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Inducible Isoform (inducible + isoform)
Selected AbstractsComputer-aided design of selective COX-2 inhibitors: comparative molecular field analysis and docking studies of some 3,4-diaryloxazolone derivativesJOURNAL OF PHYSICAL ORGANIC CHEMISTRY, Issue 7 2001G. R. Desiraju Abstract The recent discovery of a second, inducible isoform of cyclooxygenase, COX-2, has stimulated the search for highly selective non-steroidal anti-inflammatory drugs (NSAIDs). These NSAIDs have the ability to treat pain and inflammation caused by arthritis with less risk of gastrointestinal or renal toxicity. We report here the results of 3D-quantitative structure,activity relationship and docking studies, performed on a series of 3,4-diaryloxazolones. Comparative moleculer field analysis studies provided a good model with cross-validated and conventional r2 values of 0.688 and 0.969 respectively for 24 analogues in the training set with six components. Docking studies with both COX-1 and COX-2 indicate good selectivity for COX-2. The binding energies between COX-2 and some of the most active oxazolones are comparable to those of celecoxib or rofecoxib. These compounds adopt similar orientations and form similar sets of hydrogen bonds involving the sulfonyl group of the ligand and His 90, Leu 352, Ser 353, Arg 513, Phe 518 and Ser 530 residues of the receptor. Copyright © 2001 John Wiley & Sons, Ltd. [source] Melatonin inhibits the expression of the inducible isoform of nitric oxide synthase and nuclear factor kappa B activation in rat skeletal muscleJOURNAL OF PINEAL RESEARCH, Issue 1 2006Marķa Alonso Abstract:, This study investigated whether the induction of inducible nitric oxide synthase (iNOS) produced by acute exercise in rat skeletal muscle could be prevented by melatonin and whether iNOS down-regulation was related to inhibition of nuclear factor kappaB (NF- ,B) activation. Male Wistar rats received melatonin i.p. at a dose of 1.0 mg/kg body weight 30 min before being exercised for 60 min on a treadmill at a speed of 25 m/min and a 10% slope. Exercise caused a significant induction of iNOS protein levels and a marked activation of NF- ,B that were significantly prevented in rats treated with melatonin. Exercise also resulted in increased I,B kinase, (IKK,) and phosphorylated I,B, protein levels, whereas I,B, content decreased. These effects were blocked by melatonin administration. The increase in the muscle concentration of thiobarbituric acid reactive substances and in the oxidized/reduced glutathione ratio induced by exercise was partially prevented by melatonin. Our data indicate that melatonin has potent protective effects against damage caused by acute exercise in rat muscle, preventing oxidative stress, NF- ,B activation and iNOS over-expression. These findings support the view that melatonin treatment, by abolishing the IKK/NF- ,B signal transduction pathway, might block the production of noxious mediators involved in the inflammatory process. [source] PGE2 receptors rescue motor neurons in a model of amyotrophic lateral sclerosisANNALS OF NEUROLOGY, Issue 2 2004Masako Bilak PhD Recent studies suggest that the inducible isoform of cyclooxygenase, COX-2, promotes motor neuron loss in rodent models of ALS. We investigated the effects of PGE2, a principal downstream prostaglandin product of COX-2 activity, on motor neuron survival in an organotypic culture model of ALS. We find that PGE2 paradoxically protects motor neurons at physiological concentrations in this model. PGE2 exerts its downstream effects by signaling through a class of four distinct G-protein,coupled E-prostanoid receptors (EP1,EP4) that have divergent effects on cAMP. EP2 and EP3 are dominantly expressed in ventral spinal cord in neurons and astrocytes, and activation of these receptor subtypes individually or in combination also rescued motor neurons. The EP2 receptor is positively coupled to cAMP, and its neuroprotection was mimicked by application of forskolin and blocked by inhibition of PKA, suggesting that its protective effect is mediated by downstream effects of cAMP. Conversely, the EP3 receptor is negatively coupled to cAMP, and its neuroprotective effect was blocked by pertussis toxin, suggesting that its protective effect is dependent on Gi-coupled heterotrimeric signaling. Taken together, these data demonstrate an unexpected neuroprotective effect mediated by PGE2, in which activation of its EP2 and EP3 receptors protected motor neurons from chronic glutamate