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Bharat B Aggarwal - One of the best experts on this subject based on the ideXlab platform.
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cyclooxygenase cox 2 Inhibitor celecoxib abrogates tnf induced nf κb activation through inhibition of activation of iκbα kinase and akt in human non small cell lung carcinoma correlation with suppression of cox 2 synthesis
Journal of Immunology, 2004Co-Authors: Shishir Shishodia, Dimpy Koul, Bharat B AggarwalAbstract:The cyclooxygenase 2 (COX-2) Inhibitor celecoxib (also called celebrex), approved for the treatment of colon carcinogenesis, rheumatoid arthritis, and other inflammatory diseases, has been shown to induce apoptosis and inhibit angiogenesis. Because NF-kappa B plays a major role in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation, we postulated that celecoxib modulates NF-kappa B. In the present study, we investigated the effect of this drug on the activation of NF-kappa B by a wide variety of agents. We found that celecoxib suppressed NF-kappa B activation induced by various carcinogens, including TNF, phorbol ester, okadaic acid, LPS, and IL-1 beta. Celecoxib inhibited TNF-induced I kappa B alpha kinase activation, leading to suppression of I kappa B alpha phosphorylation and degradation. Celecoxib suppressed both inducible and constitutive NF-kappa B without cell type specificity. Celecoxib also suppressed p65 phosphorylation and nuclear translocation. Akt activation, which is required for TNF-induced NF-kappa B activation, was also suppressed by this drug. Celecoxib also inhibited the TNF-induced interaction of Akt with I kappa B alpha kinase (IKK). Celecoxib abrogated the NF-kappa B-dependent reporter gene expression activated by TNF, TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor 2, NF-kappa B-inducing kinase, and IKK, but not that activated by p65. The COX-2 promoter, which is regulated by NF-kappa B, was also inhibited by celecoxib, and this inhibition correlated with suppression of TNF-induced COX-2 expression. Besides NF-kappa B, celecoxib also suppressed TNF-induced JNK, p38 MAPK, and ERK activation. Thus, overall, our results indicate that celecoxib inhibits NF-kappa B activation through inhibition of IKK and Akt activation, leading to down-regulation of synthesis of COX-2 and other genes needed for inflammation, proliferation, and carcinogenesis.
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cyclooxygenase cox 2 Inhibitor celecoxib abrogates activation of cigarette smoke induced nuclear factor nf kappab by suppressing activation of ikappabalpha kinase in human non small cell lung carcinoma correlation with suppression of cyclin d1 cox 2
Cancer Research, 2004Co-Authors: Shishir Shishodia, Bharat B AggarwalAbstract:Cigarette smoke (CS) has been linked to cardiovascular, pulmonary, and malignant diseases. CS-associated malignancies including cancers of the larynx, oral cavity, and pharynx, esophagus, pancreas, kidney, bladder, and lung; all are known to overexpress the nuclear factor-kappaB (NF-kappaB)-regulated gene products cyclin D1, cyclooxygenase (COX)-2, and matrix metalloprotease-9. Whether the COX-2 Inhibitor, celecoxib, approved for the treatment of colon carcinogenesis and rheumatoid arthritis, affects CS-induced NF-kappaB activation is not known, although the role of NF-kappaB in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation is established. In our study, in which we examined DNA binding of NF-kappaB in human lung adenocarcinoma H1299 cells, we found that cigarette smoke condensate (CSC)-induced NF-kappaB activation was persistent up to 24 h, and celecoxib suppressed CSC-induced NF-kappaB activation. Celecoxib was effective even when administered 12 h after CSC treatment. This effect, however, was not cell type-specific. The activation of Inhibitory subunit of NF-kappaB kinase (IkappaB), as examined by immunocomplex kinase assay, IkappaB phosphorylation, and IkappaB degradation was also inhibited. Celecoxib also abrogated CSC-induced p65 phosphorylation and nuclear translocation and NF-kappaB-dependent reporter gene expression. CSC-induced NF-kappaB reporter activity induced by NF-kappaB inducing kinase and IkappaB alpha kinase but not that activated by p65 was also blocked by celecoxib. CSC induced the expression of NF-kappaB-regulated proteins, COX-2, cyclin D1, and matrix metalloproteinase-9, and celecoxib abolished the induction of all three. The COX-2 promoter that is regulated by NF-kappaB was activated by CSC, and celecoxib suppressed its activation. Overall, our results suggest that chemopreventive effects of celecoxib may in part be mediated through suppression of NF-kappaB and NF-kappaB-regulated gene expression, which may contribute to its ability to suppress inflammation, proliferation, and angiogenesis.
