Disease relevance of Ptgs1

• In contrast, Ptgs1-deficient mice had pancreatitis and pulmonary inflammation, which was as severe or, in some instances, more severe than in the wild-type mice [1].
• We conclude that radiation injury results in increased Cox-1 levels in crypt stem cells and their progeny, and that PGE2 produced through Cox-1 promotes crypt stem cell survival and proliferation [2].
• The role of COX in acute pancreatitis and pancreatitis-associated lung injury is not known [1].
• Collectively, these findings demonstrate the coordinated regulation of fetal and maternal PGs at the time of birth but raise concern regarding the use of selective COX inhibitors for the management of preterm labor [3].
• To establish a CRC liver metastasis model, we implanted mouse colon tumor MC-26 cells into the splenic subcapsule of BALB/c mice, after which mice were given either standard chow or chow containing the cyclooxygenase (COX)-2-specific inhibitor rofecoxib, alone or in combination with the standard antineoplastic agents, 5-fluoruracil or irinotecan [4].

Psychiatry related information on Ptgs1

• Pretreatment with COX-inhibitors rofecoxib (2 mg/kg, i.p.) or nimesulide (2.5 mg/kg, i.p.) displayed significant protection against ethanol-induced withdrawal symptoms, while naproxen (7 mg/kg, i.p.) was not effective in reversing alcohol-induced withdrawal symptoms [5].
• In this study, we investigated whether increased activity of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, potentiates disease progression in a transgenic mouse model of Alzheimer's disease [6].
• Brain concentrations of cyclooxygenase products markedly increased subsequent to hypoxia/anoxia as well as electroshock [7].

High impact information on Ptgs1

• Homozygous Ptgs1 mutant mice survive well, have no gastric pathology, and show less indomethacin-induced gastric ulceration than wild-type mice, even though their gastric prostaglandin E2 levels are about 1% of wild type [8].
• PGHS1 and PGHS2 coexist in the vasculature and in macrophages, and are upregulated together in inflammatory tissues such as rheumatoid synovia and atherosclerotic plaque [9].
• They were developed with the rationale of conserving the anti-inflammatory and analgesic actions of traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) while sparing the ability of PGHS1-derived prostaglandins to afford gastric cytoprotection [9].
• Here we show that PAF induces pulmonary edema through two mechanisms: acid sphingomyelinase (ASM)-dependent production of ceramide, and activation of the cyclooxygenase pathway [10].
• The initial cyclooxygenase reaction converts arachidonic acid (which is achiral) to prostaglandin G2 (which has five chiral centres) [11].

Chemical compound and disease context of Ptgs1

• Indomethacin, a non-selective inhibitor of COX, also inhibited paw edema in this arthritic model [12].
• The significantly increased toxicity linked to COX-2 deficiency could be mimicked using the selective COX-2 inhibitory drug, celecoxib, in COX(+/+) mice and was not due to alterations in drug-protein adduct formation, a surrogate for bioactivation and toxicity [13].
• Although plasma levels of both Ca(2+) and PTH were comparable in wild type and COX-1(-/-) mice, both were elevated in COX-2(-/-) mice consistent with primary hyperparathyroidism [14].
• Recently, the state of cyclooxygenase (COX) mRNA expression has been reported in an acetic acid-induced chronic gastric ulcer model of mice [15].
• METHODS: Mouse macrophages (Mphi), RAW 264.7, were exposed to Escherichia coli lipopolysaccharide (LPS) in the presence of cyclooxygenase inhibitors (ibuprofen or NS398) [16].

Biological context of Ptgs1

• Thymidine incorporation and apoptosis analyses further demonstrate that the NSAIDs are effective in the cyclooxygenase-null cells [17].
• Cyclooxygenase-1-selective inhibition prolongs gestation in mice without adverse effects on the ductus arteriosus [18].
• Cytokine and cyclooxygenase (COX)-2 messenger RNA was determined in the muscularis externa by reverse-transcription polymerase chain reaction [19].
• Using embryo transfer experiments, we also show that successful delivery occurs in COX-1(-/-) recipient mothers carrying wild-type pups, establishing the sufficiency of fetal PGs for parturition [3].
• Rather, cytokine and Cox-dependent alterations in brain tissue seemed to be secondary to a decline in food intake and related to subsequent stress hormone activities [20].

