Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The alpha 2-adrenoceptor selective agonist, [3H]guanabenz ([ 3H]GBZ), labels a unique population of binding sites in whole kidney which are not labeled by [3H]p-aminoclonidine ([3H]PAC). These binding sites are saturable and of high affinity (Kd = 10-12 nM). [3H]GBZ was not displaced from these sites by other alpha 1- or alpha 2-ligands, suggesting that they are non-adrenergic. This hypothesis is further supported by the insensitivity of renal guanabenz binding to regulation by guanyl nucleotides or to destruction by trypsin. Also, there appears to be no effect of guanabenz on the potency of isoproterenol in competing for beta-adrenoceptors in the kidney, which has been previously reported to be sensitive to clonidine. The absence of any effect of guanabenz on isoproterenol displacement of [3H]dihydroalprenolol in kidney suggests there are subtle differences in activation of alpha-receptors by clonidine and guanabenz in the kidney. In the brain, [3H]GBZ labels two binding sites. Part of the binding of [3H]GBZ in the brain is to sites essentially identical to the alpha 2-adrenoceptors labeled by [3H]PAC. The remainder of the binding resembles the non-adrenergic binding in kidney. The relationship of this unique binding site to the pharmacologic actions of guanabenz is currently not known.
 ...
PMID:Differential interaction of guanabenz with receptor binding sites in rat brain and kidney. 255 39

Tryptase, a mast cell serine protease, has been implicated in the pathophysiology of allergic asthma, but formal evidence to support this hypothesis has been limited by the lack of specific inhibitors for use in vivo. Therefore, in this study we examined the effects of two inhibitors of tryptase, APC 366 [N-(1-hydroxy-2-naphthoyl)-L-arginyl-L-prolinamide hydrochloride] and BABIM [bis(5-amidino-2-benzimidazolyl)methane] on antigen-induced early and late responses, airway responsiveness as measured by carbachol provocation, microvascular permeability as measured by bronchoalveolar lavage (BAL) albumin concentrations, and tissue eosinophilia from biopsies in allergic sheep. APC 366 and BABIM were administered by aerosol in all experiments. In vehicle control trials, antigen challenge resulted in peak early and late increases in specific lung resistance (SRL) of (mean +/- SE, n = 6) 259 +/- 30% and 183 +/- 27% over baseline, respectively. Treatment with APC 366 (9 mg/3 ml H2O given 0.5 h before, 4 h after, and 24 h after antigen challenge) slightly reduced the peak early response (194 +/- 41%), but significantly inhibited the late response (38 +/- 6%, p < 0.05 versus control trials). Twenty-four hours after challenge, APC 366 also completely blocked the antigen-induced airway hyperresponsiveness to inhaled carbachol observed in the control trial.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Tryptase inhibitors block allergen-induced airway and inflammatory responses in allergic sheep. 852 Jul 78

Tryptase (EC 3.4.21.59), the major secretory product of human mast cells, has become widely used as a biochemical marker for mast cells and mast cell activation, and is attracting attention as a mediator of allergic disease. However, there is little information available on the properties, or even the presence, of this protease in commonly used species of laboratory animals. We, here, report the demonstration and characterisation of this enzyme in the guinea pig lung. Tryptic activity resistant to alpha 1-proteinase inhibitor and soybean trypsin inhibitor was detected in sections of guinea pig lung tissue with the histochemical substrate Z-Gly-Pro-Arg-MNA. It was localised to mast cells and appeared to be present in all mast cells staining with Alcian Blue. A tryptic protease was purified 2400-fold from whole lung tissue by high salt extraction, cetylpyridinium chloride precipitation, heparin agarose chromatography, and gel filtration. This enzyme was found to be multimeric with a subunit of 38 kDa and a native molecular mass of 860 +/- 100 kDa. Inhibitor studies identified it as a serine protease. Like human tryptase, it was inhibited by leupeptin, benzamidine, and APC 366 (N-(1-hydroxy-2- naphthoyl)-L-arginyl(-L-prolinamide hydrochloride), but not by alpha 1-proteinase inhibitor, soybean trypsin inhibitor, or antithrombin III. Its response to changes in pH and ionic strength was similar to that of human tryptase. Differences between the guinea pig and human enzymes were seen in activity toward a panel fo 10 tryptic p_nitroanilide peptide substrates. Kinetic constants were determined for two of these: with L-Pyr-Pro-Arg-pNA the guinea pig tryptase had a similar Km but a 5-fold lower kcat than human tryptase, and with L-Pyr-Gly-Arg-pNA the guinea pig enzyme had a 10-fold lower Km and a 30% greater kcat than human counterpart. Heparin stabilised guinea pig tryptase, but did not alter its kinetic parameters as it did with human tryptase, decreasing the Km towards both substrates. The presence of a protease with similarities to human tryptase in the mast cells of guinea pigs suggests that this species may be an appropriate model to investigate the actions to tryptase in vivo, provided cognizance is taken of the differences that do exist.
 ...
PMID:Guinea pig lung tryptase. Localisation to mast cells and characterisation of the partially purified enzyme. 869 58

