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

Using mouse peritoneal cavity mast cells, we investigated the effects of FK506 and cyclosporin A (CsA) on cell proliferation and histamine release induced by anti-IgE antibody, calcium ionophore (A23 187), or neuropeptide (substance P). Both FK506 and CsA inhibited cytokine-dependent mast cell proliferation in a dose-dependent manner. The inhibitory effects of these compounds on mast cell proliferation was reversible; the removal of the chemicals from the incubation medium resulted in the reinitiation of mast cell proliferation. Flow cytometric analysis suggested that the inhibitory effect of FK506 and CsA was mostly due to G1/S boundary block, although a significant number of G2-arrested cells were also observed following FK506 treatment. Both FK506- and CsA-treated mast cells showed a similar inhibition of histamine release induced by A23187. However, CsA at higher concentrations inhibited the histamine release induced by anti-IgE antibody or substance P more markedly than FK506. Cellular histamine content was decreased by CsA treatment while FK506 had no effect. The staining properties of peritoneal mast cells changed from connective tissue-type mast cell-like to mucosal mast cell-like during CsA treatment but not during FK506 treatment. Thus FK506 and CsA have different effects on mast cell proliferation as well as histamine release, that might be associated with a phenotypic change of the cells during culture.
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PMID:Effects of FK506 and cyclosporin A on proliferation, histamine release and phenotype of murine mast cells. 884 28

To determine the roles of FK506-binding proteins, receptors for the immunosuppressant FK506, in tachykinin release, we examined the effects of the FK506 derivative ascomycin, [3S-[3R[E(1S,3S,4S)],4S,5R,8S,9E,12R,14R,15S,16R,18S,1 9S,26aR]]-8-ethyl- 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro- 5,19-dihydroxy- 3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16- dimethoxy- 4,10,12,18-tetramethyl-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotr icosine -1,7,20,21(4H,23H)-tetrone, on the contractility of the rabbit iris sphincter muscle. Ascomycin (10(-7) to 10(-5) M) caused concentration-dependent contractions, which were greatly attenuated by preexposure to rapamycin (10(-5) M), a FK506 receptor antagonist. Similarly, this contractile effect was abolished by preexposure to FK888 (10(-6) M), a tachykinin receptor antagonist, and to capsaicin (10(-5) M), a tachykinin-depleting agent. L-type voltage-dependent Ca2+ channel blockers, nicardipine (10(-5) M) and verapamil (5 x 10(-5) M), inhibited the ascomycin-induced contraction, but the N-type channel blocker omega-conotoxin (10(-6) M) did not. These results suggest that ascomycin stimulates tachykinin release by its binding to FK506-binding proteins and the subsequent activation of L-type Ca2+ channels. Thus, FK506-binding proteins may regulate muscle contractility by altering transmitter release from peripheral tachykininergic nerves.
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PMID:FK506-binding proteins regulate smooth muscle contractility by altering neurotransmitter release. 931 39

We have investigated the contractile property of cyclosporin A and FK506 in guinea-pig isolated bronchus. Cyclosporin A (10 microM) failed to significantly attenuate the excitatory non-adrenergic non-cholinergic (eNANC) and cholinergic contractile response (per cent methacholine Emax) induced by electrical field stimulation (EFS). In contrast, eNANC responses were significantly attenuated by both the neurokinin (NK)-1 and (NK)-2 receptor antagonists, N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl)-benzyl and SR48968, respectively. Cyclosporin A and FK506 caused a concentration-dependent contraction in guinea-pig isolated bronchus, which was significantly attenuated by NK-1 and NK-2 receptor antagonists. The capsaicin receptor antagonist, capsazepine (10 microM) significantly reduced the contractile response to cyclosporin A and capsaicin, but not to FK506. The N-type calcium channel blocker, omega-Conotoxin (omegaCTX: 10 nM), significantly reduced the contractile response to FK506 and the eNANC response following EFS. In contrast, omega-CTX failed to significantly reduce the contractile potency to capsaicin or cyclosporin A. In bronchial preparations desensitized by repeated application of capsaicin (1 microM), the contractile responses to both cyclosporin A (100 microM) and FK506 (100 microM), were significantly reduced. In contrast, the contractile responses to substance P and neurokinin A (10 microM) were not altered. Furthermore, repeated application of cyclosporin A (100 microM) significantly inhibited the contractile response to capsaicin (1 microM). The findings from this study would indicate that cyclosporin A and FK506 mediate contraction of guinea-pig isolated bronchus secondary to the release of neuropeptides from airway sensory nerves. However, the release of sensory neuropeptides appears to be mediated via different mechanisms for cyclosporin A and FK506, the former by stimulation of the vanilloid receptor and the latter via opening of N-type calcium channels.
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PMID:Stimulation of airway sensory nerves by cyclosporin A and FK506 in guinea-pig isolated bronchus. 988 67

