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1

Effect of 8-methoxypsoralen plus long-wave ultraviolet (PUVA) radiation on mast cells. II. In vitro PUVA inhibits degranulation of rat peritoneal mast cells induced by compound 48/80  

SciTech Connect

Rat peritoneal mast cells incubated with a histamine liberator, compound 48/80, showed a significantly reduced capacity for releasing histamine following in vitro treatment with 0.1 micrograms/ml of 8-methoxypsoralen (8-MOP) plus 1-5 J/cm2 of long-wave ultraviolet (UVA) irradiation (PUVA). No remarkable inhibition in histamine release was observed in the cells treated with 8-MOP only. Irradiation with 5 J/cm2 of UVA alone exerted an inhibitory effect on histamine release, to a lesser extent than PUVA. PUVA irradiation did not bring any decrease in cell viability or any spontaneous release of histamine from irradiated cells as shown by phase-contrast microscopy and by histamine assay, respectively. These results suggest that PUVA treatment may cause a noncytotoxic disturbance at mast cell membranes or on surface receptors, leading to a decreased capacity for secreting chemical mediators.

Toda, K.; Danno, K.; Tachibana, T.; Horio, T.

1986-07-01

2

Effect of 8-methoxypsoralen plus long-wave ultraviolet (PUVA) radiation on mast cells: PUVA suppresses degranulation of mouse skin mast cells induced by compound 48/80 or concanavalin A  

SciTech Connect

Ears of mice were treated with a 0.5% 8-MOP solution topically plus UVA radiation (1.5-2.5 J/cm2). After PUVA radiation, skin responses to intradermal injection with mast cell liberators, including compound 48/80 (2.5 mg/ml, 10 microliter) and concanavalin A (Con-A) (2.0 mg/ml), or with a mixture of 5-hydroxytryptamine (5-HT) and histamine as vasodilator (1.0 mg/ml and 50 mM, respectively) were examined with time (2 h-14 days). At each time point, an ear swelling response (ESR) was measured with a dial thickness gauge. The rate of mast cell degranulation and mast cell numbers were assessed by light microscopy using toluidine blue-stained semithin (1 micron) sections. ESR induced by compound 48/80 or Con-A was significantly suppressed dose-dependently (greater than 42% inhibition) by PUVA between 2 h-3 days postirradiation as compared with that in nonirradiated control mice, and the value returned to normal levels by 7-14 days. Compound 48/80- or Con-A-induced mast cell degranulation (%) was remarkably decreased between 2 h-3 days (greater than 48% inhibition) in accordance with the suppression in ESR and it was restored to the rates in nonirradiated controls by 7-14 days. Neither ESR nor percent degranulation was affected by UVA radiation only (less than 3.5 J/cm2) or application of 8-MOP only. 5-HT plus histamine-mediated ESR was not altered at all by PUVA throughout the experimental period. Since PUVA radiation itself at given doses did not produce measurable ESR, mast cell degranulation, or a reduction in mast cell numbers, and since PUVA did not affect a normal vascular response to vasodilator, it seemed that decreased skin reactivity to mast cell degranulators by PUVA might be due to a PUVA-induced noncytolytic alteration in mast cell release mechanisms.

Danno, K.; Toda, K.; Horio, T.

1985-08-01

3

The Effect of 8Methoxypsoralen Plus Long-Wave Ultraviolet (PUVA) Radiation on Mast Cells: PUVA Suppresses Degranulation of Mouse Skin Mast Cells Induced by Compound 48\\/80 or Concanavalin A  

Microsoft Academic Search

In order to see whether 8-methoxypsoralen (8-MOP) plus long-wave ultraviolet (UVA) radiation (PUVA) has an influence on immediate-type skin reactions, we have undertaken an animal study. Ears of mice were treated with a 0.5% 8-MOP solution topically plus UVA radiation (1.5–2.5 J\\/cm2). After PUVA radiation, skin responses to intradermal injection with mast cell liberators, including compound 48\\/80 (2.5 mg\\/ml, 10

Kiichiro Danno; Kenichi Toda; Takeshi Horio

1985-01-01

4

PUVA Inhibits DNA Replication, but not Gene Transcription at Nonlethal Dosages  

Microsoft Academic Search

The combination of psoralens and UVA radiation (PUVA photochemotherapy) is an established treatment for many skin disorders. UVA-induced psoralen–DNA interactions are assumed to contribute to the cutaneous anti-inflammatory and anti-proliferative effects of PUVA. PUVA-induced DNA modifications might interfere not only with DNA replication, but also with gene transcription of proinflammatory genes. We therefore studied the effect of PUVA on cell

Matthias Lüftl; Martin Röcken; Gerd Plewig; Klaus Degitz

1998-01-01

5

Modeling Pharmacological Inhibition of Mast Cell Degranulation as a Therapy for Insulinoma12  

PubMed Central

Myc, a pleiotropic transcription factor that is deregulated and/or overexpressed in most human cancers, instructs multiple extracellular programs that are required to sustain the complex microenvironment needed for tumor maintenance, including remodeling of tumor stroma, angiogenesis, and inflammation. We previously showed in a model of pancreatic ?-cell tumorigenesis that acute Myc activation in vivo triggers rapid recruitment of mast cells to the tumor site and that this is absolutely required for angiogenesis and macroscopic tumor expansion. Moreover, systemic inhibition of mast cell degranulation with sodium cromoglycate induced death of tumor and endothelial cells in established tumors. Hence, mast cells are required both to establish and to maintain the tumors. Whereas this intimates that selective inhibition of mast cell function could be therapeutically efficacious, cromoglycate is not a practical drug for systemic delivery in humans, and no other systemic inhibitor of mast cell degranulation has hitherto been available. PCI-32765 is a novel inhibitor of Bruton tyrosine kinase (Btk) that blocks mast cell degranulation and is currently in clinical trial as a therapy for B-cell non-Hodgkin lymphoma. Here, we show that systemic treatment of insulinoma-bearing mice with PCI-32765 efficiently inhibits Btk, blocks mast cell degranulation, and triggers collapse of tumor vasculature and tumor regression. These data reinforce the notion that mast cell function is required for maintenance of certain tumor types and indicate that the Btk inhibitor PCI-32765 may be useful in treating such diseases.

Soucek, Laura; Buggy, Joseph J; Kortlever, Roderik; Adimoolam, Shanthi; Monclus, Helena Allende; Allende, Maria Teresa Salcedo; Swigart, Lamorna Brown; Evan, Gerard I

2011-01-01

6

Gangliosides inhibit bee venom melittin cytotoxicity but not phospholipase A{sub 2}-induced degranulation in mast cells  

SciTech Connect

Sting accident by honeybee causes severe pain, inflammation and allergic reaction through IgE-mediated anaphylaxis. In addition to this hypersensitivity, an anaphylactoid reaction occurs by toxic effects even in a non-allergic person via cytolysis followed by similar clinical manifestations. Auto-injectable epinephrine might be effective for bee stings, but cannot inhibit mast cell lysis and degranulation by venom toxins. We used connective tissue type canine mast cell line (CM-MC) for finding an effective measure that might inhibit bee venom toxicity. We evaluated degranulation and cytotoxicity by measurement of {beta}-hexosaminidase release and MTT assay. Melittin and crude bee venom induced the degranulation and cytotoxicity, which were strongly inhibited by mono-sialoganglioside (G{sub M1}), di-sialoganglioside (G{sub D1a}) and tri-sialoganglioside (G{sub T1b}). In contrast, honeybee venom-derived phospholipase A{sub 2} induced the net degranulation directly without cytotoxicity, which was not inhibited by G{sub M1}, G{sub D1a} and G{sub T1b}. For analysis of distribution of G{alpha}{sub q} and G{alpha}{sub i} protein by western blotting, lipid rafts were isolated by using discontinuous sucrose gradient centrifuge. Melittin disrupted the localization of G{alpha}{sub q} and G{alpha}{sub i} at lipid raft, but gangliosides stabilized the rafts. As a result from this cell-based study, bee venom-induced anaphylactoid reaction can be explained with melittin cytotoxicity and phospholipase A{sub 2}-induced degranulation. Taken together, gangliosides inhibit the effect of melittin such as degranulation, cytotoxicity and lipid raft disruption but not phospholipase A{sub 2}-induced degranulation in mast cells. Our study shows a potential of gangliosides as a therapeutic tool for anaphylactoid reaction by honeybee sting.

Nishikawa, Hirofumi; Kitani, Seiichi, E-mail: drkitani@kaiyodai.ac.jp

2011-05-01

7

Degranulation of mast cells and inhibition of the response to secretory agents by phototoxic compounds and ultraviolet radiation  

SciTech Connect

The symptoms of cutaneous phototoxicity from coal tar compounds and the nonsteroidal anti-inflammatory drug benoxaprofen are characterized by wheal and flare formation which is mediated by histamine released from dermal mast cells. Rat serosal mast cells were used as an in vitro model system to study the direct effect of phototoxic compounds on mast cell degranulation. The coal tar compounds studied included acridine and pyrene. Combined exposure of cells to acridine and UVA (320 to 400 nm) radiation caused mast cells to degranulate, as assayed by the release of (/sup 3/H)serotonin. Maximum (/sup 3/H)serotonin release (70 to 80%) was obtained with 50 microM acridine and 300 kJ/m2 UVA. Pyrene (25 microM), when photoexcited with UVB (280 to 360 nm) radiation, caused about 80% release of (/sup 3/H)serotonin. No degranulation occurred with 20 microM benoxaprofen and UVB doses up to 7.2 kJ/m2. Trypan blue staining correlated well with degranulation caused by acridine plus UVA; however, with pyrene plus UVB there was greater (/sup 3/H)serotonin release than dye uptake. Excitation of photosensitizers with doses of UV radiation that did not cause trypan blue staining suppressed degranulation of mast cells in response to chemical stimulation. Acridine, pyrene, and benoxaprofen in the presence of UV radiation inhibited the mast cells from responding to compound 48/80 or the calcium ionophore, chlortetracycline. Two other phototoxic compounds, chlorpromazine and deoxytetracycline, also abolished degranulation by compound 48/80. These findings indicate that phototoxic compounds: (1) cause degranulation in the presence of high doses of UV radiation; and (2) suppress degranulation of mast cells in response to secretory stimuli at doses of UV radiation that do not cause release of mediator.

Gendimenico, G.J.; Kochevar, I.E.

1984-11-01

8

Toxoplasma gondii inhibits mast cell degranulation by suppressing phospholipase C?-mediated Ca2+ mobilization  

PubMed Central

Toxoplasma gondii is well-known to subvert normal immune responses, however, mechanisms are incompletely understood. In particular, its capacity to alter receptor-activated Ca2+-mediated signaling processes has not been well-characterized. In initial experiments, we found evidence that T. gondii infection inhibits Ca2+ responses to fMetLeuPhe in murine macrophages. To further characterize the mechanism of inhibition of Ca2+ mobilization by T. gondii, we used the well-studied RBL mast cell model to probe the capacity of T. gondii to modulate IgE receptor-activated signaling within the first hour of infection. Ca2+ mobilization that occurs via IgE/Fc?RI signaling leads to granule exocytosis in mast cells. We found that T. gondii inhibits antigen-stimulated degranulation in infected cells in a strain-independent manner. Under these conditions, we found that cytoplasmic Ca2+ mobilization, particularly antigen-mediated Ca2+ release from intracellular stores, is significantly reduced. Furthermore, stimulation-dependent activation of Syk kinase leading to tyrosine phosphorylation and activation of phospholipase C? is inhibited by infection. Therefore, we conclude that inhibitory effects of infection are likely due to parasite-mediated inhibition of the tyrosine kinase signaling cascade that results in reduced hydrolysis of phosphatidylinositol 4,5-bisphosphate. Interestingly, inhibition of IgE/Fc?RI signaling persists when tachyzoite invasion is arrested via cytochalasin D treatment, suggesting inhibition is mediated by a parasite-derived factor secreted into the cells during the invasion process. Our study provides direct evidence that immune subversion by T. gondii is initiated concurrently with invasion.

Smith, Norah L.; Abi Abdallah, Delbert S.; Butcher, Barbara A.; Denkers, Eric Y.; Baird, Barbara; Holowka, David

2013-01-01

9

Suppression of intracellular calcium levels and inhibition of degranulation in RBL-2H3 mast cells by the sesquiterpene lactone parthenolide.  

PubMed

Pretreatment with parthenolide for 60 min inhibited the antigen-induced degranulation of RBL-2H3 mast cells; the IC(50) value being 4.5 ± 0.4 µM. The inhibition was not due to suppression of the phosphatidylinositol 3-kinase pathway because the antigen-induced phosphorylation of Akt was not inhibited by parthenolide. The antigen-induced increase in intracellular calcium levels was prevented by parthenolide, suggesting that parthenolide inhibited the antigen-induced degranulation by suppressing an increase in intracellular calcium levels. In support of this, parthenolide was found to prevent ionomycin-induced degranulation by inhibiting an increase in intracellular calcium levels. Therefore, parthenolide inhibits the degranulation of mast cells by preventing an increase in intracellular calcium levels. PMID:20814853

Hong, Jangja; Aoyama, Suzue; Hirasawa, Noriyasu; Zee, Okpyo; Ishihara, Kenji; Hashida, Chika; Kimura, Michio; Seyama, Toshio; Ohuchi, Kazuo

2011-02-01

10

A heterobivalent ligand inhibits mast cell degranulation via selective inhibition of allergen-IgE interactions in vivo.  

PubMed

Current treatments for allergies include epinephrine and antihistamines, which treat the symptoms after an allergic response has taken place; steroids, which result in local and systemic immune suppression; and IgE-depleting therapies, which can be used only for a narrow range of clinical IgE titers. The limitations of current treatments motivated the design of a heterobivalent inhibitor (HBI) of IgE-mediated allergic responses that selectively inhibits allergen-IgE interactions, thereby preventing IgE clustering and mast cell degranulation. The HBI was designed to simultaneously target the allergen binding site and the adjacent conserved nucleotide binding site (NBS) found on the Fab of IgE Abs. The bivalent targeting was accomplished by linking a hapten to an NBS ligand with an ethylene glycol linker. The hapten moiety of HBI enables selective targeting of a specific IgE, whereas the NBS ligand enhances avidity for the IgE. Simultaneous bivalent binding to both sites provided HBI with 120-fold enhancement in avidity for the target IgE compared with the monovalent hapten. The increased avidity for IgE made HBI a potent inhibitor of mast cell degranulation in the rat basophilic leukemia mast cell model, in the passive cutaneous anaphylaxis mouse model of allergy, and in mice sensitized to the model allergen. In addition, HBI did not have any observable systemic toxic effects even at elevated doses. Taken together, these results establish the HBI design as a broadly applicable platform with therapeutic potential for the targeted and selective inhibition of IgE-mediated allergic responses, including food, environmental, and drug allergies. PMID:24489096

Handlogten, Michael W; Serezani, Ana P; Sinn, Anthony L; Pollok, Karen E; Kaplan, Mark H; Bilgicer, Basar

2014-03-01

11

Primary Human Airway Epithelial Cell-Dependent Inhibition of Human Lung Mast Cell Degranulation  

PubMed Central

Introduction Chronic mast cell activation is a characteristic feature of asthma. BEAS-2B human airway epithelial cells (AEC) profoundly inhibit both constitutive and IgE-dependent human lung mast cell (HLMC) histamine release. The aim of this study was to examine the regulation of HLMC degranulation by primary AEC from healthy and asthmatic subjects, and investigate further the inhibitory mechanism. Methods HLMC were co-cultured with both BEAS-2B and primary AEC grown as monolayers or air-liquid interface (ALI) cultures. Results Both constitutive and IgE-dependent HLMC histamine release were attenuated by BEAS-2B, primary AEC monolayers and ALI cultures. This occurred in the absence of HLMC-AEC contact indicating the presence of a soluble factor. Unlike healthy ALI AEC, asthmatic ALI-AEC did not significantly reduce constitutive histamine release. AEC inhibitory activity was transferable in primary AEC monolayer supernatant, but less active than with Transwell co-culture, suggesting that the inhibitory factor was labile. The AEC inhibitory effects were attenuated by both AEC wounding and pertussis toxin, indicating the involvement of a G0/Gi receptor coupled mechanism. Solid phase extraction of lipids (<10 kDa) removed the AEC inhibitory activity. The lipid derivatives resolvin D1 and D2 and lipoxin A4 attenuated HLMC histamine release in a dose-dependent fashion but were not detectable in co-culture supernatants. Conclusions Primary AEC suppress HLMC constitutive and IgE-dependent histamine secretion through the release of a soluble, labile lipid mediator(s) that signals through the G0/Gi receptor coupled mechanism. Manipulation of this interaction may have a significant therapeutic role in asthma.

Martin, Neil; Ruddick, Andrew; Arthur, Greer K.; Wan, Heidi; Woodman, Lucy; Brightling, Christopher E.; Jones, Don J. L.; Pavord, Ian D.; Bradding, Peter

2012-01-01

12

Systemic Effects of Ingested Lactobacillus Rhamnosus: Inhibition of Mast Cell Membrane Potassium (IKCa) Current and Degranulation  

PubMed Central

Exposure of the intestine to certain strains lactobacillus can have systemic immune effects that include the attenuation of allergic responses. Despite the central role of mast cells in allergic disease little is known about the effect of lactobacilli on the function of these cells. To address this we assessed changes in rat mast cell activation following oral treatment with a strain of Lactobacillus known to attenuate allergic responses in animal models. Sprague Dawley rats were fed with L.rhamnosus JB-1 (1×109) or vehicle control for 9 days. Mediator release from peritoneal mast cells (RPMC) was determined in response to a range of stimuli. Passive cutaneous anaphylaxis (PCA) was used to assess mast cell responses in vivo. The Ca2+ activated K+ channel (KCa3.1) current, identified as critical to mast cell degranulation, was monitored by whole cell patch-clamp. L.rhamnosus JB-1 treatment lead to significant inhibition of mast cell mediator release in response to a range of stimuli including IgE mediated activation. Furthermore, the PCA response was significantly reduced in treated rats. Patch-clamp studies revealed that RPMC from treated animals were much less responsive to the KCa3.1 opener, DCEBIO. These studies demonstrate that Ingestion of L.rhamnosus JB-1 leads to mast cell stabilization in rats and identify KCa3.1 as an immunomodulatory target for certain lactobacilli. Thus the systemic effects of certain candidate probiotics may include mast cell stabilization and such actions could contribute to the beneficial effect of these organisms in allergic and other inflammatory disorders.

Forsythe, Paul; Wang, Binxiang; Khambati, Ibrahim; Kunze, Wolfgang A.

2012-01-01

13

Inhibition of TRPM7 Channels Reduces Degranulation and Release of Cytokines in Rat Bone Marrow-Derived Mast Cells.  

PubMed

Background: mast cells play an important role in airway inflammation in asthma. The transient receptor potential melastatin-like 7 (TRPM7) channel is expressed in primary human lung mast cells and plays a critical role for cell survival. This study aimed to investigate the role of TRPM7 on degranulation and release of cytokines in rat bone marrow-derived mast cells (BMMCs). Methods: the expression levels of TRPM7 were observed by immunocytochemistry and RT-PCR between normal and asthmatic rat BMMCs. TRPM7-specific shRNA and 2-aminoethoxydiphenyl borate (2-APB) and specific shTRPM7 were used to inhibit the function of TRPM7. Degranulation levels were analyzed by beta-hexosaminidase assay. Histamine, TNF-?, IL-6 and IL-13 levels were measured by ELISA. Results: the expression of TRPM7 was significantly higher in asthmatic rat BMMCs than in the normal control group. After application of 2-APB and down-regulation of TRPM7, the beta-hexosaminidase activity and secretion of histamine, IL-6, IL-13 and TNF-? were significantly decreased in the asthmatic group compared to the control group. Conclusion: this study indicates that TRPM7 channels may be involved in the process of degranulation and release of cytokines in rat bone marrow-derived mast cells. PMID:24995695

Huang, Linjie; Ng, Ngai-Mui; Chen, Ming; Lin, Xiaoling; Tang, Tiantian; Cheng, Huihua; Yang, Cheng; Jiang, Shanping

2014-01-01

14

Anthocyanins, but not anthocyanidins, from bilberry (Vaccinium myrtillus L.) alleviate pruritus via inhibition of mast cell degranulation.  

PubMed

We have previously reported that bilberry anthocyanins exhibit an anti-pruritic effect in a mouse model of allergic contact dermatitis. It has been reported that anthocyanins are particularly sensitive to thermal treatment and are easily hydrolyzed to anthocyanidins when exposed to high temperatures. The objective of this study was to compare the anti-pruritic effect of anthocyanin-rich quality-controlled bilberry extract and anthocyanidin-rich degraded extract using a mouse model of allergic contact dermatitis. BALB/c mice with allergic contact dermatitis induced by 4 weeks of repeated application of 2,4,6-trinitro-1-chlorobenzene (TNCB) were administered Bilberon-25 orally for 4 weeks after sensitization with TNCB. The effect of Bilberon-25 on pruritus was evaluated by measurement of scratching behavior. RBL-2H3 mast cells were used to investigate the effect of Bilberon-25 on degranulation in 48/80-stimulated mast cells. Compared with nonheated Bilberon-25, the proportion of anthocyanins in heated Bilberon-25 decreased, and the proportion of anthocyanidins was increased in heated-time dependent manner. Treatment with non-heated Bilberon-25 significantly attenuated the TNCB-induced increase in scratching behavior, whereas treatment with 2 h-heated Bilberon-25 did not. Moreover, 300 ?g/mL nonheated Bilberon-25 showed significant inhibition of degranulation in RBL-2H3 mast cells, whereas 2 h-heated Bilberon-25 had no effect at any concentration studied. It is assumed that the inhibitory effect of bilberry anthocyanins on pruritus might be mediated, at least in part, by its inhibitory effect on mast cell degranulation. In conclusion, the anthocyanin-rich but not anthocyanidin-rich bilberry extract may be a useful dietary supplement for skin diseases involving pruritic symptoms, such as chronic allergic contact dermatitis, atopic dermatitis, and rhinitis. PMID:23164040

Yamaura, Katsunori; Ishiwatari, Makiko; Yamamoto, Masao; Shimada, Maki; Bi, Yuanyuan; Ueno, Koichi

2012-12-01

15

Natural vanadium-containing Jeju groundwater inhibits immunoglobulin E-mediated anaphylactic reaction and suppresses eicosanoid generation and degranulation in bone marrow derived-mast cells.  

PubMed

The high-affinity receptor for immunoglobulin E (IgE) (Fc?RI)-mediated activation of mast cells plays an important role in various allergic diseases. To assess the anti-allergic activity of natural vanadium-containing Jeju groundwater (JW), an in vivo passive cutaneous anaphylaxis (PCA) animal model and in vitro mouse bone marrow-derived mast cells (BMMCs) was used. JW inhibited cyclooxygenase-2 (COX-2)-dependent prostaglandin D(2) (PGD(2)) generation in a dose-dependent manner, with a concomitant reduction of COX-2 protein expression in IgE-induced BMMCs. In addition, JW inhibited 5-lipoxygenase (5-LOX)-dependent generation of leukotriene C(4) (LTC(4)) as well as degranulation in a dose-dependent manner. These results demonstrate that JW has dual COX-2/5-LOX inhibitory activity. In addition, vanadium pentoxide (V(2)O(5)), which is the major vanadium component of JW, also inhibited PGD(2) and LTC(4) generation as well as degranulation in IgE-induced BMMCs. Furthermore, oral administration of JW dose-dependently inhibited mast cell-dependent passive anaphylactic reaction in IgE-sensitized mice. Taken together, these results suggest that JW may be useful in regulating mast cell-mediated allergic response through the suppression of eicosanoid generation and degranulation in mast cells. PMID:22293352

Li, Xian; Lu, Yue; Yang, Ju Hye; Jin, Ye; Hwang, Seung-Lark; Chang, Hyeun Wook

2012-01-01

16

Coaggregation of Fc?RI with Fc?RIIB Inhibits Degranulation but Not Induction of Bcl-2 Family Members A1 and Bim in Mast Cells  

PubMed Central

The aggregation of high-affinity immunoglobulin E (IgE) receptors (Fc?RI) on mast cells is a critical event in the initiation of an allergic reaction. Coengagement of Fc?RI with immunoglobulin G (IgG) low-affinity receptor Fc?RIIB/CD32 inhibits degranulation and the release of inflammatory mediators from mast cells and has therefore been proposed as a new therapeutic approach for the treatment of allergies. In this study, we investigated whether Fc?RIIB, besides inhibiting degranulation, negatively regulates other signalling pathways downstream of Fc?RI. For this, we determined the phosphorylation and/or expression of proteins involved in the regulation of mast-cell apoptosis. Coaggregation led to an attenuation of Akt phosphorylation but did not inhibit phosphorylation of transcription factor Foxo3a or its proapoptotic target, Bim. Similarly, Fc?RI-dependent expression of the prosurvival gene A1 was not affected by coaggregation. Our data demonstrate that coengagement of Fc?RI and Fc?RIIB inhibits degranulation but not the signalling pathways regulating Bcl-2 family members Bim and A1.

2006-01-01

17

PUVA Treatment for Alopecia areata  

Microsoft Academic Search

Background: PUVA has been suggested as an alternative treatment modality for resistant, diffuse alopecia areata (AA). However, there are conflicting reports on its efficacy. Objective: The aim of this study was to investigate the efficacy of PUVA treatment of AA in a Turkish population. Methods: Twenty-four patients (15 female and 9 male) suffering from extensive AA for more than 1

A. Karaduman

1998-01-01

18

Photofibrosis: a further histopathological change induced by PUVA therapy via the mast cell in guttate psoriasis. Preliminary report.  

PubMed

Twenty-five psoriatic patients were studied histologically before and after PUVA therapy in order to delineate the relationship between dermal mast cells, psoriasis healing process and collagen changes. A number of mast cells were found in the psoriatic changes. A number of mast cells were found in the psoriatic lesion both before PUVA and also after PUVA therapy in 22 of the 25 patients. Fibrosis of the papillary dermis and upper reticular dermis was found in 3 cases. Increased collagen deposition and increased numbers of fibroblasts were accompanied by verticalization of ectatic and elongated blood vessels, with an overall pattern of relatively recent scarring. Mast cells were no longer detectable in the fibrosis area. We cannot exclude the possibility that PUVA therapy exerts a further stimulus on mast cell histamine and heparin degranulation in this type of psoriasis, thus leading to dermal fibrosis and blood vessel neogenesis. PMID:8073822

Borroni, G; Vignati, G; Zaccone, C; Gorani, A; Brazzelli, V; Rabbiosi, G

1994-01-01

19

PUVA therapy in lichen aureus.  

PubMed

Lichen aureus is one of the subtypes of a rare group of diseases, pigmented purpuric dermatoses. The natural course of the disease is slow evolution and slow resolution. Treatment is generally limited. We report a case of lichen aureus that responded dramatically to photochemotherapy (PUVA). PMID:11423854

Ling, T C; Goulden, V; Goodfield, M J

2001-07-01

20

Inhibition of. beta. -bungarotoxin binding to brain membranes by mast cell degranulating peptide, toxin I, and ethylene glycol bis(. beta. -aminoethyl ether)-N,N,N',N'-tetraacetic acid  

Microsoft Academic Search

The presynaptically active snake venom neurotoxin ..beta..-bungarotoxin (..beta..-Butx) is known to affect neurotransmitter release by binding to a subtype of voltage-activated K\\/sup +\\/ channels. Here the authors show that mast cell degranulating (MCD) peptide from bee venom inhibits the binding of ¹²⁵I-labeled ..beta..-Butx to chick and rat brain membranes with apparent K\\/sub i\\/ values of 180 nM and 1100 nM,

Ralf R. Schmidt; Heinrich Betz; Hubert Rehm

1988-01-01

21

Cardiovascular stress of photochemotherapy (PUVA)  

SciTech Connect

The recently devised therapy for psoriasis and related skin diseases, consisting of long-wave ultraviolet light and oral 8-methoxypsoralen (PUVA), was investigated for its cardiovascular effects. In seventeen patients, long-wave ultraviolet light therapy in a treatment enclosure (mean duration, 19.3 minutes) resulted in ambient temperatures of 39.2 degrees C +/- 2.1 degrees C (SD) and skin temperatures of 38.2 degrees C +/- 1.4 degrees C. In upright subjects, heart rate rose 30.8% to 114.4 +/- 25.2 beats per minute (bpm). Intensive room air conditioning, outside of the treatment enclosure, although significantly lowering skin and ambient temperatures, did not affect the heart rates significantly. PUVA therapy is associated with a definite cardiovascular stress when the box type of therapeutic unit is used. Possible modifications are discussed.

Ciafone, R.A.; Rhodes, A.R.; Audley, M.; Freedberg, I.M.; Abelmann, W.H.

1980-11-01

22

Effects of PUVA on the eye  

SciTech Connect

Psoriasis is a common skin disease which may be treated with 8-methoxy psoralen and long-wave ultraviolet light (PUVA). Eye protection is provided during and after treatment to prevent the development of photokeratitis and cataracts. Fifteen patients, treated with medication and ultraviolet A (UVA) had an initial complete eye examination and a repeat examination after each treatment. No patients developed cataracts but almost one-half of the patients had a mild form of photokeratoconjunctivitis. The ocular manifestations included photophobia, conjunctivitis, keratitis, and dry eyes. Tear break-up time was reduced significantly immediately after treatment for two patients but returned to normal 8 hr later. Dermatologists who employ PUVA treatments should be concerned about photokeratoconjunctivitis and the dry-eye ocular manifestations included photophobia, conjunctivitis, keratitis, and dry eyes. Tear break-up time was reduced significantly immediately after treatment for two patients but returned to normal 8 hr later. Dermatologists who employ PUVA treatments should be concerned about photokeratoconjunctivitis and the dry-eye ocular manifestations included photophobia, conjunctivitis, keratitis, and dry eyes. Tear break-up time was reduced significantly immediately after treatment for two patients but returned to normal 8 hr later. Dermatologists who employ PUVA treatments should be concerned about photokeratoconjunctivitis and the dry-eye syndrome.

Backman, H.A.

1982-01-01

23

PUVA-cream photochemotherapy for the treatment of localized scleroderma  

Microsoft Academic Search

Background: The efforts to treat localized scleroderma, including therapies with potentially hazardous side effects, are often unsatisfactory. Recently, PUVA-bath photochemotherapy has been proven highly effective in the treatment of localized scleroderma. Another form of topical PUVA therapy, 8-methoxypsoralen (8-MOP) containing cream or gel preparations, has been proven to be as effective as PUVA-bath therapy for palmoplantar dermatoses. Objective: We sought

Marcella Grundmann-Kollmann; Falk Ochsendorf; Thomas M. Zollner; Konstanze Spieth; Evelyn Sachsenberg-Studer; Roland Kaufmann; Maurizio Podda

2000-01-01

24

Cytochrome P450 CYP1B1 Interacts with 8-Methoxypsoralen (8-MOP) and Influences Psoralen-Ultraviolet A (PUVA) Sensitivity  

PubMed Central

Background There are unpredictable inter-individual differences in sensitivity to psoralen-UVA (PUVA) photochemotherapy, used to treat skin diseases including psoriasis. Psoralens are metabolised by cytochrome P450 enzymes (P450), and we hypothesised that variability in cutaneous P450 expression may influence PUVA sensitivity. We previously showed that P450 CYP1B1 was abundantly expressed in human skin and regulated by PUVA, and described marked inter-individual differences in cutaneous CYP1B1 expression. Objectives We investigated whether CYP1B1 made a significant contribution to 8-methoxypsoralen (8-MOP) metabolism, and whether individuality in CYP1B1 activity influenced PUVA sensitivity. Methods We used E. coli membranes co-expressing various P450s and cytochrome P450 reductase (CPR) to study 8-MOP metabolism and cytotoxicity assays in CYP1B1-expressing mammalian cells to assess PUVA sensitivity. Results We showed that P450s CYP1A1, CYP1A2, CYP1B1, CYP2A6 and CYP2E1 influence 8-MOP metabolism. As CYP1B1 is the most abundant P450 in human skin, we further demonstrated that: (i) CYP1B1 interacts with 8-MOP (ii) metabolism of the CYP1B1 substrates 7-ethoxyresorufin and 17-?-estradiol showed concentration-dependent inhibition by 8-MOP and (iii) inhibition of 7-ethoxyresorufin metabolism by 8-MOP was influenced by CYP1B1 genotype. The influence of CYP1B1 on PUVA cytotoxicity was further investigated in a Chinese hamster ovary cell line, stably expressing CYP1B1 and CPR, which was more sensitive to PUVA than control cells, suggesting that CYP1B1 metabolises 8-MOP to a more phototoxic metabolite(s). Conclusion Our data therefore suggest that CYP1B1 significantly contributes to cutaneous 8-MOP metabolism, and that individuality in CYP1B1 expression may influence PUVA sensitivity.

Deeni, Yusuf Y.; Ibbotson, Sally H.; Woods, Julie A.; Wolf, C. Roland; Smith, Gillian

2013-01-01

25

Mathematical model of laser PUVA psoriasis treatment  

NASA Astrophysics Data System (ADS)

In order to optimize laser PUVA psoriasis treatment we develop the mathematical model of the dynamics of cell processes within epidermis. We consider epidermis as a structure consisting of N cell monolayers. There are four kinds of cells that correspond to four epidermal strata. The different kinds of cells can exist within a given monolayer. We assume that the following cell processes take place: division, death and transition from one stratum to the following. Discrete transition of cells from stratum j to j + 1 approximates to real differentiation.

Medvedev, Boris A.; Tuchin, Valery V.; Yaroslavsky, Ilya V.

1991-05-01

26

Influence of PUVA and UVB radiation on delayed hypersensitivity in the guinea pig  

SciTech Connect

Exposure of guinea pigs to UVA (320--400 nm) radiation following administration of 8-methoxypsoralen by gavage (referred to by the acronym, PUVA) or exposure to UVB (290--320 nm) radiation, produced suppression of the cutaneous delayed hypersensitivity reaction at the site of exposure to radiation and at distant nonexposed sites. In these experiments, the animals were immunized by injection of dinitrophenyl-bovine gamma-globulin (DNP-BGG) in complete Freund's adjuvant and delayed hypersensitivity responses were provoked by intradermal injections of DNP-BGG, DNP and BGG on the flanks. Exposure to erythemogenic doses of either PUVA or UVB radiation for 7 days prior to immunization and for the 7 days between immunization and challenge (total period of radiation: 14 days) produced inhibiton of responses to each of the test substances. In addition, treatment with erythemogenic doses of PUVA either for 7 days prior to immunization or during the interval between immunization and challenge with DNP-BGG, inhibited the delayed hypersensitivity responses at the site of irradiation and at a nonexposed site. These findings suggest that in vivo exposure to nonionizing radiation leads to both local and systemic alteration of certain immune responses.

Morison, W.L.; Parrish, J.A.; Woehler, M.E.; Krugler, J.I.; Bloch, K.J.

1981-06-01

27

Microvascular leakage of plasma proteins after PUVA and UVA  

SciTech Connect

The transcapillary escape rate of albumin (TERalb), is a parameter of the leakage of macromolecules from the total microvasculature. In patients with psoriasis short-term PUVA treatment induces an increase in TERalb. In this study TERalb was measured in 3 groups of normal humans treated with PUVA, UVA and 8-methoxypsoralen. Treatment with PUVA and UVA caused a statistically significant increase in TERalb, whereas treatment with 8-methoxypsoralen did not induce any measurable changes. It is concluded that the UVA irradiation causes the abnormal leakage of macromolecules, whereas psoralen is not the responsible component. Furthermore the phenomenon can be elicited in normals and is not based on a preexisting psoriasis.

Staberg, B.; Worm, A.M.; Rossing, N.; Brodthagen, H.

1982-04-01

28

Antiangiogenic effect of methotrexate and PUVA on psoriasis.  

PubMed

Vascular endothelial growth factor (VEGF) is important factor for angiogenesis in psoriasis. Methotrexate and psoralen and ultraviolet light A (PUVA) mainly target the T cell-mediated immunopathology of psoriasis. Our work aimed at estimating VEGF mRNA in psoriatic patients and investigating whether the standard therapeutic modalities (methotrexate and PUVA) exert their antiangiogenic activity through altering VEGF levels. Twenty-four chronic plaque psoriasis patients were enrolled. Patients were divided into two groups (12 patients each); group A received intramuscular methotrexate and group B was treated by PUVA three times/week in a PUVA 1000 cabin for 10 weeks each. Twelve healthy volunteers served as controls. A skin biopsy was taken from lesional skin before and after treatment for RT-PCR detection of VEGF mRNA. Capillary perfusion scanning using LASER Doppler perfusion imaging was performed on the same psoriatic plaque before and after treatment and was also done for the controls. Following both methotrexate and PUVA, a significant reduction in the amount of VEGF mRNA (P < 0.001 and P = 0.002, respectively) and capillary perfusion (P = 0.002) occurred. These reductions were significantly higher in the methotrexate group (P < 0.001 and  P = 0.001, respectively) than in the PUVA group. The percentage of clinical improvement in the examined psoriatic plaque was significantly positively correlated with the percentage of reduction in the amount of VEGF mRNA (r = 0.850, P < 0.001) and the percentage of reduction in the capillary perfusion (r = 0.684, P < 0.001). Both modalities may exert an antiangiogenic effect. Methotrexate appears to have possibly a more potent antiangiogenic effect than PUVA. PMID:23504632

Shaker, Olfat G; Khairallah, Mongy; Rasheed, Hoda M; Abdel-Halim, Mona R; Abuzeid, Ola M; El Tawdi, Amira M; El Hadidi, Heba H; Ashmaui, Ali

2013-11-01

29

Evidence for CD8+ cell increase in long-term PUVA-treated psoriatic patients after PUVA discontinuation.  

