• Biomolecules & Therapeutics
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• v.9 no.2
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• pp.69-78
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• 2001

Cyclooxygenase (COX) is an enzyme, which catalyzes the production of prostaglandins from arachi-donic acid and exists in two isoforms (COX-1 and COX-2). COX-1 is involved in the maintenance of physiological functions such as platelet aggregation, cytoprotection in the stomach and maintenance of normal kidney function. COX-2 is induced significantly in vivo under inflammatory conditions. COX-1 and COX-2 serve different physiological and pathological functions. All commercially available nonsteroidal antiinflammatory drugs (NSAIDS) are inhibitors of both COX-1 and COX-2. Therefore, selective inhibitors of COX-2 may be effective antiinflammatory agents without the ulcerogenic effects associated with current NSAms. Since the mid 1990s, a number of reports have been appeared on the preparation and biological activity of selective COX-2 inhibitors. Recently celecoxib, and rofecoxib, the representative COX-2 inhibitors, are introduced in the drug market. In this paper the relationship of structure-activity for selective COX-2 inhibitors is reviewed.

• YAKHAK HOEJI
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• v.42 no.2
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• pp.214-219
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• 1998

Tissue distributions and association of cyclooxygenase-2 (COX-2) with inflammatory have led us to search for COX-2 selective inhibitors from natural products. Conceptually, COX- 2 selective inhibitors should be expected to retain anti-inflammatory efficacy by inhibition of PGs production while reducing or eliminating the gastric, renal and hemostatic side effects commonly associated with NSAIDs use. Thus, a logical approach to the treatment of inflammatory diseases should involve the inhibitors of COX-2. To develop new COX-2 inhibitors from natural products, two hundred crude drugs were screened by inhibiting PGD2 generation in bone marrow derived mast cells (BMMC). Among them, 6 methanol extracts of crude drugs such as, Bletillae rhizoma, Aconiti kgreani rhizoma, Belamcandae rhizoma, Nelumbinis semen, Gleniae radix, Aurantii immatri pericarpium inhibited more than 85% of BMMC COX-2 activity at a concentration 2.5${\mu}$g/ml.

• IMMUNE NETWORK
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• v.13 no.2
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• pp.75-79
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• 2013

Evidence for immunoregulatory roles of prostaglandins (PGs) is accumulating. Since our observation of PG production by human follicular dendritic cells (FDCs), we investigated the regulatory mechanism of PG production in FDC and attempted to understand the functions of released PGs in the responses of adjacent lymphocytes. Here, using FDC-like cells, HK cells, we analyzed protein expression alterations in cyclooxygenase-2 (COX-2) in the presence of IL-4 or histone deacetylase (HDAC) inhibitors. Both IL-4 and HDAC inhibitors suppressed COX-2 expression in dose-dependent manners. Their effect was specific to COX-2 and did not reach to COX-1 expression. Interestingly, HDAC inhibitors gave rise to an opposing effect on COX-2 expression in peripheral blood monocytes. Our results suggest that IL-4 may regulate COX-2 expression in FDCs by affecting chromatin remodeling and provide insight into the role of cellular interactions between T cells and FDC during the GC reaction. Given the growing interests in wide-spectrum HDAC inhibitors, the differential results on COX-2 expression in HK cells and monocytes raise cautions on their clinical use.

• Genomics & Informatics
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• v.15 no.2
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• pp.56-64
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• 2017

We have previously reported that NS-398, a cyclooxygenase-2 (COX-2)-selective inhibitor, inhibited replicative cellular senescence in human dermal fibroblasts and skin aging in hairless mice. In contrast, celecoxib, another COX-2-selective inhibitor, and aspirin, a non-selective COX inhibitor, accelerated the senescence and aging. To figure out causal factors for the senescence-modulating effect of the inhibitors, we here performed cDNA microarray experiment and subsequent Gene Set Enrichment Analysis. The data showed that several senescence-related gene sets were regulated by the inhibitor treatment. NS-398 up-regulated gene sets involved in the tumor necrosis factor ${\beta}$ receptor pathway and the fructose and mannose metabolism, whereas it down-regulated a gene set involved in protein secretion. Celecoxib up-regulated gene sets involved in G2M checkpoint and E2F targets. Aspirin up-regulated the gene set involved in protein secretion, and down-regulated gene sets involved in RNA transcription. These results suggest that COX inhibitors modulate cellular senescence by different mechanisms and will provide useful information to understand senescence-modulating mechanisms of COX inhibitors.

