UNIPROT:P20366 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phospholipase A(2) (PLA(2)) forms are expressed in spinal cord, and inhibiting spinal PLA(2) induces a potent antihyperalgesia. Here, we examined the antihyperalgesic effects after systemic and i.t. delivery of four compounds constructed with a common motif consisting of a 2-oxoamide with a hydrocarbon tail and a four-carbon tether. These molecules were characterized for their ability to block group IVA calcium-dependent PLA(2) (cPLA(2)) and group VIA calcium-independent PLA(2) (iPLA(2)) in inhibition assays using human recombinant enzyme. The rank ordering of potency in blocking group IVA cPLA(2) was AX048 (ethyl 4-[(2-oxohexadecanoyl)amino]butanoate), AX006 (4-[(2-oxohexadecanoyl)amino]butanoic acid), and AX057 (tert-butyl 4-[(2-oxohexadecanoyl)amino]butanoate) > AX010 (methyl 4-[(2-oxohexadecanoyl)amino]butanoate) and for inhibiting group VIA iPLA(2) was AX048, AX057 > AX006, and AX010. No agent altered recombinant cyclooxygenase activity. In vivo, i.t. (30 mug) and systemic (0.2-3 mg/kg i.p.) AX048 blocked carrageenan hyperalgesia and after systemic delivery in a model of spinally mediated hyperalgesia induced by i.t. substance P (SP). The other agents were without activity. In rats prepared with lumbar i.t. loop dialysis catheters, SP evoked spinal prostaglandin E(2) (PGE(2)) release. AX048 alone inhibited PGE(2) release. Intrathecal SR141617, a cannabinoid CB1 inhibitor at doses that blocked the effects of i.t. anandamide had no effect upon i.t. AX048. These results suggest that AX048 is the first systemically bioavailable compound with a significant affinity for group IVA cPLA(2), which produces a potent antihyperalgesia. The other agents, although demonstrating enzymatic activity in cell-free assays, appear unable to gain access to the intracellular PLA(2) toward which their action is targeted.
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PMID:Systemic and intrathecal effects of a novel series of phospholipase A2 inhibitors on hyperalgesia and spinal prostaglandin E2 release. 1620 28

Substance P (SP) is a neuropeptide involved in neurogenic inflammation and an agonist for NK(1), NK(2), and NK(3) receptors. SP induces prostaglandin (PG) production in various cell types, and these eicosanoids are responsible for numerous inflammatory and vascular effects. Cyclooxygenase (COX) are needed to convert arachidonic acid to PGs. The study evaluated the effect of SP on COX expression in human umbilical vein endothelial cells (HUVEC). COX-2 protein expression was upregulated by SP with a peak at 100 nM and at 20 h; in the same experimental conditions COX-1 protein expression was unchanged. A correlation between COX-2 expression and PGI(2) and PGE(2) release was detected. Dexamethasone (DEX) inhibited SP-mediated COX-2 expression. Mitogen-activated protein kinases (MAPK) p38 and p42/44 were activated by SP, whereas SB202190 and PD98059, inhibitors of these kinases, blocked COX-2 expression. 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone (DFU), an experimental selective COX-2 inhibitor, blocked SP-induced PG release. By RT-PCR and Western blot analysis, we demonstrated that NK(1) and NK(2) but not NK(3) receptors are present on HUVEC. Selective NK(1) and NK(2) agonists, namely [Sar(9), Met(O(2))(11)]SP and [beta-Ala(8)] NKA(4-10), upregulated COX-2 protein expression and PG production, whereas senktide (Suc-Asp-Phe-MePhe-Gly-Leu-Met-NH(2)), a selective NK(3) agonist, was ineffective in this respect. The NK(1) selective antagonist L703,606 ((cis)-2-(diphenylmethyl)-N-((2-iodophenyl)-methyl)-1-azabicyclo(2.2.2)octan-3-amine) and the NK(2) selective antagonist SR 48,968 ((S)-N-methyl-N-(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4 dichlorophenyl)butyl) benzamide) competitively antagonised SP-induced effects. The study shows HUVEC to possess functional NK(1) and NK(2) receptors, which mediate the ability of SP to induce expression of COX-2 in HUVEC, thus showing a previously-undetected effect of SP on endothelial cells.
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PMID:Substance P-induced cyclooxygenase-2 expression in human umbilical vein endothelial cells. 1643 8

