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)

Conditions were established to stimulate human gingival fibroblast explant cultures to synthesize milligram quantities of the metalloproteinase proenzymes, prostromelysin and procollagenase. To stimulate enzyme production, cells were treated with 1 nM recombinant human IL-1 beta for approximately 7 days under serum free conditions. Using a combination of rapid column chromatography steps, approximately 10 milligrams of prostromelysin and 5 milligrams of procollagenase were purified from 1 liter of conditioned media. Prostromelysin electrophoresed as a doublet with molecular weights of 55,57 kD, whereas, procollagenase migrated with slightly lower molecular weights of 52, 54 kD. Both proenzymes were treated with trypsin or aminophenylmercuric acetate to generate active species. The molecular weights of the active enzymes were approximately 10 kD smaller than the proenzymes. Active enzymes were inhibited by metal chelators and the natural metalloproteinase inhibitor, tissue inhibitor of metalloproteinase (TIMP), but not by the serine protease inhibitor, phenylmethylsulfonyl fluoride (PMSF). Activated stromelysin degraded a number of substrates including transferrin, proteoglycan monomer, proteoglycan aggregated with hyaluronic acid, and substance P. By contrast, collagenase degraded interstitial type I collagen and the peptide thioester, Ac-Pro-Leu-Gly-SCH(iBu)Co-Leu-GlyOEt. Identity of both enzymes were confirmed by amino-terminal protein sequence analysis as well as by immunoblot analysis using monoclonal antibodies.
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PMID:Production and purification of prostromelysin and procollagenase from IL-1 beta-stimulated human gingival fibroblasts. 217 90

The regenerating amphibian limb serves as a useful model for studying factors influencing cell proliferation and differentiation. In particular, peripheral nerves are thought to provide a stimulus for growth of the blastema, presumably via the elaboration of an as yet unidentified neurotrophic factor. In the present study, pressure ultrafiltration coupled with chromatofocusing have proven to be effective methods of partially purifying a neurotrophic factor from adult chicken brains. This chick brain growth factor (CBGF) appears to be a heat-stable, basic peptide of low molecular weight (less than 6,000). It is a potent mitogen in vitro, at nanomolar concentrations, for both blastema cells and Swiss mouse 3T3 fibroblasts. CBGF is apparently distinct from other peptide mitogens and/or neuromodulators that have been reported to stimulate blastema growth in vivo and in vitro. These include substance P, FGF from bovine brain and pituitary, EGF, transferrin (sciatin), and spinal cord growth factor (SCGF). The possible relationship of CBGF to other neural regulatory molecules is discussed.
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PMID:Partial purification of a low-molecular-weight growth factor from chicken brain. 241 55

The IM-9 human B-lymphoblast cell line grows well in a completely defined serum-free medium containing insulin, transferrin, low density lipoprotein and oleic acid in complex with fatty acid-free bovine serum albumin. Growth of the IM-9 cells is stimulated by addition of physiological concentrations of hydrocortisone to this medium. The order of growth stimulatory potency of several steroids is dexamethasone greater than hydrocortisone greater than aldosterone, whereas testosterone does not stimulate growth of the IM-9 cells. This order of potency suggests that the effect is mediated by binding to glucocorticoid receptors. Growth of the IM-9 cells is also stimulated by the neuropeptide substance P. The defined serum-free medium described in this report will be useful for further studies of the biological responses of the IM-9 cells to other hormones in the absence of interference from hormones and growth factors present in serum.
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PMID:Growth of IM-9 human lymphoblasts in serum-free medium: stimulation by glucocorticoids. 246 70

Internalization of the NK1 receptor (NK1R) and substance P was observed in cells transfected with cDNA encoding the rat NK1R by using anti-receptor antibodies and cyanine 3-labelled substance P (cy3-substance P). After incubation at 4 degrees C, NK1R immunoreactivity and cy3-substance P were confined to the plasma membrane. Within 3 min of incubation at 37 degrees C, NK1R immunoreactivity and cy3-substance P were internalized into small intracellular vesicles located beneath the plasma membrane. Fluorescein isothiocyanate-labelled transferrin and cy3-substance P were internalized into the same vesicles, identifying them as early endosomes. After 60 min at 37 degrees C, NK1R immunoreactivity was detected in larger, perinuclear vesicles. Internalization of 125I-labelled substance P was studied by using an acid wash to dissociate cell-surface label from that which has been internalized. Binding reached equilibrium after incubation for 60 min at 4 degrees C with no detectable internalization. After 10 min incubation at 37 degrees C, 83.5 +/- 1.0% of specifically bound counts were internalized. Hyperosmolar sucrose and phenylarsine oxide, which are inhibitors of endocytosis, prevented internalization of 125I-labelled substance P and accumulation of NK1R immunoreactivity into endosomes. Acidotropic agents caused retention of 125I-labelled substance P within the cell and inhibited degradation of the internalized peptide. Continuous incubation of cells with substance P at 37 degrees C reduced 125I-substance P binding at the cell surface. Therefore, substance P and its receptor are internalized into early endosomes within minutes of binding, and internalized substance P is degraded. Internalization depletes NK1Rs from the cell surface and may down-regulate the response of a cell to substance P.
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PMID:Agonist-induced internalization of the substance P (NK1) receptor expressed in epithelial cells. 752 81

