Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conscious guinea pigs were either microinjected intrapreoptically (iPO) with various doses of norepinephrine (NE) bilaterally or microdialyzed with pyrogen-free saline (PFS) or 10 micrograms/microliters NE unilaterally immediately and unilaterally or bilaterally 2 days after probe insertion. Core temperature (Tco), skin temperature (Tsk), and rate of oxygen consumption (VO2) were monitored continuously. The microinjection of low doses of NE induced Tco rises, whereas that of the highest dose (10 micrograms/microliters) caused an initial Tco fall followed by a rise. The microdialysis of PFS or NE immediately after probe insertion caused Tco rises; the former was abolished and the latter was converted into a fall by indomethacin (Indo, a prostaglandin synthase inhibitor) pretreatment. Two days later, PFS evoked no thermal response whereas NE induced a Tco fall; neither response was affected by Indo pretreatment. The falls in Tco produced by NE microdialyzed uni- or bilaterally were similar. The microdialysis of NE induced a 15% reduction in metabolic rate but no change in Tsk. These results indicate that the Tco rise induced by NE microinjected iPO is a methodological artifact mediated by PGE2, whereas the Tco fall observed in its microdialysis appears to represent the authentic physiological action of this transmitter effected by a reduction in metabolic rate.
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PMID:Validation of the hypothermic action of preoptic norepinephrine in guinea pigs. 161 36

Neutrophils constitute over 90% of cells found in the synovial fluid of rheumatoid arthritis (RA) patients. Since such fluids also contain immune complexes (IgG-IgG and IgG-IgM rheumatoid factors) and complement split products (C5, C5A, DES, ARG, C3B, etc.), all of the reactants are present for a local Arthus lesion. Moreover, neutrophils from RA patients endocytose these immune complexes and complement components in vivo and in vitro. In consequence, it has been suggested that lysosomal enzymes and other mediators of inflammation released by neutrophils after uptake of immune complexes (in the bulk phase or on the surface) account, at least in part, for rheumatoid inflammation. Secretion of lysosomal hydrolases, especially neutral proteases, which provoke tissue injury and generation of reactive oxygen species (e.g. O2) is part of a stimulus-secretion response to a variety of secretagogues, including immune complexes and complement components. However, the pathways of secretion and O2 generation are stimulus-specific and can be dissected to establish cause and effect relationships by (a) kinetic analysis, (b) varying the stimulus, (c) use of impermeant reagents to block discrete responses. Neutrophils also generate products of 11-cyclo-oxygenase (e.g., PGE2, TXA2) and of the 5- and 15-lipoxygenase (mono-, di and tri-hetes, LTB4 and their isomers). However, the cyclo-oxygenase products (except TXA2) do not cause inflammation acting alone; indeed, they inhibit the function of neutrophils, platelets, macrophages and mast cells. The most potent proinflammatory agent yet identified as a product of arachidonate is LTB4. LTB4 is a potent Ca ionophore, a strong chemo-attractant, induces local inflammation, and activates neutrophils.
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PMID:Rheumatoid arthritis. The role of neutrophil activation. 609 Mar 13

Previous comparative mapping suggested that at least five pig chromosomes (Sscr4, 6, 9, 10 and 14) share homology with human chromosome 1 (Hsap1). A significant quantitative trait loci (QTL) for fat deposition has been identified on Sscr4 that appears to be near the junction region between Sscr4 and Sscr9 relative to Hsap1. It is of interest to define the boundaries of conserved synteny between pig chromosomes and Hsap1 to use human map information to identify putative comparative positional candidates for this QTL. Eleven genes, including Janus kinase 1 (JAK1), Prostaglandin E receptor3 (PTGER3), urate oxidase (UOX), coagulation factor 3 (F3), vascular cell adhesion molecule 1 (VCAM1), ribosomal protein L5 (RPL5), POU domain, class 2, transcription factor 1 (POU2F1), coagulation factor 5 (F5), Prostaglandin endoperoxide synthase-2 (PTGS2), myosin binding protein H (MYBPH) and Antithrombin III (SERPINC1), were selected to refine the boundaries of the blocks of conserved synteny between Hsap1 and pig chromosomes. Pig sequence tagged sites (STSs) were developed and used to physically map these 11 genes using a somatic cell hybrid panel. Eight loci have been mapped by using fluorescent in situ hybridization (FISH) to improve map resolution. Heterologous FISH was used to refine the location of VCAM1 on human chromosomes. In addition, human yeast artificial chromosomes (YACs) were mapped by heterologous FISH on pig metaphases to refine the boundaries of the regions of homology between Sscr4 and Sscr9 on Hsap1. Results from this study suggest the precise break in conserved synteny on Hsap1 corresponding to the Sscr4/6 and Sscr4/9 transitions are most likely on the Hsap1p22 and Hsap1q24-25 regions, respectively. Further, our data predict that Hsap1q21-24 is a candidate region for the backfat QTL localized to Sscr4.
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PMID:Precise mapping of breakpoints in conserved synteny between human chromosome 1 and pig chromosomes 4, 6 and 9. 1204 21

