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)

Lung injury induced by acute endotoxemia is associated with increased generation of inflammatory mediators such as nitric oxide and eicosanoids, which have been implicated in the pathophysiological process. Although production of these mediators by alveolar macrophages (AM) has been characterized, the response of type II cells is unknown and was assessed in the present studies. Acute endotoxemia caused a rapid (within 1 h) and prolonged (up to 48 h) induction of nitric oxide synthase-2 (NOS-2) in type II cells but a delayed response in AM (12-24 h). In both cell types, this was associated with increased nitric oxide production. Although type II cells, and to a lesser extent AM, constitutively expressed cyclooxygenase-2, acute endotoxemia did not alter this activity. Endotoxin administration had no effect on mitogen-activated protein kinase or protein kinase B-alpha (PKB-alpha) expression. However, increases in phosphoinositide 3-kinase and phospho-PKB-alpha were observed in type II cells. The finding that this was delayed for 12-24 h suggests that these proteins do not play a significant role in the regulation of NOS-2 in this model. After endotoxin administration to rats, a rapid (within 1-2 h) activation of nuclear factor-kappaB was observed. This response was transient in type II cells but was sustained in AM. Interferon regulatory factor-1 (IRF-1) was also activated rapidly in type II cells. In contrast, IRF-1 activation was delayed in AM. These data demonstrate that type II cells, like AM, are highly responsive during acute endotoxemia and may contribute to pulmonary inflammation.
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PMID:Activation of type II alveolar epithelial cells during acute endotoxemia. 1188 Mar 15

The effect of platelet-activating factor (PAF) on protein tyrosine phosphorylation was studied in rat hippocampal slices. PAF caused an increase in the tyrosine phosphorylation of two phosphoproteins, which we identified by immunoprecipitation assays as the focal adhesion kinase p125FAK and crk-associated substrate p130Ca. The PAF effect was time- and dose-dependent. In addition, the involvement of PAF receptor was demonstrated by using PCA-4248, a specific receptor antagonist. When NO synthase was inhibited by NG-monomethyl-L-arginine (L-NMA), PAF-stimulated protein tyrosine phosphorylation was inhibited. In conclusion, our results indicate that PAF increased the tyrosine phosphorylation of both p125FAK and p130Cas proteins by the production of NO in hippocampus, suggesting that PAF may play a role in the functioning of this cerebral area.
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PMID:PAF-stimulated protein tyrosine phosphorylation in hippocampus: involvement of NO synthase. 1195 33

The immunomodulation of Narcissus tazetta lectin (NTL) on the induction of gene expression of cytokines in the mouse was studied using specific cytokine primers, total RNA isolated from mouse splenocytes and macrophages, and reverse transcription-polymerase chain reaction (RT-PCR). For comparison, a fungal antimitogenic lectin from Agaricus bisporus (ABL) was used to test and compare the acute (kinetic) induction of cytokine gene expression. NTL was able to induce the expression of IL-1beta, TNF-alpha, and immunoreactive nitric oxide synthase (NOS) in both splenocytes and macrophages in vivo after 10-day consecutive peritoneal injections of 5 mg NTL x kg(-1) x day(-1) in the mouse. Nevertheless, the expression levels of IFN-gamma and TGF-beta were markedly increased in macrophages, and the levels of IL-2 and IL-4 were up-regulated only in splenocytes. From the kinetic pattern of cytokine induction and gene expression, ABL appeared to induce the up-regulation of IL-1beta and TNF-alpha in splenocytes up to 24 h, whereas NTL showed a more sustained effect on the expression of these cytokines in macrophages. While NTL manifested TGF-beta expression at the onset of 12 and 24 h in macrophages and splenocytes, respectively, ABL induced TGF-beta in neither splenocytes nor macrophages. After injection of NTL, stem-cell factor was clearly down-regulated in macrophages at 24 and 48 h but up-regulated in splenocytes at the end of 24 h. The immunopotentiating effect of NTL is quite similar to that of LZ-8, a fungal immunomodulatory lectin isolated from the Chinese premier medicinal mushroom Ganoderma lucidium. However, the mechanism of immunomodulation of NTL still awaits to be elucidated.
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PMID:Gene expression of immunomodulatory cytokines induced by Narcissus tazetta lectin in the mouse. 1198 21

