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)

There is increasing evidence that the cutaneous nervous system modulates physiological and pathophysiological effects including cell growth and differentiation, immunity and inflammation as well as tissue repair. Both cutaneous nervous fibers and inflammatory cells are able to release neuromediators and thereby activate specific receptors on target cells in the skin or transient immunocompetent cells. Cutaneous neuromediators include classical neurotransmitters such as catecholamines and acetylcholine being released from the automatic nervous system or cutaneous cells. On the other hand neuropeptides including substance P, calcitonin gene related peptide (CRGP), vasointestinal peptide (VIP) or proopiomelanocortin (POMC) derived peptides such as alpha melanocyte stimulating hormone (alphaMSH) may be released from sensory or autonomic nerve fibers and several epidermal as well as dermal cells. Neuropeptides are known to activate a variety of cutaneous cells through high affinity neuropeptide receptors or by direct activation of intracellular G-protein signalling cascades. Via the modulation of transcription factor activation (NF-kappaB, AP-1, STAT-3) they regulate the expression of adhesion molecules and proinflammatory cytokines in different cells and thereby function as modulators of immune and inflammatory reactions. Accordingly, neuropeptides such as CGRP or alphaMSH in vitro were found to downregulate costimulatory molecule expression on dendritic cells and in vivo via the generation of suppressor T-lymphocytes to induce hapten specific tolerance. Proteinases such as tryptase or neural endopeptidase inactivate neuropeptides in the extracellular space or at the cell surface thereby terminating neuropeptide induced inflammatory or immune responses. Proteinase-activated receptors (PAR) are recently described receptors that may have high impact in regulating cutaneous neurogenic inflammation. In the skin PAR-2 being expressed on sensory neurons and endothelial cells is self activated by tethered peptide ligands that are exposed after extracellular amino-terminal cleavage by trypsin or mast cell tryptase. PAR-2 agonists were found to induce the release of CGRP and SP which mediate vasodilation, plasma extravasation as well as the expression of adhesion molecules on vascular endothelial cells and thus elicit neurogenic inflammation. These findings indicate that the neuromediator network including neuropeptide receptors as well as proteinases play an important role in the maintenance of tissue integrity and the regulation of inflammatory and immune responses in the skin.
 ...
PMID:Neuromediators--a crucial component of the skin immune system. 1241 63

Proteinase inhibitors from plants represent a form of storage protein or may be involved in plant defense mechanisms against pests and diseases. In this study, we have investigated the oedematogenic activity of DMTI (20 kDa) and DMTI-II (23 kDa), two serine proteinases inhibitors isolated from Dimorphandra mollis (Leguminosae-Mimosoideae) seeds, belonging to the Kunitz family. Paw oedema was induced in male Wistar rats, and measured before and selected times after injection of the proteinase inhibitors. Injection of DMTI-II (3-100 microg/paw) induced a dose-dependent rat paw oedema of rapid onset and short duration, whereas DMTI (3-100 microg/paw) caused a discrete response. The histamine/5-HT receptor antagonist cyproheptadine (2 mg/kg) markedly reduced the DMTI-II-induced oedema. The bradykinin B2 receptor antagonist JE 049 (0.6 mg/kg), the tachykinin NK1 receptor antagonist SR140333 (100 microg/kg) or the NK2 receptor antagonist SR48968 (1 mg/kg) all significantly reduced the DMTI-II-induced oedema. Depletion of sensory neuropeptides by capsaicin also resulted in a significant reduction of oedema formation. In rat isolated peritoneal mast cells, DMTI-II failed to directly release histamine. In conclusion, the proteinase inhibitor DMTI-II induces rat paw oedema by triggering the formation of different inflammatory mediators and pathways, where mast cells and sensory fibers seem to play a pivotal role.
 ...
PMID:Oedematogenic activity induced by Kunitz-type inhibitors from Dimorphandra mollis seeds. 1638 83

Spinal cord injury (SCI) is an extremely serious type of physical trauma observed in clinics. Especially, neuropathic pain resulting from SCI has a lasting and significant impact on most aspects of daily life. Thus, a better understanding of the molecular pathways responsible for the cause of neuropathic pain observed in SCI is important to develop effectively therapeutic agents and treatment strategies. Proteinase-activated receptors (PARs) are a family member of G-protein-coupled receptors and are activated by a proteolytic mechanism. One of its subtypes PAR2 has been reported to be engaged in mechanical and thermal hyperalgesia. Thus, in this study we specifically examined the underlying mechanisms responsible for SCI evoked-neuropathic pain in a rat model. Overall, we demonstrated that SCI increases PAR2 and its downstream pathways TRPV1 and TRPA1 expression in the superficial dorsal horn of the spinal cord. Also, we showed that blocking spinal PAR2 by intrathecal injection of FSLLRY-NH2 significantly inhibits neuropathic pain responses induced by mechanical and thermal stimulation whereas FSLLRY-NH2 decreases the protein expression of TRPV1 and TRPA1 as well as the levels of substance P and calcitonin gene-related peptide. Results of this study have important implications, i.e. targeting one or more of these signaling molecules involved in activation of PAR2 and TRPV1/TRPA1 evoked by SCI may present new opportunities for treatment and management of neuropathic pain often observed in patients with SCI.
 ...
PMID:Blocking proteinase-activated receptor 2 alleviated neuropathic pain evoked by spinal cord injury. 2659 17