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cyclooxygenase cox 2 Inhibitor celecoxib abrogates activation of cigarette smoke induced nuclear factor nf κb by suppressing activation of i κb α kinase in human non small cell lung carcinoma correlation with suppression of cyclin d1 cox 2 and matrix
Cancer Research, 2004Co-Authors: Shishir Shishodia, Bharat B AggarwalAbstract:Cigarette smoke (CS) has been linked to cardiovascular, pulmonary, and malignant diseases. CS-associated malignancies including cancers of the larynx, oral cavity, and pharynx, esophagus, pancreas, kidney, bladder, and lung; all are known to overexpress the nuclear factor-κB (NF-κB)-regulated gene products cyclin D1, cyclooxygenase (COX)-2, and matrix metalloprotease-9. Whether the COX-2 Inhibitor, celecoxib, approved for the treatment of colon carcinogenesis and rheumatoid arthritis, affects CS-induced NF-κB activation is not known, although the role of NF-κB in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation is established. In our study, in which we examined DNA binding of NF-κB in human lung adenocarcinoma H1299 cells, we found that cigarette smoke condensate (CSC)-induced NF-κB activation was persistent up to 24 h, and celecoxib suppressed CSC-induced NF-κB activation. Celecoxib was effective even when administered 12 h after CSC treatment. This effect, however, was not cell type-specific. The activation of Inhibitory subunit of NF-κB kinase (IκB), as examined by immunocomplex kinase assay, IκB phosphorylation, and IκB degradation was also inhibited. Celecoxib also abrogated CSC-induced p65 phosphorylation and nuclear translocation and NF-κB-dependent reporter gene expression. CSC-induced NF-κB reporter activity induced by NF-κB inducing kinase and IκB α kinase but not that activated by p65 was also blocked by celecoxib. CSC induced the expression of NF-κB-regulated proteins, COX-2, cyclin D1, and matrix metalloproteinase-9, and celecoxib abolished the induction of all three. The COX-2 promoter that is regulated by NF-κB was activated by CSC, and celecoxib suppressed its activation. Overall, our results suggest that chemopreventive effects of celecoxib may in part be mediated through suppression of NF-κB and NF-κB-regulated gene expression, which may contribute to its ability to suppress inflammation, proliferation, and angiogenesis.
Edward E Knaus - One of the best experts on this subject based on the ideXlab platform.