Mast cells play important roles in many pathological conditions where local hypoxia is observed, including asthma, rheumatic diseases, and certain types of cancer. Here, we investigated how expression of the hypoxia-inducible factor 1, alpha subunit gene (HIF1A), is regulated in mast cells. The product of HIF1A is hypoxia-inducible factor 1alpha (HIF-1alpha), is a major nuclear transcription factor modulating gene expression in response to hypoxic conditions. We observed that under hypoxic conditions, exposure of mast cells to ionomycin and substance P resulted in significant up-regulation of HIF1A expression as compared with resting mast cells incubated under identical conditions. The ionomycin-mediated increase in HIF-1alpha protein levels was sensitive to the transcription inhibitor actinomycin D and to inhibitors of calcineurin, cyclosporin A (CsA), and FK506. The increased HIF-1alpha protein level was paralleled by a severalfold increase in HIF-1alpha mRNA that could be also inhibited with actinomycin D and CsA. The HIF1A promoter activity was significantly increased in ionomycin-activated mast cells, and the promoter activity could be inhibited by CsA and FK506. Furthermore, in situ mutagenesis experiments showed that the ionomycin-mediated HIF1A promoter activity depends on a conservative NFAT-binding site. Thus, accumulation of HIF-1alpha in activated mast cells requires up-regulation of HIF1A gene transcription and depends on the calcineurin-NFAT signaling pathway.
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PMID:HIF-1alpha is up-regulated in activated mast cells by a process that involves calcineurin and NFAT. 1864 2

Tacrolimus ointment is used to treat various chronic inflammatory skin diseases. However, the effect of this ointment on acute neurogenic inflammation in the skin remains to be fully elucidated. Topical capsaicin and m-xylene produce tachykinin release from sensory nerves in the skin, resulting in skin plasma leakage. We investigated the effect of tacrolimus ointment (0.1%) on skin microvascular leakage induced by topical capsaicin (10 mM) and m-xylene (neat), and intracutaneous compound 48/80 (c48/80) (10 microg/ml, 50 microl/site) in two groups of rats pretreated with excessive capsaicin or its vehicle. The amount of leaked Evans blue dye reflected skin plasma leakage. Capsaicin, m-xylene or c48/80 was applied to the shaved abdomens of rats 8 h after topical application of tacrolimus ointment or its base. Desensitization with capsaicin reduced the skin response to capsaicin and m-xylene by 100% and 65%, respectively, but not to c48/80. Tacrolimus ointment significantly inhibited the skin response induced by m-xylene and c48/80, regardless of pretreatment with capsaicin. However, topical tacrolimus did not influence the skin response induced by capsaicin. We also evaluated whether topical capsaicin and m-xylene, and intracutaneous c48/80 cause mast cell degranulation in skin treated with tacrolimus. Mast cell degranulation was microscopically assessed. Topical tacrolimus only significantly suppressed degranulation induced by m-xylene and c48/80. Our data shows that tacrolimus ointment partially inhibits plasma leakage and mast cell degranulation in rat skin induced by m-xylene and c48/80 but not capsaicin, suggesting that the inhibitory effect is not associated with a reduction in neurogenic-mediated mechanisms.
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PMID:Tacrolimus hydrate ointment inhibits skin plasma extravasation in rats induced by topical m-xylene but not capsaicin. 1925 15

Itching is the most important problem in atopic dermatitis and tacrolimus has been suggested to attenuate the itching by topical application. However, the anti-itch mechanism of tacrolimus has not been well elucidated. In the present study, an allergic dermatitis accompanied by frequent scratching behaviors was induced by repeated paintings with 2,4-dinitrofluorobenzene (DNFB) acetone solution onto the mouse ear and the effects of tacrolimus and dexamethasone on the dermatitis and associated scratching behavior were comparatively examined. Repeated DNFB paintings caused a typical dermatitis accompanied by elevated serum immunoglobulin E (IgE) and frequent scratching behaviors. Both tacrolimus and dexamethasone given topically for 10 days before the final challenge significantly inhibited the ear swelling and reduced the expression of interferon-gamma mRNA. Dexamethasone inhibited the accumulation of eosinophils completely, although tacrolimus did not. Both drugs did not affect the elevation of serum IgE levels. Tacrolimus significantly inhibited the scratching behavior, whereas dexamethasone failed to affect it. Repeated DNFB challenge depleted substance P in the dermis. Treatment with tacrolimus before the final challenge completely inhibited the recovery of substance P content, whereas dexamethasone facilitated the recovery. DNFB-induced ear swelling and scratching behavior were significantly inhibited by FK888, a tachykinin NK(1) receptor antagonist. Therefore, substance P seems to participate in the induction of ear swelling and scratching behavior upon final challenge with DNFB, and depletion of substance P by tacrolimus in the dermis contributes to its inhibition of ear swelling and scratching behavior at least in part.
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PMID:Depletion of substance P, a mechanism for inhibition of mouse scratching behavior by tacrolimus. 1981 45