Magnesium is a micronutrient essential for the normal functioning of the cardiovascular system, and Mg deficiency (MgD) is frequently associated in the clinical setting with chronic pathologies such as CHF, diabetes, hypertension, and other pathologies. Animal models of MgD have demonstrated a systemic pro-inflammatory/pro-oxidant state, involving multiple tissues/organs including neuronal, hematopoietic, cardiovascular, and gastrointestinal systems; during later stages of MgD, a cardiomyopathy develops which may result from a cascade of inflammatory events. In rodent models of dietary MgD, a significant rise in circulating levels of proinflammatory neuropeptides such as substance P (SP) and calcitonin gene-related peptide among others, was observed within days (1-7) of initiating the Mg-restricted diet, and implicated a neurogenic trigger for the subsequent inflammatory events; this early "neurogenic inflammation" phase may be mediated in part, by the Mg-gated N: -methyl-D-aspartate (NMDA) receptor/channel complex. Deregulation of the NMDA receptor may trigger the abrupt release of neuronal SP from the sensory-motor C-fibers to promote the subsequent pro-inflammatory changes: elevations in circulating inflammatory cells, inflammatory cytokines, histamine, and PGE(2) levels, as well as formation of nitric oxide, reactive oxygen species, lipid peroxidation products, and depletion of key endogenous antioxidants. Concurrent elevations of tissue CD14, a high affinity receptor for lipopolyssacharide, suggest that intestinal permeability may be compromised leading to endotoxemia. If exposure to these early (1-3 weeks MgD) inflammatory/pro-oxidant events becomes prolonged, this might lead to impaired cardiac function, and when co-existing with other pathologies, may enhance the risk of developing chronic heart failure.
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PMID:The nerve-heart connection in the pro-oxidant response to Mg-deficiency. 1681 76

The aim of this study was to evaluate whether the application of tension or compression forces exerted on the periodontium during the early phase of orthodontic tooth movement is reflected by differences in the composition of the gingival crevicular fluid (GCF), at the level of interleukin-1beta (IL-1beta), substance P (SP), and prostaglandin E(2) (PGE(2)). Eighteen children (mean age 10.8 yr) starting orthodontic treatment were included in the study. Molar elastic separators were inserted mesially to two first upper or lower molars. One of the antagonist molars served as the control. GCF was collected from the mesial and distal sites of each molar, before (-7 d, 0 d) and immediately after (1 min, 1 h, 1 d, and 7 d) the placement of separators. The levels of IL-1beta, SP, and PGE(2) were determined by enzme-linked immunosorbent assay. At the orthodontically moved teeth, the GCF levels of IL-1beta, SP, and PGE(2) were significantly higher than at the control teeth in both tension and compression sides, and at almost all occasions after insertion of separators. The increase, relative to baseline values, was generally higher in tension sides. For the control teeth, the three mediators remained at baseline levels throughout the experiment. The results suggest that IL-1beta, SP, and PGE(2) levels in the GCF reflect the biologic activity in the periodontium during orthodontic tooth movement.
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PMID:Composition changes in gingival crevicular fluid during orthodontic tooth movement: comparisons between tension and compression sides. 1702 8

Activation of renal mechanosensory nerves is enhanced by a high-sodium diet and suppressed by a low-sodium diet. Angiotensin (Ang) II and endothelin (ET)-1 each contributes to the impaired responsiveness of renal mechanosensory nerves in a low-sodium diet. We examined whether stimulation of ETA receptors (Rs) contributes to Ang II-induced suppression of the responsiveness of renal mechanosensory nerves. In anesthetized rats fed a low-sodium diet, renal pelvic administration of the Ang type I receptor (AT1-R) antagonist losartan enhanced the afferent renal nerve activity (ARNA) response to increasing renal pelvic pressure 7.5 mm Hg from 7+/-2% to 15+/-2% and the prostaglandin (PG) E(2)-mediated substance P release from 0+/-1 to 8+/-1 pg/min. Adding the ETA-R antagonist BQ123 to the renal pelvic perfusate containing losartan did not produce any further enhancement of the ARNA response or PGE(2)-mediated release of substance P (17+/-3% and 8+/-1 pg/min). Likewise, renal pelvic administration of BQ123 and BQ123+losartan resulted in similar enhancements of the ARNA responses to increased renal pelvic pressure and PGE(2)-mediated substance P release. In high-sodium-diet rats, pelvic administration of Ang II reduced the ARNA response to increased renal pelvic pressure from 27+/-4% to 8+/-3% and the PGE(2)-mediated substance P release from 9+/-0 to 1+/-1 pg/min. Adding BQ123 to the renal pelvic perfusate containing Ang II restored the increases in ARNA and the PGE(2)-mediated substance P release toward control (27+/-6% and 7+/-1 pg/min). In conclusion, stimulation of ETA-R plays an important contributory role to the Ang II-mediated suppression of the activation of renal mechanosensory nerves in conditions of low-sodium diet.
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PMID:Activation of endothelin-a receptors contributes to angiotensin-induced suppression of renal sensory nerve activation. 1706 May 3