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synthesis and biological evaluation of 3 4 diphenyl 1 2 5 oxadiazole 2 oxides and 3 4 diphenyl 1 2 5 oxadiazoles as potential hybrid cox 2 Inhibitor nitric oxide donor agents
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Carlos A Velazquez, P Praveen N Rao, Robert Mcdonald, Edward E KnausAbstract:A group of 3,4-diphenyl-1,2,5-oxadiazole-2-oxides (3,4-diphenylfuroxans) and the corresponding N-desoxy 3,4-diphenyl-1,2,5-oxadiazoles (3,4-diphenylfurazans) analogs, were synthesized for in vitro evaluation as hybrid cyclooxygenase (COX) Inhibitor/nitric oxide donor agents. Reaction of 1-[4-(methylsulfonyl)phenyl]-2-phenylethene with an aqueous sodium nitrite solution in acetic acid afforded a mixture (3:1 ratio) of the inseparable 4-[4-(methylsulfonyl)phenyl]-3-phenyl-1,2,5-oxadiazole-2-oxide (13a) and 3-[4-(methylsulfonyl)phenyl]-4-phenyl-1,2,5-oxadiazole-2-oxide (13b) regioisomers. A group of related regioisomers possessing either a p-aminosulfonylphenyl (16) or a p-azidosulfonylphenyl (17), moiety were obtained by chlorosulfonation of the unsubstituted 3,4-diphenylfuroxan (10) and subsequent reaction with either ammonium hydroxide or sodium azide, respectively. The methanesulfonyl regioisomers 13a,b [COX-1 IC50=11.6 microM; COX-2 IC50=0.12 microM; COX-2 selectivity index (SI)=97] and aminosulfonyl regioisomers 16 (COX-1 IC50=9.8 microM; COX-2 IC50=0.78 microM; COX-2 SI=12), like the reference drug celecoxib (COX-1 IC50=33.1 microM; COX-2 IC50=0.07 microM; COX-2 SI=472), were potent in vitro COX-2 Inhibitors with a good COX-2 selectivity index. Release of nitric oxide (NO) from the 3,4-diphenylfuroxan compounds (10, 13a,b, 16, 17) was thiol-dependent since the % NO released was higher upon incubation in the presence of l-cysteine (0.57-3.18%) compared to that in phosphate buffer solution at pH7.4 (0.06-0.15%). Molecular modeling (docking) studies show that the methanesulfonyl (MeSO2) COX-2 pharmacophore present in regioisomers 13a,b is positioned in the vicinity of the COX-2 secondary pocket. The in vitro NO release data, COX-1/COX-2 inhibition and COX-2 SI structure-activity relationships acquired, and molecular modeling docking studies suggest that the 1,2,5-oxadiazole-2-oxide (furoxan) ring possesses beneficial features that should be present in a suitable central ring template (bioisostere) pertinent to the design novel hybrid COX-2 Inhibitor/nitric oxide donor agents with a low ulcerogenicity profile that may be free from adverse cardiovascular effects.
Flint M Beal - One of the best experts on this subject based on the ideXlab platform.
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additive neuroprotective effects of creatine and a cyclooxygenase 2 Inhibitor against dopamine depletion in the 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine mptp mouse model of parkinson s disease
Journal of Molecular Neuroscience, 2003Co-Authors: Peter Klivenyi, Gabrielle Gardian, Noel Y Calingasan, Lichuan Yang, Flint M BealAbstract:There is evidence that both inflammatory mechanisms and mitochondrial dysfunction contribute to Parkinson’s disease (PD) pathogenesis. We investigated whether the cyclooxygenase 2 (COX-2) Inhibitor rofecoxib either alone or in combination with creatine could exert neuroprotective effects in the 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine model of PD in mice. Both rofecoxib and creatine administered alone protected against striatal dopamine depletions and loss of substantia nigra tyrosine hydroxylase immunoreactive neurons. Administration of rofecoxib with creatine produced significant additive neuroprotective effects against dopamine depletions. These results suggest that a combination of a COX-2 Inhibitor with creatine might be a useful neuroprotective strategy for PD. Index Entries: Inflammation; free radicals; mitochondria; cyclooxygenase; creatine; Parkinson’s disease.
Shishir Shishodia - One of the best experts on this subject based on the ideXlab platform.