Although the cardioprotection of late preconditioning (PC) is known to be mediated by both inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), the signaling mechanism responsible for COX-2 upregulation and the interaction between iNOS and COX-2 remain unknown. A total of 122 mice were used to address this issue. In wild-type mice preconditioned with six cycles of 4-min coronary occlusion-4-min reperfusion, ischemic PC resulted in rapid activation of nuclear STAT1/3 through tyrosine phosphorylation (STAT1: 339 +/- 48% of control; STAT3: 389 +/- 46% of control) and increased STAT1/3-DNA binding activity (687 +/- 58% of control) at 30 min after PC, with subsequent upregulation of COX-2 protein (373 +/- 60% of control) and activity(increased myocardial levels of PGE2, PGF(2alpha), and 6-keto-PGF(1alpha)) at 24 h. However, COX-1 protein was not changed 24 h after ischemic PC. Pretreatment with the Janus tyrosine kinase (JAK) inhibitor AG-490 before the six occlusion-reperfusion cycles blocked both the tyrosine phosphorylation of STAT1/3 and the subsequent upregulation of COX-2 protein, demonstrating a necessary role of the JAK-STAT pathway in the induction of COX-2. Targeted disruption of the iNOS gene (iNOS-/-) did not block the increased expression of COX-2 protein 24 h after ischemic PC but completely blocked the increase in COX-2 activity, whereas targeted disruption of the COX-2 gene (COX-2-/-) did not alter ischemic PC-induced iNOS induction. Immunoprecipitation of preconditioned heart tissues with anti-COX-2 antibodies followed by immunoblotting with anti-iNOS antibodies revealed that the increased iNOS protein co-precipitated with COX-2. We conclude that (i) the upregulation of COX-2 protein expression after ischemic PC is mediated by a JAK1/2-STAT1/3-signaling cascade; (ii) COX-2 activity requires upregulated iNOS and iNOS-derived NO; and (iii) COX-2 forms complexes with iNOS, supporting a direct interaction between these two proteins. To our knowledge, this is the first evidence that myocardial COX-2 is upregulated via a JAK1/2-STAT1/3 pathway.
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PMID:Mechanism of cyclooxygenase-2 upregulation in late preconditioning. 1273 34

The non-neuronal monoamine transporters OCT1, OCT2 and EMT (human gene symbols SLC22A1-A3) efficiently transport a number of positively-charged monoamines and some small organic cations across the plasma membrane, and thus are implicated in the inactivation of released monoamine transmitters (e.g. noradrenaline, histamine, agmatine) in vivo. Although prostaglandins are full anions at physiological pH, data from a recent publication suggest efficient transport of the prostaglandins PGE2 and PGF2alpha by OCT1 and OCT2. In the present study we have reexamined transport of PGE2 by OCT2 from human (OCT2h). Uptake of substrate into monolayers of 293 cells, stably transfected to express OCT2h, was compared to uptake into non-transfected control cells. Efficiency of transport of the established substrate 3H-1-methyl-4-phenylpyridinium (MPP+), expressed as clearance, was high at 81 microl min(-1) mg protein(-1) on average. By contrast, uptake of 3H-PGE2 was virtually identical for control cells and OCT2h cells. The efficiency of transport was 0.1+/-0.6, 1.0+/-0.3, and 0.7+/-0.4 microl min(-1) mg protein(-1) for cell lysis with methanol, HClO4, and Triton X-100 respectively. Similar results were obtained with unlabeled MPP+ (192+/-12 microl min(-1) mg protein(-1)) and PGE2 (0.3+/-0.1 microl min(-1) mg protein(-1)) in LC-MS/MS analysis. We conclude that OCT2h is not capable of transporting prostaglandins. The data from the previous report may represent binding rather than transport. Our comparison of transport efficiencies confirms the notion that relevant substrates of OCT1, OCT2, and EMT must carry a positive charge.
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PMID:Are organic cation transporters capable of transporting prostaglandins? 1621 6

