Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over the years, many encouraging uncontrolled studies extolling treatments of SSc have appeared, but initial impressions were not corroborated when controlled trials were done. This article points out that certain recent studies have effectively ruled out the use of some specific therapies for the general treatment of systemic sclerosis. Thus, sufficient data has been generated to rule out the use of n-acetylcysteine, colchicine, chlorambucil, cyclofenil, and DMSO, at least in disease of longer duration. Ketanserin and prostaglandin infusions probably also belong in this group, as they affect only Raynaud's phenomenon. Angiotensin enzyme inhibitors, while probably life-saving in renal crises, do not seem to affect the underlying systemic sclerosis per se. Another group of drugs has only limited supportive data and await well-controlled trials to prove or disprove their effectiveness. These include: 5-fluorouracil, D-penicillamine, drugs affecting platelet function (dipyridamole), and para-aminobenzoic acid. There are a few treatments which have potential. Factor XIII has only limited data using controlled trials, but what does exist seems positive. Apheresis is encouraging, although the success of this treatment modality may be dependent upon a "combination" approach. Ongoing studies with gamma-interferon, photopheresis, and the mast cell stabilizer ketotifen appear exciting, and we await reports of their use in scleroderma. On another level, new insights into genomic alterations in skin fibroblasts and T-cell proto-oncogene expression have contributed to the understanding of the pathogenesis of this disease at the cellular level and new methods to measure change in disease will help gauge response to therapy. Thus, we look forward to more definitive treatment of SSc in the future.
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PMID:Treatment of generalized systemic sclerosis. 240 9

Rat mast cell granules were obtained by homogenization of highly purified rat mast cells and isolated in a Percoll gradient. DPI synthesis in rat mast cell granules was assayed by measuring the incorporation of 32P from [gamma 32P] ATP into DPI in the absence of exogenous phosphatidylinositol (PI). Lipids were isolated with methanol/chloroform/HC1 and were separated by thin-layer chromatography on oxalic acid impregnated silica gel plates. DPI areas were identified by staining with iodine, scraped and measured for 32P radioactivity. The addition of PMA to the granules caused an increase of DPI synthesis, which can be catalysed by PI kinase. Neither an inactive phorbol ester, 4-alpha-phorbol-12, 13-didecanoate, nor dimethyl sulfoxide (DMSO) used as a solvent for PMA had any effect. The effect of PMA in the DPI synthesis was dose-dependent and maximal effects were observed at 10-100 ng/ml. Dose-response curves of the effects of PMA in DPI synthesis in the granules corresponded to those of other biochemical effects of PMA in rat mast cells, such as mediator release mediated through the activation of protein kinase C. These results suggest that PMA may directly affect PI kinase or indirectly regulate its activity in rat mast cell granules.
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PMID:[Effect of phorbol myristate acetate (PMA) on diphosphoinositide (DPI) synthesis in rat mast cell granules]. 254 22

Interstitial cystitis, first described one hundred years ago, is difficult to classify in urological pathology. It essentially affects middle-aged women. Two main theories are currently proposed to explain its pathogenesis: the permeable epithelium theory and the mast cell theory. However, other factors are also involved: vascular, neurological, infectious and immune. This disease has a chronic course with no transformation of the nonulcerative form into the ulcerative form. There are no specific histological criteria, even the presence of mast cells in the bladder wall. However, histology is able to exclude other bladder disease, principally carcinoma in situ. The diagnosis is therefore based on clinical examination and endoscopy, after excluding other diseases. The essential complementary investigations are cystoscopy and cystomanometry which must be performed according to rigorous protocols. Conservative treatment is based on vesical hydrodistension, bladder retraining, bladder instillations (DMSO) and systemic treatments (sodium pentosanpolysulfate). Surgery is required in 1 to 5% of cases due to failure of medical treatment and the severity of the symptoms. Electrical or laser coagulation of the ulcers is effective. Partial cystectomy with cystoplasty is reserved for forms sparing the trigone, while cystourethrectomy and urinary diversion may be indicated in other more advanced and refractory cases.
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PMID:[Interstitial cystitis]. 771 56

The cell line HMC-1, derived from a patient with mast cell leukaemia, is the only established cell line exhibiting a phenotype similar to that of human mast cells. This paper reports on a detailed characterization of the expression of a panel of markers for various types of immature and mature haematopoietic cells in the HMC-1. We also studied the potential of HMC-1 to differentiate upon treatment with conditioned media from the human T-cell line Mo, retinoic acid or DMSO. HMC-1 was found to express several mast cell-related markers. A high expression of Kit, the receptor for stem-cell factor, was detected. The majority of the cells were stained with a MoAb against the mast cell-specific serine protease tryptase. Of particular interest was the finding that beta-tryptase mRNA, but not alpha-tryptase mRNA, was expressed in HMC-1. Using enzyme-histochemistry we were able to show that the beta-tryptase was enzymatically active, indicating that tryptase can form active homotetramers. Both heparin and chondroitin sulfate were found to be present in approximately equal amounts. HMC-1 lacked surface expression of the high-affinity IgE receptor, which was confirmed by the absence of mRNA of the alpha- and beta-chains of the IgE-receptor complex. However, a strong expression of the gamma-chain of the IgE-receptor complex was detected. A positive staining of the monocyte/macrophage marker CD68 was obtained, as well as a strong hybridization signal for the eosinophilic/basophilic-related differentiation marker the Charcot-Leyden crystal. Treatment of HMC-1 with conditioned media from the human T-cell line Mo, retinoic acid or DMSO induced only moderate changes in the surface or intracellular expression of the studied markers. The agents tested neither induced any of the monocyte/granulocyte markers examined, nor expression of the Fc epsilon RI alpha-chain.
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PMID:Phenotypic characterization of the human mast-cell line HMC-1. 819 Dec 24