• Journal of Pharmacopuncture
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• v.20 no.3
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• pp.207-212
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• 2017

Objectives: Study of the mechanisms involved in cancer progression suggests that cyclooxygenase enzymes play an important role in the induction of inflammation, tumor formation, and metastasis of cancer cells. Thus, cyclooxygenase enzymes could be considered for cancer chemotherapy. Among these enzymes, cyclooxygenase 2 (COX-2) is associated with liver carcinogenesis. Various COX-2 inhibitors cause growth inhibition of human hepatocellular carcinoma cells, but many of them act in the COX-2 independent mechanism. Thus, the introduction of selective COX-2 inhibitors is necessary to achieve a clear result. The present study was aimed to determine the growth-inhibitory effects of new analogues of chalcone epoxide as selective COX-2 inhibitors on the human hepatocellular carcinoma (HepG2) cell line. Methods: Estimation of both cell growth and the amount of prostaglandin E2 (PGE2) production were used to study the effect of selective COX-2 inhibitors on the hepatocellular carcinoma cell. Cell growth determination has done by MTT assay in 24 h, 48 h and 72 h, and PGE2 production has estimated by using ELYSA kit in 48 h and 72 h. Results: The results showed growth inhibition of the HepG2 cell line in a concentration and time-dependent manner, as well as a reduction in the formation of PGE2 as a product of COX-2 activity. Among the compounds those analogues with methoxy and hydrogen group showed more inhibitory effect than others. Conclusion: The current in-vitro study indicates that the observed significant growth-inhibitory effect of chalcone-epoxide analogues on the HepG2 cell line may involve COX-dependent mechanisms and the PGE2 pathway parallel to the effect of celecoxib. It can be said that these analogues might be efficient compounds in chemotherapy of COX-2 dependent carcinoma specially preventing and treatment of hepatocellular carcinomas.

• YAKHAK HOEJI
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• v.44 no.3
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• pp.272-278
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• 2000

The antiinflammatory mechanism of NSAIDs is attributed to the reduction of prostaglandin synthesis by the direct inhibition of cyclooxygenase. Inhibition of prostaglandin production in organs such as stomach and kidney can result in gastric lesions, nephrotoxicity and increased bleeding. In this study, newly designed COX-2 inhibitors, synthesized 1,2-benzothiazine derivatives, were screened in vitro for selectivity of COX-1 and COX-2 inhibition properties. Lead compounds in the structure-activity relationship were studied to synthesize new highly selective COX-2 inhibitors.13 determine inhibitory effect of COX-2, synthesized 1,2-benzothiazine derivatives were screened with accumulation of prostaglandin by lipopolysaccharide (LPS) in aspirin-treated macrophages and murine macropharge cell. Some of synthesized 1,2-benzothiazine derivatives were shown to be effective as selective COX-2 inhibitory activity. Others exhibited a preferential inhibition of COX-2, although some COX-1 inhibitory activity was still present. As a conclusion, simple monomer derivatives were more active than dimer derivatives. Substitution of halogen (Br, C1) on the benzothiazine nucleus slightly enhanced inhibition activity.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.347.4-348
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• 2002

Recently it has been demonstrated that selective cyclooxygenase-2 (COX-2) inhibitors retain the antiinflammatory effect but with markedly reduced GI toxicity compared to non selective inhibitors such as traditional NSAIDs. As a consequence, intense efforts have been made to develop selective COX-2 inhibtors during the last decade. Two compounds in this class. celecoxib and rofecoxib. are already in the market and are proved as potent and selective COX-2 inhibitors with much better gastric tolerance. However. there are still strong domands for a COX-2 inhibitor with improved efficacy and safety profiles. Here we report the synthesis and biological profiles of 1.5- and 4.5-disubstituted imidazole analogues as structural equivalents of cefecoxib and refecoxib. The imidazole analogues are overlapped well whth the 3D srructures of celecoxib and rofecoxib.

