相似文献
139.
We recently demonstrated the presence of estrogen synthase (aromatase) and of estrogen receptors in the dorsal horn (laminae I-II) throughout the rostrocaudal extent of the spinal cord in male and female Japanese quail. The spinal laminae I-II receive and process abundant sensory information elicited, among others, by acute noxious stimulation of the skin and resulting in rapid, reflex-like withdrawal behavior. In the present study, we demonstrate that systemic treatment with estradiol or testosterone markedly decreases the latency of the foot withdrawal in the hot water test. A simultaneous treatment with an aromatase inhibitor blocks the effects of testosterone demonstrating, hence, that they are mediated by a conversion of testosterone into an estrogen by aromatase. Furthermore, the testosterone- or estradiol-induced decrease in foot withdrawal latency is blocked by a treatment with the estradiol receptor antagonist, tamoxifen, indicating that the effects are largely mediated by the interaction of estradiol with estrogen receptors. Together, these data suggest that sex steroids modulate sensitivity to noxious stimuli possibly by a direct action at the level of the dorsal horn of the spinal cord. 相似文献
140.
Valizadeh M Schenk G Nash K Oddie GW Guddat LW Hume DA de Jersey J Burke TR Hamilton S 《Archives of biochemistry and biophysics》2004,424(2):154-162
Purple acid phosphatases are metal-containing hydrolases. While their precise biological role(s) is unknown, the mammalian enzyme has been linked in a variety of biological circumstances (e.g., osteoporosis) with increased bone resorption. Inhibition of the human enzyme is a possible strategy for the treatment of bone-resorptive diseases such as osteoporosis. Previously, we determined the crystal structure of pig purple acid phosphatase to 1.55A and we showed that it is a good model for the human enzyme. Here, a study of the pH dependence of its kinetic parameters showed that the pig enzyme is most efficient at pH values similar to those encountered in the osteoclast resorptive space. Based on the observation that phosphotyrosine-containing peptides are good substrates for pig purple acid phosphatase, peptides containing a range of phosphotyrosine mimetics were synthesized. Kinetic analysis showed that they act as potent inhibitors of mammalian and plant purple acid phosphatases, with the best inhibitors exhibiting low micromolar inhibition constants at pH 3-5. These compounds are thus the most potent organic inhibitors yet reported for the purple acid phosphatases. 相似文献