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 readily expressed in skin inflammatory disorders such as psoriasis and contact dermatitis. Spantide II is a peptide (MW 1668.76) that specifically binds to neurokinin-1 receptor (NKR-1) and blocks inflammation associated with substance P. The anti-inflammatory property of Spantide II makes it a suitable candidate to be studied as a topical formulation for the treatment of dermal inflammatory disorders. The objective of this study was to investigate the influence of pH, temperature, salt concentration and concentration on the aqueous stability of Spantide II. The stability of Spantide II was also assessed by circular dichroic (CD) spectroscopy and mass spectrometry (MS). The influence of various dermatological vehicles (ethanol, Transcutol, propylene glycol, N-methyl-2-pyrrolidone (NMP), ethyl oleate, isopropyl myristate and laurogylcol FCC (LFCC)) on the stability of Spantide II was investigated. A precise high-performance liquid chromatography (HPLC) assay was developed for analysis of Spantide II. At higher temperature (40 degrees C) the stability of Spantide II decreased with increase in pH (P < 0.05). Change in salt concentration did not appreciably affect the stability of Spantide II (P > 0.05). The concentration of Spantide II in the solution had no significant influence on its stability (P > 0.05). CD spectroscopy studies showed that Spantide II has a relatively stable alpha-helix structure in the liquid state. The stability of Spantide II was affected by the type of vehicle used in the study (P < 0.01) at different temperatures (P < 0.05). Spantide II at high temperature undergoes lysine-proline diketopiperazine degradation as evident in MS data. Spantide II was relatively more stable in ethyl oleate-ethanol, ethanol-water, ethanol and N-methyl-2-pyrrolidone. The results of this study indicate that ethyl oleate-ethanol (1:1) and ethanol-water (1:1) could be used as potential vehicles in the development of topical formulations of Spantide II.
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PMID:Preformulation stability of Spantide II, a promising topical anti-inflammatory agent for the treatment of psoriasis and contact dermatitis. 1497 97

Psoriasis, a TH1-induced disorder, is not more common in human immunodeficiency virus (HIV) infection than in the general population. However, it may appear for the first time or pre-existing psoriasis may worsen and be difficult to treat in HIV disease. The paradoxical exacerbation of psoriasis in AIDS has not been fully explained. Various explanations have been proposed including (a) the reduction of Langerhans' cells (LCs) in HIV disease, (b) the direct epidermal proliferative effect of HIV, (c) the altered cytokine profile in HIV disease, (d) HIV-induced macrophage nitric oxide (NO) production, (e) the increased CD8/CD4 T-cell ratio in HIV infection and (f) the increased colonization of skin by Staphylococcus aureus. However, the observations that (a) LCs cells play an important role in the pathogenesis of psoriasis and a variety of topical and systemic psoriasis treatments cause a reversible decrease in LC function, (b) psoriasis may improve in end-stage HIV infection, (c) overproduction of some TH2 cytokines and underproduction of IL-2 in HIV infection, and (d) the presence of NO favors a TH2 response over a TH1 response make the first four explanations difficult to interpret. Since psoriasis is exacerbated in HIV infection possibly due to the increased staphylococcal colonization, and psoriatic keratinocytes could aggravate HIV infection through production of TNF-alpha, it could be reasoned that in HIV-positive psoriatics a strong vicious cycle is present between the degree of immune deficiency and the staphylococcal colonization, explaining the poor prognosis of both AIDS and psoriasis in these patients. With reference to the studies which indicate significant involvement of substance P (SP) in the pathogenesis of psoriasis and on the other hand increased release of this agent by HIV-infected immune cells it is proposed that SP plays an important role in creating the paradox. Since in HIV-positive psoriatics the source of SP is largely immune cells not neurons, capsaicin, which exerts its action selectively on a subpopulation of neurons, could not be of significant therapeutic value. As SP significantly enhances HIV-1 replication in latently infected immune cells, psoriatic lesions, being heavily infiltrated with immune cells and having high concentrations of SP, could serve as high HIV-replication foci, with the resultant rapid progression of the infection towards AIDS. Additionally, given that lipopolysaccharide is supposed to exacerbate psoriasis, increase of gram-negative infections or cutaneous colonization with these organisms in AIDS may partly explain the paradox. Understanding the HIV-induced immunodysregulation that is associated with psoriasis in some HIV-seropositive patients may assist in the delineation of the immunopathogenesis of the disease in HIV-seronegative psoriatics.
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PMID:Paradoxical exacerbation of psoriasis in AIDS: proposed explanations including the potential roles of substance P and gram-negative bacteria. 1511 14

