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)

Associations between stress and health outcomes have now been carefully documented, but the mechanisms by which stress specifically influences disease susceptibility and outcome remain poorly understood. Recent evidence indicates that glucocorticoids (GCs) and catecholamines (CAs), the major stress hormones, inhibit systemically IL-12, TNF-alpha, and INF-gamma, but upregulate IL-10, IL-4, and TGF-beta production. Thus, during an immune and inflammatory response, the activation of the stress system, through induction of a Th2 shift may protect the organism from systemic "overshooting" with T helper lymphocyte 1 (Th1)/proinflammatory cytokines. In certain local responses and under certain conditions, however, stress hormones may actually facilitate inflammation, through induction of IL-1, IL-6, IL-8, IL-18, TNF-alpha, and CRP production, and through activation of the corticotropin-releasing hormone (CRH)/substance P(SP)-histamine axis. Autoimmunity, chronic infections, major depression, and atherosclerosis are characterized by a dysregulation of the pro/anti-inflammatory and Th1/Th2 cytokine balance. Thus, hyperactive or hypoactive stress system, and a dysfunctional neuroendocrine-immune interface associated with abnormalities of the "systemic anti-inflammatory feedback" and/or "hyperactivity" of the local proinflammatory factors may contribute to the pathogenesis of these diseases. Conditions that are associated with significant changes in stress system activity, such as acute or chronic stress, cessation of chronic stress, pregnancy and the postpartum period, or rheumatoid arthritis (RA) through modulation of the systemic or local pro/anti-inflammatory and Th1/Th2 cytokine balance, may suppress or potentiate disease activity and/or progression. Thus, stress hormones-induced inhibition or upregulation of innate and Th cytokine production may represent an important mechanism by which stress affects disease susceptibility, activity, and outcome of various immune-related diseases.
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PMID:Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases. 1685 35

Neuropeptides released from the cutaneous sensory nerve endings have neurotransmitter and immunoregulatory roles; they exert mitogenic actions and can influence the functions of different cell types in the skin. The aims of this study were a systematic investigation of the effects of the neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and galanin (GAL) on the inflammatory cytokine production (IL-1alpha, IL-8 and TNF-alpha) of the keratinocytes, and a study of their role in the production and secretion of nerve growth factor (NGF) and its precursor molecule (proNGF). Cultures of normal human keratinocytes were treated with 10(-8)M SP, CGRP, VIP or GAL for 30 min. After different time intervals, cells were harvested for total RNA isolation; in addition, cell lysates and supernatants were collected. The effects of the neuropeptides on the mRNA expressions of the different cytokines and NGF were investigated by Q-RT-PCR and the protein levels were studied by means of ELISA assays and Western blotting. Each of the four neuropeptides induced increases in the expressions of IL-1alpha, IL-8 and TNF-alpha mRNA. Increases appeared in the amount of the IL-1alpha protein in the supernatants of neuropeptide-treated cells, and the IL-8 secretion was mildly elevated, while secretion of TNF-alpha remained undetectable. The four neuropeptides increased the NGF mRNA expression to different extents. In the cell lysates of the keratinocytes, only proNGF could be detected, its concentration in the neuropeptide-treated cells being approximately twice that in the time-matched controls. Both control cultures and neuropeptide-treated cultures were found to secrete proNGF and mature NGF, but neuropeptide-treated cell cultures produced markedly higher (3-7-fold) amounts of NGF-like immunoreactive materials. The results demonstrated that neuropeptides released from cutaneous nerves after an injurious stimulus are able to induce an upregulation of IL-1alpha and IL-8 production; they are additionally able to influence the expressions of proNGF/NGF and their secretion from the keratinocytes. These findings may contribute toward an understanding of the neural influence on skin health and disease.
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PMID:Effects of the neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and galanin on the production of nerve growth factor and inflammatory cytokines in cultured human keratinocytes. 1690 78

In the present study, we examined the change of pain behaviors induced by formalin injected subcutaneously (s.c.) into the hind paw, or substance P (SP), glutamate, and pro-inflammatory cytokines (TNF-alpha, IL-1beta, and IFN-gamma) injected intrathecally (i.t.) in the mouse immobilization stress model. The mouse was restrained either once for 1h or five times for 5 days (once/day). In the formalin test, a single immobilization stress attenuated pain behaviors (licking, biting or scratching) in the second phase, while it had no effect on the pain behaviors revealed during the first phase. In addition, repeated immobilization stress attenuated pain behaviors revealed during the second phase but not in the first phase. A single as well as repeated immobilization stress decreased pain behaviors induced by substance P i.t. injection, but there were no significant changes in the glutamate test. In the pro-inflammatory cytokine pain model, a single immobilization stress decreased the pain behaviors induced by TNF-alpha, IL-1beta administered i.t. but not by IFN-gamma administered i.t. Moreover, a mouse applied with repeated immobilization stress did not show any changes in pain behaviors elicited by pro-inflammatory cytokines (TNF-alpha, IL-1beta and IFN-gamma) compared to the control group. These results suggest that a single and repeated immobilization stress differentially affects such nociceptive processing induced by formalin, SP, glutamate and pro-inflammatory cytokines in different manners.
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PMID:Changes in pain behavior induced by formalin, substance P, glutamate and pro-inflammatory cytokines in immobilization-induced stress mouse model. 1711 57