The importance of the P2 residue in determining serpin specificity was examined by making a series of substitutions in the P2 position of recombinant alpha 1-antichymotrypsin that contained an arginine P1 residue. The importance of the P2 residue in governing the association rate constant (Kon) of the serpin varied with the protease examined. For trypsin, the P2 residue played a relatively minor role, whereas the nature of this residue markedly influenced the rates of inhibition of thrombin, factor Xa, and APC. A 1000-fold difference in Kon values was observed between the fastest (P2 proline) and the slowest (P2 threonine) inhibitors of thrombin. Similar differences were observed with factor Xa; the best inhibitor (P2 glycine) displayed a 200-fold higher Kon value than the poorest (P2 threonine). The nature of the P2 residue also affected whether the interaction of the serpin with the protease resulted in inhibition of the protease or cleavage of the serpin; a P2 proline residue increased the rate of cleavage of alpha 1-antichymotrypsin by trypsin. By using mutants of thrombin, it was possible to show that the B-insertion loop, which partially occludes the active site, is important in determining the P2 specificity of this enzyme. Deletion of three amino acids from this loop yielded a protease (des-PPW) that became more like trypsin in its specificity. In addition, it was shown that Glu192 dramatically restricts thrombin's ability to accommodate a threonine in the P2 position. Taken together, the results demonstrated the importance of complementary interactions between the P2 residue of the serpin and the S2 binding site of the protease in regulating the specific interaction between serpin and protease.
 ...
PMID:Role of the P2 residue in determining the specificity of serpins. 878 2

Allergen-induced bronchoconstriction involves mast cell activation. Tryptase is a mast cell serine protease that is released during this process, but little is known about the action of tryptase in the airway. The purpose of this study was to determine: (1) if aerosolized tryptase causes bronchoconstriction, and (2) the mechanism by which this occurs. We measured mean pulmonary flow resistance (RL) in five allergic sheep before and after consecutive inhalations of 100 and 500 ng tryptase (in 2 ml total volume). Inhaled tryptase at 100 and 500 ng increased RL (mean +/- SE) by 33 +/- 12 and 122 +/- 8% (p < 0.05) over baseline. The response was reproducible upon repeat challenges. These studies were repeated in the same animals after pretreatment with aerosolized APC 366 (9 mg/3 ml), a specific tryptase inhibitor. In APC-366-treated sheep, tryptase increased RL by 10 +/- 3 and 6 +/- 2% (p < 0.05 versus control values) at 100 and 500 ng, respectively. The response to tryptase was also blocked by pretreating the sheep intravenously with the histamine H1-antagonist chlorpheniramine (2 mg/kg), in which RL increased only 5 +/- 4 and 7 +/- 6% after 100 and 500 ng tryptase. APC 366, however, did not block histamine-induced bronchoconstriction. Consistent with these findings was the observation that segmental bronchial challenge with tryptase (1 microgram) resulted in a significant increase in histamine levels in bronchoalveolar lavage. Inhaled tryptase (500 ng) also caused airway hyperresponsiveness to aerosolized carbachol 2 h after tryptase challenge. This tryptase-induced airway hyperresponsiveness could be blocked either by pretreating the sheep with APC 366 (30 min before challenge) or by treating the sheep 30 min after challenge. These results indicate that inhaled tryptase causes bronchoconstriction and airway hyperresponsiveness in allergic sheep by an event that may involve mast cell activation.
 ...
PMID:Inhaled tryptase causes bronchoconstriction in sheep via histamine release. 881 Jun