Several inflammatory skin conditions, including atopic dermatitis (AD) and psoriasis, are exacerbated by stress. Recent evidence suggests that crosstalk between mast cells, neurons and keratinocytes might be involved in such exacerbation. Mast cells are distributed widely in the skin, are present in increased numbers in AD and are located in close proximity to substance P- or neurotensin-containing neurons. Corticotropin-releasing factor (CRF), its structurally related peptide urocortin (Ucn) and their receptors are also present in the skin and their levels are increased following stress. Human mast cells synthesize and secrete both CRF and Ucn in response to immunoglobulin E receptor (FcepsilonRI) crosslinking. Mast cells also express CRF receptors, activation of which leads to the selective release of cytokines and other pro-inflammatory mediators. Thus, we propose that CRF receptor antagonists could be used together with natural molecules, such as retinol and flavonoids, to inhibit mast cell activation and provide new therapeutic options for chronic inflammatory conditions exacerbated by stress.
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PMID:Mast cells as targets of corticotropin-releasing factor and related peptides. 1549 78

Zinc-metalloproteases, such as neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), effectively control the bioavailability of peptide mediators released from sensory nerves, immune and skin cells during the cutaneous response to endogenous or exogenous noxious stimuli. Functional inactivation of NEP or ACE by transient inhibition or permanent genomic deletion results in a relative abundance of substance P (SP) and bradykinin (BK); this augments murine allergic contact dermatitis (ACD) by affecting ACD sensitization and elicitation, which involves neurokinin 1 receptors (NK1), BK receptors (B2) and an intact cutaneous sensory nervous system. Present evidence suggests that increased SP via NK(1) is capable of boosting important functions of SP- and NK1-expressing dendritic cells (DCs) and T cells (TCs) in an auto- or paracrine manner, which promotes ACD antigen sensitization. Moreover, skin inflammation or wounding in vivo, as well as treatment of epidermal and dermal cells by UV light and inflammatory mediators in vitro, regulates NEP and ACE expression and activity. Likewise, NEP and ACE are capable of processing neuroendocrine hormones, such as adrenocorticotropin and alpha-melanocyte-stimulating hormone. Thus, present data indicate that ACE and NEP, via proteolytic cleavage of peptide mediators and growth factors, represent important control factors for the inflammatory response in skin disorders such as psoriasis or allergic inflammation, but may also be capable of affecting pigmentation, cell survival, wound healing and tissue regeneration.
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PMID:Neutral endopeptidase and angiotensin-converting enzyme -- key enzymes terminating the action of neuroendocrine mediators. 1550 8

Mast cells are implicated in stress-induced inflammatory skin diseases such as psoriasis. Mechanisms of stress-induced mast cell degranulation however, are not entirely clear. Here we explore the role of activation of a Substance P (SP) receptor (NK-1) on mast cell degranulation upon exposure to stress in rats. A specific nonpeptide NK-1 antagonist, CP99994 was used to treat the rats either peripherally or intracerebroventricularly. Because increased SP activity in the brain may mediate the stress response, we also examined cutaneous mast cell degranulation after central injection of SP. Stress, as well as SP injected centrally, increased mast cell degranulation. Both central and peripheral injection of CP99994 prevented stress-induced mast cell degranulation. Surprisingly, the combination of stress with SP decreased mast cell degranulation, suggesting that high levels of SP may counteract the stress responses. Results in this animal model suggest that NK-1 antagonists may be used therapeutically to treat stress-induced inflammatory skin diseases; however, drug doses should be chosen carefully.
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PMID:NK-1 antagonist CP99994 inhibits stress-induced mast cell degranulation in rats. 1555 Jan 45

Substance P and its receptor(R) neurokinin (NK)-1 may have a role in the pathogenesis of psoriasis. Stress has been reported to play a role in the onset and exacerbation of psoriasis, which might include the substance P-NK-1 receptor(R) pathway. A feature of psoriasis, that has been correlated to the severity of stress and secretion of substance P, is pruritus. The objective of this study was to investigate the expression of substance P and the NK-1R in involved and noninvolved psoriatic skin, using a biotinylated streptavidin technique. Moreover, a possible correlation between the patient s level of chronic stress, measured by salivary cortisol samples, degree of lesional pruritus, measured by means of a visual analogue scale, and the expression of substance P- and the NK-1R, was investigated. There was a low number of substance P positive nerve fibres in noninvolved and involved skin, the major immunoreactivity for substance P being found in inflammatory cells. The number of substance P- and NK-1R positive inflammatory cells was increased in involved compared to noninvolved psoriatic skin. The substance P positive cells were mostly lymphocytes, while most of the NK-1R positive cells were mast cells. NK-1R immunoreactivity was also seen as a reticular pattern in the upper part of the epidermis of involved skin in the majority of the patients. Low cortisol ratios in the patients, being an indicator of chronic stress, were correlated to an increased number of substance P- and NK-1R positive inflammatory cells in noninvolved psoriatic skin, and higher cortisol ratios to the presence of keratinocyte NK-1R immunoreactivity in involved skin. The degree of pruritus could not be correlated to the number of substance P positive fibers nor cells. Nonneuronal substance P and its receptor NK-1 might have a role in psoriasis, also during chronic stress.
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PMID:Study of substance P and its receptor neurokinin-1 in psoriasis and their relation to chronic stress and pruritus. 1737 82

