Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00790 (PGA)
 2,475 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of cyclooxygenase and lipoxygenase metabolites of arachidonic acid in experimental esophageal were lumenally perfused for 1 h with acidified saline (pH 2.0) with or without pepsin followed by a second hour with acidified saline. Separate groups of pepsin-perfused animals were pretreated with indomethacin, a cyclooxygenase inhibitor, or BW755C, a lipoxygenase-cyclooxygenase inhibitor. Esophageal injury was graded grossly. H+ and hemoglobin fluxes were determined. Acidified saline caused no significant damage. Pepsin induced moderate injury. Indomethacin decreased pepsin-induced H+ flux by 55% without affecting the other indices. BW755C, by all measurements, dramatically increased pepsin-induced injury. In separate experiments, cyclooxygenase activity was decreased by indomethacin and BW755C by 62% and 49%, respectively. Lipoxygenase activity was decreased 74% by BW755C and was not significantly affected by indomethacin. These results suggest that esophageal cytoprotection is mediated by endogenous lipoxygenase metabolites.
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PMID:Role of arachidonic acid metabolites in acid-pepsin injury to rabbit esophagus. 250 Nov 39

Using the Fell technique of organ culture of 8-day chick embryo femoral and tibial rudiments, the effects of indomethacin, dihomo-gamma-linolenic acid and arachidonic acid on limb rudiment linear growth and differentiation were investigated. Indomethacin (50 and 100 mumol/l) elicited a statistically significant decrease in rudiment linear growth without affecting differentiation or cell structure. Dihomo-gamma-linolenic acid and arachidonic acid, both at 100 mumol/l, exerted no effect on limb rudiment linear growth or differentiation. From previous work, it has been shown that PGA1 and PGB1 caused a marked inhibition of linear growth, PGA1 being cytotoxic. The failure of the prostaglandin (PG) precursors to reproduce these effects suggests that PGA or PGB biosynthesis in embryonic chondrocytes plays no significant role in cartilage growth regulatory mechanisms. Moreover, the growth inhibitory effect of the PG cyclooxygenase inhibitor, indomethacin, suggests that a product of arachidonic acid metabolism via the cyclooxygenase pathway may promote cartilage growth.
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PMID:Effects of prostanoid precursors and indomethacin on chick embryonic cartilage growth in organ culture. 640 86

Cellular stress can initiate prostaglandin (PG) biosynthesis which, through changes in gene expression, can modulate cellular functions, including cell growth. PGA(2), a metabolite of PGE(2), induces the expression of stress response genes, including gadd153 and hsp70, in HeLa cells and human diploid fibroblasts. PGs, gadd153, and hsp70 expression are also influenced by the cellular redox status. Polyphenolic glutathione conjugates retain the ability to redox cycle, with the concomitant generation of reactive oxygen species. One such conjugate, 2,3,5-tris(glutathion-S-yl)hydroquinone (TGHQ), is a potent nephrotoxic and nephrocarcinogenic metabolite of the nephrocarcinogen, hydroquinone. We therefore investigated the effects of TGHQ on PGE(2) synthesis and gene expression in a renal proximal tubular epithelial cell line (LLC-PK(1)). TGHQ (200 microM, 2 h) increases PGE(2) synthesis (2-3-fold) in LLC-PK(1) cells with only minor (5%) reductions in cell viability. This response is toxicant-specific, since another proximal tubular toxicant, S-(1, 2-dichlorovinyl)-L-cysteine (DCVC), stimulates PGE(2) synthesis only after massive (68%) reductions in cell viability. Consistent with the ability of TGHQ to generate an oxidative stress, both deferoxamine mesylate and catalase protect LLC-PK(1) cells from TGHQ-mediated cytotoxicity. Only catalase, however, completely blocks TGHQ-mediated PGE(2) synthesis, implying a major role for hydrogen peroxide in this response. TGHQ induces the early (60 min) expression of gadd153 and hsp70. However, while inhibition of cyclooxygenase with aspirin prevents TGHQ-induced PGE(2) synthesis, it does not affect TGHQ-mediated induction of gadd153 or hsp70 expression. In contrast, a stable PGE(2) analogue, 11-deoxy-16, 16-dimethyl-PGE(2) (DDM-PGE(2)), which protects LLC-PK(1) cells against TGHQ-mediated cytotoxicity, modestly elevates the levels of gadd153 and hsp70 expression. In addition, catalase and, to a lesser extent, deferoxamine mesylate block TGHQ-induced gene expression. Therefore, although TGHQ-induced generation of reactive oxygen species is required for PGE(2) synthesis and stress gene expression, acute TGHQ-mediated increases in gadd153 and hsp70 mRNA levels are independent of PGE(2) synthesis.
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PMID:Stress- and growth-related gene expression are independent of chemical-induced prostaglandin E(2) synthesis in renal epithelial cells. 1068 35