In the present study we investigated the effects of various tachykinins on the secretory activity of rat Sertoli cells in vitro. Sertoli cells were isolated from testes of immature Sprague Dawley rats, cultured for 4 days and thereafter incubated with three concentrations (0.1 pM, 1 pM or 100 pM) of substance P (SP), neurokinin A (NKA), neuropeptide K (NPK) or neuropeptide gamma (NPG) for 24 h. Levels of transferrin and lactic acid were determined in the culture media and expressed per micrograms of cellular DNA. Among all the peptides studied, NPG exhibited the greatest stimulatory effect on the release of transferrin and lactate, with NKA and NPK being less potent and SP being the least potent. Also, the effects of tachykinins on the aromatase activity of cultured Sertoli cells, as reflected by their ability to metabolize testosterone to estradiol (E2), were studied. No stimulatory effect was observed at lower concentrations (1 pM), while at 100 pM both NPG and NKA increased estradiol levels in the medium. SP and NPK had no significant effect on estradiol levels in the medium. This study reveals that tachykinins are able to influence the secretory activity of Sertoli cells, and that some of these peptides can also enhance the aromatase activity. Thus there is a possibility that tachykinins may have a physiological role as modulators of the function of Sertoli cells.
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PMID:Effects of tachykinins on the secretory activity of rat Sertoli cells in vitro. 786 86

Previous studies have shown that patients with chronic alcohol ingestion may show a variety of morphological and functional alterations in the small intestine. In this study, we have focused on the neuroendocrine system in the duodenal mucosa in chronic alcoholics; an area little studied. Twenty-three defined chronic alcoholics admitted to the hospital for detoxification underwent clinical examination, followed by upper gastrointestinal endoscopy and blood tests on average 4 days after the most recent alcohol intake. Biopsy specimens were taken from the distal part of the descending duodenum for both immunohistochemical and routine histological examination. The control group consisted of 25 patients referred for upper endoscopy mainly because of dyspepsia (ulcer, reflux type), but who were otherwise healthy. A normal carbohydrate-deficient transferrin and a history of low alcohol consumption (<40 g/week) were required for inclusion in the control group. The tissue specimens were studied using antisera for the following neuropeptides: cholecystokinin, galanin, gastric inhibitory peptide (GIP), glucagon, motilin, neuropeptide Y, pituitary adenylyl cyclase activating peptide, secretin, serotonin, somatostatin, substance P, vasoactive intestinal polypeptide and protein gene product, as a general marker for neurones and cells of the diffuse neuroendocrine system. The density of nerve fibres was evaluated semi-quantitatively and the number of endocrine cells per unit length of mucosa was counted in sections cut perpendicularly to the mucosal surface. All the different peptidergic nerve fibres in the alcohol group showed higher densities than the corresponding controls. However, this was not a statistically significant difference. A slightly significant increase (P = 0.02) in the numbers of glucagon and GIP cells was seen in the alcohol group. Gastrointestinal symptoms were frequently present (87%) in chronic alcoholics. We suggest that chronic alcohol consumption in man may have a general effect on the peptidergic nerve system and some endocrine cell types in the duodenal mucosa.
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PMID:Neuropeptides in the duodenal mucosa of chronic alcoholic heavy drinkers. 1137 57