Atopic dermatitis is a common skin disease accompanied by intense itching. Relapsing eczema is caused by immune imbalances and skin-barrier disruption. The immunopathy and barrier dysfunction are closely related to the onset of itching and subsequent scratching, and intractable dermatitis is amplified by the itch-scratch cycle. The standard therapy for atopic dermatitis is topical corticosteroids and immunosuppressants to lessen the inflammation, along with moisturizing agents to improve the physiologic skin dysfunction. Corticosteroids are the primary treatment for the inflammation in atopic dermatitis. Some clinical trials demonstrated a tendency for the alleviation of pruritus with long-term treatment. Tacrolimus results in instant burning and itching in the short term, but they resolve a few days after the beginning of use and then are relieved. Substance P is a neuropeptide released from sensory nerve fibers and a neurotransmitter of pain and itching. Basic experimental reports indicated that the antipruritic effect of tacrolimus is probably dependent on depleting substance P, followed by transient induction. Oral administration of antihistamines and antiallergics is used as adjunctive pharmacotherapy for pruritus. It is known that second-generation antihistamines are less sedative or nonsedative drugs compared with the first generation, and the drugs have additional efficacy in blocking some chemical mediators. Japanese traditional Kampo medicines are also used for the treatment of atopic dermatitis. This paper discusses the efficacy of representative Kampo medicines in the treatment of inflammation and itching based on murine atopic dermatitis models. Information on the mechanism of action of Kampo medicines will result in more choice of pharmacotherapeutic agents for complex diseases such as atopic dermatitis.
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PMID:Treatment of the chronic itch of atopic dermatitis using standard drugs and kampo medicines. 2390 69

Background: Topical application of tacrolimus (FK506) was effective in treating atopic dermatitis (AD); however, the therapeutic efficiency is hampered by its poor penetration into the skin and local side effects of transient irritation symptoms with a burning sensation, a feeling of warmth or heat. Menthol and camphor have been widely used in topical compound formulations for adjunctive pharmacotherapy for antipruritics and analgesics owing to their cool nature, and both present skin penetration enhancing effects. Moreover, they can form a liquid eutectic oil to solubilize hydrophobic drugs. Purpose: Taking advantages of menthol/camphor eutectic (MCE), this work aims to integrate FK506 into MCE to construct a microemulsion system, i.e., FK506 MCE ME, which simultaneously enhances the percutaneous delivery and treatment efficacy, while reduces the side effects of FK506. Methods: The formulation of FK506 MCE ME was optimized and characterized. Different formulations containing FK506 were topically administered to treat 1-chloro-2, 4-dinitrobenzene (DNCB)-induced murine AD. Results: MCE solubilized FK506. FK506 in MCE ME penetrated skin in vitro more than in the commercial ointment, and MCE predominantly exerted the enhancing effects in MCE ME. FK506 MCE ME or FK506 MCE ME gel had greater effects on clinical symptoms, histological analysis, and IgE than did commercial FK506. The anti-pruritic and down-regulation of substance P effects of MCE ME vehicle mitigated the side effects of FK506 application. Conclusion: MCE ME presented the excellent properties of simultaneously enhancing the percutaneous delivery and treatment efficacy, while reducing the side effects of FK506 for AD. Therefore, MCE ME is a promising nanoscale system for FK506 to effectively treating AD with low irritation and high medication adherence. Chemical compounds studied in this article: Tacrolimus (PubChem CID: 445643); menthol (PubChem CID: 1254); camphor (PubChem CID: 2537).
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PMID:Integrating tacrolimus into eutectic oil-based microemulsion for atopic dermatitis: simultaneously enhancing percutaneous delivery and treatment efficacy with relieving side effects. 3144 50