The role of transforming growth factor alpha (TGFalpha) and prostaglandins (PGs) in the preferential growth of preneoplastic liver cells was studied. Rats received the genotoxic hepatocarcinogen N-nitrosomorpholine (NNM); placental glutathione S-transferase (GSTp) was used as a marker to identify preneoplastic foci. Preneoplastic foci expressing TGFalpha (TGFalpha(+)) grew more rapidly than TGFalpha negative (TGFalpha(-)) ones. Almost all tumours studied were positive for TGFalpha. The key enzymes of prostaglandin synthesis, cyclooxygenase I (Cox-1) and II (Cox-2), were present in all unaltered and preneoplastic cells and tended to decrease in the later stages of hepatocarcinogenesis. Immunostaining revealed that cultures of hepatocytes, isolated from NNM-treated livers by collagenase perfusion, contained 1-2% GSTp-positive (GSTp(+)) and 9% TGFalpha(+) hepatocytes; 0.6% of the cells were GSTp(+)/TGFalpha(+). Cox-1 and Cox-2 were present in all cells. DNA replication was almost exclusively associated with expression of TGFalpha. GSTp(+) hepatocytes showed a 3- to 4-fold higher probability of TGFalpha expression and of DNA synthesis than GSTp-negative (GSTp(-)) cells. PGE(2) or PGF(2alpha) increased expression of TGFalpha and DNA replication in GSTp(-) cells but not in GSTp(+) cells. PGA(2) and PGJ(2) decreased DNA synthesis in TGFalpha(+) cells without an obvious effect on the intracellular levels of TGFalpha. The Cox-2 inhibitor SC236 suppressed DNA replication preferentially in GSTp(+) cells; this inhibition was reversed by PGE(2)/F(2alpha). Indomethacin had no effect. These results suggest the following conclusions. (i) Growth regulation of preneoplastic GSTp(+) cells in culture exhibits distinct differences from GSTp(-) cells and elevated expression of TGFalpha contributes to their growth advantage. (ii) TGFalpha renders preneoplastic hepatocytes sensitive to suppression of DNA synthesis by PGA(2)/J(2). (iii) SC236, a Cox-2 inhibitor, may have preventive value in hepatocarcinogenesis.
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PMID:Role of transforming growth factor alpha and prostaglandins in preferential growth of preneoplastic rat hepatocytes. 1147 Jul 56

High concentrations of PGE(2) and PGF(2alpha) were identified by radio-immunoassay (RIA) and/or gas chromatography/mass spectrometry (GC/MS) in the hemolymph, salivary glands and saliva of the lone star tick Amblyomma americanum (L.). Binding studies indicated that PGE(2) was free and not bound to any proteins in the hemolymph. A small amount of 6-keto-PGF(1alpha) (breakdown product of PGI(2); prostacyclin) was also found in the salivary glands but not in the hemolymph or saliva. Neither PGD(2) nor PGA(2)/B(2) was detected in any tick material investigated. Although PGE(2) was found in the gut contents, only small amounts of label crossed the gut into the hemolymph during artificial feeding with labeled PGE(2), indicating that the high amounts of PGE(2) in hemolymph and salivary glands are not sequestered from the host blood meal. Isolated salivary glands and salivary gland homogenates demonstrated robust synthesis of PGE(2) at high concentrations of exogenous arachidonic acid. Synthesis by the salivary glands was monitored by measuring increasing PGE(2) with increasing arachidonic acid by RIA, GC/MS and labeled PGE(2) in the presence of labeled arachidonic acid. Synthesis was inhibited in a dose-dependent manner by indomethacin indicating that the cyclooxygenase synthesizing prostaglandins in ticks shares similarities to the enzyme found in mammals.
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PMID:Identity and synthesis of prostaglandins in the lone star tick, Amblyomma americanum (L.), as assessed by radio-immunoassay and gas chromatography/mass spectrometry. 1180 5

