Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the mechanism of the inflammatory response induced by topical application of mustard oil (0.5-20.0%/20 microliters per ear) to the mouse ear compared to that of the response to capsaicin. The dose-dependent increases in plasma extravasation and ear thickness reached a maximum at approximately 30 min after mustard oil application. Topical pretreatment of ears with capsaicin (250 micrograms/ear) diminished mustard oil-induced plasma extravasation for up to day 7 but not at day 14 after treatment. However, desensitization of the exudative response was not evoked by reapplication of mustard oil to ears. The inflammatory response to mustard oil did not differ between the ears of mast cell-deficient mice and those of the congenic normal mice. Mustard oil-induced plasma extravasation was unaffected by pretreatment with histamine H1 and 5-HT2 receptor antagonists and the capsaicin-functional inhibitor, ruthenium red, which inhibit capsaicin-induced ear oedema. The endopeptidase inhibitor, phosphoramidon, enhanced the ability of mustard oil to increase dye leakage. The tachykinin NK1 receptor antagonist, SR 140333 ((S)1-[2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)pi peridin-3-yl]ethyl]-4-phenyl-1-azoniabicyclo[2.2.2.]octane, chloride), not only inhibited mustard oil-induced plasma extravasation but also blocked the enhancement by phosphoramidon of the response to mustard oil. In contrast, the tachykinin NK2 receptor antagonist, SR 48968 ((S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4,- dichlorophenyl)butyl]benzamide), and the tachykinin NK3 receptor antagonist, SR 142801 ((S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)pro pyl)-4- phenylpiperidin-4-yl)-N-methylacetamide), had no effect on plasma extravasation. The present results demonstrated that mustard oil induces mouse skin inflammation through a mechanism different from that for capsaicin. Mediators such as histamine and 5-HT from mast cells appear to be minor factors in the response to mustard oil. In addition, evidence supports the assumption that the tachykinin NK1 receptor is involved in this model.
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PMID:Mechanism of mustard oil-induced skin inflammation in mice. 931 40

1 The aim of our study was to characterize the tachykinin receptor population in the oestrogen-primed rat uterus. For this purpose, we investigated the receptor type(s) responsible for tachykinin-induced contraction of longitudinally-arranged smooth muscle layer. The effects of substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and several of their analogues with well-defined selectivities for tachykinin NK1, NK2 and NK3 receptors were studied and their inhibition by the selective nonpeptide tachykinin receptor antagonists (S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)pip eridin-3-yl]ethyl)-4-phenyl- -azoniabicyclo[2.2.2]octane chloride (SR 140333, NK1-selective), (S)-N-methyl-N[4-(4acetylamino-4-phenylpiperidino)-2-(3,4-dichloro phenyl)butyl]benzamide (SR 48968, NK2-selective) and (R)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)prop yl)-4-phenylpiperidin-4-yl)-N- methyla-cetamide (SR 142801, NK3-selective) was evaluated. Additionally, expression of tachykinin receptor mRNA was examined by using the reverse transcription-polymerase chain reaction (RT-PCR). 2 SP, NKA, [Nle10]-NKA(4-10), the analogue with selectivity at the tachykinin NK2 receptor type, and NKB elicited concentration-dependent contractions of the rat uterus. The pD2 values were 5.95+/-0.19; 6.73+/-0.21; 7.53+/-0.12 and 5.76+/-0.21, respectively. The selective agonist for the tachykinin NK1 receptor [Sar9Met(O2)11]-SP produced a small phasic response in the nanomolar concentration range. The selective tachykinin NK3 receptor agonist [MePhe7]-NKB failed to induce any significant contraction. 