toxicity. Ann Neurol 2004;56:240,248 [source] Evidence for cocaine and methylecgonidine stimulation of M2 muscarinic receptors in cultured human embryonic lung cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2001Yinke Yang Muscarinic cholinoceptor stimulation leads to an increase in guanylyl cyclase activity and to a decrease in adenylyl cyclase activity. This study examined the effects of cocaine and methylecgonidine (MEG) on muscarinic receptors by measurement of cyclic GMP and cyclic AMP content in cultured human embryonic lung (HEL299) cells which specifically express M2 muscarinic receptors. A concentration-dependent increase in cyclic GMP production was observed in HEL299 cells incubated with carbachol, cocaine, or MEG for 24 h. The increase in cyclic GMP content was 3.6 fold for 1 ,M carbachol (P<0.01), 3.1 fold for 1 ,M cocaine (P<0.01), and 7.8 fold for 1 ,M MEG (P<0.001), respectively. This increase in cyclic GMP content was significantly attenuated or abolished by the muscarinic receptor antagonist atropine or the M2 blocker methoctramine. In contrast, cocaine, MEG, and carbachol produced a significant inhibition of cyclic AMP production in HEL299 cells. Compared to the control, HEL299 cells treated with 1 ,M cocaine decreased cyclic AMP production by 30%. MEG and carbachol at 1 ,M decreased cyclic AMP production by 37 and 38%, respectively. Atropine or methoctramine at 1 or 10 ,M significantly attenuated or abolished the cocaine-induced decrease in cyclic AMP production. However, the antagonists alone had neither an effect on cyclic GMP nor cyclic AMP production. Pretreatment of HEL299 cells with pertussis toxin prevented the cocaine-induced reduction of cyclic AMP production. Western blot analysis showed that HEL299 cells specifically express M2 muscarinic receptors without detectable M1 and M3. Incubation of HEL299 cells with cocaine, carbachol, and atropine did not alter the expression of M2 protein levels. However, the inducible isoform of nitric oxide synthase (iNOS) was induced in the presence of cocaine or carbachol and this induction was significantly attenuated after addition of atropine or methoctramine. The present data show that cocaine and MEG significantly affect cyclic GMP and cyclic AMP production in cultured HEL299 cells. Our results also show that these effects result from the drug-induced stimulation of M2 muscarinic receptors accompanied with no alterations of receptor expression. However, the induction of iNOS by cocaine may result in the increase in cyclic GMP production. British Journal of Pharmacology (2001) 132, 451,460; doi:10.1038/sj.bjp.0703819 [source] Genetic polymorphisms of cyclooxygenase-2 and colorectal adenoma risk: The Self Defense Forces Health StudyCANCER SCIENCE, Issue 3 2008Naoyuki Ueda Cyclooxygenase (COX) is a key enzyme in the formation of prostaglandins, and an inducible isoform of COX, COX-2, has been implicated in colorectal carcinogenesis. This study investigated the relation of COX-2 polymorphisms (,1195G>A, ,765G>C and 8160A>G) to colorectal adenomas in a case,control study of male officials in the Self Defense Forces (SDF). The study subjects were 455 cases of colorectal adenoma and 1052 controls with no polyps who underwent total colonoscopy. Genotypes were determined using the polymerase chain reaction,restriction fragment length polymorphism (PCR-RFLP) method with genomic DNA extracted from the buffy coat. Statistical adjustment was made for age, hospital, rank in the SDF, body mass index (BMI), cigarette smoking, and alcohol intake. A statistically non-significant decrease in the risk of colorectal adenomas was observed for the AA versus GG genotype of ,1195G>A polymorphism and for the GC versus GG genotype of ,765G>C polymorphism. None had the ,765CC genotype in either the case or control groups. No effect modification of overweight, smoking or alcohol use was observed for either ,1195G>A or ,765G>C polymorphism. The variant allele of the 8160A>G polymorphism was extremely rare. A haplotype of ,1195G, ,765G and 8160A alleles was associated with a modest increase in the risk (adjusted odds ratio [OR] 1.38, 95% confidence interval [CI] 0.99,1.91), and the increase was more evident for distal adenomas (adjusted OR 1.57, 95% CI 1.04,2.38). Another haplotype of ,1195A, ,765C and 8160A alleles showed an adjusted OR of 0.22 (95% CI 0.06,0.88). These findings add to evidence for the role of COX-2 in colorectal carcinogenesis and warrant further studies focusing on haplotypes. (Cancer Sci 2008; 99: 576,581) [source] | ||||||||||