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cyclooxygenase cox 2 Inhibitor celecoxib abrogates tnf induced nf κb activation through inhibition of activation of iκbα kinase and akt in human non small cell lung carcinoma correlation with suppression of cox 2 synthesis
Journal of Immunology, 2004Co-Authors: Shishir Shishodia, Dimpy Koul, Bharat B AggarwalAbstract:The cyclooxygenase 2 (COX-2) Inhibitor celecoxib (also called celebrex), approved for the treatment of colon carcinogenesis, rheumatoid arthritis, and other inflammatory diseases, has been shown to induce apoptosis and inhibit angiogenesis. Because NF-kappa B plays a major role in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation, we postulated that celecoxib modulates NF-kappa B. In the present study, we investigated the effect of this drug on the activation of NF-kappa B by a wide variety of agents. We found that celecoxib suppressed NF-kappa B activation induced by various carcinogens, including TNF, phorbol ester, okadaic acid, LPS, and IL-1 beta. Celecoxib inhibited TNF-induced I kappa B alpha kinase activation, leading to suppression of I kappa B alpha phosphorylation and degradation. Celecoxib suppressed both inducible and constitutive NF-kappa B without cell type specificity. Celecoxib also suppressed p65 phosphorylation and nuclear translocation. Akt activation, which is required for TNF-induced NF-kappa B activation, was also suppressed by this drug. Celecoxib also inhibited the TNF-induced interaction of Akt with I kappa B alpha kinase (IKK). Celecoxib abrogated the NF-kappa B-dependent reporter gene expression activated by TNF, TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor 2, NF-kappa B-inducing kinase, and IKK, but not that activated by p65. The COX-2 promoter, which is regulated by NF-kappa B, was also inhibited by celecoxib, and this inhibition correlated with suppression of TNF-induced COX-2 expression. Besides NF-kappa B, celecoxib also suppressed TNF-induced JNK, p38 MAPK, and ERK activation. Thus, overall, our results indicate that celecoxib inhibits NF-kappa B activation through inhibition of IKK and Akt activation, leading to down-regulation of synthesis of COX-2 and other genes needed for inflammation, proliferation, and carcinogenesis.
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cyclooxygenase cox 2 Inhibitor celecoxib abrogates activation of cigarette smoke induced nuclear factor nf kappab by suppressing activation of ikappabalpha kinase in human non small cell lung carcinoma correlation with suppression of cyclin d1 cox 2
Cancer Research, 2004Co-Authors: Shishir Shishodia, Bharat B AggarwalAbstract:Cigarette smoke (CS) has been linked to cardiovascular, pulmonary, and malignant diseases. CS-associated malignancies including cancers of the larynx, oral cavity, and pharynx, esophagus, pancreas, kidney, bladder, and lung; all are known to overexpress the nuclear factor-kappaB (NF-kappaB)-regulated gene products cyclin D1, cyclooxygenase (COX)-2, and matrix metalloprotease-9. Whether the COX-2 Inhibitor, celecoxib, approved for the treatment of colon carcinogenesis and rheumatoid arthritis, affects CS-induced NF-kappaB activation is not known, although the role of NF-kappaB in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation is established. In our study, in which we examined DNA binding of NF-kappaB in human lung adenocarcinoma H1299 cells, we found that cigarette smoke condensate (CSC)-induced NF-kappaB activation was persistent up to 24 h, and celecoxib suppressed CSC-induced NF-kappaB activation. Celecoxib was effective even when administered 12 h after CSC treatment. This effect, however, was not cell type-specific. The activation of Inhibitory subunit of NF-kappaB kinase (IkappaB), as examined by immunocomplex kinase assay, IkappaB phosphorylation, and IkappaB degradation was also inhibited. Celecoxib also abrogated CSC-induced p65 phosphorylation and nuclear translocation and NF-kappaB-dependent reporter gene expression. CSC-induced NF-kappaB reporter activity induced by NF-kappaB inducing kinase and IkappaB alpha kinase but not that activated by p65 was also blocked by celecoxib. CSC induced the expression of NF-kappaB-regulated proteins, COX-2, cyclin D1, and matrix metalloproteinase-9, and celecoxib abolished the induction of all three. The COX-2 promoter that is regulated by NF-kappaB was activated by CSC, and celecoxib suppressed its activation. Overall, our results suggest that chemopreventive effects of celecoxib may in part be mediated through suppression of NF-kappaB and NF-kappaB-regulated gene expression, which may contribute to its ability to suppress inflammation, proliferation, and angiogenesis.