Arrestins are cytosolic proteins that, upon stimulation of seven transmembrane (7TM) receptors, terminate signaling by binding to the receptor, displacing the G protein and targeting the receptor to clathrin-coated pits. Fusion of beta-arrestin1 to the C-terminal end of the neurokinin NK1 receptor resulted in a chimeric protein that was expressed to some extent on the cell surface but also accumulated in transferrin-labeled recycling endosomes independently of agonist stimulation. As expected, the fusion protein was almost totally silenced with respect to agonist-induced signaling through the normal Gq/G11 and Gs pathways. The NK1-beta-arrestin1 fusion construct bound nonpeptide antagonists with increased affinity but surprisingly also bound two types of agonists, substance P and neurokinin A, with high, normal affinity. In the wild-type NK1 receptor, neurokinin A (NKA) competes for binding against substance P and especially against antagonists with up to 1000-fold lower apparent affinity than determined in functional assays and in homologous binding assays. When the NK1 receptor was closely fused to G proteins, this phenomenon was eliminated among agonists, but the agonists still competed with low affinity against antagonists. In contrast, in the NK1-beta-arrestin1 fusion protein, all ligands bound with similar affinity independent of the choice of radioligand and with Hill coefficients near unity. We conclude that the NK1 receptor in complex with arrestin is in a high-affinity, stable, agonist-binding form probably best suited to structural analysis and that the receptor can display binding properties that are nearly theoretically ideal when it is forced to complex with only a single intracellular protein partner.
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PMID:NK1 receptor fused to beta-arrestin displays a single-component, high-affinity molecular phenotype. 1206 52

The potential for administering substance P (SP) nocitoxins for the treatment of chronic pain has been identified. To characterize treatment protocols for the spinal cord or elsewhere, binding/internalization of these compounds at the cellular targets must be understood quantitatively. Thus, a kinetic model of SP binding and intracellular trafficking has been developed from data. The eight differential equation model describes surface binding between SP and neurokinin 1 receptor, clathrin-mediated endocytosis followed by spatial translation to a perinuclear endosome where SP is sorted from its receptor, SP degradation in late endosomes/early lysosomes, and return of sorted receptor to plasma membrane via recycling endosomes. With suitably optimized parameters, the model accounts for the kinetics of total, membrane-associated, and internalized SP in cells continuously exposed to SP, as well as the fractions of internalized SP remaining intact at 30 and 60 min. Simultaneously, the model accounts for the kinetics of internalization and receptor recycling after SP preloading of membrane and subsequent exposure to SP-free media. Rate constants (min(-1)) are: 0.034 +/- 0.004 (receptor off-rate), 0.15 +/- 0.03 (internalization), 0.048 +/- 0.003 (exit from sorting endosome), 0.062 +/- 0.008 (exit of labeled SP amino acids from prelysosome), and 0.029 +/- 0.004 (receptor return from recycling endosome to plasma membrane). The SP kinetics resemble those of transferrin and its receptor at the internalization step, but are several-fold slower in the sorting and recycling steps.
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PMID:A kinetic analysis of substance P trafficking. 1253 72

Tachykinins are vasoactive and smooth muscle-contracting peptides with widespread localizations. Tachykinins have been localized in the nerve fibres that supply the testes, in the Leydig cells of different animal species, and also in Sertoli cells of the Siberian hamster testes. The presence of substance P (SP) has also been demonstrated in ejaculated human spermatozoa and in the seminal plasma. Tachykinins have been shown to inhibit the release of testosterone by testicular fragments or by isolated Leydig cells in vitro. Acting on Sertoli cells, tachykinins have been shown to stimulate the release of lactate and transferrin by these cells in vitro, and also to stimulate aromatase activity. Leydig and Sertoli cells express the Preprotachykinin A gene, and this fact strongly suggests that tachykinins can be synthesized in the testes. These findings suggest that tachykinins may have a physiological function in the testes as modulators of the functions of the different cell types contained in these organs.
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PMID:Tachykinins and their possible modulatory role on testicular function: a review. 1284 95

Larval and adult urodeles and anuran tadpoles readily regenerate their limbs via a process of histolysis and dedifferentiation of mature cells local to the amputation surface that accumulate under the wound epithelium as a blastema of stem cells. These stem cells require growth and trophic factors from the apical epidermal cap (AEC) and the nerves that re-innervate the blastema for their survival and proliferation. Members of the fibroblast growth factor (FGF) family synthesized by both AEC and nerves, and glial growth factor, substance P, and transferrin of nerves are suspected survival and proliferation factors. Stem cells derived from fibroblasts and muscle cells can transdifferentiate into other cell types during regeneration. The regeneration blastema is a self-organizing system based on positional information inherited from parent limb cells. Retinoids, which act through nuclear receptors, have been used in conjunction with assays for cell adhesivity to show that positional identity of blastema cells is encoded in the cell surface. These molecules are involved in the cell-cell signaling network that re-establishes the original structural pattern of the limb. Other systems of interest that regenerate by histolysis and dedifferentiation of pigmented epithelial cells are the neural retina and lens. Members of the FGF family are also important to the regeneration of these structures. The mechanism of amphibian regeneration by dedifferentiation is of importance to the development of a regenerative medicine, since understanding this mechanism may offer insights into how we might chemically induce the regeneration of mammalian tissues.
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PMID:Amphibian regeneration and stem cells. 1459 7


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