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)

Substance P is released from nerve endings in the heart under pathological conditions like ischemia, but its action on cardiac cells has not been investigated. This study tested the hypothesis that substance P is mitogenic to adult cardiac fibroblasts and delineated the underlying mechanism(s). Substance P, acting via neurokinin-1 (NK-1) receptors, stimulated cellular hyperplasia over a range of 1-10 micromol/l. It elicited no change in net collagen production, total protein synthesis, or cell protein content but increased (45)Ca uptake and superoxide generation. EGTA, N-acetyl-cysteine, and superoxide dismutase attenuated the hyperplastic response to substance P. A combination of substance P and EGTA enhanced superoxide generation without an increase in DNA synthesis, showing that an increase in superoxide production does not result in hyperplasia when extracellular Ca(2+) is chelated. Together, the data suggest that substance P may activate, via NK-1 receptors, a hyperplastic but not hypertrophic response in adult cardiac fibroblasts and that alterations in redox state and Ca(2+) homeostasis may act in concert to mediate its mitogenic action.
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PMID:Calcium- and superoxide anion-mediated mitogenic action of substance P on cardiac fibroblasts. 1195 52

Inflammatory bladder disorders such as interstitial cystitis (IC) deserve attention since a major problem of the disease is diagnosis. IC affects millions of women and is characterized by severe pain, increased frequency of micturition, and chronic inflammation. Characterizing the molecular fingerprint (gene profile) of IC will help elucidate the mechanisms involved and suggest further approaches for therapeutic intervention. Therefore, in the present study we used established animal models of cystitis to determine the time course of bladder inflammatory responses to antigen, Escherichia coli lipopolysaccharide (LPS), and substance P (SP) by morphological analysis and cDNA microarrays. The specific aim of the present study was to compare bladder inflammatory responses to antigen, LPS, and SP by morphological analysis and cDNA microarray profiling to determine whether bladder responses to inflammation elicit a specific universal gene expression response regardless of the stimulating agent. During acute bladder inflammation, there was a predominant infiltrate of polymorphonuclear neutrophils into the bladder. Time-course studies identified early, intermediate, and late genes that were commonly up-regulated by all three stimuli. These genes included: phosphodiesterase 1C, cAMP-dependent protein kinase, iNOS, beta-NGF, proenkephalin B and orphanin, corticotrophin-releasing factor (CRF) R, estrogen R, PAI2, and protease inhibitor 17, NFkB p105, c-fos, fos-B, basic transcription factors, and cytoskeleton and motility proteins. Another cluster indicated genes that were commonly down-regulated by all three stimuli and included HSF2, NF-kappa B p65, ICE, IGF-II and FGF-7, MMP2, MMP14, and presenilin 2. Furthermore, we determined gene profiles that identify the transition between acute and chronic inflammation. During chronic inflammation, the urinary bladder presented a predominance of monocyte/macrophage infiltrate and a concomitant increase in the expression of the following genes: 5-HT 1c, 5-HTR7, beta 2 adrenergic receptor, c-Fgr, collagen 10 alpha 1, mast cell factor, melanocyte-specific gene 2, neural cell adhesion molecule 2, potassium inwardly-rectifying channel, prostaglandin F receptor, and RXR-beta cis-11-retinoic acid receptor. We conclude that microarray analysis of genes expressed in the bladder during experimental inflammation may be predictive of outcome. Further characterization of the inflammation-induced gene expression profiles obtained here may identify novel biomarkers and shed light into the etiology of cystitis.
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PMID:Gene expression profiling of mouse bladder inflammatory responses to LPS, substance P, and antigen-stimulation. 1205 14

Senescence-accelerated mice (SAM) were established as a kind of group of related inbred strains that have been used as animal models for accelerated senescence and age-associated disorders. To analyze the characteristics of skin in SAM, the present study examined its morphology at the histological and ultrastructural levels. Histologic comparison of skin from senescence-accelerated-prone (SAM P10) and -resistant (SAM R1) mice revealed that the most characteristic features of SAM P10 were remarkable increases in the number of mast cells and in the density of collagen fibers in the dermis. Therefore, cutaneous allergic responsiveness and the proliferative activity of fibroblasts were also examined. Ultrastructurally, mast cells in the skin of SAM P10 possessed specific granules which exhibited considerable heterogeneity in electron density and various degrees of degranulation. In contrast, mast cells in the skin of control SAM R1 possessed a population of stable granules. Mast cell granules were frequently in contact with fibroblasts and were in close apposition to collagen fibers in the dermis of SAM P10. The collagen bundles were disorganized, and various diameters of collagen fibers were observed. SAM P10 demonstrated a significantly reduced wheal-and-flare reaction to histamine and tachykinins such as substance P, which suggests that skin aging may cause reduced sensitivity of mast cells and/or blood vessels to extrinsic stimuli. An in-vitro study using organ and monolayer culture demonstrated that the proliferative capacity of fibroblasts in the skin of SAM P10 was reduced in comparison with SAM R1. This is the first report that demonstrates the detailed morphological characteristics of skin in SAM P10. The findings obtained suggest that SAM P10 is a useful animal model of aged human skin, because of its many similar morphological features, including the reduction of the cutaneous allergic response, represented by neurogenic inflammation via the axon reflex, and its decreased fibroblast proliferation.
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PMID:Morphological analysis of skin in senescence-accelerated mouse P10. 1211 5