• Bulletin of the Korean Chemical Society
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• v.28 no.5
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• pp.751-757
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• 2007

To develop new COX-2 inhibitors, 1,5-diarylhydantoins and 1,5-diaryl-2-thiohydantoins were synthesized from phenylacetic acids by esterification, bromination, C-N bond formation and cyclization. Esters 1-3 were efficiently synthesized from the starting materials by reflux in absolute methanol for 3 h containing concentrated sulfuric acid as catalyst. Bromination was carried out with N-bromosuccinimide at rt in dichloromethane. Bromides 4-6 were reacted with aniline, p-anisidine, sulfanilamide in ethanol (or N,N-dimethylformamide) to provide the amines 7-15. Hydantoins and 2-thiohydantoins 16-46 were synthesized from amines 7-15 by treating them with potassium isocyanate (or potassium thiocyanate) and triethylamine. The synthetic process from alkyl α-anilinophenylacetate 7-15 to 3-alkylhydantoins was carried out in a one-pot reaction using alkyl isocyanate (alkyl isothiocyanate).

• YAKHAK HOEJI
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• v.43 no.6
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• pp.776-781
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• 1999

Dockings of 4,5-diarylpyrroles into cyclooxygenase-1 and cyclooxygenase-2 were carried out by GOLD program. The sulfonyl groups bonded to 5-phenyl ring of 4,5-diarylpyrroles are directed to Arg513 of COX-2 and Tyr385 of COX-2 docking modes of pyrroles are different from COX-1. Tyr385 and Arg120 of COX-1 and COX-2 have been recognized as important residues. Val523 of COX-2 may be also important. A new COX-2 selective inhibitors could be designed from the docking study.

• Tuberculosis and Respiratory Diseases
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• v.86 no.4
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• pp.304-318
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• 2023

Background: Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and significantly contribute to immune evasion. We investigated the effects of CAFs on the immune function of CD4+ and CD8+ T cells in non-small cell lung cancer (NSCLC). Methods: We isolated CAFs and normal fibroblasts (NFs) from tumors and normal lung tissues of NSCLC patients, respectively. CAFs were co-cultured with activated T cells to evaluate their immune regulatory function. We investigated the effect of CAF conditioned medium (CAF-CM) on the cytotoxicity of T cells. CAFs were also co-cultured with activated peripheral blood mononuclear cells and further incubated with cyclooxygenase-2 (COX2) inhibitors to investigate the potential role of COX2 in immune evasion. Results: CAFs and NFs were isolated from the lung tissues (n=8) and lymph nodes (n=3) of NSCLC patients. Immune suppressive markers, such as COX2 and programmed death-ligand 1 (PD-L1), were increased in CAFs after co-culture with activated T cells. Interestingly, CAFs promoted the expression of programmed death-1 in CD4+ and CD8+ T cells, and strongly inhibited T cell proliferation in allogenic and autologous pairs of CAFs and T cells. CAF-CM decreased the cytotoxicity of T cells. COX2 inhibitors partially restored the proliferation of CD4+ and CD8+ T cells, and downregulated the expression of COX2, prostaglandin E synthase, prostaglandin E2, and PD-L1 in CAFs. Conclusion: CAFs promote immune evasion by suppressing the function of CD4+ and CD8+ T cells via their effects on COX2 and PD-L1 in NSCLC. The immunosuppressive function of CAFs could be alleviated by COX2 inhibitors.