PubMed

Long-term PUVA-treated psoriatic patients given maintenance therapy (UVA doses greater than 1,000 J/cm2) have been demonstrated to undergo lymphopenia and a decrease in the total number of circulating CD3+ and CD4+ T cells. The aim of this study was to assess whether the impairment of T cells is detectable also in psoriatic patients after long-lasting PUVA discontinuation. A group of 34 psoriatic patients (25 males, 9 females; mean age 52.7 +/- 12.82 years), who had previously been treated by PUVA therapy (average cumulative dose 1,898.48 +/- 1,207.12 J/cm2), was studied 1 year or more after discontinuation of PUVA therapy. The patients studied failed to show any impairment in CD3+ and CD4+ cells. Nevertheless, a significant increase (p less than 0.05) in circulating CD8+ cells (both in the percentage and the total number) was detectable in PUVA patients as compared to appropriate controls. The significance and implications of this finding are not known and need further investigations. PMID:1638076

Borroni, G; Zaccone, C; Vignati, G; Fietta, A; Merlini, C; Rabbiosi, G

1992-01-01

30

Treatment of cutaneous T cell lymphomas with PUVA.  

PubMed

A series of 39 patients with CTCL was treated with PUVA over a period of 5 years, comprising 6 patients in stage IA, 13 in stage IB, 15 in stage IIA and 5 in stage IIB. PUVA treatments were administered four times weekly until clearing; a maintenance therapy employed 2 to 1 exposures per week for 2 months. Complete clinical and histological examinations were taken. We obtained a complete remission in all stage IA patients, and a partial remission in stage IB and IIA patients, who required longer treatment schedules and more frequent maintenance therapy. Stage IIB patients required additional local and/or systemic therapy to achieve a partial remission. Recurrences were observed in 33% stage IA patients, in 84% stage IB patients and in all stage IIA and IIB patients. They responded to new induction phases only in early-stage CTCL. PUVA is well accepted by patients, and compares well with other treatments. PMID:3486168

Rabbiosi, G; Carcaterra, A; Bellosta, M

1986-01-01

31

Mathematical modeling for laser PUVA treatment of psoriasis  

NASA Astrophysics Data System (ADS)

We used the Monte Carlo method to evaluate UV-A radiation penetration through human skin (epidermis and dermis). Calculations were performed for multilayered medium, refractive indices mismatch on boundaries of the sample and finite width of incident beam. The fluence rate distributions of UV-A radiation (wavelength 337 nm) within tissue are presented. In order to optimize the laser PUVA treatment of psoriasis were have developed the mathematical model of the dynamics of cell processed within epidermis. The task of optimal control for PUVA treatment is formulated.

Medvedev, Boris A.; Tuchin, Valery V.; Yaroslavsky, Ilya V.

1991-06-01

32

PUVA treatment of erythrodermic and plaque type mycosis fungoides.  

PubMed

Five patients with plaque type mycosis fungoides (MF) and five patients with erythrodermic MF responded favorably to oral psoralen photochemotherapy (PUVA). The mean total UVA irradiation dose was less for erythrodermic than for plaque type MF, but the mean number of treatments to achieve clearing was greater in the erythrodermic patients. Histologic examination at clearing revealed persistence of an inflammatory infiltrate in the lower dermis in most cases. Subsequent recurrent lesions in five patients revealed a more extensive dermal inflammatory infiltrate, although findings were not always diagnostic of MF due to a lack of epidermal involvement. Resumption of more intensive PUVA therapy again resulted in clinical clearing in all five patients. The follow-up period for six patients who received long-term PUVA maintenance ranged from 1 1/2 to 3 1/2 years. During PUVA therapy, five of ten patients developed epithelial malignancies or premalignancies, and one patient developed a malignant fibrous histiocytoma. Most of these patients had received prior treatment with electron beam and topical nitrogen mustard. PMID:6453139

Abel, E A; Deneau, D G; Farber, E M; Price, N M; Hoppe, R T

1981-04-01

33

MAST CELL DEGRANULATION IN RAT MESENTERIC VENULE: EFFECTS OF l NAME, METHYLENE BLUE AND KETOTIFEN  

Microsoft Academic Search

Mast cells are present in proximity to the microvessels, and on stimulation with inhibition of NO synthesis, are a rich source of numerous inflammatory mediators. A microcirculatory study was undertaken to clarify whether nitric oxide (NO) and activation of guanylate cyclase is involved in degranulation of perivascular mast cells in the rat mesenteric venule, and whether oral administration of ketotifen

MASAAKI KIMURA; HIRONOBU MITANI; TSUTOMU BANDOH; TETSUYA TOTSUKA; SHIGEHIRO HAYASHI

1999-01-01

34

Mast cell degranulation breaks peripheral tolerance.  

PubMed

Mast cells (MC) have been shown to mediate regulatory T-cell (T(reg))-dependent, peripheral allograft tolerance in both skin and cardiac transplants. Furthermore, T(reg) have been implicated in mitigating IgE-mediated MC degranulation, establishing a dynamic, reciprocal relationship between MC and T(reg) in controlling inflammation. In an allograft tolerance model, it is now shown that intragraft or systemic MC degranulation results in the transient loss of T(reg) suppressor activities with the acute, T-cell dependent rejection of established, tolerant allografts. Upon degranulation, MC mediators can be found in the skin, T(reg) rapidly leave the graft, MC accumulate in the regional lymph node and the T(reg) are impaired in the expression of suppressor molecules. Such a dramatic reversal of T(reg) function and tissue distribution by MC degranulation underscores how allergy may causes the transient breakdown of peripheral tolerance and episodes of acute T-cell inflammation. PMID:19681828

de Vries, V C; Wasiuk, A; Bennett, K A; Benson, M J; Elgueta, R; Waldschmidt, T J; Noelle, R J

2009-10-01

35

PUVA-treated psoriatic skin as a model for cutaneous wrinkling assessed by skin replicas.  

PubMed

Psoriatic patients may offer a useful model for PUVA-induced skin wrinkling. This study deals with the changes induced by PUVA therapy on the cutaneous microrelief of psoriatic patients assessed by surface replicas. A non-exposed body area (buttocks) was considered. The microrelief was evaluated by means of replicas analysed by an automatic image analyser. Three groups of patients were considered: 1) 10 psoriatic patients who had been undergoing PUVA treatment for the first time and who had received a total PUVA dose of 200 +/- 20 J/cm2; 2) 16 psoriatic patients in long-term PUVA treatment (> 1000 J/cm2); 3) 13 psoriatic controls whose buttocks had never been affected by psoriasis nor exposed to sunlight or PUVA. The results showed that the number and the entity of the cutaneous crests and furrows had been increased by PUVA therapy. In particular the skin pattern analysis showed significant statistical differences between the second and the third group, while no changes were evident between the first and third group (ANOVA and Tukey test for multiple comparisons). In conclusion, our findings indicate that long-term PUVA therapy causes marked changes in the cutaneous microrelief, that this phenomenon can be measured non-invasively and that the changes observed are dependent on the PUVA-dose energies received. PMID:8073823

Brazzelli, V; Borroni, G; Berardesca, E; Romano, E; Vignoli, G P; Rabbiosi, G

1994-01-01

36

Effect of methylmercury on the rat mast cell degranulation  

NASA Astrophysics Data System (ADS)

Methylmercury is the well-known neurotoxicant as weil as a modulator of the immune system. We investigated the effects of MeHg on the rat mast cell degranulation induced by nonimmunological stimuli (the selective liberator of histamine, compound 48/80, and calcium ionophore A23187) both in vivo and in vitro. In 8, 12 and 15 days afterthe final administration of MeHg we observed the suppression of calcium ionophore A23187-and 48/80-induced histamine release, which enhanced with time. In experiments in vitro incubation of peritoneal mast cells with MeHg alone in the dose range 10^{-8} to 10^{-6} did not induce mast cell degranulation, however modified the activation of mast cells by compound 48/80, and calcium ionophore A23187. We observed activation of stimulated secretion by preliminary incubation with low dose of MeHg 10^{-8} M and inhibition by dose of MeHg 10^{-6} M. These results show that MeHg treatment can modify mast cell function in vivo and in vitro and provide insight into the understanding what role this cell has in the pathogenesis of Minamata disease-comlected disorders.

Graevskaya, E. E.; Yasutake, A.; Aramai, R.; Rubin, A. B.

2003-05-01

37

PUVA-Treatment for solar urticaria and persistent light reaction  

Microsoft Academic Search

A technique is described to successfully treat patients with extreme sensitivity to UV electromagnetic wave lengths with photochemotherapy. Representative data from a patient with solar urticaria and two patients with persistent light reaction are given. Prior to treatment the threshold doses for UV-C, UV-B, and UV-A were determined. Photochemotherapy was performed with standard 8-methoxypsoralen-UV-A (PUVA) schedules. Initial treatments were very

Erhard Hölzle; Cornelia Hofmann; Gerd Plewig

1980-01-01

38

Non-Melanoma Skin Cancer Occurring in Patients Treated With PUVA Five to Ten Years After First Treatment  

Microsoft Academic Search

Continued prospective study of the 1,380 patients enrolled in the PUVA study for 10 years after first exposure to PUVA demonstrates a strong association between cumulative exposure to PUVA and an increased risk of squamous cell carcinoma of the skin. For tumors occurring at least 58 months after first treatment, after adjustment for age, sex, and area of residence, we

Robert S. Stern; Rudee Lange

1988-01-01

39

Regulation of M2-type pyruvate kinase mediated by the high-affinity IgE receptors is required for mast cell degranulation  

PubMed Central

Background and purpose: M2-type pyruvate kinase (M2PK) was found to interact directly with the ‘ITAM' region of the ? chain of the high-affinity IgE receptor (Fc?RI). Our hypothesis was that mast cell degranulation might require the Fc?RI-mediated inhibition of M2PK activity. Experimental approach: In rat basophilic leukaemia (RBL-2H3) cells, the effects of directly inhibiting M2PK or preventing the Fc?RI-mediated inhibition of M2PK (disinhibition) on degranulation was measured by hexosaminidase release. Effects of blocking the Fc?RI-mediated inhibition of M2PK was also assessed in vivo in a mouse model of allergen-induced airway hyper-responsiveness. Key results: Activation of Fc?RI in RBL-2H3 cells caused the rapid phosphorylation of tyrosine residues in M2PK, associated with a decrease in M2PK enzymatic activity. There was an inverse correlation between M2PK activity and mast cell degranulation. Fc?RI-mediated inhibition of M2PK involved Src kinase, phosphatidylinositol 3-kinase, PKC and calcium. Direct inhibition of M2PK potentiated Fc?RI-mediated degranulation and prevention of the Fc?RI-mediated inhibition of M2PK attenuated mast cell degranulation. Transfection of RBL-2H3 cells with M1PK which prevents Fc?RI-induced inhibition of M2PK, markedly reduced their degranulation and exogenous M1PK (i.p.) inhibited ovalbumin-induced airway hyper-responsiveness in vivo. Conclusions and implications: We have identified a new control point and a novel biochemical pathway in the process of mast cell degranulation. Our study suggests that the Fc?RI-mediated inhibition of M2PK is a crucial step in responses to allergens. Moreover, the manipulation of glycolytic processes and intermediates could provide novel strategies for the treatment of allergic diseases.

Ryu, H; Walker, J K L; Kim, S; Koo, N; Barak, L S; Noguchi, T; Kang, B Y; Kim, K-M

2008-01-01

40

Noncutaneous Malignant Tumors in the PUVA Follow-up Study: 1975–1996  

Microsoft Academic Search

There is concern about possible association between PUVA treatment and an increased risk of noncutaneous cancer. An alteration in the risk of cancer among persons with psoriasis has also been postulated. To test this hypothesis, for nearly two decades we have prospectively followed 1380 patients who first began PUVA treatment for psoriasis in 1975-1976. We compare the risk of noncutaneous

Robert S. Stern; Liisa H. Vakeva

1997-01-01

41

Effect of Pakistani medicinal plants on IgE/antigen- and ionophore-induced mucosal mast cells degranulation.  

PubMed

Cumulative evidence has now demonstrated the stimulation of mucosal mast cells by both allergic and non-allergic triggers and their inhibition as a potential therapeutic target in many diseases like food allergy and ulcerative colitis. Hence, we screened medicinal plants from Pakistan against antigen- and ionophore-induced degranulation of mucosal mast cells. Aqueous ethanol extracts were screened. IgE/antigen- and A23187-induced degranulation of mucosal-type murine bone marrow derived mast cells (mBMMCs) were screening assays and ?-hexosaminidase released from degranulated mBMMCs was measured. Real time-polymerase chain reaction was employed to examine the expression of TNF-? and IL-4 mRNA. Acetoxychavicol acetate, was examined by degranulation assays and real time-PCR. Among the ten plants screened against IgE/antigen stimulated degranulation, five plants; Alpinia galangal, Mentha arvensis, Myrtus communis, Polygonum bistorta and Syzygium aromaticum demonstrated significant (p<0.01) suppression of the degranulation at 100 ?g/ml. Of them, Alpinia galangal showed significant (p<0.01) inhibition at 32 mg/ml. In A23187-induced degranulation, all plants showed significant (p<0.01) inhibition at 100 ?g/ml except Tamarix dioica. Again Alpinia galangal exhibited significant (p<0.01) suppression at 32 ?g/ml. In a concentration dependent assay, Alpinia galangal revealed significant suppression at 10 ?g/ml against A23187-stimulated degranulation. Acetoxychavicol acetate demonstrated significant (p<0.01) inhibition at 3.2 ?M in IgE/antigen-treated cells and at 10 ?M in A23187-treated cells. Furthermore, both Alpinia galangal and acetoxychavicol acetate suppressed the IgE/antigen- and A23187-enhanced mRNA expression of inflammatory cytokines, TNF-a and IL-4, in mBMMCs. Our findings revealed the suppressive effect of Alpinia galangal and acetoxychavicol acetate on degranulation of mBMMCs by allergic and non-allergic stimuli, which can be utilized for future drug development against food allergy or ulcerative colitis. PMID:25016264

Zaidi, Syed Faisal; Kim, Ji-Hyun; Tomoe, Yashiro; Usmanghani, Khan; Kadowaki, Makoto

2014-07-01

42

Modulation of basophils' degranulation and allergy-related enzymes by monomeric and dimeric naphthoquinones.  

PubMed

Allergic disorders are characterized by an abnormal immune response towards non-infectious substances, being associated with life quality reduction and potential life-threatening reactions. The increasing prevalence of allergic disorders demands for new and effective anti-allergic treatments. Here we test the anti-allergic potential of monomeric (juglone, menadione, naphthazarin, plumbagin) and dimeric (diospyrin and diosquinone) naphthoquinones. Inhibition of RBL-2H3 rat basophils' degranulation by naphthoquinones was assessed using two complementary stimuli: IgE/antigen and calcium ionophore A23187. Additionally, we tested for the inhibition of leukotrienes production in IgE/antigen-stimulated cells, and studied hyaluronidase and lipoxidase inhibition by naphthoquinones in cell-free assays. Naphthazarin (0.1 µM) decreased degranulation induced by IgE/antigen but not A23187, suggesting a mechanism upstream of the calcium increase, unlike diospyrin (10 µM) that reduced degranulation in A23187-stimulated cells. Naphthoquinones were weak hyaluronidase inhibitors, but all inhibited soybean lipoxidase with the most lipophilic diospyrin, diosquinone and menadione being the most potent, thus suggesting a mechanism of competition with natural lipophilic substrates. Menadione was the only naphthoquinone reducing leukotriene C4 production, with a maximal effect at 5 µM. This work expands the current knowledge on the biological properties of naphthoquinones, highlighting naphthazarin, diospyrin and menadione as potential lead compounds for structural modification in the process of improving and developing novel anti-allergic drugs. PMID:24587235

Pinho, Brígida R; Sousa, Carla; Valentão, Patrícia; Oliveira, Jorge M A; Andrade, Paula B

2014-01-01

43

cis-Urocanic Acid Induces Mast Cell Degranulation and Release of Preformed TNF--?: A Possible Mechanism Linking UVB and cis-Urocanic Acid to Immunosuppression of Contact Hypersensitivity  

Microsoft Academic Search

The search for effective inhibitors of transdermal drug-induced contact sensitization was directed to dermal mast-cell-degranulating agents (MCDA). Human skin organ cultures were employed to test whether cis-urocanic acid (C-UA) and other potential MCDAs cause mast cell degranulation. These were then tested for their ability to inhibit the induction phase of the contact hypersensitivity reaction (CHR). C-UA at 1 ?g\\/ml significantly

John J. Wille; Agis F. Kydonieus; George F. Murphy

1999-01-01

44

Effects of cigarette smoke on degranulation and NO production by mast cells and epithelial cells  

Microsoft Academic Search

Exhaled nitric oxide (eNO) is decreased by cigarette smoking. The hypothesis that oxides of nitrogen (NOX) in cigarette smoke solution (CSS) may exert a negative feedback mechanism upon NO release from epithelial (AEC, A549, and NHTBE) and basophilic cells (RBL-2H3) was tested in vitro. CSS inhibited both NO production and degranulation (measured as release of beta-hexosaminidase) in a dose-dependent manner

Xiu M Wei; Henry S Kim; Rakesh K Kumar; Gavin J Heywood; John E Hunt; H Patrick McNeil; Paul S Thomas

2005-01-01

45

hsa-miR-4516 Mediated Downregulation of STAT3/CDK6/UBE2N Plays a Role in PUVA Induced Apoptosis in Keratinocytes.  

PubMed

Psoriasis is a chronic inflammatory skin disorder mediated by cross-talk occurring between epidermal keratinocytes, dermal vascular cells and immunocytes. Literature reveals that Signal transducer and activator of transcription 3 (STAT3), a protein involved in transmitting extracellular signals to the nucleus, is a possible important link between keratinocytes and immunocytes and is crucial to the development of psoriasis. Although photochemotherapy using UV in combination with 8 methoxypsoralen is one of the most effective therapy for moderate to severe plaque psoriasis, its mechanism of action is largely unknown. Herein, we studied the change in miRNA profiles of cultured human keratinocytes (HaCaT cells) before and after in vitro PUVA treatment by 8 methoxypsoralen and found significant up regulation of hsa-miR-4516. We for the first time demonstrate that ectopic expression of hsa-miR-4516 directly targets STAT3 protein by binding to its 3'UTR in HaCaT cells as confirmed by Luciferase reporter assays and Western blot analysis. We further show that overexpression of hsa-miR-4516 downregulates STAT3, p-STAT3, CDK6, and UBE2N proteins that are consistently upregulated in psoriasis and induces apoptosis in HaCaT cells. We also observed that anti-miR-4516 treatment was able to partially inhibit PUVA-induced apoptosis, suggesting that miR-4516 is involved in PUVA-induced apoptosis. Taken together, these results not only indicate the mechanistic involvement of hsa-miR-4516 in PUVA mediated effects by down-regulating STAT3 in HaCaT keratinocytes, but also highlight the potential of hsa-miR-4516 in development of novel therapeutic strategies. J. Cell. Physiol. 229: 1630-1638, 2014. © 2014 Wiley Periodicals, Inc. PMID:24610393

Chowdhari, Shruti; Saini, Neeru

2014-11-01

46

Induction of Mast Cell Degranulation in Skin by Ultrasound  

Microsoft Academic Search

Abstracf-Mast cells are numerous in the dermis and it is virtually inevitable that they will be exposed to ultrasound whenever it is used clinically. Their degranulation, in response to changes at their plasma membranes, induces inflammation. The degranulation of dermal mast cells in the intact skin of adult male Wistar rats (treated in vivo with ultrasound at intensities and frequencies

MARY DYSON; DOUGLAS A. LUKE

1986-01-01

47

Combining PUVA therapy with systemic immunosuppression to treat progressive diffuse morphoea.  

PubMed

Cyclosporin and mycophenolate mofetil (MMF) are immunosuppressant agents now used frequently in the field of organ transplantation. More recently cyclosporin has been used for the treatment of a number of dermatological conditions, including severe psoriasis and eczema. Extensive diffuse morphoea is very difficult to treat. PUVA, UVA and a number of immunomodulating drugs have been used to attempt improvement but are most beneficial only in early disease. Combination treatments are often used in psoriasis, for example, but are not reported in morphoea. We present the case of a patient treated initially with cyclosporin and PUVA and subsequently with MMF and PUVA, with considerable improvement in his condition. PMID:15807674

Rose, R F; Goodfield, M J D

2005-05-01

48

JNK1 controls mast cell degranulation and IL-1? production in inflammatory arthritis  

PubMed Central

Rheumatoid arthritis (RA) is a chronic inflammatory disease marked by bone and cartilage destruction. Current biologic therapies are beneficial in only a portion of patients; hence small molecules targeting key pathogenic signaling cascades represent alternative therapeutic strategies. Here we show that c-Jun N-terminal kinase (JNK) 1, but not JNK2, is critical for joint swelling and destruction in a serum transfer model of arthritis. The proinflammatory function of JNK1 requires bone marrow-derived cells, particularly mast cells. Without JNK1, mast cells fail to degranulate efficiently and release less IL-1? after stimulation via Fc? receptors (Fc?Rs). Pharmacologic JNK inhibition effectively prevents arthritis onset and abrogates joint swelling in established disease. Hence, JNK1 controls mast cell degranulation and Fc?R-triggered IL-1? production, in addition to regulating cytokine and matrix metalloproteinase biosynthesis, and is an attractive therapeutic target in inflammatory arthritis.

Guma, Monica; Kashiwakura, Jun-ichi; Crain, Brian; Kawakami, Yuko; Beutler, Bruce; Firestein, Gary S.; Kawakami, Toshiaki; Karin, Michael; Corr, Maripat

2010-01-01

49

Bath PUVA and Psoriasis: Is a Milder Treatment a Worse Treatment?  

Microsoft Academic Search

Background\\/Aim: The guidelines of the British Photodermatology Group for topical treatment with psoralen and ultraviolet light (PUVA) recommend starting UVA doses between 0.2 and 0.5 J\\/cm2, according to the phototype. Our purpose was to evaluate the therapeutic efficacy and tolerability of bath PUVA, with 8-methoxypsoralen (8-MOP), by using lower UVA doses, regardless of phototype. Methods: We compared 2 groups of

G. Delrosso; C. Bornacina; P. Farinelli; F. Bellinzona; G. Leigheb; E. Colombo

2008-01-01

50

Stimulus-Selective Regulation of Human Mast Cell Gene Expression, Degranulation and Leukotriene Production by Fluticasone and Salmeterol  

PubMed Central

Despite the fact that glucocorticoids and long acting beta agonists are effective treatments for asthma, their effects on human mast cells (MC) appear to be modest. Although MC are one of the major effector cells in the underlying inflammatory reactions associated with asthma, their regulation by these drugs is not yet fully understood and, in some cases, controversial. Using a human immortalized MC line (LAD2), we studied the effects of fluticasone propionate (FP) and salmeterol (SM), on the release of early and late phase mediators. LAD2 cells were pretreated with FP (100 nM), SM (1 µM), alone and in combination, at various incubation times and subsequently stimulated with agonists substance P, C3a and IgE/anti-IgE. Degranulation was measured by the release of ?-hexosaminidase. Cytokine and chemokine expression were measured using quantitative PCR, ELISA and cytometric bead array (CBA) assays. The combination of FP and SM synergistically inhibited degranulation of MC stimulated with substance P (33% inhibition compared to control, n?=?3, P<.05). Degranulation was inhibited by FP alone, but not SM, when MC were stimulated with C3a (48% inhibition, n?=?3, P<.05). As previously reported, FP and SM did not inhibit degranulation when MC were stimulated with IgE/anti-IgE. FP and SM in combination inhibited substance P-induced release of tumor necrosis factor (TNF), CCL2, and CXCL8 (98%, 99% and 92% inhibition, respectively, n?=?4, P<.05). Fluticasone and salmeterol synergistically inhibited mediator production by human MC stimulated with the neuropeptide substance P. This synergistic effect on mast cell signaling may be relevant to the therapeutic benefit of combination therapy in asthma.

Catalli, Adriana; Karpov, Victor; Erdos, Levente E.; Tancowny, Brian P.; Schleimer, Robert P.; Kulka, Marianna

2014-01-01

51

Does smoking influence the efficacy of bath-PUVA therapy in chronic palmoplantar eczema?  

PubMed

Bath-PUVA therapy has been described as successful treatment for palmoplantar eczema. However, our own observations showed that patients with palmoplantar eczema of the dyshidrotic or hyperkeratotic type responded only partially to bath-PUVA therapy. In order to evaluate environmental influences possibly having an impact on the efficacy of this therapy, smokers and non-smokers suffering from palmoplantar eczema treated with bath-PUVA therapy were compared. A retrospective study was conducted involving 62 patients, 39 non-smokers and 23 smokers, with palmar and/or plantar eczema resistant to local corticosteroids. Bath-PUVA therapy was performed according to the European standard regimen for oral PUVA therapy. The total number of treatments and the cumulative UVA-dose were similar in smokers and non-smokers (smokers 24+/-17.7 (mean+/-SD) and 67.6+/-51.3 J/cm2 vs. non-smokers 25.7+/-16.3 and 68.5+/-49.3 J/cm2). In the group of non-smokers, 31% showed complete remission (CR; 100% clearance), 33% partial remission (PR; more than 50% clearance) and 36% no change after treatment (NC; less than 50% clearance). In contrast, the group of smokers showed only 13% CR and 22% PR, whereas 65% exhibited NC. The differences regarding complete or partial remission between the groups were statistically significant (Student t-test for paired samples; P<0.05). Regarding the different type of eczema, bath-PUVA proved to be more successful in the dyshidrotic type of eczema as compared to the hyperkeratotic type in non-smokers (P<0.05). In the group of smokers no CR was achieved in patients suffering from the dyshidrotic form of eczema. Smoking is likely to be a reason for the failure of bath-PUVA therapy in the treatment of chronic palmoplantar eczema, in particular regarding smokers with eczema of the dyshidrotic type where no complete remission was achieved. PMID:10721861

Douwes, K E; Karrer, S; Abels, C; Landthaler, M; Szeimies, R M

2000-02-01

52

Silver nanoparticle-induced degranulation observed with quantitative phase microscopy  

NASA Astrophysics Data System (ADS)

Monitoring a degranulation process in a live mast cell is a quite important issue in immunology and pharmacology. Because the size of a granule is normally much smaller than the resolution limit of an optical microscope system, there is no direct real-time live cell imaging technique for observing degranulation processes except for fluorescence imaging techniques. In this research, we propose optical quantitative phase microscopy (QPM) as a new observation tool to study degranulation processes in a live mast cell without any fluorescence labeling. We measure the cell volumes and the cross sectional profiles (x-z plane) of an RBL-2H3 cell and a HeLa cell, before and after they are exposed to calcium ionophore A23187 and silver nanoparticles (AgNPs). We verify that the volume and the cross sectional line profile of the RBL-2H3 cell were changed significantly when it was exposed to A23187. When 50 ?g/mL of AgNP is used instead of A23187, the measurements of cell volume and cross sectional profiles indicate that RBL-2H3 cells also follow degranulation processes. Degranulation processes for these cells are verified by monitoring the increase of intracellular calcium ([Ca2+]i) and histamine with fluorescent methods.

Yang, Wenzhong; Lee, Seungrag; Lee, Jiyong; Bae, Yoonsung; Kim, Dugyoung

2010-07-01

53

IL-3 and TNF? increase Thymic Stromal Lymphopoietin Receptor (TSLPR) expression on eosinophils and enhance TSLP-stimulated degranulation  

PubMed Central

Background Thymic stromal lymphopoietin (TSLP) and eosinophils are prominent components of allergic inflammation. Therefore, we sought to determine whether TSLP could activate eosinophils, focusing on measuring the regulation of TSLPR expression on eosinophils and degranulation in response to TSLP, as well as other eosinophil activation responses. Methods Eosinophil mRNA expression of TSLPR and IL-7R? was examined by real-time quantitative PCR of human eosinophils treated with TNF? and IL-5 family cytokines, and TSLPR surface expression on eosinophils was analyzed by flow cytometry. Eosinophils were stimulated with TSLP (with and without pre-activation with TNF? and IL-3) and evaluated for release of eosinophil derived neurotoxin (EDN), phosphorylation of STAT5, and survival by trypan blue exclusion. A blocking antibody for TSLPR was used to confirm the specificity of TSLP mediated signaling on eosinophil degranulation. Results Eosinophil expression of cell surface TSLPR and TSLPR mRNA was upregulated by stimulation with TNF? and IL-3. TSLP stimulation resulted in release of EDN, phosphorylation of STAT5 as well as promotion of viability and survival. TSLP-stimulated eosinophil degranulation was inhibited by a functional blocking antibody to TSLPR. Pre-activation of eosinophils with TNF? and IL-3 promoted eosinophil degranulation at lower concentrations of TSLP stimulation. Conclusions This study demonstrates that eosinophils are activated by TSLP and that eosinophil degranulation in response to TSLP may be enhanced on exposure to cytokines present in allergic inflammation, indicating that the eosinophil has the capacity to participate in TSLP-driven allergic responses.

2012-01-01

54

Fyn kinase controls Fc{epsilon}RI receptor-operated calcium entry necessary for full degranulation in mast cells  

SciTech Connect

IgE-antigen-dependent crosslinking of the high affinity IgE receptor (Fc{epsilon}RI) on mast cells leads to degranulation, leukotriene synthesis and cytokine production. Calcium (Ca{sup 2+}) mobilization is a sine qua non requisite for degranulation, allowing the rapid secretion of stored pro-inflammatory mediators responsible for allergy symptoms. Fyn is a Src-family kinase that positively controls Fc{epsilon}RI-induced mast cell degranulation. However, our understanding of the mechanism connecting Fyn activation to secretion of pre-synthesized mediators is very limited. We analyzed Fc{epsilon}RI-dependent Ca{sup 2+} mobilization in bone marrow-derived mast cells (BMMCs) differentiated from WT and Fyn -/- knock out mice. Fyn -/- BMMCs showed a marked defect in extracellular Ca{sup 2+} influx after Fc{epsilon}RI crosslinking but not after thapsigargin addition. High concentrations of Gadolinium (Gd{sup 3+}) partially blocked Fc{epsilon}RI-induced Ca{sup 2+} influx in WT cells but, in contrast, completely inhibited Ca{sup 2+} mobilization in Fyn -/- cells. Low concentrations of an inhibitor of the canonical transient receptor potential (TRPC) Ca{sup 2+} channels (2-aminoethoxyphenyl-borane, 2-APB) blocked Fc{epsilon}RI-induced maximal Ca{sup 2+} rise in WT but not in Fyn -/- cells. Ca{sup 2+} entry through Fyn-controlled, 2-APB sensitive channels was found to be important for full degranulation and IL-2 mRNA accumulation in WT cells. Immunoprecipitation assays showed that Fyn kinase interacts with TRPC 3/6/7 channels after IgE-antigen stimulation, but its association is not related to protein tyrosine phosphorylation. Results indicate Fyn kinase mediates the receptor-dependent activation of TRPC channels that contribute to degranulation in Fc{epsilon}RI-stimulated mast cells.

Sanchez-Miranda, Elizabeth; Ibarra-Sanchez, Alfredo [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados (Cinvestav), Sede Sur, Calzada de los Tenorios 235, Col. Granjas Coapa, CP 14330 Mexico City (Mexico)] [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados (Cinvestav), Sede Sur, Calzada de los Tenorios 235, Col. Granjas Coapa, CP 14330 Mexico City (Mexico); Gonzalez-Espinosa, Claudia, E-mail: cgonzal@cinvestav.mx [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados (Cinvestav), Sede Sur, Calzada de los Tenorios 235, Col. Granjas Coapa, CP 14330 Mexico City (Mexico)] [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados (Cinvestav), Sede Sur, Calzada de los Tenorios 235, Col. Granjas Coapa, CP 14330 Mexico City (Mexico)

2010-01-22

55

Inhibitory effects of thunberginols A, B, and F on degranulations and releases of TNF-alpha and IL-4 in RBL-2H3 cells.  

PubMed

Thunberginols A, B, and F from the processed leaves of Hydrangea macrophylla var. thunbergii (Hydrangeae Dulcis Folium) substantially inhibited the degranulations by antigen and calcium ionophore A23187, and the releases of TNF-alpha and IL-4 by antigen in RBL-2H3 cells. Phyllodulcin and hydrangenol also showed significant inhibition for the antigen-induced degranulations, but their effects were weaker than those of thunberginols A, B, and F. Among them, thunberginol B showed the most potent activity. With regard to structural requirements of thunberginols for the activity, the 3,4-double bond was essential for the strong activity and the 6-hydroxyl group and lactone ring enhanced the activity. Thunberginols A, B, and F inhibited increase in intracellular free Ca2+ levels, which is an essential process for the degranulation and production of cytokines, in RBL-2H3 cells induced by antigen, but not by calcium ionophore A23187. These results suggested that these active compounds inhibited the degranulation processes both before and after increase in intracellular free Ca2+ levels. PMID:17268088

Wang, Qilong; Matsuda, Hisashi; Matsuhira, Koudai; Nakamura, Seikou; Yuan, Dan; Yoshikawa, Masayuki

2007-02-01

56

Galectin-9 Enhances Cytokine Secretion, but Suppresses Survival and Degranulation, in Human Mast Cell Line  

PubMed Central

Galectin-9 (Gal-9), a lectin having a ?-galactoside-binding domain, can induce apoptosis of Th1 cells by binding to TIM-3. In addition, Gal-9 inhibits IgE/Ag-mediated degranulation of mast cell/basophilic cell lines by binding to IgE, thus blocking IgE/Ag complex formation. However, the role of Gal-9 in mast cell function in the absence of IgE is not fully understood. Here, we found that recombinant Gal-9 directly induced phosphorylation of Erk1/2 but not p38 MAPK in a human mast cell line, HMC-1, which does not express Fc?RI. Gal-9 induced apoptosis and inhibited PMA/ionomycin-mediated degranulation of HMC-1 cells. On the other hand, Gal-9 induced cytokine and/or chemokine production by HMC-1 cells, dependent on activation of ERK1/2 but not p38 MAPK. In addition, the lectin activity of Gal-9 was required for Gal-9-mediated cytokine secretion by HMC-1 cells. These observations suggest that Gal-9 has dual properties as both a regulator and an activator of mast cells.

Iikura, Motoyasu; Niki, Toshiro; Hirashima, Mitsuomi; Iwaya, Keichi; Tsuda, Hitoshi; Nonoyama, Shigeaki; Matsuda, Akio; Saito, Hirohisa; Matsumoto, Kenji; Nakae, Susumu

2014-01-01

57

Micronucleus evaluation in mitogen-stimulated lymphocytes of PUVA treated patients.  

PubMed

PUVA describes the treatment of patients with psoralens plus an exposure to a source of UV light of 320-400 nm (UVA). Contradictory results have been reported on the chromosomal damage of PUVA when assayed by sister chromatid exchange (SCE) method. Micronucleus (MN) test is used to detect both clastogenic (breaking) and aneugenic (abnormal segregation) effect of physical/chemical agents on the chromosomes. No data have been found on the MN formation in the cells of PUVA treated patients. Frequency of micronuclei in 72 hours cultivated/mitogen-stimulated lymphocytes of patients have been evaluated at zero time and after 20, 40, 60 sessions of PUVA treatment. While the beginning MN frequency was approximately 0.22% (n=23), it raised to approximately 0.32 (n=23), approximately 0.42 (n=14) and approximately 0.53% (n=10) corresponding respectively to 20, 40 and 60 sessions. These sessions correspond reciprocally to 54+/-23, 172+/-48, 300+/-61 joules/cm2 of UVA and 13, 26, 39 mg/kg of 8-metoxypsoralen (8-MOP). While large interindividual variances were apparent, highly significant differences have been observed between initial MN frequency and after that of the 20, 40 and 60 sessions, (p = 0.000, p = 0.004, p = 0.005, reciprocally, Wilcoxon two-related samples test). The coefficient of correlation between MN frequency and UVA doses starting from zero to 60 sessions of treatment has been found as r = 0.61. This indicates a significant relationship between UVA doses and MN frequencies. However, MN inducibility and synergistic property of 8-MOP with UVA should be taken into account. Gradual MN increase during different sessions of PUVA treatment shows that--once appeared--a part of MN at least persist in the cells of patients from a few days to a few weeks. Smoking as a confounding factor seems to increase MN frequency (p = 0.053, Mann-Whitney U-test) in the beginning population, taken as the control population. This is the first report on the kinetics of MN formation during different sessions of PUVA treatment. Based on our results, we concluded that PUVA treatment causes a detectable chromosome damaging effect on the relatively profound cells/tissues of its human users. Therapists should be careful with its use, especially on the patients who may be more susceptible to carcinogenesis (e.g. immunosuppressed and/or elderly subjects). PMID:12498310

Hamurcu, Zuhal; Demirtas, Halil; Ascioglu, Ozcan; Dönmez-Altuntas, Hamiyet; Aktas, Ekrem

2002-09-01

58

Acrolein induction of oxidative stress and degranulation in mast cells.  

