Disease relevance of Ptgs2

• A Ptgs2 null mutation reduced the number and size of the intestinal polyps dramatically [1].
• Furthermore, Ptgs2-deficient mice showed minimal histologic evidence of pancreatitis, a marked attenuation in the severity of lung injury, and a significant reduction in myeloperoxidase activity [2].
• Furthermore, treating Apc delta716 mice with a novel COX-2 inhibitor reduced the polyp number more significantly than with sulindac, which inhibits both isoenzymes [1].
• Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2) [1].
• Therefore, COX-1-selective inhibitors may provide effective treatment to delay preterm labor with fewer adverse effects on fetal or neonatal health than nonselective or COX-2-selective inhibitors [3].
• We engineered mice with conditional deletion of Cox2 in neurons and glial cells to determine the relative contribution of peripheral and central COX2 to inflammatory pain hypersensitivity [4].

Psychiatry related information on Ptgs2

• Recent studies demonstrated that COX-2 expression was up-regulated in the brain of patients with Alzheimer's disease [5].
• The results of the present study suggest strongly the possible role of cyclooxygenases, particularly COX-2 inhibitors, on ethanol-induced withdrawal symptoms and the potential use of COX-2 inhibitors in their prevention and treatment [6].
• Starting at 4 weeks of age, the treated group (T group) were given a diet containing JTE-522, a selective COX-2 inhibitor, and the control group (C group) were given a control diet [7].
• The broad-spectrum MMP inhibitor (A-177430; MMPI) and the selective COX-2 inhibitor (A-285969; COX-2I) both showed dose-dependent inhibition of the number of adenomas in Min mice [8].
• The results showed that chronic treatment with flavonoids reverses cognitive deficits in aged and LPS-intoxicated mice which suggests that modulation of cyclooxygenase-2 and inducible nitric synthase by flavonoids may be important in the prevention of memory deficits, one of the symptoms related to AD [9].

High impact information on Ptgs2

• The effect is inhibited by antibodies to combinations of angiogenic factors, by NS-398 (a selective COX-2 inhibitor), and by aspirin [10].
• We demonstrate herein that the targeted disruption of COX-2, but not COX-1, in mice produces multiple failures in female reproductive processes that include ovulation, fertilization, implantation, and decidualization [11].
• Using multiple approaches, we conclude that these defects are the direct result of target organ-specific COX-2 deficiency but are not the result of deficiency of pituitary gonadotropins or ovarian steroid hormones, or reduced responsiveness of the target organs to their respective hormones [11].
• Two cyclooxygenase isozymes catalyze conversion of arachidonic acid to prostaglandin H2: constitutive COX-1 and inducible COX-2 [1].
• The prostaglandin endoperoxide H synthase isoform 2, cyclooxygenase 2 (COX-2), is induced at high levels in migratory and other responding cells by pro-inflammatory stimuli [12].

Chemical compound and disease context of Ptgs2

• CONCLUSIONS: We present strong evidence for a causal relationship between aberrant COX-2 overexpression and COX-2-mediated PG synthesis and the development of serous cystadenoma, intraductal papillary mucinous, and pancreatic intraepithelial neoplasms [13].
• Treatment with NS-398 (a COX-2 inhibitor) significantly decreased the severity of pancreatitis [2].
• Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer [14].
• Inhibition of cyclooxygenase-2 by rofecoxib attenuates the growth and metastatic potential of colorectal carcinoma in mice [15].
• Nimesulide, a COX-2 selective inhibitor used as positive control, showed similar suppressive effects on the development of ACFs in AOM-treated rats and polyps in Apc gene knockout mice [16].

Biological context of Ptgs2

• We provide evidence that this improved fertility in CD1 Ptgs2 null mice is the result of a compensatory up-regulation of Ptgs1 which does not occur in C57BL/6J/129 mice missing Ptgs2 [17].
• Here we show that Ptgs2 null mice on a CD1 background have dramatically improved female fertility including ovulation, fertilization, and implantation, giving rise to live births [17].
• Here, we developed a new genetic mouse model of selective COX2 inhibition using a gene-targeted point mutation, resulting in a Y385F substitution [18].
• Chronic inhibition of COX-2 during pregnancy (gestation days 15-18) significantly increased neonatal mortality by preventing closure of the DA after birth, whereas acute COX-2 inhibition near the end of term (gestation day 18) constricted the fetal DA [3].
• Finally, the effects of these agents were additive, indicating that COX-2 is involved in maximal induction of osteogenesis [19].