Particulates in air pollution have been strongly associated with asthma symptoms. These particulates are a conglomeration of many components, including metals, polyaromatic hydrocarbons, and lipopolysaccharide, that may cause oxidative stress upon uptake by alveolar macrophages. The objective of this study was to assess whether uptake of a model air particulate (SRM 1648) causes oxidative stress in macrophages resulting in the production of the eicosanoid mediator prostaglandin E(2) (PGE(2)) that might exacerbate asthma. SRM 1648 suspended in phosphate-buffered saline (PBS) was introduced into wells with plated RAW 264.7 monocyte/macrophages. Following incubation of SRM 1648 with RAW 264.7 macrophages, prostaglandin E(2) was measured by enzyme immunosorbent assay (EIA), and oxidative stress was assessed by the levels of intracellular reduced glutathione (GSH) as well as by the oxidation of dihydrodichlorofluorescein (H(2)DCFDA) to the fluorescent dichlorofluoresecein (DCF). The results indicated that SRM 1648 caused oxidative stress in RAW 264.7 macrophages, as shown by a compensatory increase in GSH levels in comparison to the controls of titanium dioxide and media alone. Prostaglandin E(2) levels significantly increased at the 3-, 6-, and 12-h time points. Introduction of GSH ester to buffer against oxidative stress was able to block the elevation of PGE(2). The data show that SRM 1648 causes oxidative stress in RAW 264.7 macrophages resulting in formation of the potential Th2 mediator prostaglandin E(2).
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PMID:Air pollution particulate SRM 1648 causes oxidative stress in RAW 264.7 macrophages leading to production of prostaglandin E2, a potential Th2 mediator. 1628 64

Substance P (SP) via its neurokinin-1 receptor (NK-1R) regulates several gastrointestinal functions. We previously reported that NK-1R-mediated chloride secretion in the colon involves formation of PG. PGE2 biosynthesis is controlled by cyclooxygenase-1 (COX-1) and COX-2, whose induction involves the STATs. In this study, we examined whether SP stimulates PGE2 production and COX-2 expression in human nontransformed NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells) and identified the pathways involved in this response. SP exposure time and dose dependently induced an early (1-min) phosphorylation of JAK2, STAT3, and STAT5, followed by COX-2 expression and PGE2 production by 2 h. Pharmacologic experiments showed that PGE2 production is dependent on newly synthesized COX-2, but COX-1 protein. Inhibition of protein kinase Ctheta (PKCtheta), but not PKCepsilon and PKCdelta, significantly reduced SP-induced COX-2 up-regulation, and JAK2, STAT3, and STAT5 phosphorylation. Pharmacological blockade of JAK inhibited SP-induced JAK2, STAT3, and STAT5 phosphorylation; COX-2 expression; and PGE2 production. Transient transfection with JAK2 short-interferring RNA reduced COX-2 promoter activity and JAK2 phosphorylation, while RNA interference of STAT isoforms showed that STAT5 predominantly mediates SP-induced COX-2 promoter activity. Site-directed mutation of STAT binding sites on the COX-2 promoter completely abolished COX-2 promoter activity. Lastly, COX-2 expression was elevated in colon of mice during experimental colitis, and this effect was normalized by administration of the NK-1R antagonist CJ-12,255. Our results demonstrate that SP stimulates COX-2 expression and PGE2 production in human colonocytes via activation of the JAK2-STAT3/5 pathway.
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PMID:Substance P stimulates cyclooxygenase-2 and prostaglandin E2 expression through JAK-STAT activation in human colonic epithelial cells. 1658 2