PubMed

Increases in asthma worldwide have been associated epidemiologically with expanding urban air pollution. The mechanistic relationship between airway hyper-responsiveness, inflammation, and ambient airborne triggers remains ambiguous. Acrolein, a ubiquitous aldehyde pollutant, is a product of incomplete combustion reactions. Acrolein is abundant in cigarette smoke, effluent from industrial smokestacks, diesel exhaust, and even hot oil cooking vapors. Acrolein is a potent airway irritant and can induce airway hyper-responsiveness and inflammation in the lungs of animal models. In the present study, we utilized the mast cell analog, RBL-2H3, to interrogate the responses of cells relevant to airway inflammation and allergic responses as a model for the induction of asthma-like conditions upon exposure to acrolein. We hypothesized that acrolein would induce oxidative stress and degranulation in airway mast cells. Our results indicate that acrolein at 1 ppm initiated degranulation and promoted the generation of reactive oxygen species (ROS). Introduction of antioxidants to the system significantly reduced both ROS generation and degranulation. At higher levels of exposure (above 100 ppm), RBL-2H3 cells displayed signs of severe toxicity. This experimental data indicates acrolein can induce an allergic inflammation in mast cell lines, and the initiation of degranulation was moderated by the application of antioxidants. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 908-915, 2014. PMID:23047665

Hochman, Daniel J; Collaco, Christopher R; Brooks, Edward G

2014-08-01

59

Mechanical loading promotes mast cell degranulation via RGD-integrin dependent pathways.  

PubMed

Mast cells are known to respond to a number of stimuli, such as IgE antibody-antigen complexes, pathogens, chemical compounds, and physical stimulation, resulting in the activation of these cells and subsequent release of cytokines, inflammatory mediators and granules which can influence the pathophysiology of neighboring cells. Although different forms of physical stimulation (i.e. shear stress and acupuncture) have been investigated, the effect of cyclic tensile loading on mast cell activation has not. To characterize the response of mast cells to tensile loading, RBL-2H3 cells were embedded in a 3-dimensional fibrin construct and subjected to 24h of cyclic loading at 0%, 5% or 10% peak tensile strain. Mechanical loading significantly increased RBL-2H3 cell secretion of ?-hexosaminidase (2.1- to 2.3-fold, respectively) in a load- and time-dependent manner when compared to the controls. Furthermore, no evidence of load-induced cell death or alterations in cell proliferation was observed. To determine if RGD-dependent integrins mediated the degranulation of mast cells during mechanical loading, cell-matrix interactions were inhibited by treating the cells with echistatin, a disintegrin that binds RGD-dependent integrins. Treatment with echistatin significantly attenuated load-induced degranulation without compromising cell viability. These results suggest a novel mechanism through which mechanical loading induces mast cell activation via RGD binding integrins. PMID:23261248

Fowlkes, Vennece; Wilson, Christopher G; Carver, Wayne; Goldsmith, Edie C

2013-02-22

60

Quantifying psoralen in tissues by fluorescence: dosimetry for psoralen administration followed by ultraviolet A irradiation (PUVA) to block restenosis  

NASA Astrophysics Data System (ADS)

PUVA therapy may prove effective in preventing restenosis of vessels following balloon angioplasty to open vessels narrowed by atherosclerosis. The technique relies on the ability of PUVA (psoralen administration followed by ultraviolet A irradiation) to cause crosslinks and monoadducts that prevent cellular proliferation without causing cell death. Such PUVA treatment has been successful in controlling cutaneous cell proliferation of psoriasis. The efficacy of PUVA treatment depends on the drug concentration and the light dose. The amount of light delivered is easily modified to adapt to variations in the drug concentration if the drug levels in the vessel wall are known. This paper demonstrates the feasibility of assaying psoralen levels in tissues and in serum samples using psoralen fluorescence as an indictor.

Jacques, Steven L.; Buckley, Lisa A.; Prahl, Scott A.; Gregory, Kenton W.

1994-07-01

61

An Acidic Microenvironment Increases NK Cell Killing of Cryptococcus neoformans and Cryptococcus gattii by Enhancing Perforin Degranulation  

PubMed Central

Cryptococcus gattii and Cryptococcus neoformans are encapsulated yeasts that can produce a solid tumor-like mass or cryptococcoma. Analogous to malignant tumors, the microenvironment deep within a cryptococcoma is acidic, which presents unique challenges to host defense. Analogous to malignant cells, NK cells kill Cryptococcus. Thus, as in tumor defense, NK cells must kill yeast cells across a gradient from physiologic pH to less than 6 in the center of the cryptococcoma. As acidic pH inhibits anti-tumor activities of NK cells, we sought to determine if there was a similar reduction in the anticryptococcal activity of NK cells. Surprisingly, we found that both primary human NK cells and the human NK cell line, YT, have preserved or even enhanced killing of Cryptococcus in acidic, compared to physiological, pH. Studies to explore the mechanism of enhanced killing revealed that acidic pH does not increase the effector to target ratio, binding of cytolytic cells to Cryptococcus, or the active perforin content in effector cells. By contrast, perforin degranulation was greater at acidic pH, and increased degranulation was preceded by enhanced ERK1/2 phosphorylation, which is essential for killing. Moreover, using a replication defective ras1 knockout strain of Cryptococcus increased degranulation occurred during more rapid replication of the organisms. Finally, NK cells were found intimately associated with C. gattii within the cryptococcoma of a fatal infection. These results suggest that NK cells have amplified signaling, degranulation, and greater killing at low pH and when the organisms are replicating quickly, which would help maintain microbicidal host defense despite an acidic microenvironment.

Islam, Anowara; Li, Shu Shun; Oykhman, Paul; Timm-McCann, Martina; Huston, Shaunna M.; Stack, Danuta; Xiang, Richard F.; Kelly, Margaret M.; Mody, Christopher H.

2013-01-01

62

Mast Cell Degranulation Upregulates ?6 Integrins on Epidermal Langerhans Cells  

Microsoft Academic Search

The expression of the ?6?4 and ?6?1 integrins on epidermal Langerhans cells (LC) before and after mast cell degranulation was studied in cultured human neonatal foreskin by immunohistochemistry. Twenty-four hours after addition of mast cell secretagogues, morphine sulfate, or substance P, solitary mid-epidermal cells showed staining for the integrin subunits ?6, ?4, and ?1. This expression was not observed in

Michael D. Ioffreda; Diana Whitaker; George F. Murphy

1993-01-01

63

Mast cell degranulating (MCD) peptide analogs with reduced ring structure  

Microsoft Academic Search

Mast cell degranulating (MCD) peptide, a component of bee venom, is a 22 amino acid peptide with two disulfide bridges. In this first structure-activity study of MCD peptide, three analogs were synthesized and tested: two analogs shortened by omitting sequences 6–10 and 8–13, respectively, and one analog lacking the disulfide bridge between cysteine residues 5 and 19. These analogs were

A. Buku; J. Reibman; A. Pistelli; P. Blandina; D. Gazis

1992-01-01

64

Bullous pemphigoid. Occurrence in a patient with mycosis fungoides receiving PUVA and topical nitrogen mustard therapy  

SciTech Connect

A 57-year-old woman with mycosis fungoides developed blisters within cutaneous plaques while receiving PUVA therapy and topical nitrogen mustard. Direct and indirect immunofluorescence studies showed the findings of bullous pemphigoid. Her bullous disease was controlled after cessation of these therapies and institution of prednisone and methotrexate. During the 5 months following completion of a course of electron-beam therapy, she has been free of the cutaneous manifestations of both diseases. Previous instances of PUVA-related pemphigoid have occurred in psoriatics. The role of ultraviolet light in the induction of pemphigoid is discussed, particularly with regard to its possible interaction with the altered skin of psoriasis or mycosis fungoides. Some of the rare cases of bullous mycosis fungoides might actually have represented ultraviolet-unmasked bullous pemphigoid.

Patterson, J.W.; Ali, M.; Murray, J.C.; Hazra, T.A.

1985-04-01

65

Combination therapy with oral PUVA and corticosteroid for recalcitrant alopecia areata  

Microsoft Academic Search

Alopecia areata (AA) is regarded as a tissue-specific autoimmune disease for which several therapies have been suggested to\\u000a modify the immune reaction against HFs, such as contact immunotherapy, psoralen plus ultraviolet A (PUVA), corticosteroids,\\u000a cyclosporine, minoxidil, and dithranol. However, severe type AA, such as alopecia totalis (AT) and alopecia universalis (AU),\\u000a often show resistance against these therapies. We applied a

Taisuke Ito; Masahiro Aoshima; Natsuho Ito; Izumi Uchiyama; Keiko Sakamoto; Tetsuya Kawamura; Hiroaki Yagi; Hideo Hashizume; Masahiro Takigawa

2009-01-01

66

Disinfection of cell-associated and extracellular HIV1 by PUVA treatment  

Microsoft Academic Search

To inactivate cell-associated and extracellular HIV-1 while preserving cellular surface antigens, a procedure was used based on PUVA treatment i.e. addition of psoralen to cell suspensions followed by irradiation with UVA light. T-lymphoid MT-4 cells were infected with HIV-1 strain NL4-3, 4?-aminomethyl-4,5?,8-trimethylpsoralen was added, and the cell suspension was irradiated with 20 mW\\/cm2 UVA light for 3, 4 and 5

Martin Deichmann; Georg Sczakiel; Rainer Haas

1997-01-01

67

DNA damage in human skin fibroblasts exposed to UVA light used in clinical PUVA treatment  

SciTech Connect

Human skin fibroblasts were irradiated with a clinically used UVA light source. The doses (1.1 and 3 J/cm2) were similar to those reaching the dermis during clinical PUVA treatment of psoriasis. DNA strand breaks, as determined by alkaline elution, were formed in a dose-dependent way and disappeared within 1 hr of postincubation at 37 degrees C. These findings have clinical implications since UVA-induced DNA damage may be accompanied by mutagenic and tumor promoting effects.

Bredberg, A.

1981-06-01

68

Effects of dopaminergic drugs on the mast cell degranulation and nitric oxide generation in RAW 264.7 cells.  

PubMed

Effects of dopaminergic drugs on the degranulation of mast cells (RBL-2H3 cells) and the nitric oxide production from macrophage cells (RAW 264.7) were studied. Among the dopaminergic agonists and antagonists tested, bromocriptine, 7-OH-DPAT, haloperidol, and clozapine showed potent inhibitions of mast cell degranualtion (IC50 value, 5 microM). However, these dopaminergic agents did not affect the tyrosine phosphorylations of the signaling components of the high affinity IgE receptor (FcepsilonRI), such as Syk, PLCgamma1, and PLCgamma2.; This suggested that these signaling components were not involved in the inhibition of the mast cell degranulation by these compounds. On the other hand, dopamine, bromocriptine, 7-OH-DAPT, and haloperidol markedly inhibited the nitric oxide production from RAW 264.7 cells (IC50 values, 10-20 microM). Bromocriptine, a dopamine agonist that is routinely used for the treatment of Parkinsons disease, inhibited the expression of the inducible nitric oxide synthase at an early stage of the LPS-induced protein expression in a dose-dependent manner. The results suggested that these dopaminergic agents, when used for the treatment of dopamine receptors-related diseases, such as Schizophrenia or Parkinsons disease, might have additional beneficial effects. PMID:14969346

Seol, Il-Woong; Kuo, Na Youn; Kim, Kyeong Man

2004-01-01

69

Effects of medium-term PUVA therapy on peripheral T-lymphocyte subsets in psoriatic patients.  

PubMed

Three to four months' PUVA treatment is a widely-adopted procedure to induce psoriasis remission and for the purpose of this study is called "medium-term". The 32 psoriatic patients considered revealed a statistically significant baseline decrease in OKT3+ (p less than 0.001), OKT4+ (p less than 0.001) and OKT8+ (p less than 0.001) as compared with 40 healthy controls, while OKT4/OKT8 was normal. Variance analysis within the psoriatic group failed to reveal further significant variation in the immunological parameters during the 3 months under study. Nevertheless, there was a marked trend towards a reduction in OKT4+ cells and OKT4/OKT8 as compared with baseline values after 3 months. These results suggest that "medium-term" PUVA therapy does not statistically restore the pre-existing baseline changes in T-lymphocyte subsets of the psoriatic patients. The non-statistically significant effects as regards OKT4+ may be due to the small number of patients who reached 3 months' treatment (9 patients) but could be regarded as the first step towards the significant changes described here in long-term PUVA-treated psoriatic patients. PMID:2514541

Borroni, G; Brazzelli, V; Fietta, A; Gatti, M; Bellosta, M; Vignati, G; Zaccone, C; Berardesca, E; Rabbiosi, G

1989-01-01

70

Quantitative analysis on PUVA-induced skin photodamages using optical coherence tomography  

NASA Astrophysics Data System (ADS)

Psoralen plus ultraviolet A radiation (PUVA) therapy is a very important clinical treatment of skin diseases such as vitiligo and psoriasis, but associated with an increased risk of skin photodamages especially photoaging. Since skin biopsy alters the original skin morphology and always requires an iatrogenic trauma, optical coherence tomography (OCT) appears to be a promising technique to study skin damage in vivo. In this study, the Balb/c mice had 8-methoxypsralen (8-MOP) treatment prior to UVA radiation was used as PUVA-induced photo-damaged modal. The OCT imaging of photo-damaged group (modal) and normal group (control) in vivo was obtained of mice dorsal skin at 0, 24, 48, 72 hours after irradiation respectively. And then the results were quantitatively analyzed combined with histological information. The experimental results showed that, PUVA-induced photo-damaged skin had an increase in epidermal thickness (ET), a reduction of attenuation coefficient in OCT images signal, and an increase in brightness of the epidermis layer compared with the control group. In conclusion, noninvasive high-resolution imaging techniques such as OCT may be a promising tool for photobiological studies aimed at assessing photo-damage and repair processes in vivo. It can be used to quantitative analysis of changes in photo-damaged skin, such as the ET and collagen in dermis, provides a theoretical basis for treatment and prevention of skin photodamages.

Zhai, Juan; Guo, Zhouyi; Liu, Zhiming; Xiong, Honglian; Zeng, Changchun; Jin, Ying

2009-08-01

71

Eosinophil degranulation status in allergic rhinitis: observations before and during seasonal allergen exposure.  

PubMed

Despite the fact that extensive degranulation is a likely prerequisite for a pathogenic role of eosinophils, little is known about the degranulation status of these cells in eosinophilic conditions. The present study of the ultrastructure of tissue eosinophils explores eosinophil degranulation in allergic rhinitis before and during seasonal allergen exposure. A total of 23 patients scored symptoms q.d., prior to and during the pollen season. The numbers of mucosal eosinophils and their degranulation status were determined in nasal biopsies. Furthermore, nasal lavage fluid levels of eosinophil cationic protein (ECP) and alpha2-macroglobulin were assessed as indices of eosinophil activity and plasma exudation, respectively. Seasonal allergen exposure was associated with increased nasal symptoms, increased lavage fluid levels of ECP and alpha2-macroglobulin, and increased numbers of tissue eosinophils. In the tissue, transmission electron microscopy revealed a moderate piecemeal degranulation already prior to the season (mean+/-sd 37+/-2.7% altered granules). Seasonal allergen exposure increased this degranulation (87+/-1.8%), and produced local areas with extensive deposition of granule proteins. The degree of eosinophil degranulation correlated with levels of ECP in lavage fluids obtained at histamine challenge. In conclusion, this study demonstrated that the nasal mucosa in allergic rhinitis features moderately degranulated eosinophils already at nonsymptomatic baseline conditions. In association with the development of symptomatic seasonal allergic rhinitis, the tissue deposition of eosinophil granule proteins is dramatically elevated through increased eosinophil numbers, together with markedly augmented degranulation of individual cells. PMID:15516668

Ahlstrom-Emanuelsson, C A; Greiff, L; Andersson, M; Persson, C G A; Erjefält, J S

2004-11-01

72

Cell Wall Polysaccharides of Candida albicans Induce Mast Cell Degranulation in the Gut  

PubMed Central

We investigated Candida albicans-induced mast cell degranulation in vitro and in vivo. Cell wall fraction but not culture supernatant and cell membrane fraction prepared from hyphally grown C. albicans induced ?-hexosaminidase release in RBL-2H3 cells. Cell wall mannan and soluble ?-glucan fractions also induced ?-hexosaminidase release. Histological examination of mouse forestomach showed that C. albicans gut colonization induces mast cell degranulation. However, intragastric administration of cell wall fraction failed to induce mast cell degranulation. We propose that cell wall polysaccharides are responsible for mast cell degranulation in the C. albicans-colonized gut.

SAKURAI, Atsuko; YAMAGUCHI, Natsu; SONOYAMA, Kei

2012-01-01

73

Mechanism of Peptide-induced Mast Cell Degranulation . Translocation and Patch-Clamp Studies  

Microsoft Academic Search

Substance P and other polycationic peptides are thought to stimulate mast cell degranulation via di- rect activation of G proteins. We investigated the ability of extracellularly applied substance P to translocate into mast cells and the ability of intracellularly applied substance P to stimulate degranulation. In addition, we studied by reverse transcription—-PCR whether substance P- specific receptors are present in

Dorothea Lorenz; Burkhard Wiesner; Josef Zipper; Anett Winkler; Eberhard Krause; Michael Beyermann; Manfred Lindau; Michael Bienert

1998-01-01

74

Mast cell degranulating (MCD) peptide: a prototypic peptide in allergy and inflammation  

Microsoft Academic Search

The solid phase synthesis of mast degranulating peptide (MCD peptide) raised the possibility of preparing analogs and examining the pharmacology and the proposed role of this peptide as a potential agent in allergy and inflammation. MCD peptide, a cationic 22-amino acid residue peptide with two disulfide bridges, causes mast cell degranulation and histamine release at low concentrations and has anti-inflammatory

Angeliki Buku

1999-01-01

75

Endogenous mast cell degranulation modulates cervical contractility in the guinea pig  

Microsoft Academic Search

OBJECTIVE: The purpose of this study was to investigate the effect of endogenous mast cell degranulation on the contractility of isolated cervical strips from nonpregnant and pregnant guinea pigs. STUDY DESIGN: Longitudinal cervical strips from nonpregnant and pregnant (mid and term) guinea pigs were used for isometric tension recording. Responses to the mast cell degranulating agent, compound 48\\/80, were compared

Egle Bytautiene; Yuri P. Vedernikov; George R. Saade; Roberto Romero; Robert E. Garfield

2002-01-01

76

A New Assay to Monitor the Degranulation Process in Phagocytizing Human Neutrophils  

Microsoft Academic Search

The microbicidal activity of phagocytes depends on intraphagosomal secretion (i.e., the degranulation process), during which the content of the secretory granules is discharged into the phagosome to kill ingested microorganisms. The availability of a reliable assay to quantify the extent of degranulation can be an important tool to gain a deeper insight into the mechanism of bacterial processing in phagocytes

Violetta Borelli; MariaGiovanna Perrotta; Francesca Vita; MariaRosa Soranzo; Giuliano Zabucchi

2002-01-01

77

Effects of cigarette smoke on degranulation and NO production by mast cells and epithelial cells.  

PubMed

Exhaled nitric oxide (eNO) is decreased by cigarette smoking. The hypothesis that oxides of nitrogen (NOX) in cigarette smoke solution (CSS) may exert a negative feedback mechanism upon NO release from epithelial (AEC, A549, and NHTBE) and basophilic cells (RBL-2H3) was tested in vitro. CSS inhibited both NO production and degranulation (measured as release of beta-hexosaminidase) in a dose-dependent manner from RBL-2H3 cells. Inhibition of NO production by CSS in AEC, A549, and NHTBE cells was also dose-dependent. In addition, CSS decreased expression of NOS mRNA and protein expression. The addition of NO inhibitors and scavengers did not, however, reverse the effects of CSS, nor did a NO donor (SNP) or nicotine mimic CSS. N-acetyl-cysteine, partially reversed the inhibition of beta-hexosaminidase release suggesting CSS may act via oxidative free radicals. Thus, some of the inhibitory effects of CSS appear to be via oxidative free radicals rather than a NOX-related negative feedback. PMID:16168067

Wei, Xiu M; Kim, Henry S; Kumar, Rakesh K; Heywood, Gavin J; Hunt, John E; McNeil, H Patrick; Thomas, Paul S

2005-01-01

78

IgE-induced degranulation of mucosal mast cells is negatively regulated via nicotinic acetylcholine receptors.  

PubMed

The autonomic nervous system is known to mediate mast cell activation. We investigated expression of nicotinic acetylcholine receptors (nAChRs) in mucosal-type mast cells and their contribution to the regulation of mast cell activation. Expression of mRNA of nAChR alpha4, alpha7, and beta2 subunits were detected in specially differentiated mucosal-type murine bone marrow-derived mast cells (mBMMCs). Pretreatment with non-specific nAChRs agonists, acetylcholine, nicotine and epibatidine and a specific alpha7 subunit agonist GTS-21 significantly inhibited antigen-induced degranulation of mBMMCs in a dose-dependent manner and GTS-21-induced inhibition was significantly blocked by alpha7 subunit antagonist, alpha-bungarotoxin. Furthermore, confocal microscopy also demonstrated surface binding of alpha-bungarotoxin on mBMMCs. Our findings indicate that mucosal mast cell activation may be negatively regulated mainly through nAChR alpha7 subunit, suggesting that nAChRs are involved in neuronal-mucosal mast cell interactions. PMID:18848921

Kageyama-Yahara, Natsuko; Suehiro, Yoko; Yamamoto, Takeshi; Kadowaki, Makoto

2008-12-01

79

Combination therapy with oral PUVA and corticosteroid for recalcitrant alopecia areata.  

PubMed

Alopecia areata (AA) is regarded as a tissue-specific autoimmune disease for which several therapies have been suggested to modify the immune reaction against HFs, such as contact immunotherapy, psoralen plus ultraviolet A (PUVA), corticosteroids, cyclosporine, minoxidil, and dithranol. However, severe type AA, such as alopecia totalis (AT) and alopecia universalis (AU), often show resistance against these therapies. We applied a combination therapy with oral corticosteroid and oral PUVA for intractable cases of AT and AU. These patients took 20 mg/day corticosteroid and were irradiated with UVA on the whole body 2 h after taking methoxsalen for 1 month. In all patients, the terminal hair on the whole scalp regrew after 2 months. Two patients had a relapse of hair loss 3 months after the termination of the treatment. FACS analysis revealed that the CD4+CD25(high) and CD4+CD25+FOXP3+ Treg population in PBMC was increased after the combination therapy. Furthermore, the number of infiltrating cells decreased and FOXP3+ cells were often found in lesion skin after the combination therapy. Mitogen-induced proliferation tests showed low responses against PHA and Con A after the combination therapy. Taken together, the combination therapy may modify the systemic immune system and increase the number of Treg cells, resulting in improvement of recalcitrant AA. PMID:19301021

Ito, Taisuke; Aoshima, Masahiro; Ito, Natsuho; Uchiyama, Izumi; Sakamoto, Keiko; Kawamura, Tetsuya; Yagi, Hiroaki; Hashizume, Hideo; Takigawa, Masahiro

2009-06-01

80

Ultrastructural modification of the plasma membrane in HUT 102 lymphoblasts by long-wave ultraviolet light, psoralen, and PUVA  

SciTech Connect

Ultrastructural alterations of the plasma membrane in HUT 102 lymphoblasts were assessed after a 2-h interaction with a suprapharmacologic (15 micrograms/ml) concentration of 8-MOP, 2-h irradiation with UVA (2.1 mW/cm2), and the exposure of the HUT 102 cells to PUVA under the same conditions. The dark reaction of HUT cells with 8-MOP resulted in the disappearance of microvilli, the emergence of plasma-membrane-associated spherical bodies, formation of lamellar fungiform membrane evaginations, and, in approximately 1% of the cells, formation of uropods and cell capping. Except for uropod formation and cell capping, UVA has induced the same plasma-membrane alterations, and was more deleterious to structural cytoplasmic integrity than 8-MOP. Morphologic changes of the plasma membrane in PUVA-exposed cells tended to replicate structural alterations elicited independently during the dark reaction by suprapharmacologic 8-MOP concentrations. Partial retention of microvilli by cells after PUVA was the sole exception. In light of all available evidence we conclude that psoralen during the dark reactions interacts with plasma membrane lipids by as yet undisclosed mechanisms and that in addition to lipids, membrane proteins are also the primary target of the initial interaction of HUT 102 cells with psoralen during PUVA treatment.

Malinin, G.I.; Lo, H.K.; Hornicek, F.J.; Malinin, T.I. (Georgetown Univ., Washington, DC (USA))

1990-07-01

81

Sulfur mustard primes human neutrophils for increased degranulation and stimulates cytokine release via TRPM2/p38 MAPK signaling  

SciTech Connect

Sulfur mustard (2,2?-bis-chloroethyl-sulfide; SM) has been a military threat since the World War I. The emerging threat of bioterrorism makes SM a major threat not only to military but also to civilian world. SM injury elicits an inflammatory response characterized by infiltration of neutrophils. Although SM was reported to prime neutrophils, the mechanism has not been identified yet. In the present study, we investigated the mechanism of SM-induced priming in human neutrophils. SM increased [Ca{sup 2+}]{sub i} in human neutrophils in a concentration-dependent fashion. Transient receptor potential melastatin (TRPM) 2 inhibitors (clotrimazole, econazole and flufenamic acid) and silencing of TRPM2 by shRNA attenuated SM-induced [Ca{sup 2+}]{sub i} increase. SM primed degranulation of azurophil and specific granules in response to activation by fMLP as previously reported. SB203580, an inhibitor of p38 MAPK, inhibited SM-induced priming. Neither PD98057, an ERK inhibitor, nor SP600215, a JNK inhibitor, inhibited SM-induced priming. In addition, SM enhanced phosphorylation of NF-kB p65 and release of TNF-?, interleukin (IL)-6 and IL-8. SB203580 inhibited SM-induced NF-kB phosphorylation and cytokine release. These results suggest the involvement of TRPM2/p38 MAPK pathway in SM-induced priming and cytokines release in neutrophils. -- Highlights: ? SM increased [Ca{sup 2+}]{sub i} in human neutrophils through TPRM2-mediated calcium influx. ? SM primed degranulation of azurophil and specific granules. ? SM enhanced p38 MAPK and NF-?B p65 phosphorylation in human neutrophils. ? SM enhanced release of TNF-?, interleukin (IL)-6 and IL-8 from human neutrophils. ? SB203580 inhibited SM-induced priming, NF-?B p65 phosphorylation and cytokine release.

Ham, Hwa-Yong [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of)] [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of); Hong, Chang-Won, E-mail: chyj7983@hallym.ac.kr [Department of Chemical and Biological Warfare Research, The Armed Forces Medical Research Institute, Daejeon (Korea, Republic of)] [Department of Chemical and Biological Warfare Research, The Armed Forces Medical Research Institute, Daejeon (Korea, Republic of); Lee, Si-Nae [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of)] [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of); Kwon, Min-Soo [Department of Pharmacology, School of Medicine, CHA University, Seongnam (Korea, Republic of)] [Department of Pharmacology, School of Medicine, CHA University, Seongnam (Korea, Republic of); Kim, Yeon-Ja [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of)] [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of); Song, Dong-Keun, E-mail: dksong@hallym.ac.kr [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of)] [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of)

2012-01-01

82

Technical Advance: Soluble OX40 molecule mimics regulatory T cell modulatory activity on Fc?RI-dependent mast cell degranulation  

PubMed Central

Tregs play a central role in modulating Fc?RI-dependent MC effector functions in the course of the allergic response. Cellular interaction depends on the constitutive expression of OX40 on Tregs and the OX40L counterpart on MCs. Study of OX40L signaling on MCs is hampered by the need of a highly purified molecule, which triggers OX40L specifically. We now report that sOX40 mimics the physiological activity of Treg interaction by binding to activated MCs. When treated with sOX40, activated MCs showed decreased degranulation and Ca++ influx, whereas PLC-?2 phosphorylation remained unaffected. Once injected into experimental animals, sOX40 not only located within the endothelium but also in parenchyma, where it could be found in close proximity and apparently bound to MCs. This soluble molecule triggers MC-OX40L without the requirement of Tregs, thus allowing study of OX40L signaling pathways in MCs and in other OX40L-expressing cell populations. Importantly, as sOX40 inhibits MC degranulation, it may provide an in vivo therapeutic tool in allergic disease.

Sibilano, Riccardo; Gri, Giorgia; Frossi, Barbara; Tripodo, Claudio; Suzuki, Ryo; Rivera, Juan; MacDonald, Andrew S.; Pucillo, Carlo E.

2011-01-01

83

Cycloartenyl ferulate, a component of rice bran oil-derived gamma-oryzanol, attenuates mast cell degranulation.  

PubMed

IgE-targeting therapy could provide significant progress in the treatment of allergic inflammation. In this study, we examined the effect of cycloartenyl ferulate (cycloartenol ferulic acid ester; CAF), a natural product from rice bran oil-derived gamma-oryzanol, on allergic reaction. When CAF and gamma-oryzanol were injected intradermally with anti-DNP IgE into the dorsal skin of rats, the passive cutaneous anaphylaxis reaction induced by DNP-HSA was attenuated. CAF and gamma-oryzanol also inhibited the degranulation of DNP-IgE sensitized RBL-2H3 mast cells stimulated with anti-DNP-HSA. IgE conjugated with CAF could not be detected by anti-IgE antibody in the ELISA analysis. Although incubation of IgE with CAF did not decrease the amount of IgE, it was possible to precipitate IgE by centrifugation. These results demonstrate that CAF captures IgE, prevents it from binding to FcepsilonRI, and attenuates mast cell degranulation. PMID:19577449

Oka, T; Fujimoto, M; Nagasaka, R; Ushio, H; Hori, M; Ozaki, H

2010-02-01

84

Disparity in Fc?RI-induced degranulation of primary human lung and skin mast cells exposed to adenosine  

PubMed Central

Inhaled and intravenously administered adenosine induces mast cell-mediated (histamine-dependent) bronchospasm in asthmatics without causing urticaria. A differential response to adenosine by human lung and skin mast cells is shown: low concentrations potentiate Fc?RI-induced degranulation of human lung mast cells but not that of skin mast cells. Human lung mast cells were found to express ~3-fold more A3AR mRNA than skin mast cells, suggesting the involvement of the Gi-linked A3AR. Indeed, the adenosine-induced potentiation was sensitive to inhibition by pertussis toxin, and, furthermore, could be induced with an A3AR-specific agonist. This study reveals a previously unrecognized disparity in the response to adenosine by primary human mast cells from lung and skin that might explain why adenosine induces a pulmonary but not dermatologic allergy-like response in vivo. In addition, we identify the A3AR as a potentiating receptor of Fc?RI-induced degranulation, thereby implicating it in the in vivo bronchoconstrictive response to adenosine in asthmatics.

Gomez, Gregorio; Zhao, Wei; Schwartz, Lawrence B.

2012-01-01

85

Dissociation of the 47-Kilodalton Protein Phosphorylation From Degranulation and Superoxide Production in Neutrophils  

Microsoft Academic Search

The aim for the present studies is to examine the relationship between the phosphory- lation of the 47-kDa protein and some neutrophil responses such as degranulation, the synergistic effect of PMA on calcium lonophore-induced degranulation, superoxide generation, and the priming of the oxidative burst produced by the chemotactic factor fMet-Leu-Phe and phorbol 12-myristate 13-acetate (PMA). incubation of neutrophils with the

T. F. P. Molski; J. Gomez-Cambronero; C.-K. Huang

1988-01-01

86

The src Homology 2-Containing Inositol Phosphatase (SHIP) is the Gatekeeper of Mast Cell Degranulation  

Microsoft Academic Search

To clarify the role that the src homology 2-containing inositol phosphatase (SHIP) plays in mast cell degranulation, the gene for SHIP was disrupted by homologous recombination in embryonic stem cells. Bone-marrow-derived mast cells from SHIP+\\/+, +\\/-, and -\\/- F2 littermates were compared. SHIP-\\/- mast cells were found to be far more prone to degranulation, after the crosslinking of IgE preloaded

Michael Huber; Cheryl D. Helgason; Jacqueline E. Damen; Ling Liu; R. Keith Humphries; Gerald Krystal

1998-01-01

87

Synthetic Allergen Design Reveals The Significance of Moderate Affinity Epitopes in Mast Cell Degranulation  

PubMed Central

This study describes the design of a well-defined homotetravalent synthetic allergen (HTA) system to investigate the effect of hapten-IgE interactions on mast cell degranulation. A library of DNP-variants with varying affinities for IgEDNP was generated (Kds 8.1 nM – 9.2 µM), and 8 HTAs spanning this range were synthesized via conjugation of each DNP-variant to the tetravalent scaffold. HTAs with hapten Kds < 235 nM stimulated degranulation following a bell-shaped dose response curve with maximum response occurring near the hapten Kd. HTAs with hapten Kds ? 235 nM failed to stimulate degranulation. To mimic physiological conditions, the percent of allergen specific IgE on cell surface was varied, and maximum degranulation occurred at 25% IgEDNP. These results demonstrated that moderate hapten-IgE affinities are sufficient to trigger mast cell degranulation. Moreover, this study established the HTA design as a well-defined, controllable, and physiologically relevant experimental system to elucidate the mast cell degranulation mechanism.

Handlogten, Michael W.; Kiziltepe, Tanyel; Alves, Nathan J.; Bilgicer, Basar

2012-01-01

88

Singlet oxygen generation in PUVA therapy studied using electronic structure calculations  

NASA Astrophysics Data System (ADS)

The ability of furocoumarins to participate in the PUVA (Psoralen + UV-A) therapy against skin disorders and some types of cancer, is analyzed on quantum chemical grounds. The efficiency of the process relies on its capability to populate its lowest triplet excited state, and then either form adducts with thymine which interfere DNA replication or transfer its energy, generating singlet molecular oxygen damaging the cell membrane in photoactivated tissues. By determining the spin-orbit couplings, shown to be the key property, in the intersystem crossing yielding the triplet state of the furocoumarin, the electronic couplings in the triplet-triplet energy transfer process producing the singlet oxygen, and the reaction rates and lifetimes, the efficiency in the phototherapeutic action of the furocoumarin family is predicted as: khellin < 5-methoxypsoralen (5-MOP) < 8-methoxypsoralen (8-MOP) < psoralen < 4,5',8-trimethylpsoralen (TMP) < 3-carbethoxypsoralen (3-CPS), the latter being the most efficient photosensitizer and singlet oxygen generator.

Serrano-Pérez, Juan José; Olaso-González, Gloria; Merchán, Manuela; Serrano-Andrés, Luis

2009-06-01

89

Neuropeptides degranulate serous cells of ferret tracheal glands  

SciTech Connect

To determine whether serous or mucous cells in tracheal submucosal glands respond to the neuropeptides substance P (SP) and vasoactive intestinal peptide (VIP). The authors studied the peptide-induced changes in gland cell morphology accompanying release of TVSO4-labeled macromolecules from tracheal explants of ferrets. Explants were labeled for 1 h in medium containing TVSO4 and washed for 3.5 additional hours. Base-line secretion in the absence of drugs declined between 1.5 and 3.5 h after the pulse. Between 2.5 and 3.5 h, the average percent change in counts per minute recovered per sample period was not significantly different from zero. Substance P and VIP added 4 h after labeling each increased greatly the release of TVSO4-labeled macromolecules above base line. Bethanechol, a muscarinic-cholinergic agonist, increased secretion by an average of 142% above base line. Light and electron microscopy of the control tissues showed glands with narrow lumens and numerous secretory granules. Glands treated with SP or VIP had enlarged lumens and the serous cells were markedly degranulated. These phenomena were documented by morphometry and suggest that SP and VIP cause secretion from glands at least partially by stimulating exocytosis from serous cells.

Gashi, A.A.; Borson, D.B.; Finkbeiner, W.E.; Nadel, J.A.; Basbaum, C.B.

1986-08-01

90

Luminol-dependent photoemission from single neutrophil stimulated by phorbol ester and calcium ionophore--role of degranulation and myeloperoxidase  

SciTech Connect

Luminol-dependent photonic burst from phorbol ester-treated single neutrophil was visually investigated by using an ultrasensitive photonic image intensifier microscope. Neutrophils stimulated by phorbol myristate acetate (0.1 microgram/ml) alone produced a negligible level of photonic activities in the presence of luminol (10 micrograms/ml). The additional application of 0.1 microM Ca2+ ionophore A23187 induced explosive changes of photonic burst corresponding to the distribution of neutrophils, and these photonic activities were gradually spread to extracellular space. Sodium azide, which prevents myeloperoxidase activity, inhibited Ca2+ ionophore-induced photonic burst from phorbol ester-treated neutrophil. These findings suggest a prerequisite role of degranulation and myeloperoxidase release in luminol-dependent photoemission from stimulated neutrophils.

Suematsu, M.; Oshio, C.; Miura, S.; Suzuki, M.; Houzawa, S.; Tsuchiya, M.

1988-08-30

91

Technical report: effects of PUVA treatment on the optical properties of blood/tissue storage bags during extracorporeal photochemotherapy.  

PubMed

Extracorporeal photochemotherapy (photopheresis, ECP) is a novel therapeutic method for patients who do not respond to immunosuppressive medications, and gaining interest in the treatment of Graft-vs-Host Disease. This paper is focused on the optical transmission properties of plastic bags which can be used in an independent (off-line) method of ECP, and reports the results of spectral measurements on various bags of different chemical compositions, with and without PUVA treatment. Regarding their higher and more uniform UVA transmission values, FEP based bags perform superior to the others. Considering its UVB absorption and UVA transmission properties, the EVA bag is a good choice, while Polyimide Kapton-FEP plastic film should not be considered for use in ECP. PUVA treatment of blood bags may affect their optical behaviour, and causes reduction of transmission of the material in UV range of the spectrum. PMID:17962078

Keskin, Ali Umit

2007-10-01

92

Effects of dirithromycin and erythromycylamine on human neutrophil degranulation.  