The effort to explore the specific autoimmune mechanisms of urinary bladder has long been hindered due to a lack of proper animal models. To better elucidate this issue, we developed a novel line of transgenic (Tg) mice, designated as URO-OVA mice, that express the model Ag OVA as a "self"-Ag on the bladder epithelium. URO-OVA mice are naturally tolerant to OVA and show no response to OVA stimulation. Adoptive transfer of naive OVA-specific T cells showed cell proliferation, activation, and infiltration but no bladder histopathology. In contrast, adoptive transfer of activated OVA-specific T cells induced OVA-mediated histological bladder inflammation. Increased mast cells and up-regulated mRNA expressions of TNF-alpha, nerve growth factor, and substance P precursor were also observed in the inflamed bladder. To further facilitate bladder autoimmunity study, we crossbred URO-OVA mice with OVA-specific CD8(+) TCR Tg mice (OT-I mice) to generate a dual Tg line URO-OVA/OT-I mice. The latter mice naturally acquire clonal deletion for autoreactive OT-I CD8(+) T cells (partial deletion in the thymus and severe deletion in the periphery). Despite this clonal deletion, URO-OVA/OT-I mice spontaneously develop autoimmune cystitis at 10 wk of age. Further studies demonstrated that the inflamed bladder contained infiltrating OT-I CD8(+) T cells that had escaped clonal deletion and gained effector functions before developing histological bladder inflammation. Taken together, we demonstrate for the first time that the bladder epithelium actively presents self-Ag to the immune system and induces CD8(+) T cell tolerance, activation, and autoimmune response.
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PMID:Urinary bladder epithelium antigen induces CD8+ T cell tolerance, activation, and autoimmune response. 1718 94

In the present study, we examined nociceptive behaviors on various pain models after the pretreatment of kainic acid intracerebroventricularly. We found that intracerebroventricular administration of kainic acid shows significant neuronal damage on the hippocampal CA3 region in the brain slices stained with cresyl violet. Compared to the control group, intracerebroventricular pretreatment of kainic acid significantly attenuated nocifensive behaviors induced by intraplantar formalin (only in the 2nd phase), intrathecal glutamate, TNF-alpha or IL-1beta. However, nocifensive behaviors induced by intraperitoneal acetic acid (writhing test), intrathecal substance P or IFN-gamma were not affected by the pretreatment of kainic acid. These results suggest that (1) KA-induced alterations of nocifensive behaviors are related to the neuronal death of the hippocampal formation, especially CA3 pyramidal neurons and (2) nocifensive behaviors induced by formalin, acetic acid, SP, glutamate, and pro-inflammatory cytokines were modulated in a different manner.
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PMID:The intracerebroventricular kainic acid-induced damage affects animal nociceptive behavior. 1756 85

Transient potential vanilloid 1 (TRPV1) receptor is an ion channel receptor primarily localized on sensory nerves and activated by specific stimuli to initiate and amplify pain and inflammation, as typified by murine models of scald and arthritis. Little is known of the role of TRPV1 in sepsis, an infective disease associated with inflammation. Through use of a sublethal murine model of lipopolysaccharide-induced peritoneal sepsis, we provide novel evidence that genetic deletion of TRPV1 leads to an enhanced onset of various pathological components of systemic endotoxemia. Paired studies of TRPV1 knockout (KO) and wild-type mice demonstrate significantly enhanced hypotension (56+/-2% vs. 38+/-6% decrease in blood pressure, n=12), hypothermia (13+/-3% vs. 7+/-1% decrease in core temperature, n=6), and peritoneal exudate mediator levels (TNF-alpha, 0.78+/-0.2 vs. 0.38+/-0.1 ng/ml; nitrite, for NO, 35+/-10 vs. 15+/-3 microM; n=8) in TRPV1 KO mice, indicating loss of protective effect. Findings correlated with liver edema and raised plasma levels of aspartate aminotransferase in TRPV1 KO mice. These data suggest that TRPV1 may play an important regulatory role in sepsis independent of the major sensory neuropeptide substance P. The findings are relevant to developing strategies that increase the beneficial, and reduce the harmful, components of sepsis to prevent and treat this often fatal condition.
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PMID:The transient receptor potential vanilloid 1 (TRPV1) receptor protects against the onset of sepsis after endotoxin. 1760 84

