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991.
Crystal structure analysis of warfarin binding to human serum albumin: anatomy of drug site I 总被引:3,自引:0,他引:3
Petitpas I Bhattacharya AA Twine S East M Curry S 《The Journal of biological chemistry》2001,276(25):22804-22809
Human serum albumin (HSA) is an abundant transport protein found in plasma that binds a wide variety of drugs in two primary binding sites (I and II) and can have a significant impact on their pharmacokinetics. We have determined the crystal structures at 2.5 A-resolution of HSA-myristate complexed with the R-(+) and S-(-) enantiomers of warfarin, a widely used anticoagulant that binds to the protein with high affinity. The structures confirm that warfarin binds to drug site I (in subdomain IIA) in the presence of fatty acids and reveal the molecular details of the protein-drug interaction. The two enantiomers of warfarin adopt very similar conformations when bound to the protein and make many of the same specific contacts with amino acid side chains at the binding site, thus accounting for the relative lack of stereospecificity of the HSA-warfarin interaction. The conformation of the warfarin binding pocket is significantly altered upon binding of fatty acids, and this can explain the observed enhancement of warfarin binding to HSA at low levels of fatty acid. 相似文献
992.
Chattopadhyay SK Srivastava S Sashidhara KV Tripathi AK Bhattacharya AK Negi AS 《Bioorganic & medicinal chemistry letters》2004,14(7):1729-1731
The title chiral amine, 3-(4-methoxyphenyl)-1-methylpropylamine 5 has been synthesized from naturally abundant betuligenol 1 in three steps and also in good yield. Furthermore, the versatile intermediate 3 could be manipulated for the preparation of chiral disulphide 7. The amine derivative 5 prepared from (-)-betuligenol showed significant growth inhibition and antifeedant activity. 相似文献
993.
Wright DH Abran D Bhattacharya M Hou X Bernier SG Bouayad A Fouron JC Vazquez-Tello A Beauchamp MH Clyman RI Peri K Varma DR Chemtob S 《American journal of physiology. Regulatory, integrative and comparative physiology》2001,281(5):R1343-R1360
Prostanoids exert significant effects on circulatory beds. They play a role in the response of the vasculature to adjustments in perfusion pressure and oxygen and carbon dioxide tension, and they mediate the actions of numerous factors. The role of prostanoids in governing circulation of the perinate is suggested to surpass that in the adult. Prostanoids are abundantly generated in the perinate. They have been implicated in autoregulation of blood flow as studied in brain and eyes. Prostaglandins are also dominant regulators of ductus arteriosus tone. The effects of these autacoids are mediated through specific G protein-coupled receptors. In addition to the pharmacological characterization of the prostanoid receptors, important advances in understanding the biology of these receptors have been made in the last decade. Their cloning and the development of animals with disrupted genes of these receptors have been very informative. The involvement of prostanoid receptors in the developing subject, especially on brain and ocular vasculature and on ductus arteriosus, has also begun to be investigated; the expression of these receptors changes with development. Some but not all of the ontogenic changes in these receptors are attributed to homologous regulation. Interestingly, in the process of elucidating their effects, functional perinuclear prostaglandin E2 receptors have been uncovered. This article reviews prostanoid receptors and addresses implications on the developing subject with attention to vascular physiology. 相似文献
994.
The active metabolite of vitamin D, 1 alpha,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)] has been receiving increasing attention and has come to the forefront of cancer chemoprevention research as being a regulator of cellular growth, differentiation and death. In the present study, attempts have been made to investigate the in vivo chemopreventive effect of 1,25(OH)(2)D(3) in two-stage rat liver carcinogenesis. Hepatocarcinogenesis was initiated with a single intraperitoneal injection of diethylnitrosamine [DEN] (200 mg/kg b. wt.) at week 4. After a brief recovery period of 2 weeks, all the DEN-treated rats were given phenobarbital (0.05%) in the basal diet and continued thereafter till the completion of the experiment. The results of our experiment showed that the rats which received 1,25(OH)(2)D(3) for 14 weeks (0.3 microg/100 microL propylene glycol, per os, twice a week), starting the treatment 4 weeks prior to DEN injection, exhibited maximum protective effect in maintaining the normal cellular architecture of the hepatocytes than the group of rats which received this micronutrient for only 9 weeks. Moreover, continuous supplementation of 1,25(OH)(2)D(3) maintains the concentration of hepatic microsomal cytochrome P-450 like that of normal vehicle control. Thus, long-term supplementation of 1,25(OH)(2)D(3) significantly (P < 0.001) inhibits hepatic cytosolic lipid peroxidation, thereby protecting the cell membranes from free-radical mediated damage. These results suggest that 1,25(OH)(2)D(3) is useful in the inhibition of rat liver carcinogenesis. 相似文献
995.
A standardised 50% aqueous ethanolic extract of the Indian variety of Hypericum perforatum (IHp) was examined for its putative anti-inflammatory and analgesic activity at the doses of 100 and 200 mg/kg, po. The experimental paradigms used were carrageenan induced pedal edema and cotton pellet induced granuloma for anti-inflammatory activity, whereas the tail flick, hot plate and acetic acid induced writhing methods were used to asses analgesic activity. Indomethacin (20 mg/kg, ip) was used as the standard anti-inflammatory drug. Pentazocine (10 mg/kg, ip) and aspirin (25 mg/kg, ip), both clinically used analgesics, were used as standard analgesics for comparison. IHp extract showed significant anti-inflammatory and analgesic activity at both dose levels, in all the paradigms used. Additionally, IHp potentiated the anti-inflammatory activity of indomethacin and analgesic activities of pentazocine and aspirin. 相似文献
996.