In this study, we used a specific tryptase inhibitor, APC-366 [N-(1-hydroxy-2-napthoyl)-L-arginyl-L- prolinamide hydrochloride] to investigate the effect of intradermally administered tryptase and tryptase released by antigen challenge on the immediate cutaneous reaction (ICR) in allergic sheep. The surface areas of cutaneous wheals produced by intradermal injections (0.05 ml) of 1 and 10 ng tryptase alone, tryptase combined with 3 U heparin (tryptase-heparin), or Ascaris suum antigen (10(-5) dilution) with or without pretreatment with APC-366 (1 mg/ml) were measured at 20 and 60 min after challenge. Intradermal injections of 1 and 10 ng tryptase alone (n = 7) produced an ICR of < or = 20% of that obtained after injection of histamine (5% wt/vol). Intradermal injection of tryptase-heparin (n = 7), however, resulted in 50 (1 ng) and 82% (10 ng) of the ICR to histamine (both, P < 0.05 vs. tryptase alone). APC-366 inhibited (P < 0.05) the ICR to 1 and 10 ng tryptase-heparin by > or = 70% at all times (n = 8) but had no effect on the histamine-induced ICR (n = 3). A combination of the histamine H1 antagonist chlorpheniramine (2 mg/kg iv) and the H2 antagonist metiamide (3 mg/kg iv) given 40 min before challenge (n = 8) inhibited the response to 1 and 10 ng tryptase-heparin by 42 and 62% at 20 min and by 96 and 86% at 60 min, respectively (all, P < 0.05). APC-366 also blocked the ICR to A. suum antigen by 68% (P < 0.05) in nine sheep. These results indicate that intradermal injection of tryptase-heparin can induce an ICR. This ICR can be inhibited by APC-366 or a combination of the histamine H1 and H2 antagonists, suggesting that the tryptase response is mediated by histamine. APC-366 also blocks the mast cell-mediated ICR to intradermally injected A. suum antigen. Collectively, these results suggest that tryptase may modulate mast cell histamine release.
 ...
PMID:Role of tryptase in immediate cutaneous responses in allergic sheep. 884 61

In atopic dermatitis (AD) patients, IgE molecules are demonstrated on the surface of Langerhans cells (LC). Fc epsilon RI molecules, which are present on the surface of LC in AD patients as well as normal individuals, are responsible for this binding. In this study, we have investigated phenotypic and functional characteristics of Fc epsilon RI on epidermal and dermal cell populations. Epidermal and dermal cell suspensions were prepared enzymatically with dispase followed by either trypsin or collagenase treatment, respectively. Peripheral blood basophils were negatively selected by excluding other leukocytes with surface marker staining. Consistent with previous reports, both peripheral blood basophils and epidermal LC were positively stained with anti Fc epsilon RI monoclonal antibody. In addition, an Fc epsilon RI positive population was demonstrated among dermal HLA-DR positive cells. These cells express significant amounts of HLA-DR molecules (DRHi) and co-express CD 1 a molecules, which identifies them as LC-like dendritic APC of the dermis. No other Fc epsilon RI positive population was found in the other dermal DRMid or DR- populations, except for a minor DRLo population, presumably mast cells. To analyze whether these Fc epsilon RI molecules are signal transducing for LC, intracellular calcium mobilization after crosslinking of Fc epsilon RI was measured with flow cytometry. Following crosslinking, peripheral blood basophils clearly increased intracellular calcium. On the other hand, neither normal epidermal LC nor dermal DRHiCD1a + cells changed their intracellular calcium level after Fc epsilon RI crosslinking. These data indicate that normal epidermal and dermal LC, but not basophils, are resistant to calcium flux following Fc epsilon RI engagement.
 ...
PMID:Expression, but lack of calcium mobilization by high-affinity IgE Fc epsilon receptor I on human epidermal and dermal Langerhans cells. 898 Oct 26