Chronic inflammation associated with osteoarthritis (OA) may alter normal vascular responses and contribute to joint degradation. Vascular responses to vasoactive mediators were evaluated in the medial collateral ligament (MCL) of the anterior cruciate ligament (ACL)-deficient knee. Chronic joint instability and progressive OA were induced in rabbit knees by surgical transection of the ACL. Under halothane anesthesia, laser speckle perfusion imaging (LSPI) was used to measure MCL blood flow in unoperated control (n = 12) and 6-wk ACL-transected knees (n = 12). ACh, bradykinin, histamine, substance P (SP), and prostaglandin E(2) (PGE(2)) were applied to the MCL vasculature in topical boluses of 100 microl (dose range 10(-14) to 10(-8) mol). In normal joints, ACh, bradykinin, histamine, and PGE(2) evoked a dilatory response. Substance P caused a biphasic response that was dilatory from 10(-14) to 10(-11) mol and constricting at higher doses. In ACL-deficient knees, ACh, bradykinin, histamine, and SP decreased perfusion, whereas PGE(2) had a biphasic response that decreased perfusion at 10(-14) to 10(-11) mol and was dilatory at higher concentrations. Sodium nitroprusside increased perfusion in resting and phenylephrine-precontracted vessels with no significant differences between ACL-transected and control knees. Femoral artery occlusion and release increased perfusion by 74.3 +/- 11.1% in control knees but only by 25.8 +/- 4.4% in ACL-deficient knees. The altered responsiveness of the MCL vasculature to these inflammatory mediators may indicate endothelial dysfunction in the MCL, which may contribute to the progression and severity of OA and to the adaptation of the joint in an altered mechanical environment.
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PMID:Endothelial dysfunction and decreased vascular responsiveness in the anterior cruciate ligament-deficient model of osteoarthritis. 1708 78

The anti-inflammatory and anti-allergic effects of the essential oil of Cordia verbenacea (Boraginaceae) and some of its active compounds were evaluated. Systemic treatment with the essential oil of Cordia verbenacea (300-600mg/kg, p.o.) reduced carrageenan-induced rat paw oedema, myeloperoxidase activity and the mouse oedema elicited by carrageenan, bradykinin, substance P, histamine and platelet-activating factor. It also prevented carrageenan-evoked exudation and the neutrophil influx to the rat pleura and the neutrophil migration into carrageenan-stimulated mouse air pouches. Moreover, Cordia verbenacea oil inhibited the oedema caused by Apis mellifera venom or ovalbumin in sensitized rats and ovalbumin-evoked allergic pleurisy. The essential oil significantly decreased TNFalpha, without affecting IL-1beta production, in carrageenan-injected rat paws. Neither the PGE(2) formation after intrapleural injection of carrageenan nor the COX-1 or COX-2 activities in vitro were affected by the essential oil. Of high interest, the paw edema induced by carrageenan in mice was markedly inhibited by both sesquiterpenic compounds obtained from the essential oil: alpha-humulene and trans-caryophyllene (50mg/kg, p.o.). Collectively, the present results showed marked anti-inflammatory effects for the essential oil of Cordia verbenacea and some active compounds, probably by interfering with TNFalpha production. Cordia verbenacea essential oil or its constituents might represent new therapeutic options for the treatment of inflammatory diseases.
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PMID:Anti-inflammatory and anti-allergic properties of the essential oil and active compounds from Cordia verbenacea. 1708 68

Maturational changes have been noted in neurally mediated contractile and relaxant responses in airways from New Zealand White rabbits. In this study, we focused on prostaglandins with bronchoprotective properties as potential modulators of airway tone in maturing rabbits. Tracheal rings from 1-, 2-, and 13-wk-old rabbits were assessed for neurally mediated contractile and relaxant responses produced by electrical field stimulation (EFS) of nerves in the presence and absence of the prostaglandin inhibitor, indomethacin (Indo). We also measured EFS-induced release of prostaglandin E(2) (PGE(2)) and the stable metabolite of prostacyclin, 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)). In the presence of Indo, EFS produced significant increases in contractile responses in segments from 1- and 2-wk-old animals but not in segments from 13-wk adult rabbits. Tracheal rings from 1- and 2-wk-old animals precontracted with neurokinin A (NKA) relaxed 100% in response to EFS when Indo was not in the bath. In rings from 13-wk-old animals, relaxation was 40%. With Indo, relaxation was abolished in 1-wk-old animals and reduced to 30% in the 2- and 13-wk-old groups. Buffer from baths collected after EFS had significant increases in PGE(2) and 6-keto-PGF(1alpha) released from tissues from 1- vs. 2- and 13-wk-old animals. Dose response curves to PGE(2) using tissues precontracted to NKA showed significant increases in relaxant responses in 1- and 2- vs. 13-wk-old rabbits. In rabbit airways, this study demonstrates enhanced modulation of airway tone by PGE(2) and greater release of the bronchoprotective prostaglandins PGE(2) and prostacyclin early in life.
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PMID:Modulation of airway responses by prostaglandins in young and fully grown rabbits. 1748 93