997.
Brain antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) levels were studied in the brains of early diabetic (72 hr) and long term diabetic (one month) rats. Diabetes was induced by injecting streptozotocin (50 mg/kg, i.p.) in citrate buffer. One group of diabetic rats was treated with insulin (1U/day/animal). The results indicate that early diabetic rats exhibit increased SOD and CAT activities with no alteration in the GPX activity. On the contrary, increased CAT decreased GPX activities with no alteration in the SOD activity, was noted in the long-term Diabetic rats. Insulin treatment reversed these alterations in both the groups. It can be concluded that, in diabetic condition antioxidant enzyme levels are elevated and insulin treatment attenuated these changes. Hence, diabetes mellitus, if left untreated, may initiate degenerative processes and other CNS complications due to accumulation of oxidative free radicals. 相似文献
998.
Kumar V Singh PN Jaiswal AK Bhattacharya SK 《Indian journal of experimental biology》1999,37(12):1171-1176
A standardised 50% aqueous ethanolic extract of Indian Hypericum perforatum (IHp) was investigated for its antidepressant activity on various experimental paradigms of depression, viz. behavioural despair (BD), learned helplessness (LH), tail suspension (TS) and reserpine-induced hypothermia (RIH) tests in rats and mice. Pilot studies indicated that single dose administration of IHp had very little or no acute behavioural effects, hence the IHp was administered orally at two dose levels (100 and 200 mg/kg, p.o.) once daily for three consecutive days, while imipramine (15 mg/kg, i.p.), a clinically used antidepressant agent, was administered acutely to rats (CF strain, 150 +/- 10 g) and mice (Wistar strain, 23 +/- 2 g) of either sex as the standard drug. Controls animals were treated similarly with equal volume of vehicle (0.3% carboxymethyl cellulose). Indian Hypericum perforatum extract showed significant antidepressant activity on all the paradigms of depression used. Thus IHp and imipramine treatments significantly reduced the immobility time in BD and TS tests. Significant reduction in escape failures was also observed in LH test. In RIH test IHp and imipramine inhibited reserpine induced hypothermia in a dose dependent manner. The observed antidepressant activity of IHp was qualitatively comparable to that induced by imipramine. 相似文献
999.
The freshwater bivalve, L. marginalis was experimentally exposed to 10 and 30 ppm concentrations of CdCl2 to examine filtration rate, oxygen uptake and glycogen level of liver and gills for health assessment for their reuse in the reclamation of cadmium intoxicated environments. In situ experiment was also performed for better appraisal of the filtration rate in the lake. Oxygen uptake in the treated group exceeded that of control by 15-22% during the early 24 hr after cadmium exposure, but followed an essential decline (23-30%) thereafter. The reduction of filtration rate ranged from 12-62% in laboratory to 83-85% in field trials. At the tissue level, glycogen content was reduced by 61-72% in liver and 52-63% in gill. In both tissues, glycogen content was inversely proportional to the cadmium contents of the animal. Critical appraisal of data suggests that the threshold values of cadmium in gill and liver were 50-80 microg/g dw for oxygen uptake and 50-60 microg/g for filtration rate because of marked reduction of these parameters beyond the values of cadmium. It is concluded that filtration rate, oxygen uptake of the freshwater bivalve, L. marginalis can be used as biomarker for animal health assessment and for possible reuse of the stock animals. 相似文献
1000.
NDR, a nuclear serine/threonine kinase, belongs to the subfamily of Dbf2 kinases that is critical to the morphology and proliferation of cells. The activity of NDR kinase is modulated in a Ca(2+)/S100B-dependent manner by phosphorylation of Ser281 in the catalytic domain and Thr444 in the C-terminal regulatory domain. S100B, which is a member of the S100 subfamily of EF-hand proteins, binds to a basic/hydrophobic sequence at the junction of the N-terminal regulatory and catalytic domains (NDR(62-87)). Unlike calmodulin-dependent kinases, regulation of NDR by S100B is not associated with direct autoinhibition of the active site, but rather involves a conformational change in the catalytic domain triggered by Ca(2+)/S100B binding to the junction region. To gain further insight into the mechanism of activation of the kinase, studies have been carried out on Ca(2+)/S100B in complex with the intact N-terminal regulatory domain, NDR(1-87). Multidimensional heteronuclear NMR analysis showed that the binding mode and stoichiometry of a peptide fragment of NDR (NDR(62-87)) is the same as for the intact N-terminal regulatory domain. The solution structure of Ca(2+)/S100B and NDR(62-87) has been determined. One target molecule is found to associate with each subunit of the S100B dimer. The peptide adopts three turns of helix in the bound state, and the complex is stabilized by both hydrophobic and electrostatic interactions. These structural studies, in combination with available biochemical data, have been used to develop a model for calcium-induced activation of NDR kinase by S100B. 相似文献