Recent studies in several laboratories have advanced the concept that during cellular rejection, the allograft undergoes a stress response which regulates the expression of stress proteins (or heat shock proteins, hsp) and triggers the recruitment and activation of hsp-reactive lymphocytes. In a rat model of heterotopic heart transplants we have found that allograft-infiltrating lymphocytes respond to recombinant mycobacterial hsp and irradiated syngeneic spleen cells as a source of self-APC (antigen-presenting cells). This report describes T cell clones generated by culturing ACI into Lewis rat cardiac allograft-derived lymphocytes with mycobacterial hsp71, syngeneic spleen cells and IL-2 (interleukin-2). Two groups of self-APC-reactive T cell clones have been distinguished, all of them are CD3+, CD4+, CD8-. One group is referred to as hsp71-dependent, autoreactive T cells because these clones respond to self-APC but only in the presence of hsp71. No reactivity is seen with mycobacterial hsp65 or when hsp71 is tested with allo-PC from ACI donors or third-party APC from Brown Norway (BN) rats. Treatment of hsp71 with trypsin, polymyxin B or ATP-agarose chromatography abrogates the hsp71 effect thus indicating that structurally intact hsp71 must interact with self-APC which then activate hsp71-dependent, autoreactive T cells. The second group of clones reacts to self-APC and while their response does not require the presence of hsp71, their proliferation is often augmented by hsp71 but not by hsp65. These hsp71-independent, autoreactive clones do not respond to allo-APC from ACI donors or third-party APC from BN rats. Polymyxin or trypsin treatment had no significant effect on their proliferative responses. The data with the anti-TCR-alpha beta monoclonal antibody R73 offer additional evidence for two functionally different types of self-APC reactive CD4 cells infiltrating the allograft. R73 inhibits the proliferation of self-APC induced responses of hsp-71-independent clones as well as the allo-APC induced responses of alloreactive T cell clones. In contrast, this antibody augments the responses of hsp71-dependent T cells. Moreover, these clones can also proliferate in response to self-APC when hsp71 is substituted by R73. The hsp71-dependency of self-APC reactive T cell reactivity represents a previously unrecognized mechanism of cellular immunity to allografts. This mechanism might be related to the peptide binding properties of hsp71 and the ability of stress proteins to function as molecular chaperones in antigen processing.
 ...
PMID:Identification of two types of autoreactive T lymphocyte clones cultured from cardiac allograft-infiltrating cells incubated with recombinant mycobacterial heat shock protein 71. 910 36

Hepatitis delta virus is a human pathogen that is responsible for a severe form of hepatitis affecting hepatitis B envelope Ag carriers. We have previously identified a series of hepatitis delta Ag (HDAg) epitopes that are recognized by CD4+ T cell clones isolated from infected subjects. Herein, we show that the presentation of soluble HDAg to CD4+ T cell clones that are specific for the HDAg(106-121) epitope was exceptionally unaffected by the inhibition of the APC-processing machinery when APCs were fixed with glutaraldehyde before Ag pulsing or treated with chloroquine or brefeldin A. Interestingly, 5 h of pulsing was strictly required for the efficient presentation of the HDAg(106-21) epitope by fixed APCs, suggesting that some form of extracellular processing had occurred. Indeed, fixed APCs were able to present HDAg after only 1 h of pulsing when HDAg was preincubated with serum for 5 h. More important, presentation was completely abrogated when Ag was previously incubated in medium containing serum in the presence of a potent inhibitor of trypsin activity such as the secretory leukoprotease inhibitor. These results show that HDAg may undergo extracellular processing and suggest that the generation of immunogenic epitopes directly by serum proteases could play a role in the immune response against hepatitis delta virus during infection.
 ...
PMID:Generation of an MHC class II-restricted T cell epitope by extracellular processing of hepatitis delta antigen. 960 22

The normal epithelial cell-specific 1 (NES1) gene is a recently identified novel serine protease-like gene which is down-regulated during breast cancer progression. The gene product has 34-42% identity with the members of three distinct serine protease families: the trypsin-like family, activators of kringle domain-containing growth factors, and the kallikrein family (X. L. Liu et al., (1996) Cancer Res 56, 3371-3379). Although the cDNA of this gene has been cloned, its genomic structure and chromosomal position are not as yet known. Here, we report the genomic characterization and mapping of the NES1 gene. By subcloning and sequencing a PAC clone containing the complete NES1 gene, we were able to characterize the structure of this gene. The NES1 gene spans 5.5 kb and is composed of five coding exons and one untranslated exon. The positions of the introns were similar to trypsinogen, prostate specific antigen (PSA), and tissue plasminogen activator (TPA). NES1 gene was also localized with somatic cell mapping, radiation hybrid mapping, and fluorescence in situ hybridization techniques to chromosome 19q13.3-q13.4, the same region where the human kallikrein gene family resides. Taken together, our results suggest that the NES1 gene originates from the same ancestor as trypsinogen, PSA, and TPA, but remains in close proximity to PSA.
 ...
PMID:Structural characterization and mapping of the normal epithelial cell-specific 1 gene. 964 36


1 2 3 Next >>