The aim of the present study was to quantify the release of proinflammatory biomarkers by dermal microdialysis after topical exposure with irritant chemicals, Jet fuel (JP-8) and xylene in rat skin. Occlusive dermal exposure (2h) was carried out with 230microl of JP-8 or xylene using Hill top chambers((R)). Linear microdialysis probes (10mm) were inserted in the dermis under urethane anesthesia. The dialysis fluid was pumped at a flow rate of 2microl/min and the dialysate was collected for 7h following probe insertion. The expression of substance P (SP), calcitonin-gene related peptide (CGRP) and prostaglandin E(2) (PGE(2)) in the dialysate following microdialysis was measured by enzyme immunoassay (EIA). The effect of pretreatment with an SP antagonist (SR-140333) and a PGE(2) inhibitor (celecoxib), 6 and 18h before the application of JP-8 was also assessed to further establish the sensitivity of the microdialysis set up. On similar lines, untreated and capsaicin treated control experiments were performed to compare with the SP release following JP-8 treatment. Further, we also investigated the SP release following topical application of xylene. The mean concentrations of SP after the application of JP-8 (90.01+/-3.31) and 3h after its removal (58.66+/-9.36) indicated that JP-8 induced significantly higher release of SP as compared to the baseline value (P<0.05). The release of SP following JP-8 treatment (58.66+/-9.36pg/ml) was comparable to capsaicin (58.18+/-11.29pg/ml). JP-8 exposure resulted in a significant increase (P<0.001) in PGE(2) levels over the baseline control at the end of 1 and 2h of exposure. JP-8 treatment also produced significant increase (P<0.001) in PGE(2) levels as compared to the untreated control during occlusion and 1h following its removal. There was a significant drop (P<0.05) in the PGE(2) levels by the end of 3h following exposure. Pretreatment with SR-140333 and celecoxib significantly reduced (P<0.05) SP and PGE(2) release induced by JP-8. The mean concentrations of SP following xylene exposure (25.50+/-8.80pg/ml) and 3h after its removal (34.37+/-5.61pg/ml) indicated its skin irritation potential. Unlike JP-8, xylene produced a significant increase in SP release only after the removal of occlusion. Pretreatment with SR-140333 significantly blocked the xylene induced SP release. CGRP was not detected in any of the samples. This study demonstrates that dermal microdialysis can be used to quantify skin irritation potential of JP-8 and related irritant chemicals.
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PMID:Estimation of proinflammatory biomarkers of skin irritation by dermal microdialysis following exposure with irritant chemicals. 1757 19

The anti-inflammatory and analgesic properties of different bisphosphonates have been demonstrated in both animal and human studies. Ibandronate is a third-generation bisphosphonate effective in managing different types of bone pain. In this study we investigated its effects in a standard pre-clinical model of inflammatory pain. We evaluated the effects of a single injection of different doses (0.5, 1.0, and 2.0 mg/kg i.p.) of ibandronate on inflammatory oedema and cutaneous hyperalgesia produced by the intraplantar injection of complete Freund's adjuvant (CFA) in the rat hind-paw. In addition, we measured the effects of this drug (1.0 mg/kg i.p.) on hind-paw levels of different pro-inflammatory mediators (PGE-2, SP, TNF-alpha, and IL-1beta). We also measured the levels of SP protein and of its mRNA in the ipsilateral dorsal root ganglia (DRG). Ibandronate proved able to reduce the inflammatory oedema, the hyperalgesia to mechanical stimulation, and the levels of SP in the inflamed tissue as measured 3 and 7 days following CFA-injection. This drug significantly reduced the levels of TNF-alpha and IL-1beta only on day 7. On the other hand, the levels of PGE-2 in the inflamed hind-paw were unaffected by the administration of this bisphosphonate. Finally, ibandronate blocked the overexpression of SP mRNA in DRG induced by CFA-injection in the hind-paw. These data help to complete the pharmacodynamic profile of ibandronate, while also suggesting an involvement of several inflammatory mediators, with special reference to substance P, in the analgesic action of this bisphosphonate.
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PMID:Effects of the bisphosphonate ibandronate on hyperalgesia, substance P, and cytokine levels in a rat model of persistent inflammatory pain. 1766 76

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