Anatomical context of Ptgs1

• Malignant transformation and antineoplastic actions of nonsteroidal antiinflammatory drugs (NSAIDs) on cyclooxygenase-null embryo fibroblasts [17].
• Compensatory prostaglandin E2 biosynthesis in cyclooxygenase 1 or 2 null cells [21].
• Immunohistochemistry for Cox-1 demonstrated localization in epithelial cells of the crypt in the unirradiated mouse, and in the regenerating crypt epithelium in the irradiated mouse [2].
• Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1 [2].
• Our results show that COX-1 in the uterine epithelium is the major source of PGs during labor and that COX-1(-/-) females experience parturition failure that is reversible by exogenous PGs [3].

Associations of Ptgs1 with chemical compounds

• The pharmacological target of NSAIDs is cyclooxygenase (COX, also known as PGH synthase), which catalyses the first committed step in arachidonic-acid metabolism [22].
• Indomethacin, an inhibitor of Cox-1 and Cox-2, further reduced the number of surviving crypts in irradiated mice [2].
• BACKGROUND & AIMS: Cyclooxygenase enzymes (COX) generate intermediates in the prostaglandin (PG) cascade [23].
• To determine whether prostaglandin synthesis was required for progesterone production, we analyzed the effects of PGE(2) and cyclooxygenase inhibitors on this process [24].
• Cyclooxygenase (COX) converts arachidonic acid to prostaglandin H2, which is further metabolized to prostanoids [25].

Regulatory relationships of Ptgs1

• PGHS-2 enzyme was expressed maximally after 24 h of activation whereas PGHS-1 was not influenced [26].
• It has long been proposed that the inhibition of the 5-LO could enhance the COX pathway leading to an increased PG generation [27].
• TNF-alpha preferentially promoted gene expression of cyclooxygenase (COX)-2 without affecting that of COX-1 [28].
• We herein demonstrate that PGE2 in stimulated P388D1 cells is accounted for by the inducible cyclooxygenase (COX)-2 [29].
• These cells exhibit increased basal PG production, which is due to a constitutively stimulated cytosolic phospholipase A2 and enhanced basal expression of the remaining COX isozyme [30].

Other interactions of Ptgs1

• Two isoforms of the membrane protein COX are known: COX-1, which is constitutively expressed in most tissues, is responsible for the physiological production of prostaglandins; and COX-2, which is induced by cytokines, mitogens and endotoxins in inflammatory cells, is responsible for the elevated production of prostaglandins during inflammation [22].
• Cyclooxygenase-1-dependent prostaglandin synthesis modulates tumor necrosis factor-alpha secretion in lipopolysaccharide-challenged murine resident peritoneal macrophages [31].
• Prostaglandin E2 and microsomal prostaglandin E synthase-2 expression are decreased in the cyclooxygenase-2-deficient mouse brain despite compensatory induction of cyclooxygenase-1 and Ca2+-dependent phospholipase A2 [32].
• Thus, the balance between COX and 5-LO metabolites could be of great importance in controlling macrophage functions and consequently, inflammation and tumor promotion [27].
• Activity and expression of cPLA2 and secretory PLA2 (sPLA2) enzymes, supplying AA to COX, were significantly increased [32].

Analytical, diagnostic and therapeutic context of Ptgs1

• Recently, it has been shown that inhibitors of cyclooxygenase (COX)-2 can be effective in combination with conventional chemotherapy and radiation therapy [33].
• RESULTS: Herein, we show by genetic intervention that prostaglandin E(2) in the spinal cord is mainly produced by Cox-1, and that ablation of Cox-1 fails to attenuate neurodegeneration [34].
• The increase of the enzyme activity was attributed mostly to the induction of cyclooxygenase-2 rather than cyclooxygenase-1 as judged by the inhibitory effect of NS398, Western blotting, and Northern blotting [35].
• Although no differences in basal respiratory or lung mechanical parameters were observed, COX-1 Tr mice had increased bronchoalveolar lavage fluid PGE(2) content compared with wild-type littermates (23.0 +/- 3.6 vs 8.4 +/- 1.4 pg/ml; p < 0.05) and exhibited decreased airway responsiveness to inhaled methacholine [36].
• METHODS: Immunofluorescence and western blot analysis showed constitutive expression of both COX isoforms in the normal mouse stomach [37].

References