PubMed Central

Dirithromycin and, to a lesser extent, erythromycylamine and erythromycin directly induced the release of three intragranular enzymes (lysozyme, lactoferrin, and beta-glucuronidase) from unstimulated human neutrophils. Macrolide-induced enzyme release was dependent upon the incubation time (30 to 180 min) and drug concentration. Dirithromycin was the most effective. At 120 min, release of lysozyme, beta-glucuronidase, and lactoferrin by macrolide (100 micrograms/ml)-treated cells, expressed as a percentage of total enzyme content, was, respectively, 58% +/- 8.3%, 52% +/- 10.7%, and 35% +/- 5.1% (dirithromycin); 42% +/- 3.9%, 28% +/- 5.8%, and 10% +/- 2.2% (erythromycylamine); and 35% +/- 4.0%, 19% +/- 4.3%, and 10% +/- 5.2% (erythromycin) (mean +/- standard error of the mean of three to eight experiments). The lowest macrolide concentrations which induced significant enzyme release were 10, 100, and 25 micrograms/ml, respectively, for dirithromycin, erythromycylamine, and erythromycin. Furthermore, we obtained evidence of a link between the prodegranulation effects of dirithromycin and erythromycylamine and the intragranular location of these drugs. Indeed, cell-associated drug levels increased for up to 60 min and then plateaued and declined substantially. Increasing the pH from 7 to 9 resulted in a parallel increase in drug uptake and the prodegranulation effect. Finally, when macrolide-treated neutrophils were disrupted by sonication and centrifuged, a correlation was found between lysozyme and beta-glucuronidase activities (both granule markers) and pellet-associated macrolide levels. Taken together, our results suggest that dirithromycin and erythromycylamine concentrate within neutrophil granules and then induce degranulation.

Abdelghaffar, H; Mtairag, E M; Labro, M T

1994-01-01

93

miR-142-3p enhances Fc?RI-mediated degranulation in mast cells.  

PubMed

Mast cells are immune cells derived from hematopoietic progenitors. When they are activated by stimuli, they immediately release granule-associated mediators, leading to allergic inflammation. Several factors controlling mediator release have been identified; however, little is known whether microRNAs (miRNAs) are involved in this process. miRNAs are a small class of non-coding RNAs that negatively regulate gene expression. In this study, we investigated the relationship between miRNAs and degranulation in LAD2 cells, a human mast cell line. We demonstrated that silencing of Dicer, a key enzyme of miRNA biogenesis, attenuates degranulation, indicating that miRNAs are involved in mast cell degranulation. We furthermore discovered that the overexpression of miR-142-3p enhances Fc?RI-mediated degranulation and that miR-142-3p rescues the reduction of degranulation by silencing Dicer. Similar effects were observed in bone marrow-derived mast cells obtained miR-142-3p-deficient mice. Our studies suggest that miR-142-3p is a potential therapeutic target in pathological conditions caused by mast cells, such as mastocytosis and allergies. PMID:24361879

Yamada, Yoji; Kosaka, Kyoko; Miyazawa, Tatsuya; Kurata-Miura, Kazumi; Yoshida, Tetsuo

2014-01-17

94

Diacylglycerol kinase ? regulates antigen-induced mast cell degranulation by mediating Ca(2+) influxes.  

PubMed

Diacylglycerol (DAG) is an important lipid that acts as a signaling messenger during mast cell degranulation after allergen cross-linking of immunoglobulin (Ig) E-bound Fc?RI receptors. In this study, we determined the role of diacylglycerol kinase (DGK), which negatively regulates DAG-dependent signaling by converting DAG to phosphatidic acid (PA), in the regulation of mast cell degranulation. Treating RBL (rat basophilic leukemia)-2H3 mast cells with a type I DGK inhibitor significantly reduced antigen-induced degranulation and PA production. Among type I DGK isoforms, we observed that DGK? and DGK? mRNAs were expressed in RBL-2H3 mast cells using reverse transcription polymerase chain reaction. DGK? knockdown, but not DGK?, by isoform-specific short hairpin RNAs reduced mast cell degranulation and Ca(2+) influxes from the extracellular environment. These results suggest that DGK? regulates mast cell degranulation after Fc?RI cross-linking through mobilization of intracellular Ca(2+) through Ca(2+) influxes. PMID:24513282

Sakuma, Megumi; Shirai, Yasuhito; Ueyama, Takehiko; Saito, Naoaki

2014-03-01

95

Fibronectin degradation products containing the cytoadhesive tetrapeptide stimulate human neutrophil degranulation.  

PubMed

We investigated whether adhesive glycoproteins, such as fibronectin or fibrinogen, could function to provide a nidus for neutrophil degranulation. Elastase release in recalcified plasma was normal in afibrinogenemic plasma, but 73% less in plasma depleted of fibronectin. Proteolytic digests of fibronectin, but not intact fibronectin (50-1,000 micrograms/ml), induced a concentration-dependent release of neutrophil elastase and lactoferrin. MAbs N293, which recognized the mid-molecule of fibronectin, N294, which was directed toward the 11-kD cell adhesive fragment, and N295, generated against the amino terminal of the 11-kD fragment, inhibited the release of elastase by 7, 24, and 60%, respectively. The cytoadhesive tetrapeptide portion of fibronectin, Arg-Gly-Asp-Ser (250-1,000 micrograms/ml), released 1.94 +/- 0.10 micrograms/ml of elastase from 10(7) neutrophils, in contrast to the lack of release by the control hexapeptide, Arg-Gly-Tyr-Ser-Leu-Gly. Plasmin appeared to be the enzyme responsible for fibronectin cleavage, since neutrophil elastase release in plasma that had been depleted of plasminogen was decreased and reconstitution of plasminogen-deficient plasma with purified plasminogen corrected the abnormal release. Plasmin cleaved fibronectin to multiple degradation products, each less than 200 kD. This fibronectin digest released 1.05 microgram/ml of elastase from 10(7) neutrophils. We suggest that the activation of plasminogen leads to the formation of fibronectin degradation products capable of functioning as agonists for neutrophils. PMID:2966812

Wachtfogel, Y T; Abrams, W; Kucich, U; Weinbaum, G; Schapira, M; Colman, R W

1988-05-01

96

Hypohalous acid-modified human serum albumin induces neutrophil NADPH oxidase activation, degranulation, and shape change.  

PubMed

Halogenated lipids, proteins, and lipoproteins formed in reactions with myeloperoxidase (MPO)-derived hypochlorous acid (HOCl) and hypobromous acid (HOBr) can contribute to the regulation of functional activity of cells and serve as mediators of inflammation. Human serum albumin (HSA) is the major plasma protein target of hypohalous acids. This study was performed to assess the potency of HSA modified by HOCl (HSA-Cl) and HOBr (HSA-Br) to elicit selected neutrophil responses. HSA-Cl/Br were found to induce neutrophil degranulation, generation of reactive oxygen intermediates, shape change, and actin cytoskeleton reorganization. Thus HSA-Cl/Br can initially act as a switch and then as a feeder of the "inflammatory loop" under oxidative stress. In HSA-Cl/Br-treated neutrophils, monoclonal antibodies against CD18, the ? subunit of ?2 integrins, reduced the production of superoxide anion radicals and hydrogen peroxide as well as MPO exocytosis, suggesting that CD18 contributed to neutrophil activation. HSA-Cl/Br-induced neutrophil responses were also inhibited by genistein, a broad-specificity tyrosine kinase inhibitor, and wortmannin, a phosphoinositide 3-kinase (PI3K) inhibitor, supporting the notion that activation of both tyrosine kinase and PI3K may play a role in neutrophil activation by HSA modified in MPO-dependent reactions. These results confirm the hypothesis that halogenated molecules formed in vivo via MPO-dependent reactions can be considered as a new class of biologically active substances potentially able to contribute to activation of myeloid cells in sites of inflammation and serve as inflammatory response modulators. PMID:24384524

Gorudko, Irina V; Grigorieva, Daria V; Shamova, Ekaterina V; Kostevich, Valeria A; Sokolov, Alexey V; Mikhalchik, Elena V; Cherenkevich, Sergey N; Arnhold, Jürgen; Panasenko, Oleg M

2014-03-01

97

Lymphopenia and decrease in the total number of circulating CD3+ and CD4+ T cells during 'long-term' PUVA treatment for psoriasis.  

PubMed

The relationship between high-dose PUVA treatment in psoriatic patients and peripheral T lymphocyte subsets (total number and percentage) has been studied. Of the two groups of patients considered, the first included 19 patients, all affected by chronic, progressively worsening psoriasis; they had never been previously treated by photochemotherapy. The second group included 13 psoriatic patients, who had received an average cumulative dose of 2,007.69 +/- 1,191.05 J/cm2. The 'long-term' PUVA-treated group was assessed while undergoing maintenance therapy. No significant differences were found between untreated patients and healthy controls for any of the parameters considered. A significant reduction (p less than 0.05) in the total number of lymphocytes in long-term PUVA-treated patients both versus untreated patients and controls was found. Furthermore, long-term PUVA-treated patients showed a significant reduction (p less than 0.05) in the percentage of lymphocytes as compared with controls. The reduction in the total number of CD3+ and CD4+ T cells was, moreover, significant (p less than 0.05) as compared with untreated patients. The impairment of circulating CD3+ and CD4+ T cells (total number) was only on the borderline of statistical significance vis-à-vis controls. These findings suggest the usefulness of a careful assessment of circulating T lymphocyte subsets in patients who undergo long-term PUVA therapy. PMID:1837524

Borroni, G; Zaccone, C; Vignati, G; Fietta, A; Gatti, M; Brazzelli, V; Rabbiosi, G

1991-01-01

98

Sulfur mustard primes human neutrophils for increased degranulation and stimulates cytokine release via TRPM2/p38 MAPK signaling.  

PubMed

Sulfur mustard (2,2'-bis-chloroethyl-sulfide; SM) has been a military threat since the World War I. The emerging threat of bioterrorism makes SM a major threat not only to military but also to civilian world. SM injury elicits an inflammatory response characterized by infiltration of neutrophils. Although SM was reported to prime neutrophils, the mechanism has not been identified yet. In the present study, we investigated the mechanism of SM-induced priming in human neutrophils. SM increased [Ca(2+)](i) in human neutrophils in a concentration-dependent fashion. Transient receptor potential melastatin (TRPM) 2 inhibitors (clotrimazole, econazole and flufenamic acid) and silencing of TRPM2 by shRNA attenuated SM-induced [Ca(2+)](i) increase. SM primed degranulation of azurophil and specific granules in response to activation by fMLP as previously reported. SB203580, an inhibitor of p38 MAPK, inhibited SM-induced priming. Neither PD98057, an ERK inhibitor, nor SP600215, a JNK inhibitor, inhibited SM-induced priming. In addition, SM enhanced phosphorylation of NF-kB p65 and release of TNF-?, interleukin (IL)-6 and IL-8. SB203580 inhibited SM-induced NF-kB phosphorylation and cytokine release. These results suggest the involvement of TRPM2/p38 MAPK pathway in SM-induced priming and cytokines release in neutrophils. PMID:22036725

Ham, Hwa-Yong; Hong, Chang-Won; Lee, Si-Nae; Kwon, Min-Soo; Kim, Yeon-Ja; Song, Dong-Keun

2012-01-01

99

Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts  

PubMed Central

Background The purpose of this study was to test the hypothesis that mast cells that are present in fibrotic regions of cancer can suppress the growth of tumor cells through an indirect mechanism involving peri-tumoral fibroblasts. Methods We first immunostained a wide variety of human cancers for the presence of degranulated mast cells. In a subsequent series of controlled in vitro experiments, we then co-cultured UACC-812 human breast cancer cells with normal fibroblasts in the presence or absence of different combinations and doses of mast cell tryptase, mast cell heparin, a lysate of the human mast cell line HMC-1, and fibroblast growth factor-7 (FGF-7), a powerful, heparin-binding growth factor for breast epithelial cells. Results Degranulating mast cells were localized predominantly in the fibrous tissue of every case of breast cancer, head and neck cancer, lung cancer, ovarian cancer, non-Hodgkin's lymphoma, and Hodgkin's disease that we examined. Mast cell tryptase and HMC-1 lysate had no significant effect on the clonogenic growth of cancer cells co-cultured with fibroblasts. By contrast, mast cell heparin at multiple doses significantly reduced the size and number of colonies of tumor cells co-cultured with fibroblasts, especially in the presence of FGF-7. Neither heparin nor FGF-7, individually or in combination, produced any significant effect on the clonogenic growth of breast cancer cells cultured without fibroblasts. Conclusion Degranulating mast cells are restricted to peri-tumoral fibrous tissue, and mast cell heparin is a powerful inhibitor of clonogenic growth of tumor cells co-cultured with fibroblasts. These results may help to explain the well-known ability of heparin to inhibit the growth of primary and metastatic tumors.

Samoszuk, Michael; Kanakubo, Emi; Chan, John K

2005-01-01

100

Defective cytotoxic lymphocyte degranulation in syntaxin-11-deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients  

PubMed Central

Familial hemophagocytic lymphohistiocytosis (FHL) is typically an early onset, fatal disease characterized by a sepsislike illness with cytopenia, hepatosplenomegaly, and deficient lymphocyte cytotoxicity. Disease-causing mutations have been identified in genes encoding perforin (PRF1/FHL2), Munc13-4 (UNC13D/FHL3), and syntaxin-11 (STX11/FHL4). In contrast to mutations leading to loss of perforin and Munc13-4 function, it is unclear how syntaxin-11 loss-of-function mutations contribute to disease. We show here that freshly isolated, resting natural killer (NK) cells and CD8+ T cells express syntaxin-11. In infants, NK cells are the predominant perforin-containing cell type. NK cells from FHL4 patients fail to degranulate when encountering susceptible target cells. Unexpectedly, IL-2 stimulation partially restores degranulation and cytotoxicity by NK cells, which could explain the less severe disease progression observed in FHL4 patients, compared with FHL2 and FHL3 patients. Since the effector T-cell compartment is still immature in infants, our data suggest that the observed defect in NK-cell degranulation may contribute to the pathophysiology of FHL, that evaluation of NK-cell degranulation in suspected FHL patients may facilitate diagnosis, and that these new insights may offer novel therapeutic possibilities.

Bryceson, Yenan T.; Rudd, Eva; Zheng, Chengyun; Edner, Josefine; Ma, Daoxin; Wood, Stephanie M.; Bechensteen, Anne Grete; Boelens, Jaap J.; Celkan, Tiraje; Farah, Roula A.; Hultenby, Kjell; Winiarski, Jacek; Roche, Paul A.; Nordenskjold, Magnus

2007-01-01

101

Effect of eosinophil-degranulating estrogens on spleen eosinophils and white pulp\\/red pulp ratio  

Microsoft Academic Search

A role for eosinophils in the immune reaction has not been yet established. Considering that these leukocytes accumulate in lymphoid organs under glucocorticoid stimulation, we explored the possibility that they participate in the depression of immune reactions induced by these hormones and that they degranulate to exert this action. In this context, we investigated the dose effect of three estrogens

A. N. Tchernitchin; W. Carter; J. Soto; P. Baumann

1990-01-01

102

Charcot-Leyden crystal protein in the degranulation and recovery of activated basophils  

Microsoft Academic Search

The Charcot-Leyden crystal (CLC) protein, a prominent cell constituent unique to eosinophils and basophils, possesses lysophospholipase activity. This ac- tivity and the extracellular deposition and formation of CLC in tissues and body fluids in association with eo- sinophils suggest an extracellular function for this protein in inflammation. During degranulation, basophils release granule-derived mediators of inflammation. We postu- lated that CLC

Linnie M. Golightly; Larry L. Thomas; Ann M. Dvorak; Steven J. Ackerman

1992-01-01

103

The role of SHIP in mast cell degranulation and IgE-induced mast cell survival  

Microsoft Academic Search

Atopic disorders are on the increase in the Western world and are due, at least in part, to an overactive mast cell response. A better understanding of the intracellular signalling pathways that regulate both mast cell degranulation and the secretion of arachidonic acid metabolites and inflammatory cytokines could help in the treatment of these disorders. The src homology 2-containing inositol-polyphosphate

Michael Huber; Janet Kalesnikoff; Michael Reth; Gerald Krystal

2002-01-01

104

CNS INDUCED NEUROGENIC CYSTITIS IS ASSOCIATED WITH BLADDER MAST CELL DEGRANULATION IN THE RAT  

Microsoft Academic Search

Purpose: To determine if bladder mast cell degranulation is involved in the genesis of neuro- genic cystitis induced by pseudorabies virus (PRV) invasion of the central nervous system (CNS). Materials and Methods: Rats received a total of 4 3 10 6 plaque forming units (pfu) of PRV-Bartha in the abductor caudalis dorsalis (ACD) muscle. Granulated bladder mast cells per mm

LUC JASMIN; GABRIELLA JANNI; PETER T. OHARA; SAMUEL D. RABKIN

2000-01-01

105

Mast cell degranulation during abdominal surgery initiates postoperative ileus in mice  

Microsoft Academic Search

Background & Aims: Inflammation of the intestinal muscularis following manipulation during surgery plays a crucial role in the pathogenesis of postoperative ileus. Here, we evaluate the role of mast cell activation in the recruitment of infiltrates in a murine model. Methods: Twenty-four hours after control laparotomy or intestinal manipulation, gastric emptying was determined. Mast cell degranulation was determined by measurement

Wouter J. de Jonge; Frans O. The; Dennis van der Coelen; Roelof J. Bennink; Pieter H. Reitsma; Sander J. van Deventer; René M. Van den Wijngaard; Guy E. Boeckxstaens

2004-01-01

106

Mast Cell Degranulation in the Evolution of Acute Eruptive Guttate Psoriasis Vulgaris  

Microsoft Academic Search

Clinically normal psoriatic skin (CNPS) and psoriatic lesions (PLs) were studied for mast cell degranulation (MCD) in patients with acute eruptive guttate psoriasis vulgaris (AEGP) following penicillin-treated acute streptococcal throat infection. The clinically manifest duration of psoriasis at the time of the biopsies was 2, 5, 10, 14, or 21 days. Two types of MCD were distinguished. Type I was

Isser Brody

1984-01-01

107

Ultraviolet B irradiation of skin induces mast cell degranulation and release of tumour necrosis factor-?  

Microsoft Academic Search

In the ‘sunburn’ response in skin, dermal blood vessels are activated and traffic of dendritic Langerhans' cells altered. While these changes have been attributed to the cytokine TNF-?, the source of this acutely released TNF has not been identified. This report demonstrates that the ‘sunburn’ response, both in vivo and in vitro, is accompanied by rapid degranulation of cutaneous mast

Laurence J Walsh

1995-01-01

108

Chlorine inhalation produces nasal congestion in allergic rhinitics without mast cell degranulation  

Microsoft Academic Search

Seasonal allergic rhinitic (SAR) subjects are more sensitive to nasal irritants than nonrhinitic (NR) subjects; however, the mechanism underlying this difference is unclear. This study sought to determine whether irritant-induced nasal congestion involves mast cell degranulation. Eight SAR and eight NR subjects were exposed to both 1.0 parts per million chlorine and ® ltered air in separate visits; exposures were

D. Shusterman; J. Balmes; P. C. Avila; M. A. Murphy; E. Matovinovic

2003-01-01

109

Inflammatory mediators in dengue virus infection in children: interleukin-8 and its relationship to neutrophil degranulation  

Microsoft Academic Search

The chemokine interleukin-8 (IL-8) has chemoattractant activity for neutrophils and is able to activate and degranulate these cells. We investigated whether IL-8 may exert these effects in children with dengue virus infection. Circulating levels of IL-8, neutrophilic elastase (a constituent of the azurophilic granula of neutrophils), and lactoferrin, released from specific granula, were measured in 186 children with dengue virus

M. Juffrie; Meer van der G. M; C. E. Hack; K. Haasnoot; A. J. P. Veerman; L. G. Thijs

2000-01-01

110

Two modes of lytic granule fusion during degranulation by natural killer cells  

Microsoft Academic Search

Lytic granules in cytotoxic lymphocytes, which include T cells and natural killer (NK) cells, are secretory lysosomes that release their content upon fusion with the plasma membrane (PM), a process known as degranulation. Although vesicle exocytosis has been extensively studied in endocrine and neuronal cells, much less is known about the fusion of lytic granules in cytotoxic lymphocytes. Here, we

Dongfang Liu; Jose A Martina; Xufeng S Wu; John A Hammer III; Eric O Long

2011-01-01

111

REVIEW: The contribution of medical physics to the development of psoralen photochemotherapy (PUVA) in the UK: a personal reminiscence  

NASA Astrophysics Data System (ADS)

Psoralen photochemotherapy (PUVA) is the combined treatment of skin disorders with a photosensitizing drug (Psoralen) and UltraViolet A radiation. The introduction of PUVA therapy has arguably been the most important development in dermatology over the past 30 years and from the first days of the treatment being introduced in the UK, British medical physicists were an integral part of the effort to establish it. Medical physicists have contributed to this development in a number of ways, from designing irradiation units in the early days of the technique, through to collaborating with dermatologists in prosecuting clinical and experimental studies aimed at improving patient outcomes. That the dose of UVA radiation is administered quantitatively, and not qualitatively, has probably been the single most important contribution made by several medical physicists over this period. However, despite concerns that were expressed almost 30 years ago about the accuracy with which UVA doses are administered to patients, the medical physics community still has some way to go before we can be satisfied that statements about UVA irradiance and dose can be made with confidence.

Diffey, Brian

2006-07-01

112

UVA/UVA1 phototherapy and PUVA photochemotherapy in connective tissue diseases and related disorders: a research based review  

PubMed Central

Background Broad-band UVA, long-wave UVA1 and PUVA treatment have been described as an alternative/adjunct therapeutic option in a number of inflammatory and malignant skin diseases. Nevertheless, controlled studies investigating the efficacy of UVA irradiation in connective tissue diseases and related disorders are rare. Methods Searching the PubMed database the current article systematically reviews established and innovative therapeutic approaches of broad-band UVA irradiation, UVA1 phototherapy and PUVA photochemotherapy in a variety of different connective tissue disorders. Results Potential pathways include immunomodulation of inflammation, induction of collagenases and initiation of apoptosis. Even though holding the risk of carcinogenesis, photoaging or UV-induced exacerbation, UVA phototherapy seems to exhibit a tolerable risk/benefit ratio at least in systemic sclerosis, localized scleroderma, extragenital lichen sclerosus et atrophicus, sclerodermoid graft-versus-host disease, lupus erythematosus and a number of sclerotic rarities. Conclusions Based on the data retrieved from the literature, therapeutic UVA exposure seems to be effective in connective tissue diseases and related disorders. However, more controlled investigations are needed in order to establish a clear-cut catalogue of indications.

Breuckmann, Frank; Gambichler, Thilo; Altmeyer, Peter; Kreuter, Alexander

2004-01-01

113

Alteration of lymphocyte functions by 8-methoxypsoralen and longwave ultraviolet radiation. I. Suppressive effects of PUVA on T-lymphocyte migration in vitro  

SciTech Connect

We investigated the influence of 8-methoxypsoralen (8-MOP) plus long-wave ultraviolet radiation (PUVA) on lymphocyte migration in vitro. Nylon wool-purified, mouse splenic T lymphocytes showed locomotive responses to casein, normal mouse serum (NMS), and zymosan-activated mouse serum (ZAS). Migratory responses to casein and NMS, and to ZAS were remarkably suppressed in lymphocytes exposed to 0.5 J/cm2 UVA plus 0.1 micrograms/ml 8-MOP and to 0.8 J/cm2 UVA plus 8-MOP, respectively. The PUVA treatment used in the present study had no effect on random movement and lymphocyte viability. T lymphocytes cultured in the absence of mitogenic agent for 24 h demonstrated a greater increase in their migration activity than noncultured cells, while lymphocytes cultured after 1.0 J/cm2 PUVA pretreatment remained low. These findings suggest that the therapeutic effect of PUVA on inflammatory skin disorders may be due in part to the suppression of lymphocyte migration.

Okamoto, H.; Takigawa, M.; Horio, T.

1985-03-01

114

Interactions of mast cell degranulating peptides with model membranes: a comparative biophysical study.  

PubMed

In the last decade, there has been renewed interest in biologically active peptides in fields like allergy, autoimmune diseases and antibiotic therapy. Mast cell degranulating peptides mimic G-protein receptors, showing different activity levels even among homologous peptides. Another important feature is their ability to interact directly with membrane phospholipids, in a fast and concentration-dependent way. The mechanism of action of peptide HR1 on model membranes was investigated comparatively to other mast cell degranulating peptides (Mastoparan, Eumenitin and Anoplin) to evidence the features that modulate their selectivity. Using vesicle leakage, single-channel recordings and zeta-potential measurements, we demonstrated that HR1 preferentially binds to anionic bilayers, accumulates, folds, and at very low concentrations, is able to insert and create membrane spanning ion-selective pores. We discuss the ion selectivity character of the pores based on the neutralization or screening of the peptides charges by the bilayer head group charges or dipoles. PMID:19328184

Dos Santos Cabrera, Marcia Perez; Arcisio-Miranda, Manoel; da Costa, Laiana Cristina; de Souza, Bibiana Monson; Broggio Costa, Sabrina Thaís; Palma, Mario Sérgio; Ruggiero Neto, João; Procopio, Joaquim

2009-06-01

115

Mast cell degranulation mediates compound 48/80-induced hyperalgesia in mice  

PubMed Central

Mast cells mediate allergies, hypersensitivities, host defense, and venom neutralization. An area of recent interest is the contribution of mast cells to inflammatory pain. Here we found that specific, local activation of mast cells produced plantar hyperalgesia in mice. Basic secretagogue compound 48/80 induced plantar mast cell degranulation accompanied by thermal hyperalgesia, tissue edema, and neutrophil influx in the hindpaws of ND4 Swiss mice. Blocking mast cell degranulation, neutrophil extravasation, and histamine signaling abrogated these responses. Compound 48/80 also produced edema, pain, and neutrophil influx in WT C57BL/6 but not in genetically mast cell-deficient C57BL/6-KitW-sh/W-sh mice. These responses were restored following plantar reconstitution with bone marrow-derived cultured mast cells.

Chatterjea, Devavani; Wetzel, Abigail; Mack, Madison; Engblom, Camilla; Allen, Juliann; Mora-Solano, Carolina; Paredes, Luisa; Balsells, Evelyn; Martinov, Tijana

2012-01-01

116

Evaluation of an in vitro degranulation challenge procedure for equine pulmonary mast cells.  

PubMed Central

Pulmonary mast cells (PMC) are important components of the inflammatory process in equine allergic lung diseases such as heaves. Very little, however, is known of the degranulation kinetics of these cells and thus, their pathophysiologic role remains largely speculative. The purpose of this study was to develop a repeatable protocol for in vitro equine PMC degranulation. Five mature horses (sex: 2 M, 3 F; age: 8.8 +/- 6.5 y), historically free of pulmonary disease and normal on clinical respiratory examination, arterial blood gas analysis, pulmonary mechanics testing and histamine inhalation challenge, were studied. Bronchoalveolar lavage was performed on 4 separate occasions, at least 2 d apart, in a different lung lobe on each occasion. The lavage fluid was concentrated by centrifugation. Cells were resuspended in modified HEPES/Tyrode, assessed for viability by Trypan blue exclusion, and PMC concentration determined. Cell inocula containing 30,000 PMC were incubated with 10(-8) to 6 x 10(-5) M A23187. Cells were then separated by centrifugation and histamine release (HR) was determined by fluorometric assay. The procedure was readily performed and yielded sufficient PMC for 30 to 60 inocula per lavage. Maximal HR (34.4 +/- 16.1%) was obtained with 10(-5) M A23187. The degranulation process was largely complete by 20 min but cell lysis was negligible. The challenge was repeatable within horse and produced a mean coefficient of variability of 23.0% following 20 min incubation with 10(-5) M A23187. We conclude that equine PMC degranulation can be repeatably performed in vitro and speculate that this protocol may be useful in further studies on the pathophysiology and treatment of equine allergic lung diseases.

Hare, J E; Viel, L; Conlon, P D; Marshall, J S

1998-01-01

117

IgE-mediated mast cell degranulation and recovery monitored by time-lapse photography  

Microsoft Academic Search

Background: Mast cells are long-lived resident cells that are of great importance in an allergic reaction. It has previously been suggested that after IgE-mediated degranulation mast cells can undergo regranulation. Such a process is probably of great importance with respect to the severity and perpetuation of the allergic response. Objective: Our purpose was to investigate whether mast cells recover from

Zou Xiang; Mats Block; Carl Löfman; Gunnar Nilsson

2001-01-01

118

Ultraviolet-B Radiation Suppresses Mast Cell Degranulation Induced by Compound 48\\/80  

Microsoft Academic Search

This study was designed to investigate the effect of middle-wave ultraviolet (UVB) radiation on mast cell functions using mouse ear skin as an in vivo model. Groups of UVB-irradiated BALB\\/c mice were given an intradermal injection of the mast cell degranulator compound 48\\/80 into ears at various time intervals (30 min-7 days) after a single exposure to a bank of

Kiichiro Danno; Ken-ichi Toda; Takeshi Horio

1986-01-01

119

POSSIBLE ROLE OF ADRENERGIC COMPONENT AND CARDIAC MAST CELL DEGRANULATION IN PRECONDITIONING-INDUCED CARDIOPROTECTION  

Microsoft Academic Search

The present study was designed to investigate the role of adrenergic component and cardiac mast cell degranulation in the cardioprotective effect of ischaemic preconditioning. Isolated rat hearts were subjected to 30 min of global ischaemia followed by 30 min of reperfusion. Ischaemic\\/norepinephrine (100 ?m) preconditioning markedly reduced ischaemia–reperfusion-induced release of lactate dehydrogenase (LDH) and creatine kinase (CK) in coronary effluent

VINAY PARIKH; MANJEET SINGH

1999-01-01

120

Mast Cell Degranulation Induces Delayed Rectal Allodynia in Rats: Role of Histamine and 5HT  

Microsoft Academic Search

Visceral hypersensitivity is a common feature offunctional bowel disorders, where an increased number ofmast cells have often been described. Thus, weinvestigated the effect of an experimental mast cell degranulation induced by BrX-537A on somatic(tail heating) and visceral (rectal distension)sensitivity in rats and the involvement of histamineand\\/or serotonin on this last response. After BrX-537Aadministration, the latency of tail withdrawal reflex wasshortened

Anne-Marie Coelho; Jean Fioramonti; Lionel Bueno

1998-01-01

121

Fc?RI -INDUCED ACTIVATION BY LOW ANTIGEN CONCENTRATIONS RESULTS IN NUCLEAR SIGNALS IN THE ABSENCE OF DEGRANULATION  

PubMed Central

High affinity IgE receptor (Fc?RI)-induced activation of mast cells results in degranulation and generation of leukotrienes and cytokines. Fc?RI-induced mast cell activation was analyzed at a single cell basis using a rat basophilic leukemia (RBL-2H3) cell line transfected with a reporter plasmid containing three tandem NFAT (nuclear factor of activated T cells) binding sites fused to enhanced green fluorescent protein (GFP). Surprisingly, with this sensitive detection system, there is activation of IgE sensitized cells at concentrations of antigen as low as 10pg/ml, which was 10-fold lower than was detected by degranulation. There were differences in signaling pathways leading to degranulation compared to NFAT-mediated gene activation. Both signaling to NFAT activation and degranulation required Syk and calcineurin. However inhibitors of the phosphatidylinositol 3-kinase pathway blocked degranulation but did not NFAT activation. The results also indicate that NFAT was activated at lower intracellular signals compared to degranulation. Therefore, Fc?RI activation can result in nuclear signals in the absence of the release of mediators.

Grodzki, Ana Cristina G.; Moon, Kyungduk D.; Berenstein, Elsa H.; Siraganian, Reuben P.

2009-01-01

122

Differences in the behavior of cytoplasmic granules and lipid bodies during human lung mast cell degranulation  

PubMed Central

We used a morphometric and autoradiographic approach to analyze changes in specific cytoplasmic granules and cytoplasmic lipid bodies associated with human lung mast cell degranulation. Mast cells were dissociated from lung tissue by enzymatic digestion and were then enriched to purities of up to 99% by countercurrent centrifugation elutriation and recovery from columns containing specific antigen bound to Sepharose 6 MB. Degranulation was induced by goat anti-IgE. At various intervals after stimulation, parallel aliquots of cells were recovered for determination of histamine release or were fixed for transmission electron microscopy. We found that lipid bodies, electron- dense structures that lack unit membranes, were present in both control and stimulated mast cells. Autoradiographic analysis showed that lipid bodies represented the major repository of 3H-label derived from [3H]arachidonic acid taken up from the external milieu. By contrast, the specific cytoplasmic granules contained no detectable 3H-label. In addition, lipid bodies occurred in intimate association with degranulation channels during mast cell activation, but the total volume of lipid bodies did not change during the 20 min after stimulation with anti-IgE. This result stands in striking contrast to the behavior of specific cytoplasmic granules, the great majority of which (77% according to aggregate volume) exhibited ultrastructural alterations during the first 20 min of mast cell activation. These observations establish that mast cell cytoplasmic granules and cytoplasmic lipid bodies are distinct organelles that differ in ultrastructure, biochemistry, and behavior during mast cell activation.

1984-01-01

123

A novel human immunoglobulin Fc?–Fc? bifunctional fusion protein inhibits Fc?RI-mediated degranulation  

Microsoft Academic Search

Human mast cells and basophils that express the high-affinity immunoglobulin E (IgE) receptor, Fc? receptor 1 (Fc?RI), have key roles in allergic diseases. Fc?RI cross-linking stimulates the release of allergic mediators. Mast cells and basophils co-express Fc?RIIb, a low affinity receptor containing an immunoreceptor tyrosine-based inhibitory motif and whose co-aggregation with Fc?RI can block Fc?RI-mediated reactivity. Here we designed, expressed

Daocheng Zhu; Christopher L. Kepley; Min Zhang; Ke Zhang; Andrew Saxon

2002-01-01

124

Atropine inhibits the degranulation of Paneth cells in ex-germ-free mice  

Microsoft Academic Search

Previous studies have shown that the secretory products of Paneth cells contain antibacterial agents (lysozyme, IgA) that are affected by the bacterial milieu in the intestine. To investigate whether Paneth-cell secretion is controlled via cholinergic mechanisms, the ultrastructure of Paneth cells was studied in four animal groups: (1) germfree (GF) control mice (Jcl: ICR [GN], male, 13 weeks old), (2)

Yohichi Satoh

1988-01-01

125

Inhibitory effects of water-soluble low-molecular-weight ?-(1,3-1,6) D-glucan isolated from Aureobasidium pullulans 1A1 strain black yeast on mast cell degranulation and passive cutaneous anaphylaxis.  