The influence of cyclooxygenase (COX) and NO synthase inhibitors on antinociceptive action of acetaminophen (ACETA) was studied in rats. ACETA increased the nociceptive threshold for both mechanical (Randall-Selitto test) and chemical stimuli (writhing test). In both models the existence of ceiling dose of ACETA was observed. Indomethacin (IND), an inhibitor preferentially acting on COX-1, as well as nimesulide (NIM) and celecoxib (CECOX), i.e. respectively preferential and selective inhibitors of COX-2, markedly decreased the antinociceptive activity of ACETA in Randall-Selitto test. In contrast, IND increased, whereas both NIM and CECOX did not have any effect on ACETA action in writhing test. Pretreatment with LG-nitro-L-arginine (L-NO-ARG), an unspecific inhibitor of NO synthase, 7-nitroindazole (7-NI), relatively specific inhibitor of neuronal NO synthase, and L-N6(1-iminoethyl)lysine (L-NIL), relatively selective inhibitor of inducible NO synthase, significantly increased the action of the lower doses of ACETA (50 and 100 mg/kg) in writhing test, whereas it did not modify the effects of the higher doses. Similar effect of L-NO-ARG and 7-NI was observed in Randall-Selitto test, whereas L-NIL did not influence the action of ACETA. The possible involvement of COX and NO synthase systems in antinociceptive activity of ACETA is discussed.
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PMID:Effect of cyclooxygenase and NO synthase inhibitors on antinociceptive action of acetaminophen. 1199 80

Lymnaea stagnalis were exposed to hypoxic and chemical challenges while ventilation, heart rate and metabolism were monitored. Hypoxia increased ventilatory behavior, but this response was eliminated by immersion in 0.75 mM nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7 NI). 7 NI also suppressed ventilatory behavior under normoxia. 10.0 mM L-arginine (ARG, the NOS substrate) increased ventilatory behavior under normoxia, but dampened the hypoxic response. The heart-rate response to NOS inhibition exhibited dose-dependent contradictory characteristics. Under both normoxia and hypoxia 0.25 mM 7 NI increased heart rate, while 0.75 mM 7 NI suppressed it. The effect of 0.50 mM 7 NI depended on whether normoxia or hypoxia was coincident; under normoxia 0.50 mM 7 NI increased heart rate, while under hypoxia this concentration suppressed heart rate. Exposure to ARG did not elicit dose-dependent contradictory responses. Heart rate increased when treated with 10.0 mM ARG under normoxia and hypoxia, while 1.0 mM ARG increased heart rate only under hypoxia. Metabolic responses to NOS inhibition also exhibited dose-dependent contradictory changes. V.O2 decreased over 60% in response to 0.75 mM 7 NI, and baseline V.O2 was restored when exposure ceased. In contrast, 0.25 mM 7 NI increased V.O2 10%, and the increase continued after exposure ceased. 0.50 mM 7 NI decreased V.O2 40%, but V.O2 increased when exposure ceased. ARG had only the effect of increasing V.O2, and only at 10.0 mM concentration. Based on these results and on NO's known role as a neuromodulator, we conclude that the cardio-respiratory responses to hypoxia are, in part, mediated by NO.
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PMID:Nitric oxide mediates metabolism as well as respiratory and cardiac responses to hypoxia in the snail lymnaea stagnalis. 1250 2

Abnormal proliferation of keratinocytes in the skin appears crucial to the pathogenesis of psoriasis, but the underlying mechanisms remain unknown. Nitric oxide (NO), released from keratinocytes at high concentrations, is considered a key inhibitor of cellular proliferation and inducer of differentiation in vitro. Although high-output NO synthesis is suggested by the expression of inducible NO synthase (iNOS) mRNA and protein in psoriasis lesions, the pronounced hyperproliferation of psoriatic keratinocytes may indicate that iNOS activity is too low to effectively deliver anti-proliferative NO concentrations. Here we show that arginase 1 (ARG1), which substantially participates in the regulation of iNOS activity by competing for the common substrate L-arginine, is highly overexpressed in the hyperproliferative psoriatic epidermis and is co-expressed with iNOS. Expression of L-arginine transporter molecules is found to be normal. Treatment of primary cultured keratinocytes with Th1-cytokines, as present in a psoriatic environment, leads to de novo expression of iNOS but concomitantly a significant down-regulation of ARG1. Persistent ARG1 overexpression in psoriasis lesions, therefore, may represent a disease-associated deviation from normal expression patterns. Furthermore, the culturing of activated keratinocytes in the presence of an ARG inhibitor results in a twofold increase in nitrite accumulation providing evidence for an L-arginine substrate competition in human keratinocytes. High-output NO synthesis is indeed associated with a significant decrease in cellular proliferation as shown by down-regulation of Ki67 expression in cultured keratinocytes but also in short-term organ cultures of normal human skin. In summary, our data demonstrate for the first time a link between a human inflammatory skin disease, limited iNOS activity, and ARG1 overexpression. This link may have substantial implications for the pathophysiology of psoriasis and the development of new treatment strategies.
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PMID:Arginase 1 overexpression in psoriasis: limitation of inducible nitric oxide synthase activity as a molecular mechanism for keratinocyte hyperproliferation. 1463 38