We describe prostaglandin (PG) biosynthesis by isolated midgut preparations from tobacco hornworms, Manduca sexta. Microsomal-enriched midgut preparations yielded four PGs, PGA/B(2), PGD(2), PGE(2) and PGF(2alpha), all of which were confirmed by analysis on gas chromatography--mass spectrometry (GC--MS). PGA and PGB are double bond isomers which do not resolve on TLC but do resolve by GC; for convenience, we use the single term PGA(2) for this product. PGA(2) was the major product under most conditions. The midgut preparations were sensitive to reaction conditions, including radioactive substrate, protein concentration (optimal at 1mg/reaction), reaction time (optimal at 0.5 min), temperature (optimal at 22 degrees C), buffer pH (highest at pH 6), and the presence of a co-factor cocktail composed of reduced glutathione, hydroquinine and hemoglobin. In vitro PG biosynthesis was inhibited by two cyclooxygenase inhibitors, indomethacin and naproxen. Subcellular localization of PG biosynthetic activity in midgut preparations, determined by ultracentrifugation, revealed the presence of PG biosynthetic activity in the cytosolic and microsomal fractions, although most activity was found in the cytosolic fractions. This is similar to other invertebrates, and different from mammalian preparations, in which the activity is exclusively associated with the microsomal fractions. Midgut preparations from M. sexta pupae, adult cockroach, Periplaneta americana, and corn ear worms, Helicoverpa zea, also produced the same four major PG products. We infer that insect midguts are competent to biosynthesize PGs, and speculate they exert important, albeit unrevealed, actions in midgut physiology.
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PMID:Prostaglandin biosynthesis by midgut tissue isolated from the tobacco hornworm, Manduca sexta. 1188 78

Secretory type IIA phospholipase A(2) (sPLA(2)-IIA) is a critical enzyme involved in inflammatory diseases. We have previously identified alveolar macrophages (AMs) as the major pulmonary source of lipopolysaccharide (LPS)-induced sPLA(2)-IIA expression in a guinea pig model of acute lung injury (ALI). Here, we examined the role of arachidonic acid (AA) in the regulation of basal and LPS-induced sPLA(2)-IIA expression in AMs. We showed that both AA and its nonmetabolizable analog, 5,8,11,14-eicosatetraynoic acid (ETYA), inhibited sPLA(2)-IIA synthesis in unstimulated AMs. However, only AA inhibited sPLA(2)-IIA expression in LPS-stimulated cells, suggesting that this effect requires metabolic conversion of AA. Indeed, cyclooxygenase inhibitors abolished this down-regulation. Prostaglandins PGE(2), PGA(2), and 15d-PGJ(2) also inhibited the LPS-induced sPLA(2)-IIA expression. Nuclear factor-kappaB (NF-kappaB) was found to regulate sPLA(2)-IIA expression in AMs. Both AA and ETYA inhibited basal activation of NF-kappaB but had no effect on LPS-induced NF-kappaB translocation, suggesting that suppression of sPLA(2)-IIA synthesis by AA in LPS-stimulated cells occurs via a NF-kappaB-independent pathway. 15-Deoxy-Delta(12,14)-PGJ(2) and ciglitazone, which are, respectively, natural and synthetic ligands for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), inhibited LPS-induced sPLA(2)-IIA synthesis, whereas PPAR-alpha ligands were ineffective. Moreover, electrophoretic mobility shift assay showed PPAR activation by AA and PPAR-gamma ligands in LPS-stimulated AMs. Our results suggest that the down-regulation of basal sPLA(2)-IIA expression is unrelated to the metabolic conversion of AA but is dependent on the impairment of NF-kappaB activation. In contrast, the inhibition of LPS-stimulated sPLA(2)-IIA expression is mediated by cyclooxygenase-derived metabolites of AA and involves a PPAR-gamma-dependent pathway. These findings provide new insights for the treatment of ALI.
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PMID:Arachidonic acid differentially affects basal and lipopolysaccharide-induced sPLA(2)-IIA expression in alveolar macrophages through NF-kappaB and PPAR-gamma-dependent pathways. 1190 Dec 17

Glutathione transferases (GSTs) are a large family of enzymes that can be divided into different classes based on structure. There has been considerable interest in the ability of GSTs to conjugate and inactivate endogenously derived reactive lipid peroxidation products that contain alpha,beta-unsaturated carbonyl moieties such as 4-hydroxyalkenals. One enzyme with prominent activity toward these substrates is human GST A4-4. Recently, we described a novel series of compounds termed A(2)/J(2)-isoprostanes (IsoPs) that are formed endogenously in humans from the free radical-initiated peroxidation of arachidonic acid. These compounds contain alpha,beta-unsaturated carbonyl groups and have structures similar to cyclooxygenase-derived PGA(2) and PGJ(2). Because of their chemical reactivity, these compounds may mediate tissue injury associated with oxidant stress. Herein, we report that the A-ring IsoP 15-A(2t)-IsoP (8-iso-PGA(2)) is efficiently conjugated to glutathione (GSH) by human GST A4-4 with a k(cat)/K(m) value of >200 s(-)(1) mM(-)(1). The k(cat)/K(m) value for conjugation of 15-A(2t)-IsoP by the homologous rat GST A4-4 is >2000 s(-)(1) mM(-)(1). Similar high enzyme activities were observed when PGA(2) was used as a substrate. In contrast, the human GSTs A1-1, M1-1, M2-2, P1-1, and T1-1 and rat GST T2-2 did not significantly metabolize 15-A(2t)-IsoP. These studies have therefore defined a potentially important route by which cyclopentenone IsoPs are metabolized that may serve as a mechanism for the inactivation of these highly reactive compounds.
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PMID:The cyclopentenone product of lipid peroxidation, 15-A(2t)-isoprostane (8-isoprostaglandin A(2)), is efficiently conjugated with glutathione by human and rat glutathione transferase A4-4. 1223 Apr 3