A liquid chromatography/high-field asymmetric waveform ion mobility spectrometry/tandem mass spectrometry (LC-FAIMS-MS/MS) semi-quantitative method was developed for the simultaneous determination of prostaglandin (PG) E2, PGD2, PGF(2alpha), 6-keto-PGF(1alpha), and thromboxane (TX) B2. Diluted samples containing these prostanoids and their tetra-deuterium-substituted internal standards were analyzed by LC followed by either selected reaction monitoring (LC-SRM) or FAIMS and selected reaction monitoring (LC-FRM). FAIMS reduced background noise, separated the isobaric ions PGE2 and PGD2, and separated dynamically interchanging TXB2 anomers. This is the first report of the separation of interconverting anomers by FAIMS. Generally, the LC-FRM chromatograms were more selective than the LC-SRM chromatograms. Its potential was demonstrated by analysis of prostanoids in guinea pig lumbar spinal cord homogenate.
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PMID:Simultaneous analysis of prostanoids using liquid chromatography/high-field asymmetric waveform ion mobility spectrometry/tandem mass spectrometry. 1662 69

Osteoblast interactions with extracellular matrix (ECM) proteins are known to influence many cell functions, which may ultimately affect osseointegration of implants with the host bone tissue. Some adhesion-mediated events include activation of focal adhesion kinase, and subsequent changes in the cytoskeleton and cell morphology, which may lead to changes in adhesion strength and cell responsiveness to mechanical stimuli. In this study we examined focal adhesion kinase activation (FAK), F-actin cytoskeleton reorganization, adhesion strength, and osteoblast responsiveness to fluid shear when adhered to type I collagen (ColI), glass, poly-L-lysine (PLL), fibronectin (FN), vitronectin (VN), and serum (FBS). In general, surfaces that bind cells through integrins (FN, VN, FBS) elicited the highest adhesion strength, FAK activation, and F-actin stress fiber formation after both 15 and 60 minutes of adhesion. In contrast, cells attached through non-integrin mediated means (PLL, glass) showed the lowest FAK activation, adhesion strength, and little F-actin stress fiber formation. When subjected to steady fluid shear using a parallel plate flow chamber, osteoblasts plated on FN released significantly more PGE2 compared to those on glass. In contrast, PGE2 release of osteoblasts attached to FN or glass was not different in the absence of fluid shear, suggesting that differences in binding alone are insufficient to alter PGE2 secretion. The increased adhesion strength as well as PGE2 secretion of osteoblasts adhered via integrins may be due to increased F-actin fiber formation, which leads to increased cell stiffness.
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PMID:Substrate modulation of osteoblast adhesion strength, focal adhesion kinase activation, and responsiveness to mechanical stimuli. 1671 Oct 67

Myofibroblasts are pathogenic in pulmonary fibrotic disease due to their exuberant production of matrix rich in collagen that interferes with gas exchange and the ability of these cells to contract and distort the alveolar space. Transforming growth factor-beta1 (TGF-beta1) is a well-known inducer of myofibroblast differentiation. TGF-beta1-induced transformation of fibroblasts to apoptosis-resistant myofibroblasts is adhesion-dependent and focal adhesion kinase (FAK)-mediated. Prostaglandin E(2) (PGE(2)) inhibits this differentiation via E prostanoid receptor 2 (EP2) signaling and cAMP elevation, but whether PGE(2) does so by interfering with TGF-beta1 signaling is unknown. Thus we examined the effects of PGE(2) in the presence and absence of TGF-beta1 stimulation on candidate signaling pathways in human lung fibroblasts. We now demonstrate that PGE(2) does not interfere with TGF-beta1-induced Smad phosphorylation or its translocation to the nucleus. Rather, PGE(2) has dramatic effects on cell shape and cytoskeletal architecture and disrupts the formation of appropriate focal adhesions. PGE(2) treatment diminishes TGF-beta1-induced phosphorylation of paxillin, STAT-3, and FAK and, in turn, limits activation of the protein kinase B (PKB/Akt) pathway. These alterations do not, however, result in increased apoptosis within the first 24 h of treatment. Interestingly, the effects of PGE(2) stimulation alone do not always mirror the effects of PGE(2) in the presence of TGF-beta1, indicating that the context for EP2 signaling is different in the presence of TGF-beta1. Taken together, our results demonstrate that PGE(2) has the potential to limit TGF-beta1-induced myofibroblast differentiation via adhesion-dependent, but Smad-independent, pathways.
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PMID:PGE(2) inhibition of TGF-beta1-induced myofibroblast differentiation is Smad-independent but involves cell shape and adhesion-dependent signaling. 1755 99


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