Our previous studies have shown that heparin, a competitive inhibitor of inositol triphosphate receptors, inhibits airway anaphylaxis in vivo. In the present study, we tested the hypothesis that heparin blocks immunologically induced tracheal smooth muscle (TSM) contraction in vitro. TSM was obtained from sheep allergic to Ascaris suum antigen, and was suspended in an organ bath containing oxygenated (95% O2, 5% CO2) Krebs-Henseleit buffer at 39 degrees C. After an equilibration period, the tissues were treated with heparin dissolved in 10 microliters DMSO, at concentrations of 1, 10, or 100 U/ml (final concentration in the bath). Two types of controls were used: vehicle (10 microliters DMSO)-treated tissues and tissues treated with the anti-asthmatic nedocromil sodium (10(-5) M). After 30 min pretreatment, tissues were challenged with 10, 30 and 100 microliters of antigen. Contractions induced by antigen were expressed as percentage of the contraction elicited by the maximum effective concentration of acetylcholine (ACh, 10(-2) M). Antigen produced dose-dependent increases in tension, which were blocked by heparin and nedocromil sodium; maximal inhibition was 43 and 52%, respectively. Neither heparin nor nedocromil sodium affected the dose-response curve or the maximum response to Ach. The addition of the heparin preservative (benzyl alcohol) did not reverse ACh-induced contractions, or inhibit antigen-induced contractile responses. These results suggest that heparin blocks immunologically induced TSM contraction, without affecting the contractile response to the airway smooth muscle agonist, ACh. This action of heparin is similar to that of the anti-asthmatic nedocromil sodium and may be related to inhibition of mast cell mediator release.
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PMID:Protective effect of heparin on immunologically induced tracheal smooth muscle contraction in vitro. 864 83

LAMA-84, a human leucocytic cell line, which upon establishment was described as having megakaryocytic, erythroid and granulocytic characteristics, was analysed for expression of various differentiation markers. In addition to some of the previously described phenotypic characteristics, this cell line was found to express mRNA for several proteins characteristic for basophilic leucocytes and mast cells. The authors show that LAMA-84 cells express mRNA for the mast cell tryptase, the proteoglycan core protein, carboxypeptidase A and the alpha and beta chains of the high affinity IgE receptor (Fc epsilon RI). The authors examined the potential of LAMA-84 to differentiate in serum-free medium or after DMSO or PMA treatment. Depending on the inducing factor, surface expression of the Fc epsilon RI alpha-chain was increased from 20% to 35-50% of the cells and mRNA levels for tryptase were increased in serum-free medium and after DMSO treatment. LAMA-84 was found to express CD13, CDw17, CD29, CD33, CD40, CD45 and CD117. Furthermore, mRNA for the eosinophil/basophil markers Charcot-Leyden crystal (CLC) protein and the major basic protein (MBP), as well as the erythrocyte differentiation marker alpha-globin, was detected. However, the authors observed only trace amounts of mRNA for another erythroid differentiation marker (glycophorin), trace amounts of the megakaryocytic marker GPIIIa, and no detectable level of GPIb alpha. By comparing the expression pattern of a panel of differentiation markers in LAMA-84, and a second human cell line (KU812) expressing a basophil phenotype, it is evident that these cell lines, which presently are the only two cell lines identified with basophilic characteristics, share a large number of phenotypic characteristics.
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PMID:Characterization of a human basophil-like cell line (LAMA-84). 869 92

Previous studies have shown that acute, oral administration of malathion increased the generation of a humoral immune response, stimulated macrophage function and caused mast cell degranulation and histamine release. In this study, the effect of acute administration of various doses of malathion via oral and dermal routes to mice and rats on serum levels of histamine was evaluated. Oral administration of malathion to mice led to an increase in the level of serum histamine 4 and 8 h after administration. At 4 h after administration, the peak in serum histamine levels was observed at a dose of 10 mg/kg malathion. At 8 h, a maximal effect was observed at a dose of 700 mg/kg and the response was more prolonged than at lower doses. At 12 and 24 h after administration, the level of histamine in the serum of treated mice was comparable to controls. A similar pattern was observed in rats. However, the time point at which histamine levels returned to control was 8 rather than 12 h. After application of malathion to the skin of mice or rats in dimethyl sulphoxide (DMSO), the level of histamine in the blood was also increased. As before, the peak increase was observed at 4 h after administration and the level had returned to control levels within 8 h (slight increase at 8 h in rats) after application. However, after dermal application the maximal levels of histamine in the serum were noted at the highest doses of malathion. The no effect levels for histamine in the blood after malathion administration to these two species by these two routes are as follows: (1) Mice, oral in corn oil, 0.1 mg/kg; (2) Rats, oral in corn oil, 0.1 mg/kg; (3) Mice, dermal in DMSO, 2 mg/kg; (4) Rats, dermal in DMSO--not determined (2 mg/kg low effect level).
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PMID:Effect of acute administration of malathion by oral and dermal routes on serum histamine levels. 956 49