3 In the presence of the neutral endopeptidase inhibitor phosphoramidon (1 microM), the log concentration-response curves to exogenous tachykinins and their analogues were shifted significantly leftwards. The pD2 values were 6.12+/-0.10, 8.04+/-0.07, 7.89+/-0.03 and 6.59+/-0.07 for SP, NKA, [Nle10]-NKA(4-10) and NKB, respectively. In the presence of phosphoramidon (1 microM), [Sar9Met(O2)11]-SP (1 nM - 0.3 microM) induced concentration-dependent contractions of increasing amplitude when only one concentration of drug was applied to each uterine strip and the pD2 value was 7.61+/-0.89. [MePhe7]-NKB induced small, inconsistent contractions and, therefore, a pD2 value could not be calculated. 4 In experiments performed in the presence of phosphoramidon (1 microM), SR 48968 (3 nM - 0.1 microM) caused parallel and rightward shifts in the log concentration-response curves of NKA. The calculated pKB value was 9.16+/-0.08 and the slope of the Schild regression was 1.28+/-0.24. SR 48968 (0.1 microM) also antagonized responses to SP with an apparent pKB value of 7.63+/-0.13. SR 48968 (0.1 microM) inhibited contractions elicited by NKB (1 nM - 3 microM) and [Nle10]-NKA(4-10) (0.1 nM - 3 microM) but had no effect on the response evoked by [Sar9Met(O2)11]-SP (0.1 microM). 5 SR 140333 (0.1 microM) inhibited responses to SP with an apparent pKB value of 7.19+/-0.22. This compound did not significantly affect responses to NKA, [Nle10]-NKA(4-10) and NKB, but suppressed [Sar9Met(O2)11]-SP (0.1 microM)-induced contraction. SR 142801 (0.1 microM) had no effect on responses to natural tachykinins or their analogues. 6 Total RNA was extracted from some of the uteri used in functional studies. RT-PCR assays revealed single bands corresponding to the expected product sizes encoding cDNA for tachykinin NK1 (587 base pairs) and NK2 receptors (491 base pairs) (n=6 different animals). A very low abundance transcript corresponding to the 325 base pairs product expected for the tachykinin NK3 receptor was detected. 7 The present data show that functionally active tachykinin NK1 and NK2 receptors are expressed in the oestrogen-primed rat uterus. The NK2 receptor type seems to be the most important one involved in the contractile responses elicited by tachykinins. NK3 receptors are present in trace amounts and seem not to be involved in tachykinin-induced contractions.
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PMID:Characterization of tachykinin receptors in the uterus of the oestrogen-primed rat. 948 14

The activity of substance P (SP) in the rat thymus seems to be tightly controlled by its bioavailability. In this study, we provide evidence for the expression of the SP-degrading enzyme, neutral endopeptidase (NEP)/CD10, by rat thymocyte subsets, and we illustrate its involvement in the in vivo SP/neurokinin-1 receptor (NK(1)R)-mediated regulation of thymocyte survival and proliferation. NEP/CD10 was expressed at both mRNA and protein levels on a substantial portion (45.5%) of CD5(+) thymocytes, namely on the CD4(+)CD8(+) (double positive; DP) and CD4(+) subsets. Continuous administration of thiorphan, a specific NEP/CD10 inhibitor, by means of miniosmotic pumps, enhanced rat thymocyte preprotachykinin-A (PPT-A) and NK(1)R mRNA expression as well as SP and NK(1)R protein levels in an NK(1)R-dependent manner. Thiorphan increased CD10(+)CD4(+) and CD10(+)DP thymocyte numbers, and an NK(1)R antagonist, (S)1-{2-[3(3-4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)-piperidine-3-yl]ethyl}-4-pheny-1-azoniabicyclo[2.2.2]octane, chloride (SR140333), abrogated these stimulatory effects. In addition, the NEP/CD10 inhibitor stimulated interleukin (IL)-2 production, IL-2 receptor alpha chain expression, and concanavalin A-induced proliferation of CD5(+) thymocytes, and it inhibited spontaneous and NK(1)R-dependent thymocyte apoptosis. The thiorphan-protective antiapoptotic and proliferative effects involved the activation of Akt serine-threonine kinase, subsequent up-regulation of survivin mRNA, down-regulation of procaspase-3 mRNA levels, and suppression of caspase-3 activity, which were inhibited by SR140333 and mimicked by exogenous SP administration. Overall, our findings suggest that by controlling SP availability, NEP/CD10 negatively regulates thymocyte homeostasis and development.
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PMID:Thiorphan-induced survival and proliferation of rat thymocytes by activation of Akt/survivin pathway and inhibition of caspase-3 activity. 1862 88