Inactivation of the p53 tumor suppressor gene usually involves somatic mutation or binding of viral oncoproteins to the p53 protein. However, several types of malignant and premalignant tissues harbor a genetically wild-type, but transcriptionally inactive, form of p53, often localized in the cytoplasm. Electrophilic prostaglandins (PGs) are known to sequester and inactivate p53 in the cytoplasm, an effect that is likely to occur when cyclooxygenase (COX)-2 levels become elevated during colon carcinogenesis. We determined the localization and expression of p53 in the presence of PGA(1) and celecoxib, a selective COX-2 inhibitor in human colon cell lines HCT-116 (wild-type p53) and HT-29 (mutant p53). In the absence of treatment, p53 protein accumulated preferentially in the nucleus in both cell lines. We observed that the total cellular levels of p53 protein increased with exposure time and concentration of PGA(1). By contrast, p21 protein levels remained unchanged as a function of time and concentration of PGA(1). In the presence of 20 micro M PGA(1), p53 accumulated preferentially in the cytosol. The nuclear:cytosol ratios of p53 were 31 and 2.1 in the controls and in the presence of PGA(1) in HCT-116 cells but were 22 and 4, respectively, in HT-29 cells. Treatment with 50 micro M celecoxib for 24 h did not significantly change p53 expression and localization. However, in the presence of 100 micro M celecoxib, p53 levels increased in the nucleus. The nuclear:cytosol ratios were then 31 (control) and 60 (100 micro M celecoxib) in HCT-116 cells and 22 (control) and 36 (100 micro M celecoxib) in HT-29 cells. These results indicate that electrophilic PGs cause wild-type p53 accumulation in the cytosol where it is inactive. Inhibition of COX-2 by celecoxib appears to alleviate this effect on p53 by reducing electrophilic PG synthesis. Thus, COX-2 inhibition of electrophilic PG formation appears to protect p53 tumor suppressor function.
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PMID:Inhibition of COX-2 in colon cancer cell lines by celecoxib increases the nuclear localization of active p53. 1508 16

Cyclopentenone isoprostanes (IsoPs), A(2)/J(2)-IsoPs, are one class of IsoPs formed via the free radical-initiated peroxidation of arachidonic acid. These compounds, which are structurally similar to cyclooxygenase-derived PGA(2) and PGJ(2), contain highly reactive alpha,beta-unsaturated carbonyl moieties. A(2)/J(2)-IsoPs are generated in vivo in humans esterified in glycerophospholipids. Unlike other classes of IsoPs, however, cyclopentenone IsoPs cannot be detected in the free form; we postulated that this might be due to their rapid adduction to various thiol-containing biomolecules via Michael addition. Recently, we reported that the A-ring IsoP, 15-A(2t)-IsoP, is efficiently conjugated with glutathione in vitro by certain human and rat glutathione transferases (GSTs), with the isozyme GSTA4-4 displaying the highest activity. Herein, we examined the metabolic disposition of 15-A(2t)-IsoP in HepG2 cells. We report that 15-A(2t)-IsoP is primarily metabolized by these cells via conjugation to glutathione. Within 6 h, approximately 60% of 15-A(2t)-IsoP added to HepG2 cells was present in the form of a water soluble conjugate(s). Structural characterization of the adduct(s) by liquid chromatography-tandem mass spectrometry revealed four major conjugates. These include the intact 15-A(2t)-IsoP-GSH conjugate, the GSH conjugate in which the carbonyl at C-9 of 15-A(2t)-IsoP is reduced, and the corresponding cysteine conjugates. These studies thus show that the primary pathway of metabolic disposition of endogenously derived cyclopentenone IsoPs occurs via conjugation with thiols.
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PMID:The cyclopentenone product of lipid peroxidation, 15-A2t-isoprostane, is efficiently metabolized by HepG2 cells via conjugation with glutathione. 1472 15


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