Anatomical context of Ptgs2

• PGHS1 and PGHS2 coexist in the vasculature and in macrophages, and are upregulated together in inflammatory tissues such as rheumatoid synovia and atherosclerotic plaque [18].
• Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma [20].
• Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair [19].
• To elucidate the mechanism involved in reduced bone formation, osteoblastogenesis was studied in bone marrow stromal cell cultures obtained from COX-2(-/-) and wild-type mice [19].
• Similarly, intramembranous bone formation on the calvaria was reduced 60% in COX-2(-/-) mice following in vivo injection of FGF-1 compared with either COX-1(-/-) or wild-type mice [19].

Associations of Ptgs2 with chemical compounds

• Results also reveal that PGE2, but not PGI2, is the major PG at implantation sites where Ptgs2 and microsomal type PGE synthases but not PGI synthases are co-expressed [21].
• It is known that Ptgs2 expression and Ptgs2-derived prostacyclin (PGI2) synthesis at implantation sites are needed for implantation in the mouse (a rodent that needs ovarian estrogen for implantation) [21].
• Mice lacking COX-2 have normal inflammatory responses to treatments with tetradecanoyl phorbol acetate or with arachidonic acid [12].
• Here we report the structures of unliganded murine COX-2 and complexes with flurbiprofen, indomethacin and SC-558, a selective COX-2 inhibitor, determined at 3.0 to 2.5 A resolution [22].
• BMMCs stimulated by KL + IL-10 for 10 h exhibited a delayed phase of PGD2 generation, which was dependent on de novo induction of PGHS-2 [23].
• Taken together with a recent crystal structure of a lumiracoxib-COX-2 complex, the kinetic analyses presented herein of the inhibition of mutant COX-2s by lumiracoxib allows the definition of the molecular basis of COX-2 inhibition [24].

Physical interactions of Ptgs2

• Enhancement of LPS-inducible COX-2 expression and C/EBP DNA binding by C2 was abrogated in dominant-negative mutant of JNK1 [JNK1(-)] cells [25].
• Luciferase reporter constructs with alterations in presumptive cis-acting transcriptional regulatory elements demonstrate that the cyclic AMP-response element and two nuclear factor interleukin-6 (CCAAT/enhancer-binding protein (C/EBP)) sites of the COX-2 promoter are required for optimal endotoxin-dependent induction [26].
• NF-kappaB DNA binding activity was selectively affected in the COX-2-/- mice compared to the wild type as there was no significant change in NFATc DNA binding activity [27].
• Conversely, IL-1 beta stabilized the COX-2 protein without affecting its mRNA level [28].
• Double mutation of the AhR and CREB-binding sites showed synergy in repressing COX-2 promoter activity as did mutation of all three sites [29].

Enzymatic interactions of Ptgs2

• A number of 1,5-diarylimidazoles has been synthesized and evaluated for their inhibitory activities of COX-2 catalyzed PGE2 production [30].

Regulatory relationships of Ptgs2

• Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals [31].
• IL-4 inhibited the induction of PGHS-2 expression and the accompanying cytokine-initiated delayed PGD2 generation with an IC50 of approximately 6 ng/ml [23].
• Tumor necrosis factor-alpha inversely regulates prostaglandin D2 and prostaglandin E2 production in murine macrophages. Synergistic action of cyclic AMP on cyclooxygenase-2 expression and prostaglandin E2 synthesis [32].
• To study the role of JNK in tonicity-stimulated COX-2 expression, IMCD-3 cell lines stably transfected with dominant-negative mutants of three JNKs (JNK-1, -2, and -3) were used [33].
• MAPK mediation of hypertonicity-stimulated cyclooxygenase-2 expression in renal medullary collecting duct cells [33].

Other interactions of Ptgs2

• Cox-1 is thought to be a constitutively expressed enzyme, and the expression of Cox-2 is inducible by cytokines or other stimuli in a variety of cell types [34].
• JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease [35].
• Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice [36].
• Our results raise the possibility that deprivation of COX-2 of its substrate by the suppression of cPLA2 mRNA expression is an additional mechanism used by NSAIDs to inhibit tumorigenesis [37].
• Transcriptional roles of nuclear factor kappa B and nuclear factor-interleukin-6 in the tumor necrosis factor alpha-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells [38].

Analytical, diagnostic and therapeutic context of Ptgs2

• Here we present an animal model of COX-2 deficiency that was generated by gene targeting [39].
• These findings suggest that premature fetal DA closure or neonatal patent DA observed following indomethacin tocolysis in women may result from the inhibition of COX-2 [3].
• RESULTS: The Northern blots revealed an approximately threefold increase in the level of COX-2 messenger RNA in Min mouse adenoma compared with normal mucosa [40].
• Quantitative polymerase chain reaction (PCR) showed equal expression of COX-1 and COX-2 in the antrum [41].
• COX-1 and COX-2 proteins were assessed by Western blot [42].

References