It remains undetermined whether continuous endothelial nitric oxide (NO) overexpression exerts angiogenic action. We surgically induced hindlimb ischemia in transgenic mice overexpressing endothelial NO synthase in the endothelium (eNOS-Tg) and studied neocapillary formation, ischemia-induced vascular endothelial growth factor (VEGF) expression, cGMP accumulation, and Akt/PKB signaling. Laser Doppler imaging revealed a markedly increased recovery of blood perfusion in ischemic limbs of eNOS-Tg mice (44% increase) compared with that in wild-type mice. Angiography showed a marked increase in basal and ischemia-induced collateral vessel formation in eNOS-Tg mice. Basal capillary densities and tissue cGMP levels were increased in eNOS-Tg mice (1.8-fold and 1.6-fold versus wild-type mice, respectively). Ischemia-induced neocapillary formation and cGMP accumulation were markedly increased in eNOS-Tg mice (3.6-fold and 4.1-fold versus preischemia levels, respectively), whereas those in wild-type mice were much less (1.8-fold and 1.5-fold, respectively). Basal and time-dependent VEGF expression in ischemic muscles did not differ between eNOS-Tg and wild-type mice. Basal and VEGF-mediated Akt phosphorylation in aortas was similar between eNOS-Tg and wild-type mice. Aortic basal eNOS expression was increased 3.3-fold, and VEGF-mediated eNOS phosphorylation was markedly induced in aortas of eNOS-Tg compared with preischemia levels (4.2-fold), whereas much smaller changes were observed in wild-type mice (1.8-fold increase). Our study demonstrates that overexpression of eNOS protein causes a marked increase in neocapillary formation in response to tissue ischemia without affecting ischemia-induced VEGF expression or VEGF-mediated Akt phosphorylation.
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PMID:Enhancement of ischemia-induced angiogenesis by eNOS overexpression. 2370 57

Nitric oxide (NO) is a retrograde messenger involved in the processes of learning and memory. The role of the endothelial isoform of nitric oxide synthase (eNOS) in striatal synaptic plasticity was investigated in eNOS-deficient (eNOS(-/-)) and wild type (WT) mice. Tetanic stimulation of cortical afferents in WT mice evoked either long-term potentiation (LTP), or long-term depression (LTD) of cortico-striatal transmission. Both these plasticity related phenomena were NMDA-receptor-dependent; LTD was blocked by sulpiride, a dopamine D2-receptor antagonist. LTP occurrence in slices from eNOS(-/-) mice was significantly reduced when compared with WT mice. The NOS inhibitor NL-ARG reduced the occurrence of LTP and increased the occurrence of LTD in WT mice, resembling the balance of LTP/LTD in eNOS(-/-) mice. Impairment of NO-synthesis thus shifts striatal plasticity towards LTD. This indicates a possible involvement of eNOS from endothelia in neuronal modulation.
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PMID:Cortico-striatal synaptic plasticity in endothelial nitric oxide synthase deficient mice. 1257 25

The physiological role of nitric oxide in the control of striatal dopamine release has not been fully established, therefore, the effect of neuronally produced nitric oxide (NO) on striatal dopamine (DA) efflux were investigated using in vivo microdialysis in anaesthetised and conscious rats. In the anaesthetised rat, the nitric oxide synthase inhibitors N(G)-nitro-L-arginine methylester (L-NAME) and 7-nitroindazole monosodium salt (7-NINA) produced concentration-dependent increases in DA efflux. The L-NAME (1 mM)- and 7-NINA (1 mM)-induced increase was reduced by co-administration with the NO precursor, L-arginine (L-ARG; 1 mM) by 37% and 54% respectively, and was prevented by tetrodotoxin (TTX, 1 microM). Similarly, in conscious rats, L-NAME (1 mM) and 7-NINA (1 mM) increased DA efflux to 161% and 166% of basal efflux respectively. These data suggest that neuronally produced NO inhibits striatal DA efflux through an indirect mechanism.
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PMID:Inhibition of neuronal nitric oxide synthase increases dopamine efflux from rat striatum. 1265 63

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


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