Diffuse intimal thickening (DIT) that develops as a physiologic adaptation in the arterial wall has been implicated to have a predilection for atherosclerosis. We histologically investigated the lipid accumulation process in the human coronary DIT by focusing on the localization of normal and oxidized low-density lipoproteins (LDLs). Immunohistochemistry for apolipoprotein B 100 (a major apolipoprotein of LDL) and 8-iso-prostaglandin F(2alpha) (an oxidative product in LDL) showed substantial accumulation of oxidized relative to normal LDLs in the deep layers of DIT (52/139 segments). Subendothelial deposition of normal rather than oxidized LDLs, known as an early event of fatty streak formation, was less frequently found (13/139 segments). In contrast with fibrofatty lesions, lipid accumulation localized deep in DIT was characterized by fine lipid droplets scattered in the preserved tissue and by its association with neither macrophage accumulation nor apoptosis in the constituent cells. On the other hand, the deep intimal location of lipid accumulation clearly coincided with increased type I and type III collagen and elastic fibers but rarely with sulfated proteoglycans including decorin, which were all strongly expressed in advanced lesions. This lipid accumulation was found only in sites with DIT of more than 200 micro m, occasionally extending to the inner media and involving neovessel formation around it. The presence of deep intimal lipid accumulation was associated with reduced endothelium-dependent relaxation to substance P in isolated coronary rings. These results suggest that normal and oxidized LDLs accumulate preferably in the nutritional border zone of established DIT involving local extracellular matrix alterations but independently of inflammatory or apoptotic processes. This may contribute to the functional and morphologic abnormalities seen in human coronary atherogenesis that progresses slowly with age.
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PMID:Normal and oxidized low density lipoproteins accumulate deep in physiologically thickened intima of human coronary arteries. 1237 78

To reveal whether neuropeptides and cytokines affect the pathogenesis of tennis elbow, expressions of substance P, calcitonin gene-related peptide, interleukin 1 alpha, and transforming growth factor beta1 at the origin of the extensor carpi radialis brevis muscle were investigated in patients with tennis elbow (n = 10). Innervation in the origin was determined with use of the protein gene product 9.5. Substance P-like immunoreactivity and calcitonin gene-related peptide-like immunoreactivity were observed in the nerve fibers around small vessels without apparent infiltration of inflammatory cells. Cells showing positive interleukin 1 alpha or transforming growth factor beta1 immunoreactivity were noted in small vessels and the dense collagen meshwork in 5 of 10 cases. The results suggested that these neuropeptides and cytokines might promote inflammation and stimulate proliferation and matrix synthesis of fibroblasts, contributing to the pathology of tennis elbow.
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PMID:Expression of neuropeptides and cytokines at the extensor carpi radialis brevis muscle origin. 1246 81

The purpose of the study was to investigate interactions between myocardial nitric oxide synthase (NOS) and myocardial fibrosis, both of which determine left ventricular (LV) preload reserve in patients with nonischemic dilated cardiomyopathy (DCM). In previous animal experiments, chronic inhibition of NOS induced myocardial fibrosis and limited LV preload reserve. Twenty-eight DCM patients underwent LV catheterization, balloon caval occlusions (BCO; n = 8), intracoronary substance P infusion (n = 8), and procurement of LV endomyocardial biopsies for determinations of collagen volume fraction (CVF), of gene expression of NOS2, NOS3, heme oxygenase (HO)-1, and TNF-alpha, and of NOS2 protein. CVF was unrelated to the intensity of NOS2, NOS3, HO-1, or TNF-alpha gene expression or of NOS2 protein expression. Preload recruitable LV stroke work (PR-LVSW) correlated directly with NOS2 gene expression (P = 0.001) and inversely with CVF (P = 0.04). High CVF (>10%) reduced baseline LVSW and PR-LVSW at each level of NOS2 gene expression. In DCM, myocardial fibrosis is unrelated to the intensity of myocardial gene expression of NOS, antioxidative enzymes (HO-1), or cytokines (TNF-alpha) and blunts NOS2-related recruitment of LV preload reserve.
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PMID:Myocardial fibrosis blunts nitric oxide synthase-related preload reserve in human dilated cardiomyopathy. 1248 14