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cyclooxygenase cox 2 Inhibitor celecoxib abrogates activation of cigarette smoke induced nuclear factor nf κb by suppressing activation of i κb α kinase in human non small cell lung carcinoma correlation with suppression of cyclin d1 cox 2 and matrix
Cancer Research, 2004Co-Authors: Shishir Shishodia, Bharat B AggarwalAbstract:Cigarette smoke (CS) has been linked to cardiovascular, pulmonary, and malignant diseases. CS-associated malignancies including cancers of the larynx, oral cavity, and pharynx, esophagus, pancreas, kidney, bladder, and lung; all are known to overexpress the nuclear factor-κB (NF-κB)-regulated gene products cyclin D1, cyclooxygenase (COX)-2, and matrix metalloprotease-9. Whether the COX-2 Inhibitor, celecoxib, approved for the treatment of colon carcinogenesis and rheumatoid arthritis, affects CS-induced NF-κB activation is not known, although the role of NF-κB in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation is established. In our study, in which we examined DNA binding of NF-κB in human lung adenocarcinoma H1299 cells, we found that cigarette smoke condensate (CSC)-induced NF-κB activation was persistent up to 24 h, and celecoxib suppressed CSC-induced NF-κB activation. Celecoxib was effective even when administered 12 h after CSC treatment. This effect, however, was not cell type-specific. The activation of Inhibitory subunit of NF-κB kinase (IκB), as examined by immunocomplex kinase assay, IκB phosphorylation, and IκB degradation was also inhibited. Celecoxib also abrogated CSC-induced p65 phosphorylation and nuclear translocation and NF-κB-dependent reporter gene expression. CSC-induced NF-κB reporter activity induced by NF-κB inducing kinase and IκB α kinase but not that activated by p65 was also blocked by celecoxib. CSC induced the expression of NF-κB-regulated proteins, COX-2, cyclin D1, and matrix metalloproteinase-9, and celecoxib abolished the induction of all three. The COX-2 promoter that is regulated by NF-κB was activated by CSC, and celecoxib suppressed its activation. Overall, our results suggest that chemopreventive effects of celecoxib may in part be mediated through suppression of NF-κB and NF-κB-regulated gene expression, which may contribute to its ability to suppress inflammation, proliferation, and angiogenesis.
Qiuling Song - One of the best experts on this subject based on the ideXlab platform.
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thiocarbamate directed tandem olefination intramolecular sulfuration of two ortho c h bonds application to synthesis of a cox 2 Inhibitor
Organic Letters, 2018Co-Authors: Yingwei Zhao, Shaoyu Mai, Qiuling SongAbstract:A palladium-catalyzed dual ortho C–H bond activation of aryl thiocarbamates is developed. This tandem reaction initiates by thiocarbamate-directed ortho C–H palladation, which leads to favorable olefin insertion rather than reductive elimination. The oxidative Heck reaction followed by another C–H activation and sulfuration affords the dual-functionalized products. This reaction provides a concise route to the S,O,C multisubstituted benzene skeleton which could be successfully applied for the synthesis of a COX-2 Inhibitor.
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Thiocarbamate-Directed Tandem Olefination–Intramolecular Sulfuration of Two Ortho C–H Bonds: Application to Synthesis of a COX‑2 Inhibitor
2018Co-Authors: Yingwei Zhao, Shaoyu Mai, Qiuling SongAbstract:A palladium-catalyzed dual ortho C–H bond activation of aryl thiocarbamates is developed. This tandem reaction initiates by thiocarbamate-directed ortho C–H palladation, which leads to favorable olefin insertion rather than reductive elimination. The oxidative Heck reaction followed by another C–H activation and sulfuration affords the dual-functionalized products. This reaction provides a concise route to the S,O,C multisubstituted benzene skeleton which could be successfully applied for the synthesis of a COX-2 Inhibitor