PubMed

We investigated the effects of water-soluble low-molecular-weight ?-(1,3-1,6) D-glucan isolated from Aureobasidium pullulans 1A1 strain black yeast (LMW-?-glucan) on mast cell-mediated anaphylactic reactions. Although it is known that LMW-?-glucan has anti-tumor, anti-metastatic and anti-stress effects, the roles of LMW-?-glucan in immediate-type allergic reactions have not been fully investigated. We examined whether LMW-?-glucan could inhibit mast cell degranulation and passive cutaneous anaphylaxis (PCA). LMW-?-glucan dose-dependently inhibited the degranulation of both rat basophilic leukemia (RBL-2H3) and cultured mast cells (CMCs) activated by calcium ionophore A23187 or IgE. However, LMW-?-glucan had no cytotoxicity towards RBL-2H3 cells and CMCs. Furthermore, orally administered LMW-?-glucan inhibited the IgE-induced PCA reaction in mice. These results show LMW-?-glucan to be a possible compound for the effective therapeutic treatment of allergic diseases. PMID:22232243

Sato, Harumi; Kobayashi, Yuko; Hattori, Atsushi; Suzuki, Toshio; Shigekawa, Munekazu; Jippo, Tomoko

2012-01-01

126

Effect of low-intensity laser therapy on mast cell degranulation in human oral mucosa  

Microsoft Academic Search

Little is known about the physiological mechanisms related to low-intensity laser therapy (LILT), particularly in acute inflammation\\u000a and subsequent wound healing. The objective of this study was to verify the effect of LILT on mast cell degranulation. Epulis\\u000a fissuratum tissues from eight patients were used. One part of the lesion was irradiated with an AsGaAl laser (??=? 670 nm,\\u000a 8.0 J\\/cm2, 5 mW,

Iris Sawasaki; Vinicius R. Geraldo-Martins; Martha S. Ribeiro; Márcia M. Marques

2009-01-01

127

Study of cell degranulation with simultaneous microscope imaging and capillary electrophoresis  

SciTech Connect

The physical release of single granules from individual rat peritoneal mast cells (RPMCs) was monitored by video recording of the degranulating cells by a high-resolution charge-coupled device (CCD) microscope system. The bright granular core disappears from the image as the vesicular content is dissolved on contact with the extra-cellular fluid. After a fixed time delay, the exocytotic product, serotonin, was detected by capillary electrophoresis coupled with laser-induced native fluorescence (LINF-CE). The timing of the two events is mostly correlated, which supports a fast release mechanism of the granular products. {copyright} {ital 1999} {ital Society for Applied Spectroscopy}

Su, H.; Yeung, E.S. [Ames Laboratory-USDOE and Department of Chemistry, Iowa State University, Ames, Iowa 50011 (United States)] [Ames Laboratory-USDOE and Department of Chemistry, Iowa State University, Ames, Iowa 50011 (United States)

1999-07-01

128

Influence of a mindfulness meditation-based stress reduction intervention on rates of skin clearing in patients with moderate to severe psoriasis undergoing phototherapy (UVB) and photochemotherapy (PUVA)  

Microsoft Academic Search

OBJECTIVE: This study tests the hypothesis that stress reduction methods based on mindfulness meditation can positively influence the rate at which psoriasis clears in patients undergoing phototherapy or photochemotherapy treatment.\\u000aMETHODS: Thirty-seven patients with psoriasis about to undergo ultraviolet phototherapy (UVB) or photochemotherapy (PUVA) were randomly assigned to one of two conditions: a mindfulness meditation-based stress reduction intervention guided by

Jon Kabat-Zinn; Elizabeth V. Wheeler; Timothy Light; Anne Skillings; Mark J. Scharf; Thomas G. Cropley; David W. Hosmer; Jeffrey D. Bernhard

1998-01-01

129

Lack of Evidence for a Role of Mast Cell Degranulation in Acute Hypoxia \\/Reoxygenation-induced Injury in the Isolated Rat Heart  

Microsoft Academic Search

In the present study, we evaluated the potential role of mast cell degranulation in acute hypoxia \\/reoxygenation-induced injury to cardiomyocytes in the isolated rat heart. Histamine release was determined to delineate the extent of mast cell degranulation, whereas the release of creatine kinase (CK) and lactate dehydrogenase (LDH) was assessed to quantitate the extent of irreversible injury to cardiomyocytes. The

Charles M. C. J. van Haaster; Wim Engels; Adriaan M. Duijvestijn; Paul J. M. R. Lemmens; Gerard Hornstra; Ger J. Van der Vusse

1996-01-01

130

Crucial role of the hydrophobic pocket region of Munc18 protein in mast cell degranulation  

PubMed Central

The function of the Munc18-1 protein hydrophobic pocket, which interacts with the syntaxin-1 N-terminal peptide, has been highly controversial in neurosecretion. Recent analysis of patients with familial hemophagocytic lymphohistiocytosis type 5 has identified the E132A mutation in the hydrophobic pocket of Munc18-2, prompting us to examine the role of this region in the context of immune cell secretion. Double knockdown of Munc18-1 and Munc18-2 in RBL-2H3 mast cells eliminates both IgE-dependent and ionomycin-induced degranulation and causes a significant reduction in syntaxin-11 without altering expressions of the other syntaxin isoforms examined. These phenotypes were effectively rescued on reexpression of wild-type Munc18-1 or Munc18-2 but not the mutants (F115E, E132A, and F115E/E132A) in the hydrophobic pocket of Munc18. In addition, these mutants show that they are unable to directly interact with syntaxin-11, as tested through protein interaction experiments. Our results demonstrate the crucial roles of the hydrophobic pocket of Munc18 in mast cell degranulation, which include the regulation of syntaxin-11. We also suggest that the functional importance of this region is significantly different between neuronal and immune cell exocytosis.

Bin, Na-Ryum; Jung, Chang Hun; Piggott, Christopher; Sugita, Shuzo

2013-01-01

131

alpha-Tocopherol enhances degranulation in RBL-2H3 mast cells.  

PubMed

Based on the observation that 3 months alpha-tocopherol supplementation caused an up-regulation of the mRNA of vesicular transport proteins in livers of mice, the functional relevance was investigated in RBL-2H3 cells, a model for mast cell degranulation. In total, 24 h incubation with 100 muM alpha-tocopherol enhanced the basal and phorbol-12-myristyl-13-acetate/ionomycin-stimulated release of beta-hexosaminidase and cathepsin D as measured by enzymatic analysis as well as Western blotting and immunocytochemistry, respectively. beta-Tocopherol exerted the same effect, whereas alpha-tocopheryl phosphate and trolox were inactive, indicating that both the side chain and the 6-OH group at the chroman ring are essential for activation of degranulation. alpha-Tocopherol did not induce mRNA expression of soluble NSF-attachment protein receptor (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) proteins, such as N-ethylmaleimide sensitive fusion protein, complexin-2, SNAP23 or syntaxin-3, in the RBL-2H3 cell model. In view of the well known alpha-tocopherol-mediated activation of protein phosphatases, which regulate soluble NSF-attachment protein receptor activities by dephosphorylation, underlying mechanisms are discussed in terms of preventing oxidative inactivation of protein phosphatases and so far unknown functions in certain membrane domains. PMID:20169586

Hemmerling, Jana; Nell, Sandra; Kipp, Anna; Schumann, Sara; Deubel, Stefanie; Haack, Michael; Brigelius-Flohé, Regina

2010-05-01

132

Critical role of the carboxyl terminus of proline-rich tyrosine kinase (Pyk2) in the activation of human neutrophils by tumor necrosis factor: separation of signals for the respiratory burst and degranulation.  

PubMed

Transduction of Tat-tagged fusion proteins confirmed a hypothesis based on pharmacologic inhibitors (Fuortes, M., M. Melchior, H. Han, G.J. Lyon, and C. Nathan. 1999. J. Clin. Invest. 104:327-335) that proline-rich tyrosine kinase (Pyk2) plays a critical role in the activation of adherent human neutrophils, and allowed an analysis of individual Pyk2 domains not possible with chemical inhibitors. Acting as a dominant negative, the COOH terminus of Pyk2 fused to a Tat peptide (Tat-CT), but not other regions of Pyk2, specifically inhibited the respiratory burst of cells responding to tumor necrosis factor (TNF), Salmonella, or Listeria, while sparing responses induced by phorbol ester. Tat-CT suppressed TNF-triggered cell spreading and the phosphorylation of endogenous Pyk2 and the associated tyrosine kinase Syk without blocking the ability of neutrophils to degranulate and kill bacteria. Thus, separate signals control the respiratory burst and degranulation, and a normal rate of killing of some bacteria can be sustained by granule products in conjunction with a minimal residual respiratory burst. Inhibition of select inflammatory functions without impairment of antibacterial activity may commend the Pyk2 pathway as a potential target for antiinflammatory therapy. PMID:12515814

Han, Hyunsil; Fuortes, Michele; Nathan, Carl

2003-01-01

133

Apoptosis, mast cell degranulation and collagen breakdown in the pathogenesis of loxoscelism in subcutaneously implanted sponges.  

PubMed

Envenomation by the Loxosceles spider causes loxoscelism, a pattern of signs and symptoms that primarily manifests in the dermonecrotic form. Our studies have shown that a mouse subcutaneous sponge implantation model may be useful in evaluating the effects of Loxosceles similis venom. This model provides an ideal microenvironment in which to study loxoscelism; however, it is still important to evaluate its pathogenesis and to observe the effects of L. similis venom for longer time periods than those in previous studies of this model. The aims of this study are: (1) to histologically characterize the effects of L. similis crude venom in a subcutaneous sponge implant; (2) to quantify the mast cells present in the implant and to measure their degranulation activity; (3) to quantify collagen subtypes I and III; and (4) to verify, quantify, and evaluate the effects of apoptosis in the implant on the pathogenesis of loxoscelism at 1 h, 4 h, and 24 h after injecting the venom. Thirty Swiss mice (6-8 weeks old, male) were subcutaneously implanted with polyester-polyurethane sponge discs. Fourteen days post-implantation, the animals were divided into six groups (5 animals per group): three control groups (C1h, C4h, and C24h), in which the mice received 30 ?l injections of intra-implant saline, and three treated groups (T1h, T4h, and T24h), in which the mice received 30 ?l (0.5 ?g) injections of L. similis crude venom at 1 h, 4 h, and 24 h intervals. After each time interval, the animals were euthanized, and the implants were harvested and processed for light and electron microscopic analyses. The following results were observed in the implants harvested from the treated groups: acute inflammation with marked edema, thrombus, and vasculitis, as well as increased levels of mast cells and mast cell degranulation, and apoptosis in giant cells. Furthermore, degradation of collagen types I and III was observed. An analysis of the ultrastructure revealed apoptosis in various cell types. The present results suggest that apoptosis in some cell types associated with an increase in mast cell degranulation and the degradation of collagen fibers are important in the pathogenesis of loxoscelism therefore may explain the difficulty in repairing the ulcer is commonly observed in severe cases of loxoscelism cutaneous in humans. PMID:24657389

Pereira, Núbia Braga; Campos, Paula Peixoto; Parreiras, Patrícia Martins; Chiarini-Garcia, Hélio; Socarrás, Teresa Oviedo; Kalapothakis, Evanguedes; Andrade, Silvia Passos; Moro, Luciana

2014-06-01

134

Complexin II regulates degranulation in RBL-2H3 cells by interacting with SNARE complex containing syntaxin-3  

Microsoft Academic Search

Recent studies have revealed that SNARE proteins are involved in the exocytotic release (degranulation) in mast cells. However, the roles of SNARE regulatory proteins are poorly understood. Complexin is one such regulatory protein and it plays a crucial role in exocytotic release. In this study, we characterized the interaction between SNARE complex and complexin II in mast cells by GST

Satoshi Tadokoro; Mamoru Nakanishi; Naohide Hirashima

2010-01-01

135

Increased number of non-degranulated mast cells in pancreatic ductal adenocarcinoma but not in acute pancreatitis.  

PubMed

Increasing evidence indicates that tumor microenvironment (TME) is crucial in tumor survival and metastases. Inflammatory cells accumulate around tumors and strangely appear to be permissive to their growth. One key stroma cell is the mast cell (MC), which can secrete numerous pro- and antitumor molecules. We investigated the presence and degranulation state of MC in pancreatic ductal adenocarcinoma (PDAC) as compared to acute ancreatitis (AP). Three different detection methods: (a) toluidine blue staining, as well as immunohistochemistry for (b) tryptase and (c) c-kit, were utilized to assess the number and extent of degranulation of MC in PDAC tissue (n=7), uninvolved pancreatic tissue derived from tumor-free margins (n=7) and tissue form AP (n=4). The number of MC detected with all three methods was significantly increased in PDAC, as compared to normal pancreatic tissue derived from tumor-free margins (p<0.05). The highest number of MC was identified by c-kit, 22.2?7.5 per high power field (HPF) in PDAC vs 9.7?5.1 per HPF in normal tissue. Contrary to MC in AP, where most of the detected MC were found degranulated, MC in PDAC appeared intact. In conclusion, MC are increased in number, but not degranulated in PDAC, suggesting that they may contribute to cancer growth by permitting selective release of pro-tumorogenic molecules. PMID:25004833

Karamitopoulou, E; Shoni, M; Theoharides, T C

2014-01-01

136

Degranulation of individual mast cells in response to Ca2+ and guanine nucleotides: an all-or-none event  

PubMed Central

Widespread experience indicates that application of suboptimal concentrations of stimulating ligands (secretagogues) to secretory cells elicits submaximal extents of secretion. Similarly, for permeabilized secretory cells, the extent of secretion is related to the concentration of applied intracellular effectors. We investigated the relationship between the extent of secretion from mast cells (assessed as the release of hexosaminidase) and the degranulation (exocytosis) responses of individual cells. For permeabilized mast cells stimulated by the effector combination Ca2+ plus GTP-gamma-S and for intact cells stimulated by the Ca2+ ionophore ionomycin, we found that exocytosis has the characteristics of an all-or-none process at the level of the individual cells. With a suboptimal stimulus, the population comprised only totally degranulated cells and fully replete cells. In contrast, a suboptimal concentration of compound 48/80 applied to intact cells induced a partial degree of degranulation. This was determined by observing the morphological changes accompanying degranulation by light and electron microscopy and also as a reduction in the intensity of light scattered at 90 degrees, indicative of a change in the cell-refractive index. These results may be explained by the existence of a threshold sensitivity to the combined effectors that is set at the level of individual cells and not at the granule level. We used flow cytometry to establish the relationship between the extent of degranulation in individual rat peritoneal mast cells and the extent of secretion in the population (measured as the percentage release of total hexosaminidase). For comparison, secretion was also elicited by applying the Ca2+ ionophore ionomycin or compound 48/80 to intact cells. For permeabilized cells and also for intact cells stimulated with the ionophore, levels of stimulation that generate partial secretion gave rise to bimodal frequency distributions of 90 degrees light scatter. In contrast, a partial stimulus to secretion by compound 48/80 resulted in a single population of partially degranulated cells, the degree of degranulation varying across the cell population. The difference between the all-or-none responses of the permeabilized or ionophore-treated cells and the graded responses of cells activated by compound 48/80 is likely to stem from differences in the effective calcium stimulus. Whereas cell stimulated with receptor-directed agonists can undergo transient and localized Ca2+ changes, a homogeneous and persistent stimulus is sensed at every potential exocytotic site in the permeabilized cells.

1993-01-01

137

Human eosinophil adhesion and degranulation stimulated with eotaxin and RANTES in vitro: Lack of interaction with nitric oxide  

PubMed Central

Background Airway eosinophilia is considered a central event in the pathogenesis of asthma. The toxic components of eosinophils are thought to be important in inducing bronchial mucosal injury and dysfunction. Previous studies have suggested an interaction between nitric oxide (NO) and chemokines in modulating eosinophil functions, but this is still conflicting. In the present study, we have carried out functional assays (adhesion and degranulation) and flow cytometry analysis of adhesion molecules (VLA-4 and Mac-1 expression) to evaluate the interactions between NO and CC-chemokines (eotaxin and RANTES) in human eosinophils. Methods Eosinophils were purified using a percoll gradient followed by immunomagnetic cell separator. Cell adhesion and degranulation were evaluated by measuring eosinophil peroxidase (EPO) activity, whereas expression of Mac-1 and VLA-4 was detected using flow cytometry. Results At 4 h incubation, both eotaxin (100 ng/ml) and RANTES (1000 ng/ml) increased by 133% and 131% eosinophil adhesion, respectively. L-NAME alone (but not D-NAME) also increased the eosinophil adhesion, but the co-incubation of L-NAME with eotaxin or RANTES did not further affect the increased adhesion seen with chemokines alone. In addition, L-NAME alone (but not D-NAME) caused a significant cell degranulation, but it did not affect the CC-chemokine-induced cell degranulation. Incubation of eosinophils with eotaxin or RANTES, in absence or presence of L-NAME, did not affect the expression of VLA-4 and Mac-1 on eosinophil surface. Eotaxin and RANTES (100 ng/ml each) also failed to elevate the cyclic GMP levels above baseline in human eosinophils. Conclusion Eotaxin and RANTES increase the eosinophil adhesion to fibronectin-coated plates and promote cell degranulation by NO-independent mechanisms. The failure of CC-chemokines to affect VLA-4 and Mac-1 expression suggests that changes in integrin function (avidity or affinity) are rather involved in the enhanced adhesion.

Lintomen, Leticia; Franchi, Gilberto; Nowill, Alexandre; Condino-Neto, Antonio; de Nucci, Gilberto; Zanesco, Angelina; Antunes, Edson

2008-01-01

138

Adhesion- and degranulation-promoting adapter protein is required for efficient thymocyte development and selection.  

PubMed

Adhesion- and degranulation-promoting adapter protein (ADAP) is required in TCR-induced activation and proliferation of peripheral T cells. Loss of ADAP also impairs TCR-initiated inside-out activation of the integrin LFA-1 (CD11a/CD18, alphaLbeta2). In this study, we demonstrate that ADAP-deficient CD4/CD8 double-positive (DP) cells have a diminished ability to proliferate, and that these DP thymocytes up-regulate CD69 poorly in vivo. Moreover, in both MHC class I- and class II-restricted TCR transgenic models, loss of ADAP interferes with both positive and negative selection. ADAP deficiency also impairs the ability of transgene-bearing DP thymocytes to form conjugates with Ag-loaded presenting cells. These findings suggest that ADAP is critical for thymocyte development and selection. PMID:16709827

Wu, Jennifer N; Gheith, Shereen; Bezman, Natalie A; Liu, Qing-Hua; Fostel, Lindsey V; Swanson, Andrew M; Freedman, Bruce D; Koretzky, Gary A; Peterson, Erik J

2006-06-01

139

Lesional skin chemokine CTACK/CCL27 expression in mycosis fungoides and disease control by IFN-? and PUVA therapy  

PubMed Central

Recruitment of neoplastic T cells to skin is a critical step in the pathogenesis of mycosis fungoides (MF) lesions. Cutaneous T-cell attracting chemokine (CTACK)/CCL27 attracts memory T cells to skin, resulting in increased cutaneous expression. The interactions between neoplastic cells and skin immune system require further elucidation. CTACK/CCL27 expression and density of dendritic cells (DC), CD8+ and CD4+ lymphocytes were investigated in skin lesions of 52 early-stage MF patients treated by interferon (IFN)-? in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA). Skin lesion biopsies obtained at diagnosis and after treatment were studied by immunohistochemistry. Initial CTACK/CCL27 expression was abnormal/suprabasal in 36 patients. Normal/basal CTACK/CCL27 expression tended to correlate with a high DC density and low CD4+ cell density in the neoplastic infiltrate. Treatment induced a significant increase in CTACK/CCL27 expression (?2 test: P=0.004). Overall, 33 patients relapsed [median event-free survival (EFS), 46 months] during follow-up (median, 92.5 months, range, 43–165). Normal/basal CTACK/CCL27 expression at the end of treatment correlated with lower rates of recurrence and a longer median EFS (111 months vs. 39 months with suprabasal expression; log rank test: P=0.031). CTACK/CCL27 overexpression in early-stage MF might thus be related to a balance between neoplastic cells and immunomodulant DC. Normal CTACK/CCL27 expression after treatment designates a subset of patients with favorable disease behavior. The mechanisms underpinning CTACK/CCL27 overexpression after therapy in the remaining patients, who are at greater risk of recurrence, warrant further investigation.

Goteri, Gaia; Rupoli, Serena; Campanati, Anna; Costagliola, Antonello; Sabato, Simona; Stramazzotti, Daniela; Picardi, Paola; Canafoglia, Lucia; Pulini, Stefano; Ganzetti, Giulia; Offidani, Anna Maria; Leoni, Pietro

2009-01-01

140

Considerations of the structure of sesquiterpene lactones on biological activity: influence of the alpha-methylene-gamma-lactone moiety on mast cell degranulation.  

PubMed

Mast cell degranulation was quantitated by measuring percentage of histamine release, 45Ca2+ ion influx, or c-AMP cellular levels after stimulation with various concentrations of the sesquiterpene lactones hymenovin, helenalin, or tenulin. Hymenovin and helenalin, which contain an alpha-methylene-gamma-lactone moiety, produced extensive degranulation. Alkylation of the alpha-methylene-gamma-lactone group of these compounds with the amino acid cysteine before mast cell stimulation drastically reduced the capacity of these lactones to stimulate histamine release. Tenulin, which does not contain an alpha-methylene-gamma-lactone moiety, generally stimulated degranulation approximately equal to that of cysteine-treated hymenovin or helenalin. These data indicate that sesquiterpene lactones containing alpha-methylene-gamma-lactone are potent stimulators of mast cell degranulation. This phenomenon may have a significant role in the toxicity of some sesquiterpene lactones of poisonous plants when ingested by livestock. PMID:6195945

Elissalde, M H; Ivie, G W; Rowe, L D; Elissalde, G S

1983-10-01

141

The effect of vasoactive intestinal peptide (VIP) on mast cell invasion\\/degranulation in testicular interstitium of immobilized + cold stressed and ?-endorphin-treated rats  

Microsoft Academic Search

The effect of VIP on mast cell invasion\\/degranulation in testicular interstitium of stressed (immobilization and cold) and ?-endorphin-treated rats were investigated. Fifty-three Wistar male rats were used in four series of experiments. Initially, the effect of immobilization and cold stress on mast cell invasion and degranulation in testicular interstitium was examined in three age group of rats: 15 (n =

Ne?e Tunçel; Firdevs Gürer; Erinç Aral; Kubilay Uzuner; Yasemin Aydin; Cengiz Bayçu

1996-01-01

142

Complexin II regulates degranulation in RBL-2H3 cells by interacting with SNARE complex containing syntaxin-3.  

PubMed

Recent studies have revealed that SNARE proteins are involved in the exocytotic release (degranulation) in mast cells. However, the roles of SNARE regulatory proteins are poorly understood. Complexin is one such regulatory protein and it plays a crucial role in exocytotic release. In this study, we characterized the interaction between SNARE complex and complexin II in mast cells by GST pull-down assay and in vitro binding assay. We found that the SNARE complex that interacted with complexin II consisted of syntaxin-3, SNAP-23, and VAMP-2 or -8, whereas syntaxin-4 was not detected. Recombinant syntaxin-3 binds to complexin II by itself, but its affinity to complexin II was enhanced upon addition of VAMP-8 and SNAP-23. Furthermore, the region of complexin II responsible for binding to the SNARE complex, was near the central alpha-helix region. These results suggest that complexin II regulates degranulation by interacting with the SNARE complex containing syntaxin-3. PMID:19932892

Tadokoro, Satoshi; Nakanishi, Mamoru; Hirashima, Naohide

2010-01-01

143

Corticotropin-Releasing Hormone Induces Skin Mast Cell Degranulation and Increased Vascular Permeability, A Possible Explanation for Its Proinflammatory Effects  

Microsoft Academic Search

Mast cells are involved in atopic disorders, often exacerbated by stress, and are located perivascularly close to sympathetic and sen- sory nerve endings. Mast cells are activated by electrical nerve stim- ulation and millimolar concentrations of neuropeptides, such as sub- stance P (SP). Moreover, acute psychological stress induces CRH- dependent mast cell degranulation. Intradermal administration of rat\\/human CRH (0.1-10 mM)

THEOHARIS C. THEOHARIDES; LEENA K. SINGH; WILLIAM BOUCHER; XINZHU PANG; RICHARD LETOURNEAU; ELIZABETH WEBSTER; GEORGE CHROUSOS

1998-01-01

144

Impaired degranulation but enhanced cytokine production after Fc?RI stimulation of diacylglycerol kinase ?-deficient mast cells  

PubMed Central

Calcium and diacylglycerol are critical second messengers that together effect mast cell degranulation after allergen cross-linking of immunoglobulin (Ig)E-bound Fc?RI. Diacylglycerol kinase (DGK)? is a negative regulator of diacylglycerol-dependent signaling that acts by converting diacylglycerol to phosphatidic acid. We reported previously that DGK??/? mice have enhanced in vivo T cell function. Here, we demonstrate that these mice have diminished in vivo mast cell function, as revealed by impaired local anaphylactic responses. Concordantly, DGK??/? bone marrow–derived mast cells (BMMCs) demonstrate impaired degranulation after Fc?RI cross-linking, associated with diminished phospholipase C? activity, calcium flux, and protein kinase C–?II membrane recruitment. In contrast, Ras-Erk signals and interleukin-6 production are enhanced, both during IgE sensitization and after antigen cross-linking of Fc?RI. Our data demonstrate dissociation between cytokine production and degranulation in mast cells and reveal the importance of DGK activity during IgE sensitization for proper attenuation of Fc?RI signals.

Olenchock, Benjamin A.; Guo, Rishu; Silverman, Michael A.; Wu, Jennifer N.; Carpenter, Jeffery H.; Koretzky, Gary A.; Zhong, Xiao-Ping

2006-01-01

145

Lack of neutrophil degranulation in low-dose endotoxin inhalation based on a novel intracellular assay.  

PubMed

To study the nature of endotoxin or lipopolysaccharide (LPS) induced inflammation, we developed a method of quantifying intracellular human neutrophil elastase (HNE) in lysed sputum polymorphs as a means to study the degranulation status of LPS-recruited neutrophils. Induced sputum, blood and exhaled nitric oxide (NO) were collected from 10 healthy non-atopic human subjects after inhaling a single 15 microg dose of Escherichia coil LPS in an open study. At 6 hours, LPS inhalation caused significant increase of sputum and blood neutrophils but without parallel increase in myeloperoxidase, HNE or interleukin-8 (IL-8) in sputum sol and blood, or exhaled NO. Intracellular HNE in lysed sputum polymorphs or purified blood neutrophils did not show any significant changes between inhaled LPS and saline, nor was there any appreciable change in percentage HNE release induced by N-Formyl-Met-Leu-Phe (fMLP) in vitro. We concluded that in healthy humans, the transient neutrophilic inflammation induced by a single dose of inhaled 15 microg LPS is mainly characterized by cell recruitment, not enhanced secretion of granular mediators or increased exhaled NO based on our experimental conditions. PMID:17136881

Loh, L C; Lo, W H; Kanabar, V; O'Connor, B J

2006-01-01

146

Echinometrin: a novel mast cell degranulating peptide from the coelomic liquid of Echinometra lucunter sea urchin.  

PubMed

Echinometra lucunter is an abundant sea urchin found in Brazilian waters. Accidents caused by this animal are common and are characterized by the penetration of the spines in the skin, which raises an inflammatory reaction through mechanical trauma as well as by the presumable action of toxins. Additionally, there have been reports of inflammatory reaction after the consumption of raw sea urchin eggs. In this work, we have isolated a peptide from E. lucunter coelomic fluid that could elicit inflammatory reactions, such as paw edema, leukocyte recruitment and diminishment of the pain threshold. This peptide was termed Echinometrin. Moreover, the peptide administration was able to produce in vivo degranulation of mouse mast cells, in a dose-response manner. The peptide was 'de novo' sequenced by mass spectrometry and its synthetic analog could reproduce all the observed effects. Sequence alignment indicates that this peptide is comprised in vitellogenin, an abundant nutrient protein present in the gametogenic cells of sea urchins, making it possible that echinometrin would be a cryptide with pro-inflammatory effects. PMID:23948330

Sciani, Juliana Mozer; Sampaio, Marlos Cortez; Zychar, Bianca Cestari; Gonçalves, Luis Roberto de Camargo; Giorgi, Renata; Nogueira, Thiago de Oliveira; de Melo, Robson Lopes; Teixeira, Catarina de Fátima Pereira; Pimenta, Daniel Carvalho

2014-03-01

147

Enhanced innate immune responses in a brood parasitic cowbird species: degranulation and oxidative burst  

USGS Publications Warehouse

We examined the relative effectiveness of two innate immune responses in two species of New World blackbirds (Passeriformes, Icteridae) that differ in resistance to West Nile virus (WNV). We measured degranulation and oxidative burst, two fundamental components of phagocytosis, and we predicted that the functional effectiveness of these innate immune responses would correspond to the species' relative resistance to WNV. The brown-headed cowbird (Molothrus ater), an obligate brood parasite, had previously shown greater resistance to infection with WNV, lower viremia and faster recovery when infected, and lower subsequent antibody titers than the red-winged blackbird (Agelaius phoeniceus), a close relative that is not a brood parasite. We found that cowbird leukocytes were significantly more functionally efficient than those of the blackbird leukocytes and 50% more effective at killing the challenge bacteria. These results suggest that further examination of innate immunity in the cowbird may provide insight into adaptations that underlie its greater resistance to WNV. These results support an eco-immunological interpretation that species like the cowbird, which inhabit ecological niches with heightened exposure to parasites, experience evolutionary selection for more effective immune responses.

Hahn, D. Caldwell; Summers, Scott G.; Genovese, Kenneth J.; He, Haiqi; Kogut, Michael H.

2013-01-01

148

Synergistic effect of heparin and chemotactic factor on polymorphonuclear leukocyte aggregation and degranulation.  

PubMed Central

The in vitro effects of therapeutic amounts of polyanionic heparin on human polymorphonuclear leukocytes (PMN) aggregation and on the release of cationic lactoferrin from PMN-specific granules were investigated. Incubation of 1 X 10(7) human PMNs with 0.3 unit/ml of heparin followed by stimulation with the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) 2 X 10(-7) M significantly increased PMN aggregation, compared with controls. Cytochalasin B potentiated aggregation, which was further increased by incubation of the PMNs with heparin. Similarly, heparin also increased PMN degranulation and lactoferrin release following stimulation with FMLP with or without cytochalasin B, compared with controls. In addition, human lactoferrin complexed with heparin on a sucrose density gradient and caused a significant shift in the migration of 3H-heparin. Finally, rabbits pretreated with intravenous heparin resulting in prolongation of their activated partial thromboplastin time (APTT) to 1.5 to 2.5 times baseline had more profound reduction in PMN counts following a challenge with the secretagogue phorbol myristate acetate (PMA). These studies demonstrate that heparin can interact synergistically with chemotactic stimuli known to evoke lactoferrin release, which in turn leads to enhancement of PMN aggregation. Our data further suggest that heparin may be contraindicated in the treatment of syndromes with increased PMN aggregation such as endotoxin-induced Schwartzman-type reactions.

Cairo, M. S.; Allen, J.; Higgins, C.; Baehner, R. L.; Boxer, L. A.

1983-01-01

149

Two modes of lytic granule fusion during degranulation by natural killer cells  

PubMed Central

Lytic granules in cytotoxic lymphocytes, which include T cells and natural killer (NK) cells, are secretory lysosomes that release their content upon fusion with the plasma membrane (PM), a process known as degranulation. Although vesicle exocytosis has been extensively studied in endocrine and neuronal cells, much less is known about the fusion of lytic granules in cytotoxic lymphocytes. Here, we used total internal reflection fluorescence microscopy to examine lytic granules labeled with fluorescently tagged Fas ligand (FasL) in the NK cell line NKL stimulated with phorbol ester and ionomycin and in primary NK cells activated by physiological receptor–ligand interactions. Two fusion modes were observed: complete fusion, characterized by loss of granule content and rapid diffusion of FasL at the PM; and incomplete fusion, characterized by transient fusion pore opening and retention of FasL at the fusion site. The pH-sensitive green fluorescence protein (pHluorin) fused to the lumenal domain of FasL was used to visualize fusion pore opening with a time resolution of 30?ms. Upon incomplete fusion, pHluorin emission lasted several seconds in the absence of noticeable diffusion. Thus, we conclude that lytic granules in NK cells undergo both complete and incomplete fusion with the PM, and propose that incomplete fusion may promote efficient recycling of lytic granule membrane after the release of cytotoxic effector molecules.

Liu, Dongfang; Martina, Jose A; Wu, Xufeng S; Hammer III, John A; Long, Eric O

2011-01-01

150

Apoptosis-induced proteinase 3 membrane expression is independent from degranulation.  

PubMed

Proteinase 3 (PR3) and human neutrophil elastase (HNE) are serine proteinases stored in the azurophilic granules of neutrophils. In contrast to HNE, PR3 is the target of antineutrophil cytoplasm antibodies (ANCA) in Wegener's granulomatosis. The mechanisms leading to the membrane expression of PR3 and HNE are still unclear and appear to be critical to understand the pathophysiological role of ANCA. Stably transfected rat basophilic cell lines (RBL) with PR3 or HNE were used to analyze the PR3 and HNE secretion mechanisms and differentiate between them. RBL cells were lacking endogenous PR3 and HNE. They were stably transfected with HNE or PR3 or an inactive mutant of PR3 (PR3S203A). Using the calcium ionophore A23187 as a secretagogue, higher serine proteinase activity was secreted in the supernatant of RBL/HNE than in RBL/PR3. It is interesting that PR3 and PR3/S203A were also expressed at the plasma membrane, thus demonstrating that serine protease activity was not required for plasma membrane expression. In contrast, no expression of plasma membrane HNE could be detected in RBL/HNE. Apoptosis induced by etoposide was evaluated by DNA fragmentation, the presence of cytoplasmic histone-associated DNA fragments, and annexin V labeling. No membrane HNE was detected in RBL/HNE. In contrast, in RBL/PR3 and in RBL/PR3S203A, the membrane expression of PR3 and PR3S203A increased with etoposide concentrations and appeared closely related to annexin V labeling. Our data suggest that membrane PR3 originates from two distinct pools, the granular pool mobilized following degranulation or a plasma membrane pool mobilized upon apoptosis. PMID:14525959

Durant, Stéphanie; Pederzoli, Magali; Lepelletier, Yves; Canteloup, Sandrine; Nusbaum, Patrick; Lesavre, Philippe; Witko-Sarsat, Véronique

2004-01-01

151

Dermal mast cells in scleroderma: their skin density, tryptase/chymase phenotypes and degranulation.  

PubMed

To determine the distribution, tryptase/chymase phenotypes and degranulation of mast cells (MCs) in the dermis of patients with scleroderma, we examined MC density in the skin of 22 patients with systemic sclerosis (SSc) and 11 with localized scleroderma (LSc). We used antitryptase and antichymase antibodies after Carnoy's fixation. Detailed reports of two representative patients with SSc and LSc are included. In the scleroedematous stage (grade 1) showing oedema in both papillary and reticular dermis with variable homogenization of collagen bundles in the reticular dermis, MC skin density was variable in each specimen although MC skin density, as a whole, was significantly increased as compared with normal skin (P < 0.05). In the sclerotic stage (grade 2) characterized by homogenization of collagen bundles in the entire dermis, MC skin density was significantly decreased as compared with normal skin (P < 0.005). LSc showed changes similar to those in SSc. The ratio of MCTC cells (both tryptase- and chymase-positive MC) to MCT cells (tryptase-positive but chymase-negative MC) was variable in SSc and LSc. MCT cells were exclusively dominant in three patients with SSc and two with LSc. In a patient with SSc (patient 1) showing remarkable perivascular and interstitial oedema in the upper dermis, MC skin density was increased in the oedematous portion and tryptase-positive granules were distributed in extracellular locations. In another patient with LSc (patient 2), tryptase positivity increased and chymase positivity decreased in both number and intensity as the skin sclerosis progressed. MCs must have variable interactions with the lesional skin in SSc and LSc. The present study suggests that MCs are involved in the development of interstitial oedema. PMID:9580789

Akimoto, S; Ishikawa, O; Igarashi, Y; Kurosawa, M; Miyachi, Y

1998-03-01

152

Omega-3 fatty acids modulate Weibel-Palade body degranulation and actin cytoskeleton rearrangement in PMA-stimulated human umbilical vein endothelial cells.  

PubMed

Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) produce cardiovascular benefits by improving endothelial function. Endothelial cells store von Willebrand factor (vWF) in cytoplasmic Weibel-Palade bodies (WPBs). We examined whether LC n-3 PUFAs regulate WPB degranulation using cultured human umbilical vein endothelial cells (HUVECs). HUVECs were incubated with or without 75 or 120 µM docosahexaenoic acid or eicosapentaenoic acid for 5 days at 37 °C. WPB degranulation was stimulated using phorbol 12-myristate 13-acetate (PMA), and this was assessed by immunocytochemical staining for vWF. Actin reorganization was determined using phalloidin-TRITC staining. We found that PMA stimulated WPB degranulation, and that this was significantly reduced by prior incubation of cells with LC n-3 PUFAs. In these cells, WPBs had rounded rather than rod-shaped morphology and localized to the perinuclear region, suggesting interference with cytoskeletal remodeling that is necessary for complete WPB degranulation. In line with this, actin rearrangement was altered in cells containing perinuclear WPBs, where cells exhibited a thickened actin rim in the absence of prominent cytoplasmic stress fibers. These findings indicate that LC n-3 PUFAs provide some protection against WBP degranulation, and may contribute to an improved understanding of the anti-thrombotic effects previously attributed to LC n-3 PUFAs. PMID:24217286

Bürgin-Maunder, Corinna S; Brooks, Peter R; Russell, Fraser D

2013-11-01

153

DOCK5 functions as a key signaling adaptor that links Fc?RI signals to microtubule dynamics during mast cell degranulation.  

PubMed

Mast cells play a key role in the induction of anaphylaxis, a life-threatening IgE-dependent allergic reaction, by secreting chemical mediators that are stored in secretory granules. Degranulation of mast cells is triggered by aggregation of the high-affinity IgE receptor, Fc?RI, and involves dynamic rearrangement of microtubules. Although much is known about proximal signals downstream of Fc?RI, the distal signaling events controlling microtubule dynamics remain elusive. Here we report that DOCK5, an atypical guanine nucleotide exchange factor (GEF) for Rac, is essential for mast cell degranulation. As such, we found that DOCK5-deficient mice exhibit resistance to systemic and cutaneous anaphylaxis. The Rac GEF activity of DOCK5 is surprisingly not required for mast cell degranulation. Instead, DOCK5 associated with Nck2 and Akt to regulate microtubule dynamics through phosphorylation and inactivation of GSK3?. When DOCK5-Nck2-Akt interactions were disrupted, microtubule formation and degranulation response were severely impaired. Our results thus identify DOCK5 as a key signaling adaptor that orchestrates remodeling of the microtubule network essential for mast cell degranulation. PMID:24913231

Ogawa, Kana; Tanaka, Yoshihiko; Uruno, Takehito; Duan, Xuefeng; Harada, Yosuke; Sanematsu, Fumiyuki; Yamamura, Kazuhiko; Terasawa, Masao; Nishikimi, Akihiko; Côté, Jean-François; Fukui, Yoshinori

2014-06-30

154

Omega-3 Fatty Acids Modulate Weibel-Palade Body Degranulation and Actin Cytoskeleton Rearrangement in PMA-Stimulated Human Umbilical Vein Endothelial Cells  

PubMed Central

Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) produce cardiovascular benefits by improving endothelial function. Endothelial cells store von Willebrand factor (vWF) in cytoplasmic Weibel-Palade bodies (WPBs). We examined whether LC n-3 PUFAs regulate WPB degranulation using cultured human umbilical vein endothelial cells (HUVECs). HUVECs were incubated with or without 75 or 120 µM docosahexaenoic acid or eicosapentaenoic acid for 5 days at 37 °C. WPB degranulation was stimulated using phorbol 12-myristate 13-acetate (PMA), and this was assessed by immunocytochemical staining for vWF. Actin reorganization was determined using phalloidin-TRITC staining. We found that PMA stimulated WPB degranulation, and that this was significantly reduced by prior incubation of cells with LC n-3 PUFAs. In these cells, WPBs had rounded rather than rod-shaped morphology and localized to the perinuclear region, suggesting interference with cytoskeletal remodeling that is necessary for complete WPB degranulation. In line with this, actin rearrangement was altered in cells containing perinuclear WPBs, where cells exhibited a thickened actin rim in the absence of prominent cytoplasmic stress fibers. These findings indicate that LC n-3 PUFAs provide some protection against WBP degranulation, and may contribute to an improved understanding of the anti-thrombotic effects previously attributed to LC n-3 PUFAs.