The present study was designed to investigate further the mechanisms involved in the antinociception caused by diphenyl diselenide in behavioral model of pain in mice. Diphenyl diselenide (1-100 mg/kg), given orally, produced significant inhibition of the biting behavior induced by intrathecal (i.t.) injection of glutamate (175 nmol/site) and N-methyl-d-aspartate (NMDA; 450 pmol/site), with mean ID(50) values of 45.92 (39.74-60.4) and 55.77 (36.52-77.5) mg/kg respectively. However, diphenyl diselenide completely failed to affect the nociception induced by alpha-amino-3-hydroxy-5-mehtyl-4-isoxazolepropionic acid (AMPA; 135 pmol/site), (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD; 50 nmol/site) and kainate (110 pmol/site). This compound also reduced the nociceptive response induced by substance P (SP) (135 ng/site, i.t.), interleukin 1beta (IL-1beta; 1 pg/site), tumor necrosis factor-alpha (TNF-alpha; 0.1 pg/site), bradykinin (BK; 0.1 microg/site) and capsaicin (30 ng/site) with mean ID(50) values of 16.22, 7.06, 6.06, 4.18 and 7.90 mg/kg, respectively. Together, these results indicate that diphenyl diselenide produced antinociception at spinal sites, with a possible interaction with glutamatergic pathways, more specifically via interaction with NMDA receptors, peptidergic or vanilloid systems.
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PMID:Spinal mechanisms of antinociceptive action caused by diphenyl diselenide. 1761 8

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

Our previous studies have shown that norepinephrine (NE) upregulates proinflammatory cytokines by activating alpha(2)-adrenoceptor. Therefore, modulation of the sympathetic nervous system represents a novel treatment for sepsis. We have also shown that a novel stomach-derived peptide, ghrelin, is downregulated in sepsis and that its intravenous administration decreases proinflammatory cytokines and mitigates organ injury. However, it remains unknown whether ghrelin inhibits sympathetic activity through central ghrelin receptors [i.e., growth hormone secretagogue receptor 1a (GHSR-la)] in sepsis. To study this, sepsis was induced in male rats by cecal ligation and puncture (CLP). Ghrelin was administered through intravenous or intracerebroventricular injection 30 min before CLP. Our results showed that intravenous administration of ghrelin significantly reduced the elevated NE and TNF-alpha levels at 2 h after CLP. NE administration partially blocked the inhibitory effect of ghrelin on TNF-alpha in sepsis. GHSR-la inhibition by the administration of a GHSR-la antagonist, [d-Arg(1),d-Phe(5), d-Trp(7,9),Leu(11)]substance P, significantly increased both NE and TNF-alpha levels even in normal animals. Markedly elevated circulating levels of NE 2 h after CLP were also significantly decreased by intracerebroventricular administration of ghrelin. Ghrelin's inhibitory effect on NE release was completely blocked by intracerebroventricular injection of the GHSR-1a antagonist or a neuropeptide Y (NPY)/Y(1) receptor antagonist. However, ghrelin's downregulatory effect on TNF-alpha release was only partially diminished by these agents. Thus ghrelin has sympathoinhibitory properties that are mediated by central ghrelin receptors involving a NPY/Y1 receptor-dependent pathway. Ghrelin's inhibitory effect on TNF-alpha production in sepsis is partially because of its modulation of the overstimulated sympathetic nerve activation.
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PMID:Ghrelin inhibits sympathetic nervous activity in sepsis. 1791 50

Interstitial cystitis (IC) is a chronic inflammatory condition of the urinary bladder with a strong autoimmune component. Currently, the major challenge in IC treatment is the development of effective therapies. RDP58 is a novel d-amino acid decapeptide with potent immunosuppressive activity. In this study, we investigated whether RDP58 was effective as an intravesical agent for treating bladder autoimmune inflammation in a transgenic mouse model (URO-OVA mice). URO-OVA mice were adoptively transferred with syngeneic activated splenocytes of OT-I mice transgenic for the OVA-specific CD8(+) TCR for cystitis induction and treated intravesically with RDP58 at days 0 and 3. Compared with controls, the RDP58-treated bladders showed markedly reduced histopathology and expressions of mRNAs and proteins of TNF-alpha, NGF and substance P. To determine whether the inhibition of bladder inflammation by RDP58 was due to the interference with effector T cells, we treated the cells with RDP58 in vitro. Cells treated with RDP58 showed reduced production of TNF-alpha and IFN-gamma as well as apoptotic death. Collectively, these results indicate that RDP58 is effective for treating T cell-mediated experimental autoimmune cystitis and may serve as a useful intravesical agent for the treatment of autoimmune-associated bladder inflammation such as IC.
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PMID:RDP58 inhibits T cell-mediated bladder inflammation in an autoimmune cystitis model. 1816 70


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