The aim of this study was to evaluate the influence of selected neuropeptides on itching in psoriatic individuals. Fifty-nine patients (43 pruritic and 16 non-pruritic) with psoriasis were included in the study. The severity of psoriasis, measured using the Psoriasis Area and Severity Index scale, ranged between 2 and 43.7 points. The intensity of pruritus was evaluated using a Visual Analogue Scale. The plasma levels of substance P, vasoactive intestinal peptide, calcitonin gene-related peptide and neuropeptide Y were measured radioimmunologically. The plasma level of neuropeptide Y was significantly decreased in patients with pruritus compared with those without pruritus (21.6 +/- 39.6 pg/ml and 144.3 +/- 385.7 pg/ml, respectively; p=0.03). Levels of other neuropeptides did not differ significantly between pruritic and non-pruritic patients; however, a tendency to lower plasma levels of substance P and vasoactive intestinal peptide in patients with itching was noted. Moreover, a significant negative correlation was observed between pruritus severity and levels of substance P (r = -0.36; p=0.02), as well as between pruritus severity and plasma levels of vasoactive intestinal peptide (r = -0.34; p=0.03). The imbalance of neuropeptide activity in the sera of pruritic subjects may suggest a role for neuropeptides in perception of itching in psoriatic individuals.
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PMID:Plasma neuropeptides and perception of pruritus in psoriasis. 1759 31

Perceived stress has long been allied with disturbances of the dynamic equilibrium established between the nervous, endocrine and immune systems, thus triggering or aggravating disease manifestation. Several common skin diseases are now acknowledged to be worsened by psychological stress, particularly immunodermatoses such as atopic dermatitis, psoriasis, seborrheic eczema, prurigo nodularis, lichen planus, chronic urticaria, alopecia areata and pruritus sine materia. Itch (pruritus) is perhaps the most common symptom associated with a majority of these inflammatory skin diseases, and acute as well as chronic stress perceptions are recognized to trigger or enhance pruritus. A wealth of mediators released systemically or locally in the skin in response to stress increase sensory innervation, upregulate the production of other pruritogenic agents, perpetuate (neurogenic) inflammation and lower the itch threshold. In the present review, we explore recent frontiers in both stress and pruritus research and portray the perpetuation of chronic skin inflammation and itch as a neuroendocrine-immune 'misalliance'. We argue that key candidate molecules of the stress response with strong pruritogenic potential, such as nerve growth factor, corticotropin-releasing hormone and substance P, and mast cells, which may be considered as 'central cellular switchboards of pruritogenic inflammation', need to be further explored systematically in order to develop more effective therapeutic combination strategies for itch management in chronic, stress-vulnerable inflammatory skin diseases.
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PMID:From the brain-skin connection: the neuroendocrine-immune misalliance of stress and itch. 1770 57

Psychiatric co-morbidity is very frequently associated with psoriasis. Depression is observed in numerous patients with psoriasis. Early detection and treatment are very important. There is a vicious circle psoriasis- alteration of quality of life- depression, but psoriasis improvement is not always followed by an improvement of depression. A contrario, it is obvious that a depressive patient has a bad observance of treatment. Links between psoriasis and depression are not only psychopathological. Biological factors, such as increase of blood amounts of substance P and TNF or decrease of serotonine could also explain this association.
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PMID:[Depression and psoriasis]. 1846 93

Psoriasis, a chronic inflammatory skin disease, is believed to be exacerbated by stress. The exact mechanism of this phenomenon is not fully understood, however, it has been postulated that different substances released from dermal nerve endings during stress may take part in initiation or modulation of psoriasis. One of the most interesting group of mediators are polypeptides, also named as neuropeptides, that possess vasoactive properties. It was documented that these polypeptides could not only be released from nerve endings, but may also be directly synthesised in the skin and liberated from numerous dermal cells. Moreover, these substances are not only released by different cells, but may activate various cell types showing a wide spectrum of biological actions. Thus, this complex system of interactions seems to be important component of psoriatic pathological reaction. The significant role of these neuromediators has also been postulated in other chronic skin diseases, like palmoplantar pustulosis, atopic and irritant eczema, rosacea, lichen sclerosus, vitiligo, pigmented urticaria or prurigo nodularis. Among different neuropeptides, substance P, calcitonin gene-related peptide, vasoactive intestinal peptide (VIP) and neuropeptide Y have been mostly studied in psoriasis.
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PMID:Vasoactive peptides in the pathogenesis of psoriasis. 1883 70


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