Burgin-Maunder, Corinna S.; Brooks, Peter R.; Russell, Fraser D.

2013-01-01

155

TNF-alpha neutralizing antibody blocks thermal sensitivity induced by compound 48/80-provoked mast cell degranulation  

PubMed Central

Background: Neuro-inflammatory circuits in the tissue regulate the complex pathophysiology of pain. Protective nociceptive pain serves as an early warning system against noxious environmental stimuli. Tissue-resident mast cells orchestrate the increased thermal sensitivity following injection of basic secretagogue compound 48/80 in the hind paw tissues of ND4 mice. Here we investigated the effects of pre-treatment with TNF-? neutralizing antibody on compound 48/80-provoked thermal hyperalgesia. Methods: We treated ND4 Swiss male mice with intravenous anti-TNF-? antibody or vehicle 30 minutes prior to bilateral, intra-plantar compound 48/80 administration and measured changes in the timing of hind paw withdrawal observed subsequent to mice being placed on a 51oC hotplate. We also assessed changes in tissue swelling, TNF-? gene expression and protein abundance, mast cell degranulation, and neutrophil influx in the hind paw tissue. Findings: We found that TNF-? neutralization significantly blocked thermal hyperalgesia, and reduced early tissue swelling. TNF-? neutralization had no significant effect on mast cell degranulation or neutrophil influx into the tissue, however. Moreover, no changes in TNF-? protein or mRNA levels were detected within 3 hours of administration of compound 48/80. Interpretation:  The neutralizing antibodies likely target pre-formed TNF-? including that stored in the granules of tissue-resident mast cells. Pre-formed TNF-?, released upon degranulation, has immediate effects on nociceptive signaling prior to the induction of neutrophil influx. These early effects on nociceptors are abrogated by TNF-? blockade, resulting in compromised nociceptive withdrawal responses to acute, harmful environmental stimuli.

Chatterjea, Devavani

2013-01-01

156

Pharmacologic Inhibition of Mast Cell Degranulation Prevents Left Ventricular Remodeling Induced by Chronic Volume Overload in Rats  

Microsoft Academic Search

BackgroundLeft ventricular (LV) hypertrophy and dilation are important compensatory responses to chronic volume overload; however, the mechanisms responsible for this LV remodeling have not been well characterized. Previous observations that the number of myocardial mast cells are increased in congestive heart failure (CHF) suggested the hypothesis that mast cells might be involved in the ventricular remodeling induced by a chronic

Gregory L. Brower; Joseph S. Janicki

2005-01-01

157

Synthesis of 3-substituted isocoumarins and their inhibitory effects on degranulation of RBL-2H3 cells induced by antigen.  

PubMed

Eleven 3-substituted isocoumarins and a benzylidenephthalide were synthesized through thermal cyclization reaction of delta- and gamma-ketoamides, respectively. Subsequent deprotection of the hydroxyl groups of the resulting isocoumarin and benzylidenephthalide compounds afforded thunberginols A, B, and F, respectively, which originated from the processed leaves of Hydrangea macrophylla SERINGE var. thunbergii MAKINO. The synthesized isocoumarins and thunberginols were evaluated for their anti-allergic activity, in which thunberginol B exhibited the highest inhibitory potency on the degranulation of RBL-2H3 cells induced by antigen. Structure-activity relationship studies were carried out to determine the necessary substituents on the 3-phenylisocoumarin skeleton for inhibitory activity. PMID:18758098

Kurume, Ai; Kamata, Yasuhiro; Yamashita, Masayuki; Wang, Qilong; Matsuda, Hisashi; Yoshikawa, Masayuki; Kawasaki, Ikuo; Ohta, Shunsaku

2008-09-01

158

UDP-glucose acting at P2Y 14 receptors is a mediator of mast cell degranulation  

Microsoft Academic Search

UDP-glucose (UDPG), a glycosyl donor in the biosynthesis of carbohydrates, is an endogenous agonist of the G protein-coupled P2Y14 receptor. RBL-2H3 mast cells endogenously express a P2Y14 receptor at which UDPG mediates degranulation as indicated by ?-hexosaminidase (HEX) release. Both UDPG and a more potent, selective 2-thio-modified UDPG analog, MRS2690 (diphosphoric acid 1-?-d-glucopyranosyl ester 2-[(2-thio)uridin-5?-yl] ester), caused a substantial calcium

Zhan-Guo Gao; Yi Ding; Kenneth A. Jacobson

2010-01-01

159

Actin cytoskeleton reorganization correlates with polarization of secretory vesicle and cell morphology in the degranulation of mast cell subtypes in human colon tissues.  

PubMed

Mast cells play a central role in the intestinal immune response. To investigate the relationship between degranulation, cell polarization and the reorganization of actin cytoskeleton of mast cells, we used fluorescence or gold labeling methods to identify different mast cell subtypes in human colon. The reorganization of filamentous actin was visualized and then the polarization of secretory vesicles, as well as cell surfaces, was analyzed by fluorescence microscopy and electron microscopy. Our results first showed a diversity of filamentous actin assembly or disassembly within the contacting cell membrane of different mast cell subtypes. The polarization and degranulation of secretory vesicles was not only accompanied with the assembly and disassembly of filamentous actin at the cell periphery, but also with changes of cell surface polarization. Our study provides an insight into the local membranous structures and suggested correlations of cytoskeleton arrangement with the polarization of secretory vesicles and cell surface configuration during mast cell degranulation. PMID:24161690

Lin, Jue-Long; Chen, Chun-Gui; Shen, Zhi-Zhong; Piao, Zhong-Xian; Li, Wei-Qiu; Liu, Liu; Xu, Li-Yan; Li, En-Min

2014-03-01

160

[Human basophil degranulation test (HBDT) for diagnosis of respiratory allergic disorders. A study of eighty-four HDBT performed in forty-seven patients (author's transl)].  

PubMed

The HBDT uses basophils of patients with respiratory allergic disorders. In this simple method the basophils are stained by toluidine blue and the erythrocytes are destroyed. The basophils are then exposed to solutions containing different concentrations of the antigen. The basophil degranulation rate in response to a given antigen can be determined. The test is positive if the degranulation rate is over 50% and negative if the rate is under 30%. Our clinical study induces 47 patients. The correlate rate between HBDT and skin tests is 81,5%. This test's technical simplicity allows it's routine use by a non specialized laboratory. PMID:6275523

Rouquette, A M; Lugassy, D; Vacheron, F; Combrisson, A; Akoun, G

161

Mast cell CD30 ligand is upregulated in cutaneous inflammation and mediates degranulation-independent chemokine secretion  

PubMed Central

Mast cells are involved in many disorders where the triggering mechanism that leads to degranulation and/or cytokine secretion has not been defined. Several chronic inflammatory diseases are associated with increased mast cell numbers and upregulation of the TNF receptor family member CD30, but the role of elevated CD30 expression is poorly understood. Here we report what we believe to be a novel way to activate mast cells with CD30 that leads to degranulation-independent secretion of chemokines. CD30 induced a de novo synthesis and secretion of the chemokines IL-8, macrophage inflammatory protein-1? (MIP-1?), and MIP-1?, a process involving the MAPK/ERK pathway. Mast cells were found to be the predominant CD30 ligand–positive (CD30L-positive) cell in the chronic inflammatory skin diseases psoriasis and atopic dermatitis, and both CD30 and CD30L expression were upregulated in lesional skin in these conditions. Furthermore, the number of IL-8–positive mast cells was elevated both in psoriatic and atopic dermatitis lesional skin as well as in ex vivo CD30-treated healthy skin organ cultures. In summary, characterization of CD30 activation of mast cells has uncovered an IgE-independent pathway that is of importance in understanding the entirety of the role of mast cells in diseases associated with mast cells and CD30 expression. These diseases include Hodgkin lymphoma, atopic dermatitis, and psoriasis.

Fischer, Marie; Harvima, Ilkka T.; Carvalho, Ricardo F.S.; Moller, Christine; Naukkarinen, Anita; Enblad, Gunilla; Nilsson, Gunnar

2006-01-01

162

Acute Immobilization Stress Triggers Skin Mast Cell Degranulation via Corticotropin Releasing Hormone, Neurotensin, and Substance P: A Link to Neurogenic Skin Disorders  

Microsoft Academic Search

Many skin disorders, such as atopic dermatitis and psoriasis, worsen during stress and are associated with increased numbers and activation of mast cells which release vasoactive, nociceptive, and proinflammatory mediators. Nontraumatic acute psychological stress by immobilization has been shown to induce mast cell degranulation in the rat dura and colon. Moreover, intradermal injection of corticotropin-releasing hormone (CRH) or its analogue

Leena K. Singh; Xinzhu Pang; Nicholas Alexacos; Richard Letourneau; Theoharis C. Theoharides

1999-01-01

163

Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts  

Microsoft Academic Search

BACKGROUND: The purpose of this study was to test the hypothesis that mast cells that are present in fibrotic regions of cancer can suppress the growth of tumor cells through an indirect mechanism involving peri-tumoral fibroblasts. METHODS: We first immunostained a wide variety of human cancers for the presence of degranulated mast cells. In a subsequent series of controlled in

Michael Samoszuk; Emi Kanakubo; John K Chan

2005-01-01

164

Fc?RI-mediated mast cell degranulation requires calcium-independent microtubule-dependent translocation of granules to the plasma membrane  

PubMed Central

The aggregation of high affinity IgE receptors (Fc? receptor I [Fc?RI]) on mast cells is potent stimulus for the release of inflammatory and allergic mediators from cytoplasmic granules. However, the molecular mechanism of degranulation has not yet been established. It is still unclear how Fc?RI-mediated signal transduction ultimately regulates the reorganization of the cytoskeleton and how these events lead to degranulation. Here, we show that Fc?RI stimulation triggers the formation of microtubules in a manner independent of calcium. Drugs affecting microtubule dynamics effectively suppressed the Fc?RI-mediated translocation of granules to the plasma membrane and degranulation. Furthermore, the translocation of granules to the plasma membrane occurred in a calcium-independent manner, but the release of mediators and granule–plasma membrane fusion were completely dependent on calcium. Thus, the degranulation process can be dissected into two events: the calcium-independent microtubule-dependent translocation of granules to the plasma membrane and calcium-dependent membrane fusion and exocytosis. Finally, we show that the Fyn/Gab2/RhoA (but not Lyn/SLP-76) signaling pathway plays a critical role in the calcium-independent microtubule-dependent pathway.

Nishida, Keigo; Yamasaki, Satoru; Ito, Yukitaka; Kabu, Koki; Hattori, Kotaro; Tezuka, Tohru; Nishizumi, Hirofumi; Kitamura, Daisuke; Goitsuka, Ryo; Geha, Raif S.; Yamamoto, Tadashi; Yagi, Takeshi; Hirano, Toshio

2005-01-01

165

A microplate assay to assess chemical effects on RBL-2H3 mast cell degranulation: effects of triclosan without use of an organic solvent.  

PubMed

Mast cells play important roles in allergic disease and immune defense against parasites. Once activated (e.g. by an allergen), they degranulate, a process that results in the exocytosis of allergic mediators. Modulation of mast cell degranulation by drugs and toxicants may have positive or adverse effects on human health. Mast cell function has been dissected in detail with the use of rat basophilic leukemia mast cells (RBL-2H3), a widely accepted model of human mucosal mast cells(3-5). Mast cell granule component and the allergic mediator ?-hexosaminidase, which is released linearly in tandem with histamine from mast cells(6), can easily and reliably be measured through reaction with a fluorogenic substrate, yielding measurable fluorescence intensity in a microplate assay that is amenable to high-throughput studies(1). Originally published by Naal et al.(1), we have adapted this degranulation assay for the screening of drugs and toxicants and demonstrate its use here. Triclosan is a broad-spectrum antibacterial agent that is present in many consumer products and has been found to be a therapeutic aid in human allergic skin disease(7-11), although the mechanism for this effect is unknown. Here we demonstrate an assay for the effect of triclosan on mast cell degranulation. We recently showed that triclosan strongly affects mast cell function(2). In an effort to avoid use of an organic solvent, triclosan is dissolved directly into aqueous buffer with heat and stirring, and resultant concentration is confirmed using UV-Vis spectrophotometry (using ?280 = 4,200 L/M/cm)(12). This protocol has the potential to be used with a variety of chemicals to determine their effects on mast cell degranulation, and more broadly, their allergic potential. PMID:24300285

Weatherly, Lisa M; Kennedy, Rachel H; Shim, Juyoung; Gosse, Julie A

2013-01-01

166

Histochemical study of cardiac mast cells degranulation and collagen deposition: interaction with the cathecolaminergic system in the rat.  

PubMed

Although their role in the cardiovascular system is still largely unknown, mast cells are present in the myocardium of both experimental animals and humans. Interestingly, cathecolaminergic nerve fibres and mast cells are often described in close morphological and functional interactions in various organs. In the present study we investigated the effects of chronic interference with beta-adrenergic receptors (via either sympathectomy or beta-blockade) on cardiac mast cell morphology/activation and on interstitial collagen deposition. In rats subjected to chemical sympathectomizy with the neurotoxin 6-hydroxydopamine (6-OHDA) we observed a significant increase of mast cell density, and in particular of degranulating mast cells, suggesting a close relationship between the cardiac catecholaminergic system and mast cell activation. In parallel, chronic 6-OHDA treatment was associated with increased collagen deposition. The influence of the beta-adrenergic receptor component was investigated in rats subjected to chronic propranolol administration, that caused a further significant increase in mast cell activation associated with a lower extent of collagen deposition when compared to chemical sympathectomy. These data are the first demonstration of a close relationship between rat cardiac mast cell activation and the catecholaminergic system, with a complex interplay with cardiac collagen deposition. Specifically, abrogation of the cardiac sympathetic efferent drive by chemical sympathectomy causes mast cell activation and interstitial fibrosis, possibly due to the local effects of the neurotoxin 6-hydroxydopamine. In contrast, beta-adrenergic blockade is associated with enhanced mast cell degranulation and a lower extent of collagen deposition in the normal myocardium. In conclusion, cardiac mast cell activation is influenced by beta-adrenergic influences. PMID:16864125

Facoetti, A; Fallarini, S; Miserere, S; Bertolotti, A; Ferrero, I; Tozzi, R; Gatti, C; Palladini, G; Perlini, S; Nano, R

2006-01-01

167

Polydatin (PD) inhibits IgE-mediated passive cutaneous anaphylaxis in mice by stabilizing mast cells through modulating Ca{sup 2+} mobilization  

SciTech Connect

Mast cells play a key role in the pathogenesis of asthma and are a promising target for therapeutic intervention in asthma. This study investigated the effects of polydatin (PD), a resveratrol glucoside, on mast cell degranulation upon cross-linking of the high-affinity IgE receptors (Fc?RI), as well as the anti-allergic activity of PD in vivo. Herein, we demonstrated that PD treatment for 30 min suppressed Fc?RI-mediated mast cell degranulation in a dose-dependent manner. Concomitantly, PD significantly decreased Fc?RI-mediated Ca{sup 2+} increase in mast cells. The suppressive effects of PD on Fc?RI-mediated Ca{sup 2+} increase were largely inhibited by using LaCl{sub 3} to block the Ca{sup 2+} release-activated Ca{sup 2+} channels (CRACs). Furthermore, PD significantly inhibited Ca{sup 2+} entry through CRACs evoked by thapsigargin (TG). Knocking down protein expression of Orai1, the pore-forming subunit of CRACs, significantly decreased PD suppression of Fc?RI-induced intracellular Ca{sup 2+} influx and mast cell degranulation. In a mouse model of mast cell-dependent passive cutaneous anaphylaxis (PCA), in vivo PD administration suppressed mast cell degranulation and inhibited anaphylaxis. Taken together, our data indicate that PD stabilizes mast cells by suppressing Fc?RI-induced Ca{sup 2+} mobilization mainly through inhibiting Ca{sup 2+} entry via CRACs, thus exerting a protective effect against PCA. -- Highlights: ? Polydatin can prevent the pathogenesis of passive cutaneous anaphylaxis in mice. ? Polydatin stabilizes mast cells by decreasing Fc?RI-mediated degranulation. ? Polydatin suppresses Ca{sup 2+} entry through CRAC channels in mast cells.

Yuan, Meichun [Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen 518060 (China) [Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen 518060 (China); Department of Physiology, Hubei University of Medicine, Shiyan (China); Li, Jianjie [State Key Laboratory of Respiratory Disease for Allergy at Shengzhen University, Shenzhen 518060 (China)] [State Key Laboratory of Respiratory Disease for Allergy at Shengzhen University, Shenzhen 518060 (China); Lv, Jingzhang [Shenzhen Entry-Exit Inspection and Quarantine Bureau, Shenzhen 518045 (China)] [Shenzhen Entry-Exit Inspection and Quarantine Bureau, Shenzhen 518045 (China); Mo, Xucheng; Yang, Chengbin [State Key Laboratory of Respiratory Disease for Allergy at Shengzhen University, Shenzhen 518060 (China)] [State Key Laboratory of Respiratory Disease for Allergy at Shengzhen University, Shenzhen 518060 (China); Chen, Xiangdong [Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen 518060 (China)] [Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen 518060 (China); Liu, Zhigang [State Key Laboratory of Respiratory Disease for Allergy at Shengzhen University, Shenzhen 518060 (China)] [State Key Laboratory of Respiratory Disease for Allergy at Shengzhen University, Shenzhen 518060 (China); Liu, Jie, E-mail: ljljz@yahoo.com [Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen 518060 (China)] [Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen 518060 (China)

2012-11-01

168

Bromophenacyl Bromide Binding to the Actin-Bundling Protein l-Plastin Inhibits Inositol Trisphosphate-Independent Increase in Ca2+ in Human Neutrophils  

Microsoft Academic Search

Ligation of IgG Fc receptors on polymorphonuclear leukocytes causes an increase in the concentration of free intracytoplasmic Ca2+ ([Ca2+]_i) which arises from release of intracellular stores but is independent of inositol 1,4,5-trisphosphate. We found that bromophenacyl bromide (BPB), an alkylating agent which inhibits leukocyte degranulation, adherence, and phagocytosis, inhibited IgG-stimulated increases in [Ca2+]_i with an IC50 of 0.2 mu M.

Carlos Rosales; Samuel L. Jones; David McCourt; Eric J. Brown

1994-01-01

169

Histamine release, formation of prostaglandin-like activity (SRS-C) and mast cell degranulation by the direct lytic factor (DLF) and phospholipase A of cobra venom  

Microsoft Academic Search

The effect of Direct Lytic Factor (DLF) and phospholipase A (ph-ase A) from cobra venom, alone and in combination, on mast cell degranulation, histamine release and formation of prostaglandin-like activity (SRS-C) was studied in perfused guinea-pig lungs and in mast cell-containing rat peritoneal cell suspensions. For comparison, the effect of equivalent doses of whole cobra venom was investigated.1.Cobra venom caused

B. Damerau; L. Lege; H.-D. Oldigs; W. Vogt

1975-01-01

170

NTAL phosphorylation is a pivotal link between the signaling cascades leading to human mast cell degranulation following Kit activation and FcRI aggregation  

Microsoft Academic Search

Aggregation of high-affinity receptors for immunoglobulin E (FcRI) on the surface of mast cells results in degranulation, a response that is potentiated by binding of stem cell factor (SCF) to its receptor Kit. We observed that one of the major initial signaling events associated with FcRI- mediated activation of human mast cells (HuMCs) is the rapid tyrosine phosphory- lation of

Christine Tkaczyk; Vaclav Horejsi; Shoko Iwaki; Petr Draber; Lawrence E. Samelson; Anne B. Satterthwaite; Dong-Ho Nahm; Dean D. Metcalfe; Alasdair M. Gilfillan

2004-01-01

171

NTAL phosphorylation is a pivotal link between the signaling cascades leading to human mast cell degranulation following Kit activation and Fc epsilon RI aggregation.  

PubMed

Aggregation of high-affinity receptors for immunoglobulin E (Fc epsilon RI) on the surface of mast cells results in degranulation, a response that is potentiated by binding of stem cell factor (SCF) to its receptor Kit. We observed that one of the major initial signaling events associated with Fc epsilon RI-mediated activation of human mast cells (HuMCs) is the rapid tyrosine phosphorylation of a protein of 25 to 30 kDa. The phosphorylation of this protein was also observed in response to SCF. This protein was identified as non-T-cell activation linker (NTAL), an adaptor molecule similar to linker for activated T cells (LAT). Unlike the Fc epsilon RI response, SCF induced NTAL phosphorylation in the absence of detectable LAT phosphorylation. When SCF and antigen were added concurrently, there was a marked synergistic effect on NTAL phosphorylation, however, SCF did not enhance the phosphorylation of LAT induced by Fc epsilon RI aggregation. Fc epsilon RI- and SCF-mediated NTAL phosphorylation appear to be differentially regulated by Src kinases and/or Kit kinase, respectively. Diminution of NTAL expression by silencing RNA oligonucleotides in HuMCs resulted in a reduction of both Kit- and Fc epsilon RI-mediated degranulation. NTAL, thus, appears to be an important link between the signaling pathways that are initiated by these receptors, culminating in mast cell degranulation. PMID:15010370

Tkaczyk, Christine; Horejsi, Vaclav; Iwaki, Shoko; Draber, Petr; Samelson, Lawrence E; Satterthwaite, Anne B; Nahm, Dong-Ho; Metcalfe, Dean D; Gilfillan, Alasdair M

2004-07-01

172

TiO2, CeO2 and ZnO nanoparticles and modulation of the degranulation process in human neutrophils.  

PubMed

Inflammation is frequently associated with nanoparticle (NP) exposures. Given that excessive polymorphonuclear neutrophil cell degranulation is a common feature of inflammatory disorders, and since these cells are key players in inflammation, we decided to test the hypothesis that NPs could act as modulators of degranulation in human neutrophils. TiO2, CeO2 and ZnO NPs slightly down-regulated cell surface expression of the granule marker CD35, but increased CD66b and CD63 expression, as assessed by flow cytometry. In addition, expression of myeloperoxidase, MMP-9 and albumin stored in azurophil, specific/gelatinase and secretrory granules, respectively, was significantly increased in the supernatants of NPs-induced neutrophils when compared to untreated cells. Moreover, NPs were more potent than the classical bacterial tripeptide N-formyl-methionine-leucine-phenylalanine (fMLP) agonist. Finally, TiO2 and CeO2 markedly increased the enzymatic activity of MMP-9 released into the supernatant, as assessed by gelatin zymography, while ZnO exerted only a modest effect. We conclude that NPs can differentially affect all steps involved during neutrophil degranulation, namely, cell surface expression of granule markers, liberation of proteins in the supernatants and enzymatic activity. These results are expected to be helpful to understand the toxicity of TiO2, CeO2 and ZnO. PMID:23726862

Babin, Kim; Antoine, Francis; Goncalves, David Miguel; Girard, Denis

2013-07-31

173

The Bcl10-Malt1 complex segregates Fc?RI-mediated nuclear factor ?B activation and cytokine production from mast cell degranulation  

PubMed Central

Mast cells are pivotal effector cells in IgE-mediated allergic inflammatory diseases. Central for mast cell activation are signals from the IgE receptor Fc?RI, which induce cell degranulation with the release of preformed mediators and de novo synthesis of proinflammatory leukotrienes and cytokines. How these individual mast cell responses are differentially controlled is still unresolved. We identify B cell lymphoma 10 (Bcl10) and mucosa-associated lymphoid tissue 1 (Malt1) as novel key regulators of mast cell signaling. Mice deficient for either protein display severely impaired IgE-dependent late phase anaphylactic reactions. Mast cells from these animals neither activate nuclear factor ?B (NF-?B) nor produce tumor necrosis factor ? or interleukin 6 upon Fc?RI ligation even though proximal signaling, degranulation, and leukotriene secretion are normal. Thus, Bcl10 and Malt1 are essential positive mediators of Fc?RI-dependent mast cell activation that selectively uncouple NF-?B–induced proinflammatory cytokine production from degranulation and leukotriene synthesis.

Klemm, Stefanie; Gutermuth, Jan; Hultner, Lothar; Sparwasser, Tim; Behrendt, Heidrun; Peschel, Christian; Mak, Tak W.; Jakob, Thilo; Ruland, Jurgen

2006-01-01

174

A truncated splice-variant of the Fc?RI? receptor subunit is critical for microtubule formation and degranulation in mast cells.  

PubMed

Human linkage analyses have implicated the MS4A2-containing gene locus (encoding Fc?RI?) as a candidate for allergy susceptibility. We have identified a truncation of Fc?RI? (t-Fc?RI?) in humans that contains a putative calmodulin-binding domain and thus, we sought to identify the role of this variant in mast cell function. We determined that t-Fc?RI? is critical for microtubule formation and degranulation and that it may perform this function by trafficking adaptor molecules and kinases to the pericentrosomal and Golgi region in response to Ca2+ signals. Mutagenesis studies suggest that calmodulin binding to t-Fc?RI? in the presence of Ca2+ could be critical for t-Fc?RI? function. In addition, gene targeting of t-Fc?RI? attenuated microtubule formation, degranulation, and IL-8 production downstream of Ca2+ signals. Therefore, t-Fc?RI? mediates Ca2+ -dependent microtubule formation, which promotes degranulation and cytokine release. Because t-Fc?RI? has this critical function, it represents a therapeutic target for the downregulation of allergic inflammation. PMID:23643722

Cruse, Glenn; Beaven, Michael A; Ashmole, Ian; Bradding, Peter; Gilfillan, Alasdair M; Metcalfe, Dean D

2013-05-23

175

Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative.  

PubMed

In response to various exogenous stimuli, mast cells (MCs) release a wide variety of inflammatory mediators stored in their cytoplasmic granules and this release initiates subsequent allergic reactions. Lysophosphatidylserine (lysoPS) has been known as an exogenous inducer to potentiate histamine release from MCs, though even at submicromolar concentrations. In this study, through SAR studies on lysoPS against MC degranulation, we identified lysoPT, a threonine-containing lysophospholipid and its 2-deoxy derivative as novel strong agonists. LysoPT and its 2-deoxy derivative induced histamine release from MCs both in vitro and in vivo at a concentration less than one-tenth that of lysoPS. Notably, lysoPT did not activate a recently proposed lysoPS receptor on MCs, GPR34, demonstrating the presence of another undefined receptor reactive to both lysoPS and lysoPT that is involved in MC degranulation. Thus, the present strong agonists, lysoPT and its 2-deoxy derivative, will be useful tools to understand the mechanisms of lysoPS-induced activation of degranulation of MCs. PMID:19743861

Iwashita, Masazumi; Makide, Kumiko; Nonomura, Taro; Misumi, Yoshimasa; Otani, Yuko; Ishida, Mayuko; Taguchi, Ryo; Tsujimoto, Masafumi; Aoki, Junken; Arai, Hiroyuki; Ohwada, Tomohiko

2009-10-01

176

JunB is required for IgE-mediated degranulation and cytokine release of mast cells.  

PubMed

Mast cells are effector cells of IgE-mediated immune responses frequently found at the vicinity of blood vessels, the margins of diverse tumors and at sites of potential infection and inflammation. Upon IgE-mediated stimulation, mast cells produce and secrete a broad spectrum of cytokines and other inflammatory mediators. Recent work identified JunB, a member of the AP-1 transcription factor family, as critical regulator of basal and induced expression of inflammatory mediators in fibroblasts and T cells. To study the impact of JunB on mast cell biology, we analyzed JunB-deficient mast cells. Mast cells lacking JunB display a normal in vivo maturation, and JunB-deficient bone marrow cells in vitro differentiated to mast cells show no alterations in proliferation or apoptosis. But these cells exhibit impaired IgE-mediated degranulation most likely due to diminished expression of SWAP-70, Synaptotagmin-1, and VAMP-8, and due to impaired influx of extracellular calcium. Moreover, JunB-deficient bone marrow mast cells display an altered cytokine expression profile in response to IgE stimulation. In line with these findings, the contribution of JunB-deficient mast cells to angiogenesis, as analyzed in an in vitro tube formation assay on matrigel, is severely impaired due to limiting amounts of synthesized and secreted vascular endothelial growth factor. Thus, JunB is a critical regulator of intrinsic mast cell functions including cross-talk with endothelial cells. PMID:17982078

Textor, Björn; Licht, Alexander H; Tuckermann, Jan P; Jessberger, Rolf; Razin, Ehud; Angel, Peter; Schorpp-Kistner, Marina; Hartenstein, Bettina

2007-11-15

177

Platelet degranulation and glycoprotein IIbIIIa opening are not related to bleeding phenotype in severe haemophilia A patients.  

PubMed

Recently we reported data suggesting that platelets could compensate for the bleeding phenotype in severe haemophilia A (HA). The aim of this study was to confirm these results in a larger population with a detailed characterisation of clinical phenotype. Patients with diagnostic severe HA (FVIII:C <1%) were scored for clinical phenotype by integrating data on age at first joint bleed, joint damage, bleeding frequency and FVIII consumption. Phenotype was defined as onset of joint bleeding-score + arthropathy-score + joint bleeding-score + (2* treatment intensity-score). After a washout period of three days, blood was collected for measurement of basal level of platelet activation, platelet reactivity, endothelial cell activation and presence of procoagulant phospholipids in plasma. Thirty-three patients with severe HA were included, 13 patients with a mild, 12 patients with an average and eight patients with a severe clinical phenotype. No relevant differences in basal level of platelet activation, platelet reactivity, endothelial cell activation and procoagulant phospholipids between all three groups were observed. The mean annual FVIII consumption per kg did not correlate with the platelet P-selectin expression and glycoprotein (GP)IIbIIIa activation on platelets. In conclusion, variability in clinical phenotype in patients with diagnostic severe HA is not related to platelet activation or reactivity, measured as platelet degranulation and platelet GPIIbIIIa opening. PMID:24477967

van Bladel, E R; Schutgens, R E G; Fischer, K; de Groot, P G; Roest, M

2014-06-01

178

Induction of adherence and degranulation of polymorphonuclear leukocytes: a new expression of the invasive phenotype of Shigella flexneri.  

PubMed Central

In the present study, the ability of Shigella flexneri to activate polymorphonuclear neutrophils (PMN) was examined. The invasive serotype 5 strain M90T induced strong PMN adherence, which was dependent on both the multiplicity of infection and the duration of incubation. When tested under the same experimental conditions, the noninvasive strain BS176 (cured of the 220-kb virulence plasmid) was less efficient. Indeed, incubation of PMN for 2 h with either M90T or BS176 (multiplicity of infection, 100) induced 51.8% +/- 10.5% and 15.2% +/- 4.2% adherence, respectively (n = 3; P < 0.05). Stronger PMN activation by M90T was confirmed by evaluating PMN degranulation induced by the two strains. Whereas M90T triggered significant PMN secretion, BS176 did not. M90T strains with mutations in ipa genes were then analyzed. When PMN were incubated with these mutants, their activation was of the same intensity as that obtained with BS176. These data provide the first evidence for PMN activation induced by S. flexneri, a process which appears to be mediated by Ipa invasins.

Renesto, P; Mounier, J; Sansonetti, P J

1996-01-01

179

Adhesion and Degranulation Promoting Adapter Protein (ADAP) Is a Central Hub for Phosphotyrosine-Mediated Interactions in T Cells  

PubMed Central

TCR stimulation leads to an increase in cellular adhesion among other outcomes. The adhesion and degranulation promoting adapter protein (ADAP) is known to be rapidly phosphorylated after T cell stimulation and relays the TCR signal to adhesion molecules of the integrin family. While three tyrosine phosphorylation sites have been characterized biochemically, the binding capabilities and associated functions of several other potential phosphotyrosine motifs remain unclear. Here, we utilize in vitro phosphorylation and mass spectrometry to map novel phosphotyrosine sites in the C-terminal part of human ADAP (486–783). Individual tyrosines were then mutated to phenylalanine and their relevance for cellular adhesion and migration was tested experimentally. Functionally important tyrosine residues include two sites within the folded hSH3 domains of ADAP and two at the C-terminus. Furthermore, using a peptide pulldown approach in combination with stable isotope labeling in cell culture (SILAC) we identified SLP-76, PLC?, PIK3R1, Nck, CRK, Gads, and RasGAP as phospho-dependent binding partners of a central YDDV motif of ADAP. The phosphorylation-dependent interaction between ADAP and Nck was confirmed by yeast two-hybrid analysis, immunoprecipitation and binary pulldown experiments, indicating that ADAP directly links integrins to modulators of the cytoskeleton independent of SLP-76.

Sylvester, Marc; Kliche, Stefanie; Lange, Sabine; Geithner, Sabine; Klemm, Clementine; Schlosser, Andreas; Grossmann, Arndt; Stelzl, Ulrich; Schraven, Burkhart; Krause, Eberhard; Freund, Christian

2010-01-01

180

Britanin Suppresses IgE/Ag-Induced Mast Cell Activation by Inhibiting the Syk Pathway  

PubMed Central

The aim of this study was to determine whether britanin, isolated from the flowers of Inula japonica (Inulae Flos), modulates the generation of allergic inflammatory mediators in activated mast cells. To understand the biological activity of britanin, the authors investigated its effects on the generation of prostaglandin D2 (PGD2), leukotriene C4 (LTC4), and degranulation in IgE/Ag-induced bone marrow-derived mast cells (BMMCs). Britanin dose dependently inhibited degranulation and the generations of PGD2 and LTC4 in BMMCs. Biochemical analyses of IgE/Ag-mediated signaling pathways demonstrated that britanin suppressed the phosphorylation of Syk kinase and multiple downstream signaling processes, including phospholipase C?1 (PLC?1)-mediated calcium influx, the activation of mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase and p38), and the nuclear factor-?B (NF-?B) pathway. Taken together, the findings of this study suggest britanin suppresses degranulation and eicosanoid generation by inhibiting the Syk-dependent pathway and britanin might be useful for the treatment of allergic inflammatory diseases.

Lu, Yue; Li, Xian; Park, Young Na; Kwon, Okyun; Piao, Donggen; Chang, Young-Chae; Kim, Cheorl-Ho; Lee, Eunkyung; Son, Jong Keun; Chang, Hyeun Wook

2014-01-01

181

Britanin Suppresses IgE/Ag-Induced Mast Cell Activation by Inhibiting the Syk Pathway.  

PubMed

The aim of this study was to determine whether britanin, isolated from the flowers of Inula japonica (Inulae Flos), modulates the generation of allergic inflammatory mediators in activated mast cells. To understand the biological activity of britanin, the authors investigated its effects on the generation of prostaglandin D2 (PGD2), leukotriene C4 (LTC4), and degranulation in IgE/Ag-induced bone marrow-derived mast cells (BMMCs). Britanin dose dependently inhibited degranulation and the generations of PGD2 and LTC4 in BMMCs. Biochemical analyses of IgE/Ag-mediated signaling pathways demonstrated that britanin suppressed the phosphorylation of Syk kinase and multiple downstream signaling processes, including phospholipase C?1 (PLC?1)-mediated calcium influx, the activation of mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase and p38), and the nuclear factor-?B (NF-?B) pathway. Taken together, the findings of this study suggest britanin suppresses degranulation and eicosanoid generation by inhibiting the Syk-dependent pathway and britanin might be useful for the treatment of allergic inflammatory diseases. PMID:25009699

Lu, Yue; Li, Xian; Park, Young Na; Kwon, Okyun; Piao, Donggen; Chang, Young-Chae; Kim, Cheorl-Ho; Lee, Eunkyung; Son, Jong Keun; Chang, Hyeun Wook

2014-05-01

182

Immune Response to Snake Envenoming and Treatment with Antivenom; Complement Activation, Cytokine Production and Mast Cell Degranulation  

PubMed Central

Background Snake bite is one of the most neglected public health issues in poor rural communities worldwide. In addition to the clinical effects of envenoming, treatment with antivenom frequently causes serious adverse reactions, including hypersensitivity reactions (including anaphylaxis) and pyrogenic reactions. We aimed to investigate the immune responses to Sri Lankan snake envenoming (predominantly by Russell's viper) and antivenom treatment. Methodology/Principal Findings Plasma concentrations of Interleukin (IL)-6, IL-10, tumor necrosis factor ? (TNF?), soluble TNF receptor I (sTNFRI), anaphylatoxins (C3a, C4a, C5a; markers of complement activation), mast cell tryptase (MCT), and histamine were measured in 120 Sri Lankan snakebite victims, both before and after treatment with antivenom. Immune mediator concentrations were correlated with envenoming features and the severity of antivenom-induced reactions including anaphylaxis. Envenoming was associated with complement activation and increased cytokine concentrations prior to antivenom administration, which correlated with non-specific systemic symptoms of envenoming but not with coagulopathy or neurotoxicity. Typical hypersensitivity reactions to antivenom occurred in 77/120 patients (64%), satisfying criteria for a diagnosis of anaphylaxis in 57/120 (48%). Pyrogenic reactions were observed in 32/120 patients (27%). All patients had further elevations in cytokine concentrations, but not complement activation, after the administration of antivenom, whether a reaction was noted to occur or not. Patients with anaphylaxis had significantly elevated concentrations of MCT and histamine. Conclusions/Significance We have demonstrated that Sri Lankan snake envenoming is characterized by significant complement activation and release of inflammatory mediators. Antivenom treatment further enhances the release of inflammatory mediators in all patients, with anaphylactic reactions characterised by high levels of mast cell degranulation but not further complement activation. Anaphylaxis is probably triggered by non allergen-specific activation of mast cells and may be related to the quality of available antivenom preparations, as well as a priming effect from the immune response to the venom itself.