Most patients suffering from breast carcinoma do not die due to the primary tumor but from the development of metastases. Active migration of cancer cells is a prerequisite for development of these metastases. We used time-lapse videomicroscopy and computer-assisted cell tracking of MDA-MB-468 human breast carcinoma cells, which were incorporated into a three-dimensional collagen matrix, in order to analyze the migratory activity of these cells in response to different neurotransmitters. Our results show that met-enkephalin, substance P, bombesin, dopamine, and norepinephrine have a stimulatory effect on the migration of the breast cancer cells; moreover, these cells show positive chemotaxis towards norepinephrine as was analyzed by the directionality and persistence on a single-cell basis. Gamma-aminobutyric acid (GABA) however has an inhibitory effect. Endorphin and leu-enkephalin, as well as histamin and acetylcholine, had no influence on the migratory activity of the cells. In summary, we provide evidence for a strong regulatory involvement of neurotransmitters in the regulation of breast cancer cell migration, which might provide the basis for the use of the pharmacological agonists and antagonists for the chemopreventive inhibition of metastasis development.
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PMID:Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. 1288 99

Natural killer (NK) cells and cytotoxic T lymphocytes (CTL), the functional coordination of which are governed by various signal substances, are crucial in the body's defense of tumor and virus-infected cells. We investigated the role of various neurotransmitters and hormones on the regulation of functional parameters, including NK cell cytotoxicity, and the migration of NK cells and CTL within a three-dimensional collagen lattice. Using peripheral blood CTL and NK cells, we show that the neurotransmitters endorphin, histamine and substance P increase NK cell cytotoxicity, while norepinephrine inhibits cytotoxicity. Moreover, substance P reduces migratory activity, while norepinephrine increases NK cell and CTL migration. Furthermore, all three steroid hormones which were investigated, namely cortisone, testosterone, and estradiol, had regulatory influence on both cytotoxicity and migration of NK cells. These results further specify the functional basis of the complex interconnection between the immune and neuro-endocrine systems.
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PMID:Neurotransmitters regulate the migration and cytotoxicity in natural killer cells. 1468 20

The active migration of tumor cells, a crucial requirement for metastasis development and cancer progression, is regulated by signal substances including neurotransmitters. We investigated the migration of tumor cells within a three-dimensional collagen matrix using time-lapse videomicroscopy and computer-assisted analysis of the migration path. Tumor cell migration is induced by norepinephrine, dopamine and substance P. We show that this induced migration, using MDA-MB-468 breast and PC-3 prostate carcinoma cells, can be inhibited by using specific, clinically established receptor antagonists to the beta2-adrenoceptor, the D2 receptor, or the neurokinin-1 receptor, respectively. All of the investigated neurotransmitters significantly activated the cyclic adenosine-monophosphate response element binding protein (CREB). Furthermore, microarray analysis revealed changes of gene expression toward a highly motile tumor cell type, including an upregulation of the alpha2 integrin, which is an essential adhesion receptor for collagen in migration. The gene for the tumor suppressor gelsolin was downregulated. These 2 critical alterations were confirmed on the protein level by flow-cytometry and immunoblotting, respectively. Neurotransmitters thus induce a metastatogenic tumor cell type by directly regulating gene expression and increased migratory activity, which can be prevented by established neurotransmitter antagonists.
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PMID:Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. 1535 35

The feline urogenital junction is situated between the extratesticular rete and the spacious initial segments of the efferent ductules. The rete epithelium is cuboidal to low columnar. The rete cells forming the junction rest on a wavy basal lamina, display deep mutual invaginations, possess central nuclei with several infoldings and form a distinct border with the columnar epithelial cells of the initial segments of the ductuli efferentes. The epithelium of the initial segments is composed of ciliated cells and non-ciliated principal cells. The latter are the dominating type and characterized by an apical brush-border and a supranuclear endocytotic apparatus. The stroma of the extratesticular rete contains an abundance of collagen whereas contractile cells are here generally absent. In contrast, the initial segments of the efferent ductules are surrounded by elastic fibres and a layer of contractile cells. All nerves for the feline urogenital junction come from the nervus spermaticus superior. In the epididymal head, small nerve bundles deviate into the septa between the ductules. Single fibres establish a dense network within the muscular coat of the ductuli. At the transition to the extratesticular rete, this network ends abruptly. Nerve fibres in the confines of the rete are associated with blood vessels or proceed to the testicular interior, but establish no relationships with the rete epithelium or the myofibroblasts of the mediastinum. The nervous network in the walls of the efferent ductules and their initial segments is not only composed of sympathetic but also parasympathetic, non-myelinated fibres. Particularly noteworthy is the abundance of calcitonin gene-related peptide (CGRP)- and substance P (SP)-containing axons around the initial segments. Both neuroproteins are consistent markers for sensory neurones. Taken together, it can be assumed that the entry of seminal fluid and spermatozoa into the efferent ductules is controlled by a regulatory nervous chain provided with afferent and efferent components.
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PMID:Morphology and innervation pattern of the feline urogenital junction. 1554 Sep 89


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