Chronic gut inflammation is associated with radical oxygen species (ROS) genesis. ROS may activate certain transcription factors such as nuclear factor kappa beta (NF-kappaB), which regulates cyclooxygenase-2 (COX-2). Diquat, a food contaminant, is responsible for oxidative stress. This work aimed to establish the involvement of ROS and prostanoids on diquat-induced gastrointestinal inflammation and mast cell hyperplasia. Diquat increased gastrointestinal MPO activity and mast cell number. Its effect on gastric MPO activity was reversed by PD 138,387 (a COX-2 selective inhibitor) and PDTC (an inhibitor of NF-kappaB activation) but not by DMSO (a hydroxyl radical scavenger) and allopurinol (a xanthine oxidase inhibitor). In contrast, increased jejunal MPO activity was blocked by both DMSO, PD 138,387, and PDTC, while allopurinol enhanced it. PD 138,387 and PDTC reduced gastrointestinal mast cell number while DMSO and allopurinol did not Diquat-induced inflammation involves a gastrointestinal NF-kappaB activation and COX-2 dependent proinflammatory prostanoid synthesis. Furthermore, the hydroxyl radical is involved in intestinal but not gastric inflammation.
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PMID:Pathways involved in mild gastrointestinal inflammation induced by a low level exposure to a food contaminant. 1206 6

Infection with Salmonella typhimurium can produce multiple organ dysfunctions. However, document concerning with gastric hemorrhagic ulcers occur in this infectious disease is lacking. The aim was to study modulation of gastric hemorrhagic ulcer by oxidative stress and mast cell histamine in S. typhimurium-infected rats. Additionally, the protective effects of drugs, such as ofloxacin, lysozyme chloride, ketotifen, ranitidine, and several antioxidants, including exogenous glutathione (GSH), allopurinol and dimethylsulfoxide (DMSO) were evaluated. Male Wistar rats were injected intrajejunally with a live culture of S. typhimurium (1 x 10(10) colony-forming units/rat) and followed by deprivation of food for 36 h. Age-matched control rats received sterilized vehicle only. Rat stomachs were irrigated for 3 h with either normal saline or a simulated gastric juice containing 100 mM HCl, 17.4 mM pepsin and 54 mM NaCl. S. typhimurium caused aggravation of offensive factors, including enhancing gastric acid back-diffusion, mucosal lipid peroxide generation, histamine release, microvascular permeability and hemorrhagic ulcer, as well as an attenuation of defensive substances, such as mucosal GSH and mucus level. Intragastric irrigation of gastric juice caused further aggravation of these gastric biochemical parameters. This exacerbation of ulcerogenic factors was abolished by pretreatment of ofloxacin and lysozyme chloride. Antioxidants, such as reduced GSH, allopurinol and DMSO also produced significant (P < 0.05) amelioration of gastric damage in S. typhimurium infected rats. In conclusion, gastric oxidative stress and histamine play pivotal roles in the formation of hemorrhagic ulcers that were effectively ameliorated by ofloxacin, lysozyme chloride, ketotifen, ranitidine, diamine oxidase and various antioxidants in S. typhimurium-infected rats.
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PMID:Modulation of gastric hemorrhage and ulceration by oxidative stress and histamine release in Salmonella typhimurium-infected rats. 1625 43

Dimethylsulfoxide (DMSO), a universal solvent, is frequently used to dissolve various classes of chemicals for the evaluation of their biological activities. In one such evaluation, we noticed that DMSO itself caused cellular proliferation and interfered with high affinity IgE receptor (FcepsilonRI)-mediated degranulation of mast cells. DMSO caused cellular proliferation of RBL-2H3 cells by phosphorylating both extracellular-signal regulated kinase (ERK) and M2-type pyruvate kinase (M2PK) through which the enzymatic activity of M2PK was reduced. Allergenic activation of FcepsilonRI caused the tyrosine phosphorylations of signaling components of FcepsilonRI, such as Syk, PLCgamma1, PLCgamma2, ERK, and M2PK. In these allergenic activated RBL-2H3 cells, DMSO specifically inhibited FcepsilonRI-mediated tyrosine phosphorylation of M2PK, blocked FcepsilonRI-mediated inhibition of the enzymatic activity of M2PK, and then inhibited FcepsilonRI-mediated degranulation. These results suggest that DMSO causes cellular proliferation and mast cell degranulation through differential modulation of M2PK in resting and allergenic activated cells.
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PMID:Distinct effects on M2-type pyruvate kinase are involved in the dimethylsulfoxide-induced modulation of cellular proliferation and degranulation of mast cells. 2009 Dec 79


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