Stone, Shelley F.; Isbister, Geoffrey K.; Shahmy, Seyed; Mohamed, Fahim; Abeysinghe, Chandana; Karunathilake, Harendra; Ariaratnam, Ariaranee; Jacoby-Alner, Tamara E.; Cotterell, Claire L.; Brown, Simon G. A.

2013-01-01

183

Signaling mechanisms of inhibition of phospholipase D activation by CHS111 in formyl peptide-stimulated neutrophils  

Microsoft Academic Search

A selective phospholipase D (PLD) inhibitor 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) inhibited the O2? generation and cell migration but not degranulation in formyl-Met-Leu-Phe (fMLP)-stimulated rat neutrophils. A novel benzyl indazole compound 2-benzyl-3-(4-hydroxymethylphenyl)indazole (CHS-111), which inhibited O2? generation and cell migration, also reduced the fMLP- but not phorbol ester-stimulated PLD activity (IC50 3.9±1.2?M). CHS-111 inhibited the interaction of PLD1 with ADP-ribosylation factor (Arf)

Ling-Chu Chang; Tai-Hung Huang; Chi-Sen Chang; Ya-Ru Tsai; Ruey-Hseng Lin; Pin-Wen Lee; Mei-Feng Hsu; Li-Jiau Huang; Jih-Pyang Wang

2011-01-01

184

Inhibitory effects of sesquiterpene lactones isolated from Eupatorium chinense L. on IgE-mediated degranulation in rat basophilic leukemia RBL-2H3 cells and passive cutaneous anaphylaxis reaction in mice.  

PubMed

Sesquiterpene lactones (SQTLs) have been shown to suppress the degranulation as inferred by histamine release in rat basophilic leukemia RBL-2H3 cells. In this study, we isolated the 9 kinds of SQTLs from Eupatorium chinense L. and examined the effects of these SQTLs on the degranulation in RBL-2H3 cells. The chemical structures of two novel compounds (SQTL-3 and 8) were determined. All the SQTLs suppressed the degranulation from Ag-stimulated RBL-2H3 cells. To disclose the inhibitory mechanism of degranulation by SQTLs, we examined the activation of intracellular signaling molecules such as Lyn, Syk, and PLCgammas and intracellular free Ca(2+) concentration ([Ca(2+)]i). None of these SQTLs showed the activation of Syk and PLCgammas. The intracellular free Ca(2+) concentration ([Ca(2+)]i) was elevated by Fc epsilonRI activation, but SQTLs treatment reduced the elevation of [Ca(2+)]i by suppressing Ca(2+) influx. Thus, it was suggested that the suppression of Ag-stimulated degranulation by these SQTLs is mainly due to the decreased Ca(2+) influx. Furthermore, in order to clarify the in vivo effect of SQTL-rich extract, we administered SQTL-rich extract to the type I allergic model mice and measured the passive cutaneous anaphylaxis (PCA) reaction induced by IgE-antigen complex. The SQTLs remarkably suppressed PCA reaction in a dose-dependent manner. Thus, it was suggested that SQTLs would be a candidate as an anti-allergic agent. PMID:19318257

Itoh, Tomohiro; Oyama, Masayoshi; Takimoto, Norihiko; Kato, Chihiro; Nozawa, Yoshinori; Akao, Yukihiro; Iinuma, Munekazu

2009-04-15

185

Interleukin-33 amplifies IgE synthesis and triggers mast cell degranulation via interleukin-4 in na?ve mice1  

PubMed Central

Background The regulation and function of IgE in healthy individuals and in antigen-naïve animals is not well understood. IL-33 administration increases serum IgE in mice with unknown mechanism. We tested the hypothesis that IL-33 provides an antigen-independent stimulus for IgE production and mast cell degranulation. Methods IL-33 was administered to naïve wild-type (WT), nude and ST2?/?, IL-4?/?, IL4R??/? and T-or B-cell-specific IL-4R??/? mice. IgEand cytokines were quantified by ELISA. T- and B-lymphocyte numbers and CD40L expression were determined by flow cytometry. Anaphylaxis was measured by temperature, mast cell degranulation and histamine release. Results IL-33 enhanced IgE production in naïve WT, T-IL-4R??/? but not in ST2?/?, IL-4?/?, IL-4R??/? or B-cell-specific IL-4R??/? mice, demonstrating IL-33 specificity and IL-4 dependency. Moreover, IL-4 was required for IL-33-induced B-cell proliferation and T-cell CD40L expression, which promotes IgE production. IL-33-induced IL-4 production was mainly from innate cells including mast cells and eosinophils. IL-33 increased mast cell surface IgE and triggered degranulation and systemic anaphylaxis in allergen-naïve WT but not in IL-4R??/? mice. Conclusion IL-33 amplifies IgE synthesis and triggers anaphylaxis in naïve mice via IL-4, independent of allergen. IL-33 may play an important role in nonatopic allergy and idiopathic anaphylaxis.

Komai-Koma, M; Brombacher, F; Pushparaj, P N; Arendse, B; McSharry, C; Alexander, J; Chaudhuri, R; Thomson, N C; McKenzie, A N J; McInnes, I; Liew, F Y; Xu, D

2012-01-01

186

Balance of apoptotic and anti-apoptotic marker and perforin granule release in squamous intraepithelial lesions. HIV infection leads to a decrease in perforin degranulation.  

PubMed

Cell-mediated cytotoxicity plays an important role in the regulation to HPV-associated cervical intraepithelial neoplasia. HIV co-infection is related to poorer prognosis and more rapid clinical progression to cancer. We evaluated the presence of cervical inflammatory cells, apoptotic (Bax, Bcl-2, FasL, NOS2, perforin) markers and the degranulating expressing cell marker (CD107a) in low and high squamous intraepithelial lesions (LSIL and HSIL, respectively) from HIV-negative and -positive women. Higher percentage of cervical CD4(+), CD8(+) T cells and macrophage were observed in LSIL and HSIL groups when compared with control, especially in epithelium and basal layer of epithelium. However, progression from LSIL to HSIL did not change the frequency of inflammatory cells. HIV-infection lead to a reduction on cervical CD4(+) T cell infiltration and an increased CD8(+) T cell distribution in LSIL groups. A balance between pro- and anti-apoptotic protein expressions was verified. Bax-expressing cells were present in all groups and were rarely expressed in keratinocytes in the epithelium in LSIL and control groups, but notably decreased in HSIL group. However, its frequency was enhanced in the basal layer of the epithelium meanly in LSIL group. Bcl2-expressing cells in the epithelium and the stroma were enhanced in HSIL group when compared with LSIL group. HIV-infection did not interfere in both expressions NOS2 expression was located on keratinocytes in both LSIL and HSIL groups when compared with control group. There were few FasL cervical expressing cells in all groups. Indeed, perforin was identified in few cervical cells. However, CD107a, a surface marker for cellular degranulation was significantly higher in epithelium, basal layer of epithelium and stroma in LSIL and HSIL, respectively, when compared with control group. These results support that HIV infection may induce reduction on inflammatory cervical cell degranulation corroborating to carcinogenesis process. This is the first description on the role of HIV in downregulation of perforin degranulation in the cervical lesions and it might be related to carcinogenesis. PMID:23791892

Fernandes, Ana Teresa G; da Rocha, Natalia Pereira; Avvad, Elyzabeth; Grinsztejn, Beatriz J; Russomano, Fabio; Tristão, Aparecida; Quintana, Marcel de Souza Borges; Perez, Mauricio A; Conceição-Silva, Fátima; Bonecini-Almeida, Maria da Gloria

2013-10-01

187

Angiopoietin1 inhibits mast cell activation and protects against anaphylaxis.  

PubMed

Since morbidity and mortality rates of anaphylaxis diseases have been increasing year by year, how to prevent and manage these diseases effectively has become an important issue. Mast cells play a central regulatory role in allergic diseases. Angiopoietin1 (Ang-1) exhibits anti-inflammatory properties by inhibiting vascular permeability, leukocyte migration and cytokine production. However, Ang-1's function in mast cell activation and anaphylaxis diseases is unknown. The results of our study suggest that Ang-1 decreased lipopolysaccharide (LPS)-induced pro-inflammatory cytokines production of mast cells by suppressing I?B phosphorylation and NF-?B nuclear translocation. Ang-1 also strongly inhibited compound 48/80 induced and Fc?RI-mediated mast cells degranulation by decreasing intracellular calcium levels in vitro. In vivo lentivirus-mediated delivery of Ang-1 in mice exhibited alleviated leakage in IgE-dependent passive cutaneous anaphylaxis (PCA). Furthermore, exogenous Ang-1 intervention treatment prevented mice from compound 48/80-induced mesentery mast cell degranulation, attenuated increases in pro-inflammatory cytokines, relieved lung injury, and improved survival in anaphylaxis shock. The results of our study reveal, for the first time, the important role of Ang-1 in the activation of mast cells, and identify a therapeutic effect of Ang-1 on anaphylaxis diseases. PMID:24586553

Yao, Jun-Hua; Cui, Ming; Li, Meng-Tao; Liu, Yi-Nan; He, Qi-Hua; Xiao, Jun-Jun; Bai, Yun

2014-01-01

188

Human melanoma-specific CD8+ T-cells from metastases are capable of antigen-specific degranulation and cytolysis directly ex vivo  

PubMed Central

The relatively low frequencies of tumor Ag-specific T-cells in PBMC and metastases from cancer patients have long precluded the analysis of their direct ex vivo cytolytic capacity. Using a new composite technique that works well with low cell numbers, we aimed at determining the functional competence of melanoma-specific CD8+ T-cells. A multiparameter flow cytometry based technique was applied to assess the cytolytic function, degranulation and IFN? production by tumor Ag-specific CD8+ T-cells from PBMC and tumor-infiltrated lymph nodes (TILN) of melanoma patients. We found strong cytotoxicity by T-cells not only when they were isolated from PBMC but also from TILN. Cytotoxicity was observed against peptide-pulsed target cells and melanoma cells presenting the naturally processed endogenous antigen. However, unlike their PBMC-derived counterparts, T-cells from TILN produced only minimal amounts of IFN?, while exhibiting similar levels of degranulation, revealing a critical functional dichotomy in metastatic lesions. Our finding of partial functional impairment fits well with the current knowledge that T-cells from cancer metastases are so-called exhausted, a state of T-cell hyporesponsiveness also found in chronic viral infections. The identification of responsible mechanisms in the tumor microenvironment is important for improving cancer therapies.

Mahnke, Yolanda D.; Devevre, Estelle; Baumgaertner, Petra; Matter, Maurice; Rufer, Nathalie; Romero, Pedro; Speiser, Daniel E.

2012-01-01

189

Antiallergic and Antiasthmatic Effects of a Novel Enhydrazinone Ester (CEE-1): Inhibition of Activation of Both Mast Cells and Eosinophils.  

PubMed

Activation of mast cells and eosinophils is a fundamental process in the pathophysiology of allergic diseases. We have previously reported that the novel enhydrazinone ester CEE-1 (ethyl 4-phenylhydrazinocyclohex-3-en-2-oxo-6-phenyl-1-oate) possesses potent anti-inflammatory activity. We have now tested whether the compound also possesses antiallergic and antiasthmatic effects in vitro and in vivo. The compound significantly inhibited degranulation and leukotriene C4 (LTC4) release from activated human eosinophils, as well as IgE-dependent degranulation and LTC4 release from passively sensitized rat basophilic leukemia cells and bone marrow-derived mouse mast cells. In human eosinophils, the drug was more potent in inhibiting degranulation than LTC4 release {IC50 = 0.4 ?M [confidence interval (CI): 0.1-0.9] versus 3.8 ?M (CI: 0.9-8.3)}, whereas in mast cells the reverse was essentially the case. The drug did not affect stimulus-induced calcium transients in eosinophils but significantly inhibited early phosphorylation of extracellular signal-regulated kinases 1/2 and p38-mitogen-activated protein kinases (MAPK). In vivo, topical application of 4.5-15 mg/kg of the compound significantly inhibited allergen-induced passive cutaneous anaphylaxis in mice. Similarly, in the mouse asthma model, the intranasal administration of 6.5-12.5 mg/kg of the compound significantly inhibited bronchial inflammation and eosinophil accumulation in bronchial lavage fluid, as well as abolishing airway hyper-responsiveness to methacholine. These results show that CEE-1 inhibits the activation of both mast cells and eosinophils in vitro, probably by blocking MAPK-activation pathways, and that these effects are translated into antiallergic and antiasthmatic effects in vivo. The compound, therefore, has potential application in the treatment of asthma and other allergic diseases. PMID:24917545

Ezeamuzie, Charles I; El-Hashim, Ahmed Z; Renno, Waleed M; Edafiogho, Ivan O

2014-08-01

190

Inhibition of eosinophils degranulation by Ketotifen in a patient with milk allergy, manifested as bronchial asthma—an electron microscopic study  

Microsoft Academic Search

Electron microscopic studies provided evidence that a patient with cow's milk allergy, manifested as bronchial asthma, has prominent eosinophil granule discharge, attributable to the release of cytotoxic major basic protein (MBP). This finding illustrates a critical role of eosiniphil MBP in anaphylactic injury induced by food allergen. Patient white blood cells pretreated with Ketotifen revealed intact ultrastructure of eosinophils granules

Wojciech K. Podleski; Bernard A. Panaszek; James L. Schmidt; Robert B. Burns

1984-01-01

191

Cutaneous mast cell degranulation in rats receiving injections of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) and/or its vehicle: possible clinical implications.  

PubMed

Human recombinant interleukin-1 receptor antagonist (rhIL-1ra), a 17.2 kd protein is currently in clinical trials for the treatment of rheumatoid arthritis (RA). Skin reactions in some patients with RA prompted investigation of a possible pathogenesis involving nonimmunologically mediated mast cell degranulation. Rats injected intradermally with 20 microliters of rhIL-1ra (100 or 200 mg/ml) or the rhIL-1ra vehicle CSEP (10 mmol/L Na-citrate, 0.5 mmol/L ethylenediaminetetraacetic acid (EDTA), 0.1% polysorbate 80, 140 mmol/L NaCl, pH 6.5) had marked (15x or 10x, respectively) Evans blue dye permeability increases as compared with rats injected with phosphate-buffered saline solution (PBS) or bovine serum albumin (BSA). The permeability changes were reduced or eliminated by subcutaneous or local treatment with the antihistamine diphenhydramine. Histologic evaluation of skin sections from rats injected intradermally with CSEP or rhIL-1ra in CSEP revealed mast cell degranulation and edema, features not seen in sites injected with PBS or BSA in PBS. Components of the vehicle were investigated individually for their capacity to cause the reaction. Na-citrate (10 mmol/L) induced a greater increase in permeability than did EDTA (0.5 mmol/L) or polysorbate 80 (0.1%), and all produced reactions that were significantly greater than those occurring at PBS-injected sites. Evans blue dye permeability increases after subcutaneous injection of 1 ml of rhIL-1ra (100 mg/ml) in CSEP (with and without diphenhydramine) or rhIL-1ra in PBS were evaluated.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7706905

Bendele, A; Colloton, M; Vrkljan, M; Morris, J; Sabados, K

1995-04-01

192

Food allergen--induced mast cell degranulation is dependent on PI3K-mediated reactive oxygen species production and upregulation of store-operated calcium channel subunits.  

PubMed

The importance of Ca(2+) influx via store-operated calcium channels (SOCs) leading to mast cell degranulation is well known in allergic disease. However, the underlying mechanisms are not fully understood. With food-allergic rat model, the morphology of degranulated mast cell was analysed by toluidine blue stain and electron microscope. Ca(2+) influx via SOCs was checked by Ca(2+) imaging confocal microscope. Furthermore, the mRNA and protein expression of SOCs subunits were investigated using qPCR and Western blot. We found that ovalbumin (OVA) challenge significantly increased the levels of Th2 cytokines and OVA-specific IgE in allergic animals. Parallel to mast cell activation, the levels of histamine in serum and supernatant of rat peritoneal lavage solution were remarkably increased after OVA treatment. Moreover, the Ca(2+) entry through SOCs evoked by thapsigargin was increased in OVA-challenged group. The mRNA and protein expressions of SOC subunits, stromal interaction molecule 1 (STIM1) and Orail (calcium-release-activated calcium channel protein 1), were dramatically elevated under food-allergic condition. Administration of Ebselen, a scavenger of reactive oxygen species (ROS), significantly attenuated OVA sensitization-induced intracellular Ca(2+) rise and upregulation of SOCs subunit expressions. Intriguingly, pretreatment with PI3K-specific inhibitor (Wortmannin) partially abolished the production of ROS and subsequent elevation of SOCs activity and their subunit expressions. Taken together, these results imply that enhancement of SOC-mediated Ca(2+) influx induces mast cell activation, contributing to the pathogenesis of OVA-stimulated food allergy. PI3K-dependent ROS generation involves in modulating the activity of SOCs by increasing the expressions of their subunit. PMID:23672459

Yang, B; Yang, C; Wang, P; Li, J; Huang, H; Ji, Q; Liu, J; Liu, Z

2013-07-01

193

Modulation of degranulation and superoxide generation in human neutrophils by unsaturated fatty acids of odd carbon numbers  

Microsoft Academic Search

Unsaturated fatty acids of odd carbons, 13:1(12), 17:1(10trans), 19:1(7) and 19:1(10) inhibited release of myeloperoxidase (MPO) from fMet-Leu-Phe-cytochalasin B-treated neutrophils. The inhibitory effect was smaller than that of aseanostatins which have been isolated as microbial-derived free fatty acids with a methyl blanch (i-14:0 and ai-15:0) (Journal of Antibiotics (1991) 44, 524–532). These unsaturated fatty acids also inhibited lactoferrin release by

Akiko Ishida-Okawara; Tomoko Tsuchiya; Hiroyuki Nunoi; Satoshi Mizuno; Kazuo Suzuki

1996-01-01

194

Participation of Xanthine-Xanthine Oxidase System and Neutrophils in Development of Acute Gastric Mucosal Lesions in Rats with a Single Treatment of Compound 48\\/80, a Mast Cell Degranulator  

Microsoft Academic Search

The participation of xanthine-xanthine oxidaseand neutrophils in the development of acute gastricmucosal lesions was examined in rats injected once withcompound 48\\/80, a mast cell degranulator. Gastric mucosal lesions appeared 0.5 hr after compound48\\/80 injection and developed at 3 hr. The formation ofgastric mucosal lesions at 0.5 hr after compound 48\\/80injection was prevented by pretreatment with anti-neutrophil antiserum and NPC 14686,

Y. Ohta; T. Kobayashi; I. Ishiguro

1999-01-01

195

ROLE OF ENDOGENOUS SEROTONIN AND HISTAMINE IN THE PATHOGENESIS OF GASTRIC MUCOSAL LESIONS IN UNANAESTHETISED RATS WITH A SINGLE TREATMENT OF COMPOUND 48\\/80, A MAST CELL DEGRANULATOR  

Microsoft Academic Search

In unanaethetised rats with a single injection of compound 48\\/80, a mast cell degranulator (0.75 mg kg?1, i.p.), gastric lesions occurred with increased serum serotonin and histamine levels and reduced gastric mucosal blood flow at 0.5 h after the injection and developed at 3 h. Pretreatment with either cyproheptadine (a serotonin and histamine antagonist) or methysergide (a serotonin antagonist) prevented

YOSHIJI OHTA; TAKASHI KOBAYASHI; ISAO ISHIGURO

1999-01-01

196

Mature eosinophils stimulated to develop in human-cord blood mononuclear cell cultures supplemented with recombinant human interleukin-5. II. Vesicular transport of specific granule matrix peroxidase, a mechanism for effecting piecemeal degranulation.  

PubMed Central

The mechanism of piecemeal degranulation by human eosinophils was investigated. Mature eosinophils that developed in rhIL-5-containing conditioned media from cultured human cord blood mononuclear cells were prepared for ultrastructural studies using a combined technique to image eosinophil peroxidase by cytochemistry in the same sections on which postembedding immunogold was used to demonstrate Charcot-Leyden crystal protein. Vesicular transport of eosinophil peroxidase from the specific granule matrix compartment to the cell surface was associated with piecemeal degranulation. This process involved budding of eosinophil peroxidase-loaded vesicles and tubules from specific granules. Some eosinophil peroxidase that was released from eosinophils remained bound to the cell surface; some was free among the cultured cells. Macrophages and basophils bound the released eosinophil peroxidase to their plasma membranes, internalized it in endocytotic vesicles, and stored it in their respective phagolysosomes and secretory granules. Charcot-Leyden crystal protein was diffusely present in the nucleus and cytoplasm of IL-5-stimulated mature eosinophils. Extensive amounts were generally present in granule-poor and subplasma membrane areas of the cytoplasm in contrast to eosinophil peroxidase, which was secreted and bound to the external surface of eosinophil plasma membranes. These studies establish vesicular transport as a mechanism for emptying the specific eosinophil granule matrix compartment during IL-5-associated piecemeal degranulation. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9

Dvorak, A. M.; Ackerman, S. J.; Furitsu, T.; Estrella, P.; Letourneau, L.; Ishizaka, T.

1992-01-01

197

Escherichia coli exposure inhibits exocytic SNARE-mediated membrane fusion in mast cells.  

PubMed

Mast cells orchestrate the allergic response through the release of proinflammatory mediators, which is driven by the fusion of cytoplasmic secretory granules with the plasma membrane. During this process, SNARE proteins including Syntaxin4, SNAP23 and VAMP8 play a key role. Following stimulation, the kinase IKK? interacts with and phosphorylates the t-SNARE SNAP23. Phosphorylated SNAP23 then associates with Syntaxin4 and the v-SNARE VAMP8 to form a ternary SNARE complex, which drives membrane fusion and mediator release. Interestingly, mast cell degranulation is impaired following exposure to bacteria such as Escherichia coli. However, the molecular mechanism(s) by which this occurs is unknown. Here, we show that E. coli exposure rapidly and additively inhibits degranulation in the RBL-2H3 rat mast cell line. Following co-culture with E. coli, the interaction between IKK? and SNAP23 is disrupted, resulting in the hypophosphorylation of SNAP23. Subsequent formation of the ternary SNARE complex between SNAP23, Syntaxin4 and VAMP8 is strongly reduced. Collectively, these results demonstrate that E. coli exposure inhibits the formation of VAMP8-containing exocytic SNARE complexes and thus the release of VAMP8-dependent granules by interfering with SNAP23 phosphorylation. PMID:24494924

Wesolowski, Jordan; Paumet, Fabienne

2014-05-01

198

Effect of Scrophularia buergeriana extract on the degranulation of mast cells and ear swelling induced by dinitrofluorobenzene in mice.  

PubMed

Scrophularia buergeriana Miquel (Scrophulariaceae, SB) is a biennial plant native to Korea, northern China, and Japan that plays an important role in traditional medicine. The dried root of SB has long been used in oriental medicine for treatment of fever, swelling, constipation, pharyngitis, neuritis, and laryngitis. In the present study, we evaluated the ethanol extract of SB (SBE) to determine if it exerted any anti-allergic effects that had not previously been demonstrated. SBE markedly inhibited ?-hexosaminidase and histamine release and suppressed the expression of tumor necrosis factor-? and interleukin-4 cytokines by RBL-2H3 mast cells. In addition, topical treatment with SBE effectively reduced allergic inflammation in a dinitrofluorobenzene-induced contact hypersensitivity mouse model. These results strongly suggest that SBE is a promising source of anti-allergic agents. PMID:21318391

Kim, Jin-Kyung; Kim, Yoon Hee; Lee, Hee Hwan; Lim, Soon Sung; Park, Kyung Woo

2012-02-01

199

Mycoepoxydiene inhibits antigen-stimulated activation of mast cells and suppresses IgE-mediated anaphylaxis in mice.  

PubMed

Mycoepoxydiene (MED) is a polyketide isolated from a marine fungus associated with mangrove forest. It has been shown that MED has many kinds of effects such as anti-cancer and anti-inflammatory activities. However, its effects on anaphylaxis are still unknown. Mast cells play a pivotal role in IgE-mediated allergic response. Aggregation of the high affinity IgE receptor (Fc?RI) on the surface of mast cell activates a cascade of signaling events leading to the degranulation and cytokine production in mast cells. Our study showed that MED could significantly suppress antigen-stimulated degranulation and cytokine production in mast cells and IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. Furthermore, we found that MED suppressed antigen-induced activation of Syk, and subsequently inhibited the phosphorylation of PLC?1, Akt, and MAPKs such as extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 in mast cells. Collectively, our study demonstrates that MED can inhibit the activation of mast cells and protect mice from mast cell-mediated allergic response through inhibiting the activation of Syk. These results suggest that MED is a potential compound for developing a promising anti-anaphylaxis drug. PMID:23859869

Xia, Xiao-chun; Chen, Qiang; Liu, Kun; Mo, Ping-li; Zhu, Jing-wei; Zhuang, Ming-qiang; Shen, Yue-mao; Yu, Chun-dong

2013-10-01

200

Mast cell-mediated allergic response is suppressed by Sophorae flos: inhibition of SRC-family kinase.  

PubMed

Complementary and alternative medicines are considered as a promising direction for the development of anti-allergic therapies in oriental countries. We screened approximately 100 oriental herbal medicines for anti-allergic activity. Sophorae flos exhibited the most potent effect on degranulation in antigen-stimulated mast cells. We further investigated the effect of Sophorae flos on the IgE-mediated allergic response in vivo and its mechanism of action in mast cells. Sophorae flos exhibited a significant inhibitory effect on degranulation in antigen-stimulated mast cells with IC(50) values of approximately 31.6 microg/mL (RBL-2H3 mast cells) and approximately 47.8 microg/mL (bone marrow-derived mast cells). Sophorae flos also suppressed the expression and secretion of TNF-alpha and IL-4 in the cells and IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. Sophorae flos inhibited the activating phosphorylation of Syk and LAT in mast cells. Further downstream, activating phosphorylation of Akt and the prototypic MAP kinases, namely, p38, ERK1/2, and JNK, were also inhibited. These results suggest that Sophorae flos inhibits the Src family kinase-dependent signaling cascades in mast cells and may thus exert anti-allergic activity. PMID:18641055

Lee, Jun Ho; Kim, Jie Wan; Ko, Na Young; Mun, Se Hwan; Kim, Do Kyun; Kim, Ju Dong; Won, Hyung Sik; Shin, Hwa Sup; Kim, Hyung Sik; Her, Erk; Kim, Young Mi; Choi, Wahn Soo

2008-10-01

201

Raft localization of type I Fc? receptor and degranulation of RBL-2H3 cells exposed to decavanadate, a structural model for V2O5.  

PubMed

Vanadium oxides (VOs) have been identified as low molecular weight sensitizing agents associated with occupational asthma and compromised pulmonary immunocompetence. Symptoms of adult onset asthma result, in part, from increased signal transduction by Type I Fc? receptors (Fc?RI) leading to release of vasoactive compounds including histamine from mast cells. Exposure to (VOs) typically occurs in the form of particles which are insoluble. Upon contact with water or biological fluids, (VOs) form a series of soluble oxoanions, one of which is decavanadate, V10O28(6-) abbreviated V10, which is structurally related to a common vanadium oxide, that is vanadium pentoxide, V2O5. Here we investigate whether V10 may be initiating plasma membrane events associated with activation of Fc?RI signal transduction. We show that exposure of RBL-2H3 cells to V10 causes a concentration-dependent increase in degranulation of RBL-2H3 and, in addition, an increase in plasma membrane lipid packing as measured by the fluorescent probe, di-4-ANEPPDHQ. V10 also increases Fc?RI accumulation in low-density membrane fragments, i.e., lipid rafts, which may facilitate Fc?RI signaling. To determine whether V10 effects on plasma membrane lipid packing were similarly observed in Langmuir monolayers formed from dipalmitoylphosphatidylcholine (DPPC), the extent of lipid packing in the presence and absence of V10 and vanadate was compared. V10 increased the surface area of DPPC Langmuir monolayers by 6% and vanadate decreased the surface area by 4%. These results are consistent with V10 interacting with this class of membrane lipids and altering DPPC packing. PMID:23861175

Al-Qatati, Abeer; Fontes, Fabio L; Barisas, B George; Zhang, Dongmei; Roess, Deborah A; Crans, Debbie C

2013-09-01

202

Priming of human polymorphonuclear neutrophilic leukocytes by insulin-like growth factor I: increased phagocytic capacity, complement receptor expression, degranulation, and oxidative burst.  

PubMed

Insulin-like growth factor I (IGF-I) is a GH-dependent peptide regulating mammalian growth that seems to be of importance for the normal development and function of the immune system. Polymorphonuclear neutrophilic leukocytes (PMNLs) are terminally differentiated phagocytes essential for host defense, and in the present study, recombinant human IGF-I was shown to be a powerful primer of mature human PMNLs. IGF-I augmented the PMNL phagocytosis of both immunoglobulin G-opsonized Staphylococcus aureus and complement-opsonized Candida albicans. In addition, the growth factor increased PMNL complement receptor expression [complement receptors 1 (CD35) and 3 (CD11b)] and primed the cells to stronger f-met-leu-phe-induced degranulation of both specific and azurophilic granules [markers: CD11b, CD35 and CD67 (specific granules); CD63 (azurophilic granules)]. In contrast, IGF-I did not alter the PMNL surface expression of Fc gamma RI (CD64), Fc gamma RII (CDw32), or Fc gamma RIII (CD16). PMNLs exposed to IGF-I increased their f-met-leu-phe and phorbol myristate acetate-induced oxidative burst, as evaluated by hydrogen peroxide production, whereas IGF-I did not influence PMNL actin polymerization. The priming of PMNLs by IGF-I was dependent on time and concentration, and saturating amounts of a monoclonal antibody to the IGF-I receptor blocked the priming of PMNLs by this peptide. These experiments demonstrate that IGF-I can selectively stimulate mature PMNL functions, providing further evidence for the interaction between the immune and the endocrine systems. PMID:7775645

Bjerknes, R; Aarskog, D

1995-06-01

203

Macelignan inhibits histamine release and inflammatory mediator production in activated rat basophilic leukemia mast cells.  

PubMed

Type I allergy is characterized by the release of granule-associated mediators, lipid-derived substances, cytokines, and chemokines by activated mast cells. To evaluate the anti-allergic effects of macelignan isolated from Myristica fragrans Houtt., we determined its ability to inhibit calcium (Ca(2+)) influx, degranulation, and inflammatory mediator production in RBL-2 H3 cells stimulated with A23187 and phorbol 12-myristate 13-acetate. Macelignan inhibited Ca(2+) influx and the secretion of ?-hexosaminidase, histamine, prostaglandin E(2), and leukotriene C(4); decreased mRNA levels of cyclooxygenase-2, 5-lipoxygenase, interleukin-4 (IL-4), IL-13, and tumor necrosis factor-?; and attenuated phosphorylation of Akt and the mitogen-activated protein kinases extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase. These results indicate the potential of macelignan as a type I allergy treatment. PMID:22729280

Han, Young Sun; Kim, Myung-Suk; Hwang, Jae-Kwan

2012-10-01

204

Adenosine closes the K+ channel KCa3.1 in human lung mast cells and inhibits their migration via the adenosine A2A receptor  

PubMed Central

Human lung mast cells (HLMC) express the Ca2+-activated K+ channel KCa3.1, which opens following IgE-dependent activation. This hyperpolarises the cell membrane and potentiates both Ca2+ influx and degranulation. In addition, blockade of KCa3.1 profoundly inhibits HLMC migration to a variety of diverse chemotactic stimuli. KCa3.1 activation is attenuated by the ?2adrenoceptor through a G?s-coupled mechanism independent of cyclic AMP. Adenosine is an important mediator that both attenuates and enhances HLMC mediator release through the G?s-coupled A2A and A2B adenosine receptors, respectively. We show that at concentrations that inhibit HLMC degranulation (10–5–10–3 M), adenosine closes KCa3.1 both dose-dependently and reversibly. KCa3.1 suppression by adenosine was reversed partially by the selective adenosine A2A receptor antagonist ZM241385 but not by the A2B receptor antagonist MRS1754, and the effects of adenosine were mimicked by the selective A2A receptor agonist CGS21680. Adenosine also opened a depolarising current carried by non-selective cations. As predicted from the role of KCa3.1 in HLMC migration, adenosine abolished HLMC chemotaxis to asthmatic airway smooth muscle-conditioned medium. In summary, the G?s-coupled adenosine A2A receptor closes KCa3.1, providing a clearly defined mechanism by which adenosine inhibits HLMC migration and degranulation. A2A receptor agonists with channel-modulating function may be useful for the treatment of mast cell-mediated disease.

Duffy, S Mark; Cruse, Glenn; Brightling, Christopher E; Bradding, Peter

2007-01-01

205

Adenosine closes the K+ channel KCa3.1 in human lung mast cells and inhibits their migration via the adenosine A2A receptor.  

PubMed

Human lung mast cells (HLMC) express the Ca2+-activated K+ channel KCa3.1, which opens following IgE-dependent activation. This hyperpolarises the cell membrane and potentiates both Ca2+ influx and degranulation. In addition, blockade of KCa3.1 profoundly inhibits HLMC migration to a variety of diverse chemotactic stimuli. KCa3.1 activation is attenuated by the beta2adrenoceptor through a Galphas-coupled mechanism independent of cyclic AMP. Adenosine is an important mediator that both attenuates and enhances HLMC mediator release through the Galphas-coupled A2A and A2B adenosine receptors, respectively. We show that at concentrations that inhibit HLMC degranulation (10(-5)-10(-3) M), adenosine closes KCa3.1 both dose-dependently and reversibly. KCa3.1 suppression by adenosine was reversed partially by the selective adenosine A2A receptor antagonist ZM241385 but not by the A2B receptor antagonist MRS1754, and the effects of adenosine were mimicked by the selective A2A receptor agonist CGS21680. Adenosine also opened a depolarising current carried by non-selective cations. As predicted from the role of KCa3.1 in HLMC migration, adenosine abolished HLMC chemotaxis to asthmatic airway smooth muscle-conditioned medium. In summary, the Galphas-coupled adenosine A2A receptor closes KCa3.1, providing a clearly defined mechanism by which adenosine inhibits HLMC migration and degranulation. A2A receptor agonists with channel-modulating function may be useful for the treatment of mast cell-mediated disease. PMID:17474152

Duffy, S Mark; Cruse, Glenn; Brightling, Christopher E; Bradding, Peter

2007-06-01

206

Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells  

PubMed Central

Background Renin released by ischemia/reperfusion (I/R) from cardiac mast cells activates a local renin-angiotensin system (RAS). This exacerbates norepinephrine release and reperfusion arrhythmias (VT/VF), making RAS a new therapeutic target in myocardial ischemia. Methods and Results We investigated whether ischemic preconditioning (IPC) prevents cardiac RAS activation in guinea-pig hearts ex-vivo. When I/R (20-min ischemia/30-min reperfusion) was preceded by IPC (2×5-min I/R cycles), renin and norepinephrine release and VT/VF duration were markedly decreased, a cardioprotective anti-RAS effect. Activation and blockade of adenosine A2b/A3-receptors, and activation and inhibition of PKC?, mimicked and prevented, respectively, the anti-RAS effects of IPC. Moreover, activation of A2b/A3-receptors, or activation of PKC?, prevented degranulation and renin release elicited by peroxide in cultured mast cells (HMC-1). Activation and inhibition of mitochondrial aldehyde dehydrogenase type-2 (ALDH2) also mimicked and prevented, respectively, the cardioprotective anti-RAS effects of IPC. Furthermore, ALDH2 activation inhibited degranulation and renin release by reactive aldehydes in HMC-1. Notably, PKC? and ALDH2 were both activated by A2b/A3-receptor stimulation in HMC-1, and PKC? inhibition prevented ALDH2 activation. Conclusions The results uncover a signaling cascade initiated by A2b/A3-receptors, which triggers PKC?-mediated ALDH2 activation in cardiac mast cells, contributing to IPC-induced cardioprotection by preventing mast-cell renin release and the dysfunctional consequences of local RAS activation. Thus, unlike classical IPC where cardiac myocytes are the main target, cardiac mast cells are the critical site at which the cardioprotective anti-RAS effects of IPC develop.

Koda, Kenichiro; Salazar-Rodriguez, Mariselis; Corti, Federico; Chan, Noel Yan-Ki; Estephan, Racha; Silver, Randi B.; Mochly-Rosen, Daria; Levi, Roberto

2010-01-01

207

Concurrent inhibition of Kit- and Fc?RI-mediated signaling  

PubMed Central

Although primarily required for the growth, differentiation, and survival of mast cells, Kit ligand (stem cell factor) is also required for optimal antigen-mediated mast cell activation. Therefore, concurrent inhibition of Kit- and Fc?RI-mediated signaling would be an attractive approach for targeting mast cell-driven allergic reactions. To explore this concept, we examined the effects of hypothemycin, a molecule which we identified as having such properties, in human and mouse mast cells. Hypothemycin blocked Kit activation and Kit-mediated mast cell adhesion in a similar manner to the well characterized Kit inhibitor imatinib mesylate (imatinib). In contrast to imatinib, however, hypothemycin also effectively inhibited Fc?RI-mediated degranulation and cytokine production in addition to the potentiation of these responses via Kit. The effect of hypothemycin on Kit-mediated responses could be explained by its inhibition of Kit kinase activity, whereas the inhibitory effects on Fc?RI-dependent signaling was at the level of Btk activation. As hypothemycin also significantly reduced the mouse passive cutaneous anaphylaxis response in vivo, these data provide proof of principle for a coordinated approach for the suppression of mast cell activation and provides a rationale for the development of compounds with a similar therapeutic profile.

Jensen, Bettina M.; Beaven, Michael A.; Iwaki, Shoko; Metcalfe, Dean D.; Gilfillan, Alasdair M.

2009-01-01

208

Co-aggregation of FcgammaRII with FcepsilonRI on human mast cells inhibits antigen-induced secretion and involves SHIP-Grb2-Dok complexes.  

PubMed

Signaling through the high affinity IgE receptor FcepsilonRI on human basophils and rodent mast cells is decreased by co-aggregating these receptors to the low affinity IgG receptor FcgammaRII. We used a recently described fusion protein, GE2, which is composed of key portions of the human gamma1 and the human epsilon heavy chains, to dissect the mechanisms that lead to human mast cell and basophil inhibition through co-aggregation of FcgammaRII and FcepsilonRI. Unstimulated human mast cells derived from umbilical cord blood express the immunoreceptor tyrosine-based inhibitory motif-containing receptor FcgammaRII but not FcgammaRI or FcgammaRIII. Interaction of the mast cells with GE2 alone did not cause degranulation. Co-aggregating FcepsilonRI and FcgammaRII with GE2 1) significantly inhibited IgE-mediated histamine release, cytokine production, and Ca(2+) mobilization, 2) reduced the antigen-induced morphological changes associated with mast cell degranulation, 3) reduced the tyrosine phosphorylation of several cellular substrates, and 4) increased the tyrosine phosphorylation of the adapter protein downstream of kinase 1 (p62(dok); Dok), growth factor receptor-bound protein 2 (Grb2), and SH2 domain containing inositol 5-phosphatase (SHIP). Tyrosine phosphorylation of Dok was associated with increased binding to Grb2. Surprisingly, in non-stimulated cells, there were complexes of phosphorylated SHIP-Grb2-Dok that were lost upon IgE receptor activation but retained under conditions of Fcepsilon-Fcgamma co-aggregation. Finally, studies using mast cells from Dok-1 knock-out mice showed that IgE alone triggers degranulation supporting an inhibitory role for Dok degranulation. Our results demonstrate how human FcepsilonRI-mediated responses can be inhibited by co-aggregation with FcgammaRIIB and implicate Dok, SHIP, and Grb2 as key intermediates in regulating antigen-induced mediator release. PMID:15151996

Kepley, Christopher L; Taghavi, Sharven; Mackay, Graham; Zhu, Daocheng; Morel, Penelope A; Zhang, Ke; Ryan, John J; Satin, Leslie S; Zhang, Min; Pandolfi, Pier P; Saxon, Andrew

2004-08-20

209

Markers of Mast Cell Degranulation  

Microsoft Academic Search

Mast cells are the primary effector cells of immediate hypersensitivity reactions in humans. Upon mast cell activation both preformed and newly synthesized mediators are secreted. Histamine can be measured by fluorometric assays, radioenzymatic assays, and immunoassays. These methods have been applied to plasma and urine to detect histamine that had been releasedin vivoand to release histaminein vitrofrom basophils and mast

Angela Duff Hogan; Lawrence B. Schwartz

1997-01-01

210

Kalanchoe pinnata inhibits mast cell activation and prevents allergic airway disease.  

PubMed

Aqueous extract of Kalanchoe pinnata (Kp) have been found effective in models to reduce acute anaphylactic reactions. In the present study, we investigate the effect of Kp and the flavonoid quercetin (QE) and quercitrin (QI) on mast cell activation in vitro and in a model of allergic airway disease in vivo. Treatment with Kp and QE in vitro inhibited degranulation and cytokine production of bone marrow-derived mast cells following IgE/Fc?RI crosslinking, whereas treatment with QI had no effect. Similarly, in vivo treatment with Kp and QE decreased development of airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and production of IL-5, IL-13 and TNF. In contrast, treatment with QI had no effect on these parameters. These findings demonstrate that treatment with Kp or QE is effective in treatment of allergic airway disease, providing new insights to the immunomodulatory functions of this plant. PMID:21802918

Cruz, E A; Reuter, S; Martin, H; Dehzad, N; Muzitano, M F; Costa, S S; Rossi-Bergmann, B; Buhl, R; Stassen, M; Taube, C

2012-01-15

211

Inhibition by glucocorticoids of the mast cell-dependent weal and flare response in human skin in vivo  

PubMed Central

This study examines the relative contributions made by inhibition of mast cell degranulation, reduction of mast cell recruitment and maturation, and lowering the responsiveness of the vasculature to histamine, in the inhibition by glucocorticoids of the weal and flare in human skin. One forearm of healthy human volunteers was treated for 24?h (n=6) or daily for 21 days (n=10) with 0.05% clobetasol propionate. The other arm served as control. Weal and flare responses were elicited by intradermal injection of 20??l of 0.3?mM codeine. The areas of the responses were measured using scanning laser Doppler imaging. Microdialysis was used to assess histamine release. Mast cell numbers and tissue histamine content were assessed in 4-mm punch biopsies. Histamine (20??l of 1??M i.d.) was used to assess the status of the vasculature. No significant effects were seen at 24?h. At 21 days, clobetasol reduced the areas of the codeine-induced weal and flare responses by 59 and 58% respectively (both P=0.006). Mast cell numbers were reduced by 47%, (P=0.014) and total tissue histamine content by 52% (P=0.006). Codeine-induced histamine release was reduced by 44% (P=0.022). The weal, but not the flare, induced by histamine was significantly inhibited (P=0.019). Echography revealed a 15% thinning of the skin by clobetasol. These results demonstrate that reduction of the weal and flare responses to codeine following clobetasol treatment, results primarily from reduced mast cell numbers and tissue histamine content rather than inhibition by corticosteroids of mast cell degranulation.

Cole, Zoe A; Clough, Geraldine F; Church, Martin K

2001-01-01

212

Disruption of SLP-76 Interaction with Gads Inhibits Dynamic Clustering of SLP-76 and Fc?RI Signaling in Mast Cells†  

PubMed Central

We developed a confocal real-time imaging approach that allows direct observation of the subcellular localization pattern of proteins involved in proximal Fc?RI signaling in RBL cells and primary bone marrow-derived mast cells. The adaptor protein Src homology 2 (SH2) domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) is critical for Fc?RI-induced calcium flux, degranulation, and cytokine secretion. In this study, we imaged SLP-76 and found it in the cytosol of unstimulated cells. Upon Fc?RI cross-linking, SLP-76 translocates to the cell membrane, forming clusters that colocalize with the Fc?RI, the tyrosine kinase Syk, the adaptor LAT, and phosphotyrosine. The disruption of the SLP-76 interaction with its constitutive binding partner, Gads, through the mutation of SLP-76 or the expression of the Gads-binding region of SLP-76, inhibits the translocation and clustering of SLP-76, suggesting that the interaction of SLP-76 with Gads is critical for appropriate subcellular localization of SLP-76. We further demonstrated that the expression of the Gads-binding region of SLP-76 in bone marrow-derived mast cells inhibits Fc?RI-induced calcium flux, degranulation, and cytokine secretion. These studies revealed, for the first time, that SLP-76 forms signaling clusters following Fc?RI stimulation and demonstrated that the Gads-binding region of SLP-76 regulates clustering of SLP-76 and Fc?RI-induced mast cell responses.

Silverman, Michael A.; Shoag, Jonathan; Wu, Jennifer; Koretzky, Gary A.

2006-01-01

213

5-Methoxy-8-(2-hydroxy-3-buthoxy-3-methylbutyloxy)-psoralen isolated from Angelica dahurica inhibits cyclooxygenase-2 and 5-lipoxygenase in mouse bone marrow-derived mast cells.  

PubMed

5-Methoxy-8-(2-hydroxy-3-buthoxy-3-methylbutyloxy)-psoralen (MP) is a medicinal herbal product isolated from Angelica dahurica that inhibits the cyclooxygenase-2 (COX-2)-dependent phase of prostaglandin D(2) (PGD(2)) generation in bone marrow-derived mast cells (IC(50), 23.5 microM). Western blotting with specific anti-COX-2 antibodies showed that the decrease in PGD(2) production was accompanied by a decrease in COX-2 protein levels. In addition, this compound consistently inhibited the production of leukotriene C(4) in a dose dependent manner, (IC(50), 2.5 microM). These results demonstrate that MP inhibits both cyclooxygenase-2 and 5-lipoxygenase activity. Furthermore, this compound also inhibited the degranulation reaction (IC(50), 4.1 microM). Therefore, this compound might provide a basis for novel anti-inflammatory drug development. PMID:18481018

Hua, Jin Mei; Moon, Tae Chul; Hong, Tae Gyun; Park, Kyong Min; Son, Jong Keun; Chang, Hyeun Wook

2008-05-01

214

PUVA-therapy for alopecia areata  

Microsoft Academic Search

Alopecia areata is, besides androgenetic alopecia, the most common cause of hair loss. Spontaneous remissions occur. If all hairs of the head (alopecia totalis) or all hairs of the body (alopecia universalis seu maligna) are lost, the prognosis for regrowth is poor. Treatment for alopecia areata is still unsatisfactory. Topical, intralesional, or systemic corticosteroids are being tried besides many other

Irving Weissmann; Cornelia Hofmann; Gisela Wagner; Gerd Plewig; Otto Braun-Falco

1978-01-01

215

Paeonol inhibits anaphylactic reaction by regulating histamine and TNF-alpha.  

PubMed

Paeonol, a major phenolic component of Moutan Cortex, was known to have antiaggregatory, antioxidant and antiinflammatory activities. In the present study, we tried to elucidate the effects of paeonol on anaphylactic reaction and its mode of action. Paeonol significantly inhibited histamine release from the rat peritoneal mast cells (RPMCs) treated with compound 48/80, a mast cell degranulator. The release of tumor necrosis factor (TNF)-alpha mast cell activating cytokine was significantly suppressed in RBL-2H3 mast cells pretreated with anti-dinitrophenyl (DNP) immunoglobulin E (IgE) in a dose-dependent manner. Paeonol significantly inhibited IgE production in B cells activated by anti-CD40 mAb, recombinant interleukin-4 (rIL-4) and recombinant histamine releasing factor (rHRF). Paeonol effectively downregulated the expression of IL-4 in the activated B cells by reverse transcription-polymerase chain reaction (RT-PCR). We also confirmed that paeonol effectively inhibited anaphylactic shock in mice by 90% at a dose of 0.5 mg/mouse versus PBS treated control 2 h after the i.p. injection of compound 48/80. These results suggest that paeonol has antianaphylatic activity by regulating histamine and TNF-alpha. PMID:14996419

Kim, Sung Hoon; Kim, Seung-Ae; Park, Mi-Kyung; Kim, Seung-Hyung; Park, Young-Doo; Na, Ho-Jeong; Kim, Hyung-Min; Shin, Min-Kyu; Ahn, Kyoo-Seok

2004-02-01

216

Piperine inhibits type II phosphatidylinositol 4-kinases: a key component in phosphoinositides turnover.  

PubMed

Piperine has been shown to have anti-inflammatory properties. The molecular mechanisms by which it mediates anti-inflammatory activities remain elusive. Type II phosphatidylinositol 4-kinase(s) are key components in Fc?RI receptor-mediated signaling leading to inflammatory mediators release in RBL-2H3 cells. The effects of piperine on IgE-mediated signaling and mast cell degranulation were investigated. Pretreatment of RBL-2H3 cells with piperine inhibited IgE-induced activation of type II PtdIns 4-kinase(s). In vitro lipid kinase assays showed piperine-inhibited type II PtdIns 4-kinase activity in a dose-dependent fashion with no effect on PtdIns 3-kinase activity. Concomitantly, pretreatment of RBL-2H3 cells with piperine also inhibited IgE-induced ?-hexosaminidase release in RBL-2H3 cells. These results suggest that type II PtdIns 4-kinases are part of piperine-mediated anti-inflammatory signaling mechanisms. PMID:24671493

Bojjireddy, Naveen; Sinha, Ranjeet Kumar; Subrahmanyam, Gosukonda

2014-08-01

217

Exocytosis acts as a modulator of the ILT4-mediated inhibition of neutrophil functions.  

PubMed

Neutrophils play a major role in inflammatory responses and immune defense against pathogens. Even though expression of inhibitory receptors has been reported on neutrophils, their role remains poorly defined. Here we show that primary human neutrophils expressed immunoglobulin-like transcript 4 (ILT4) inhibitory receptor and that this expression was induced during differentiation of the myelomonoblast PLB-985 cell line into "neutrophil-like" cells. Functional assays indicated that human leukocyte antigen G, the preferred ligand of ILT4, inhibited the phagocytic function of neutrophils. ILT4 engagement also impaired reactive oxygen species production induced through CD32a and both receptors were found colocalized into neutrophil lipid rafts. Moreover, neutrophil degranulation induced through inflammatory stimuli increased ILT4 expression as a result of the rapid translocation of an intracellular pool to the cell surface. Consequently to this ILT4 up-regulation, the human leukocyte antigen G-mediated inhibition of neutrophil phagocytic function was enhanced. Finally, we found that ILT4 up-regulation induced on healthy donor neutrophils following stimulation was impaired in presence of plasma from patients with sepsis. Similarly, ILT4 up-regulation was inhibited in neutrophils from septic patients. Altogether, our results reveal a unique mechanism of regulation of neutrophil functions through ILT4 and its exocytosis that may have implications in inflammatory disorders. PMID:24133137

Baudhuin, Jeremy; Migraine, Julie; Faivre, Valerie; Loumagne, Laure; Lukaszewicz, Anne-Claire; Payen, Didier; Favier, Benoit

2013-10-29

218

Synergistic Signals for Natural Cytotoxicity Are Required to Overcome Inhibition by c-Cbl  

PubMed Central

SUMMARY To safeguard from “permissive” NK cell reactivity towards target cells, activation by receptors such as NKG2D and 2B4 includes a requirement for synergistic coactivation. How synergy occurs is not known. Synergistic phosphorylation of PLC-?2, Ca2+ mobilization, and degranulation triggered by NKG2D and 2B4 coengagement were blocked by Vav1 knockdown, but enhanced by knockdown of the ubiquitin ligase c-Cbl. c-Cbl inhibits Vav1-dependent signals, as c-Cbl knockdown did not rescue the Vav1 defect. Moreover, c-Cbl knockdown and Vav1 overexpression each circumvented the requirement for synergy, as NKG2D or 2B4 alone became sufficient for activation. Thus, synergy does not require strict complementation but, rather, enhanced Vav1 signals to overcome inhibition by c-Cbl. Inhibition of cytotoxicity by CD94-NKG2A binding to HLA-E on target cells was dominant over synergistic activation, even after c-Cbl knockdown. Therefore, NK cell activation by synergizing receptors is regulated at the level of Vav1 by a hierarchy of inhibitory mechanisms.

Kim, Hun Sik; Das, Asmita; Gross, Catharina C.; Bryceson, Yenan T.; Long, Eric O.

2010-01-01

219

Activation of the high-affinity immunoglobulin E receptor Fc epsilon RI in RBL-2H3 cells is inhibited by Syk SH2 domains.  

PubMed Central

Antigen-mediated aggregation of the high-affinity receptor for immunoglobulin E, Fc epsilon RI, results in the activation of multiple signaling pathways, leading to the release of mediators of the allergic response. One of the earliest responses to receptor stimulation is the tyrosine phosphorylation of the beta and gamma subunits of Fc epsilon RI and the association of the tyrosine kinase Syk with the phosphorylated receptor. This association is mediated by the SH2 domains of Syk and is believed to be critical for activating signaling pathways resulting in mediator release. To examine the importance of the interaction of Syk with Fc epsilon RI in signaling events following receptor activation, we introduced a protein containing the SH2 domains of Syk into streptolysin O-permeabilized RBL-2H3 cells. The Syk SH2 domains completely inhibited degranulation and leukotriene production following receptor aggregation, and they blocked the increase in protein tyrosine phosphorylation observed after receptor activation. Inhibition was specific for Fc epsilon RI-mediated signaling, since degranulation of cells activated by alternative stimuli was not blocked by the Syk SH2 domains. A protein containing a point mutation in the carboxy-terminal SH2 domain which abolishes phosphotyrosine binding was not inhibitory. In addition, inhibition of degranulation was reversed by pretreatment of the SH2 domains with a tyrosine phosphorylated peptide corresponding to the tyrosine-based activation motif found in the gamma subunit of Fc epsilon RI, the nonphosphorylated peptide had no effect. The association of Syk with the tyrosine-phosphorylated gamma subunit of the activated receptor was blocked by the Syk SH2 domains, and deregulation in cells activated by clustering of Syk directly without Fc epsilon RI aggregation was not affected by the Syk SH2 domains. These results demonstrate that the association of Syk with the activated Fc epsilon RI is critical for both early and late events following receptor activation and confirm the key role Syk plays in signaling through the high-affinity IgE receptor.

Taylor, J A; Karas, J L; Ram, M K; Green, O M; Seidel-Dugan, C

1995-01-01

220

Combined exposure of peripubertal male rats to the endocrine-disrupting compound atrazine and power-frequency electromagnetic fields causes degranulation of cutaneous mast cells: a new toxic environmental hazard?  

PubMed

The effects of single and combined treatments of the endocrine-disrupting compound atrazine and the power-frequency electromagnetic fields (EMFs) were investigated on cutaneous mast cells in juvenile/peripubertal male Wistar rats. Animals were divided into six groups: (1) 4 h/day exposure to EMFs (50 Hz), (2) 20 mg/kg of body weight (bw) of atrazine, (3) 200 mg/kg bw of atrazine, (4) EMFs with 20 mg/kg bw of atrazine, (5) EMFs with 200 mg/kg bw of atrazine, and (6) control. Both the atrazine and the combined treatments, but not the single EMF exposure, increased the number of degranulated mast cells. Statistically significant differences were demonstrated between the control and both of the combined treatments (p<0.01 and p<0.001, respectively). Additionally, low and high doses of atrazine combined with the EMFs were found significantly different when compared to the EMF group alone (both at p<0.001). Considering the biological importance of mast cells in cutaneous immune reactions, future studies should reveal whether combined exposures to chemical and physical environmental agents pose a serious health risk. PMID:20148244

Rajkovic, Vesna; Matavulj, Milica; Johansson, Olle

2010-08-01

221

5-Lipoxygenase Inhibition of the Fructus of Foeniculum vulgare and Its Constituents  

PubMed Central

The fruits of Foeniculum vulgare (Foeniculi Fructus) have been widely used in Chinese medicine as an antiemetic, ameliorating stomach ailments and as an analgesic. In order to establish its potential for antiallergic use, inhibitory actions of the fruiton 5-lipoxgenase (5-LOX) and ?-hexosaminidase release were evaluated. The 70% ethanol extract of this plant material (FR) considerably inhibited 5-LOX-catalyzed leukotriene production from A23187-induced rat basophilic leukemia (RBL)-1 cells. The IC50 was 3.2 ?g/ml. From this extract, 12 major compounds including sabinene, fenchone, ?-terpinene, ?-pinene, limonene, p-anisylacetone, p-anisylaldehyde, estragole (4-allylanisole), trans-anethole, scopoletin, bergapten and umbelliferone were isolated. And it was found that several terpene derivatives including ?-terpinene and fenchone as well as phenylpropanoid, trans-anethole, showed considerable inhibitory action of 5-LOX. In particular, the IC50 of trans-anethole was 51.6 ? M. In contrast, FR and the isolated compounds did not show considerable inhibitory activity on the degranulation reaction of ?-hexosaminidase release from antigen-treated RBL-2H3 cells. Against arachidonic acid-induced ear edema in mice, FR and trans-anethole showed significant inhibition by oral administration at doses of 100-400 mg/kg. In conclusion, FR and several major constituents are 5-LOX inhibitors and they may have potential for treating 5-LOX-related disorders.

Lee, Je Hyeong; Lee, Dong Ung; Kim, Yeong Shik; Kim, Hyun Pyo

2012-01-01

222

Nobiletin and tangeretin ameliorate scratching behavior in mice by inhibiting the action of histamine and the activation of NF-?B, AP-1 and p38.  

PubMed

Nobiletin and tangeretin are polymethoxy flavonoids that are abundantly present in the pericarp of Citrus unshiu (family Rutaceae) and the fruit of Citrus depressa (family Rutaceae). They exhibit various biological activities, including anti-inflammatory and anti-asthmatic effects. To evaluate the anti-allergic effects of nobiletin and tangeretin, we measured their inhibitory effects in histamine- or compound 48/80-induced scratching behavioral mice. Nobiletin and tangeretin potently inhibited scratching behavior, as well as histamine-induced vascular permeability. Furthermore, they inhibited the expression of the allergic cytokines, IL-4 and TNF-? as well as the activation of their transcription factors NF-?B, AP-1 and p38 in histamine-stimulated skin tissues. They also inhibited the expression of IL-4 and TNF-? and the activation of NF-?B and c-jun in PMA-stimulated RBL-2H3 cells. Furthermore, nobiletin and tangeretin inhibited protein kinase C (PKC) activity and the IgE-induced degranulation of RBL-2H3 cells. These agents showed potent anti-histamine effect through the Magnus test when guinea pig ileum was used. Based on these results, nobiletin and tangeretin may ameliorate scratching behavioral reactions by inhibiting the action of histamine as well as the activation of the transcription factors NF-?B and AP-1 via PKC. PMID:23938254

Jang, Se-Eun; Ryu, Kwon-Ryeol; Park, Sung-Hwan; Chung, Suna; Teruya, Yuto; Han, Myung Joo; Woo, Je-Tae; Kim, Dong-Hyun

2013-11-01

223

n-3 Long-chain PUFA reduce allergy-related mediator release by human mast cells in vitro via inhibition of reactive oxygen species.  

PubMed

Increased n-6 and reduced n-3 long-chain PUFA (LC-PUFA) intake in Western diets may contribute to the increased prevalence of allergic diseases. Key effector cells in allergy are mast cells (MC). The aim of the present study was to investigate the effects of n-6 v. n-3 LC-PUFA on MC phenotype. Human MC lines (LAD2 and HMC-1) were incubated for 24 h with either arachidonic acid (AA, n-6 LC-PUFA) or the n-3 LC-PUFA EPA or DHA. The effects of these three LC-PUFA on degranulation, mediator secretion and reactive oxygen species (ROS) generation were assessed. ROS, mitogen-activated protein kinase (MAPK) or NF-?B inhibitors were used to unravel signalling pathways involved in cytokine secretion. AA, EPA or DHA did not reduce IgE-mediated degranulation by LAD2 cells. However, AA increased PGD? and TNF-? secretion by ionomycin/phorbol 12-myristate 13-acetate-stimulated HMC-1, whereas EPA and DHA more prominently inhibited IL-4 and IL-13 secretion. Suppression of IL-4 and IL-13 release by LC-PUFA correlated with reduced ROS generation. IL-4 and IL-13 release by activated HMC-1 was abrogated using ROS inhibitors. Inhibition of MAPK signalling, but not NF-?B, downstream of ROS reduced IL-13 secretion by activated HMC-1. Combined incubation of EPA or DHA with MAPK inhibitors further suppressed IL-13 secretion. In conclusion, the n-6 LC-PUFA AA enhanced pro-inflammatory mediator production by MC, while the n-3 LC-PUFA EPA as well as DHA more effectively suppressed ROS generation and IL-4 and IL-13 release. This suggests that dietary supplementation with EPA and/or DHA may alter the MC phenotype, contributing to a reduced susceptibility to develop and sustain allergic disease. PMID:23021516

van den Elsen, Lieke W J; Nusse, Yvette; Balvers, Martin; Redegeld, Frank A; Knol, Edward F; Garssen, Johan; Willemsen, Linette E M

2013-05-28

224

Cell-impermeant pyridinium derivatives of psoralens as inhibitors of keratinocyte growth 1 1 Abbreviations: BQ, 1,4-benzoquinone; DEPC, diethyl pyrocarbonate; DMEM, Dulbecco’s Modified Eagle Medium; EGF, epidermal growth factor; FADU, fluorescent analysis of DNA unwinding; 4?-Pyr-H 2TMP, 4?-pyridinium-4?,5?-dihydro-4,4?,8-trimethylpsoralen; 5?-Pyr-H 2TMP, 5?-pyridinium-4?,5?-dihydro-4,5?,8-trimethylpsoralen; H 2TMP, 4?,5?-dihydro-4,5?,8-trimethylpsoralen; IFN-?, interferon-?; NOS2, inducible nitric oxide synthase; LB, Luria-Bertani broth; PUVA, psoralen plus UVA light; RT-PCR, reverse transcription-polymerase chain reaction; TdR, thymidine; TMP, 4,5?,8-trimethylpsoralen; and UVA light, ultraviolet light in the range of 320–400 nm  

Microsoft Academic Search

Psoralens such as 8-methoxypsoralen and 4,5?,8-trimethylpsoralen (TMP) are used in photochemotherapy for the treatment of a variety of epidermal proliferative diseases. Sequential treatments of the skin with psoralens plus ultraviolet light in the range of 320–400 nm (UVA light), referred to as PUVA therapy, results in the suppression of abnormal keratinocyte growth. With the recognition that the psoralens are phototoxic

Thomas M. Mariano; Anna M. Vetrano; Shannon L. Gentile; Diane E. Heck; Marilyn S. Whittemore; Christophe D. Guillon; Ivan Jabin; Robert D. Rapp; Ned D. Heindel; Jeffrey D. Laskin

2002-01-01

225

Methods of Inhibiting Inflammation.  

National Technical Information Service (NTIS)

The invention provides a method of inhibiting inflammation in a mammal, by administering to the mammal composition containing a compound which inhibits the expression or activity of a microsomal triglyceride transfer protein.

R. S. Blumberg

2004-01-01

226

Methods of Inhibiting Inflammation.  

National Technical Information Service (NTIS)

The invention provides a method of inhibiting inflammation in a mammal, by administering to the mammal composition containing a compound which inhibits the expression or activity of a microsomal triglyceride transfer protein.

R. S. Blumberg

2005-01-01

227

Mature eosinophils stimulated to develop in human cord blood mononuclear cell cultures supplemented with recombinant human interleukin-5. Part I. Piecemeal degranulation of specific granules and distribution of Charcot-Leyden crystal protein.  

PubMed Central

Human cord blood mononuclear cells were cultured for 35 days in media containing recombinant human interleukin 5 (rhIL-5) supplemented with a fraction of the culture supernatant of phytohemagglutinin (PHA)-stimulated human T lymphocytes from which interleukin 2 (IL-2) was eliminated. Cultured cells were studied by electron microscopy and an immunogold procedure to detect subcellular site(s) of Charcot-Leyden crystal (CLC) protein. The majority of cells (greater than 70%) developing in this system were mature eosinophils, with descending frequency of other cells, including macrophages, mature basophils, eosinophilic myelocytes, and mature neutrophils. Mature eosinophils were characterized by increased numbers of primary granules, small granules, tubulovesicular structures, and decreased secondary granules. These eosinophils showed extensive piecemeal degranulation (PMD) characterized by partially empty and empty secondary granule chambers in the cytoplasm. Small, smooth vesicles were evident within empty granule chambers as well as adjacent to them. Eosinophils formed close associations with phagocytic macrophages that contained both standard-shaped and irregularly shaped CLC within phagolysosomes. Subcellular sites of CLC protein were demonstrated by immunogold in eosinophils and macrophages arising in these cultures. Charcot-Leyden crystal protein was present in the nuclear matrix and extraorganellar cytoplasm of eosinophils. Primary granules and some cytoplasmic vesicles were labeled for CLC protein, but full and empty secondary granules and the extensive network of tubulovesicles were not. Charcot-Leyden crystals were absent from eosinophils, nor were they present in the extracellular space. Charcot-Leyden crystals were absent from eosinophils, nor were they present in the extracellular space. Charcot-Leyden crystals within phagosomes of macrophages were labeled by the immunogold procedure for CLC protein. These results demonstrate that rhIL-5-supplemented, PHA-stimulated, T-cell-conditioned media induced the development of mature human eosinophils from cord blood cells. These eosinophils underwent PMD of secondary granule contents. Immunogold analysis showed eosinophil CLC protein in the cytoplasm, nucleus, and primary granules of eosinophils. Macrophages also were present in these cultures. They contained CLC protein-containing crystals in their phagosomes, suggesting active sequestration of eosinophil CLC protein by macrophages in vitro. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10

Dvorak, A. M.; Furitsu, T.; Letourneau, L.; Ishizaka, T.; Ackerman, S. J.

1991-01-01

228

Uptake of donor lymphocytes treated with 8-methoxypsoralen and ultraviolet A light by recipient dendritic cells induces CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T cells and down-regulates cardiac allograft rejection  

SciTech Connect

Extracorporeal photopheresis (ECP) is an effective immunomodulatory therapy and has been demonstrated to be beneficial for graft-vs-host disease and solid-organ allograft rejection. ECP involves reinfusion of a patient's autologous peripheral blood leukocytes treated ex vivo with 8-methoxypsoralen and UVA light radiation (PUVA). Previous studies focused only on ECP treatment of recipient immune cells. Our study is the first to extend the target of ECP treatment to donor immune cells. The results of in vitro co-culture experiments demonstrate uptake of donor PUVA-treated splenic lymphocytes (PUVA-SPs) by recipient immature dendritic cells (DCs). Phagocytosis of donor PUVA-SPs does not stimulate phenotype maturation of recipient DCs. In the same co-culture system, donor PUVA-SPs enhanced production of interleukin-10 and interferon-{gamma} by recipient DCs and impaired the subsequent capability of recipient DCs to stimulate recipient naive T cells. Phagocytosis of donor PUVA-SP (PUVA-SP DCs) by recipient DCs shifted T-cell responses in favor of T helper 2 cells. Infusion of PUVA-SP DCs inhibited cardiac allograft rejection in an antigen-specific manner and induced CD4{sup +}CD25{sup high}Foxp3{sup +} regulatory T cells. In conclusion, PUVA-SP DCs simultaneously deliver the donor antigen and the regulatory signal to the transplant recipient, and thus can be used to develop a novel DC vaccine for negative immune regulation and immune tolerance induction.

Zheng, De-Hua [Organ Transplant Center, Chinese PLA 309th Hospital, No. 17A Hei-Shan-Hu Road, Beijing 100091 (China)] [Organ Transplant Center, Chinese PLA 309th Hospital, No. 17A Hei-Shan-Hu Road, Beijing 100091 (China); Dou, Li-Ping [Department of Hematology, Chinese PLA General Hospital, No. 28 Fu-Xing Road, Beijing 100853 (China)] [Department of Hematology, Chinese PLA General Hospital, No. 28 Fu-Xing Road, Beijing 100853 (China); Wei, Yu-Xiang; Du, Guo-Sheng; Zou, Yi-Ping; Song, Ji-Yong; Zhu, Zhi-Dong; Cai, Ming; Qian, Ye-Yong [Organ Transplant Center, Chinese PLA 309th Hospital, No. 17A Hei-Shan-Hu Road, Beijing 100091 (China)] [Organ Transplant Center, Chinese PLA 309th Hospital, No. 17A Hei-Shan-Hu Road, Beijing 100091 (China); Shi, Bing-Yi, E-mail: shibingyi@medmail.com.cn [Organ Transplant Center, Chinese PLA 309th Hospital, No. 17A Hei-Shan-Hu Road, Beijing 100091 (China)] [Organ Transplant Center, Chinese PLA 309th Hospital, No. 17A Hei-Shan-Hu Road, Beijing 100091 (China)

2010-05-14

229

Histamine H4-receptors inhibit mast cell renin release in ischemia/reperfusion via protein kinase C ?-dependent aldehyde dehydrogenase type-2 activation.  

PubMed

Renin released by ischemia/reperfusion (I/R) from cardiac mast cells (MCs) activates a local renin-angiotensin system (RAS) causing arrhythmic dysfunction. Ischemic preconditioning (IPC) inhibits MC renin release and consequent activation of this local RAS. We postulated that MC histamine H4-receptors (H4Rs), being G?i/o-coupled, might activate a protein kinase C isotype-? (PKC?)-aldehyde dehydrogenase type-2 (ALDH2) cascade, ultimately eliminating MC-degranulating and renin-releasing effects of aldehydes formed in I/R and associated arrhythmias. We tested this hypothesis in ex vivo hearts, human mastocytoma cells, and bone marrow-derived MCs from wild-type and H4R knockout mice. We found that activation of MC H4Rs mimics the cardioprotective anti-RAS effects of IPC and that protection depends on the sequential activation of PKC? and ALDH2 in MCs, reducing aldehyde-induced MC degranulation and renin release and alleviating reperfusion arrhythmias. These cardioprotective effects are mimicked by selective H4R agonists and disappear when H4Rs are pharmacologically blocked or genetically deleted. Our results uncover a novel cardioprotective pathway in I/R, whereby activation of H4Rs on the MC membrane, possibly by MC-derived histamine, leads sequentially to PKC? and ALDH2 activation, reduction of toxic aldehyde-induced MC renin release, prevention of RAS activation, reduction of norepinephrine release, and ultimately to alleviation of reperfusion arrhythmias. This newly discovered protective pathway suggests that MC H4Rs may represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure. PMID:24696042

Aldi, Silvia; Takano, Ken-ichi; Tomita, Kengo; Koda, Kenichiro; Chan, Noel Y-K; Marino, Alice; Salazar-Rodriguez, Mariselis; Thurmond, Robin L; Levi, Roberto

2014-06-01

230

Spikes timed through inhibition  

PubMed Central

Purkinje cells in the brain region known as the cerebellum act by inhibiting their target neurons. A paper in this issue provides an explanation for how this inhibition might be used to control the timing of action potentials. But experts are not equally convinced about the functional relevance of this finding.

Medina, Javier F.; Khodakhah, Kamran

2014-01-01

231

Inhibition in Multiclass Classification  

Microsoft Academic Search

The role of inhibition is investigated in a multiclass support vector machine formalism inspired by the brain structure of insects. The so-called mushroom bodies have a set of output neurons, or classification functions, that compete with each to encode a particular input. Strongly active output neurons depress or inhibit the remaining outputs without knowing which is correct or incorrect. Accordingly,

Ramón Huerta; Shankar Vembu; José M. Amigó; Thomas Nowotny; Charles Elkan

232

Inhibition in Multiclass Classification  

Microsoft Academic Search

The role of inhibition is investigated in a multiclass support vector machine formalism inspired by the brain structure of insects. The so-called mushroom bodies have a set of output neurons, or classification functions, that compete with each other to encode a particular input. Strongly active output neurons depress or inhibit the remaining outputs without knowing which is correct or incorrect.

Ramón Huerta; Shankar Vembu; José M. Amigó; Thomas Nowotny; Charles Elkan

2012-01-01

233

Inhibition of selectin binding  

DOEpatents

This invention provides compositions for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, these composition scan be used to palliate certain inflammatory and immunological conditions.

Nagy, Jon O. (Rodeo, CA); Spevak, Wayne R. (Albany, CA); Dasgupta, Falguni (New Delhi, IN); Bertozzi, Caroline (Albany, CA)

2001-10-09

234

Inhibition of selectin binding  

DOEpatents

This invention provides compositions for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, these composition scan be used to palliate certain inflammatory and immunological conditions.

Nagy, Jon O. (Rodeo, CA); Spevak, Wayne R. (Albany, CA); Dasgupta, Falguni (New Delhi, IN); Bertozzi, Caroline (Albany, CA)

1999-01-01

235

Inhibition of selectin binding  

DOEpatents

This invention provides a system for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, this system can be used to palliate certain inflammatory and immunological conditions.

Nagy, Jon O. (Rodeo, CA); Spevak, Wayne R. (Albany, CA); Dasgupta, Falguni (New Delhi, IN); Bertozzi, Carolyn (Albany, CA)

1999-10-05

236

Inhibition of hair growth  

US Patent & Trademark Office Database

A method of inhibiting hair growth in a mammal includes applying, to an area of skin from which reduced hair growth is desired, a dermatologically acceptable composition containing a non-steroidal suppressor of angiogenesis.

2000-07-25

237

Antigene Oligomers Inhibit Transcription.  

National Technical Information Service (NTIS)

Transcription of a gene in a mammalian cell is methylase-independently inhibited by contacting the cell with a nucleic acid oligomer of 12-28 bases complementary for a partially single-stranded target genomic sequence of the gene.

B. A. Janowski D. R. Corey

2006-01-01

238

Inhibition of Autoxidation.  

National Technical Information Service (NTIS)

Methods for inhibiting the autoxidation of organic substrates are reviewed. Antioxidants can be divided into two broad groups according to whether they reduce the rate of chain initiation (preventive antioxidants) or interfere with the normal propagation ...

K. U. Ingold

1967-01-01

239

Psychotherapy by reciprocal inhibition  

Microsoft Academic Search

Reciprocal inhibition is a process of relearning whereby in the presence of a stimulus a non-anxiety-producing response is\\u000a continually repeated until it extinguishes the old, undesirable response. A variety of the techniques based on reciprocal\\u000a inhibition, such as systematic desensitization, avoidance conditioning, and the use of assertion, are described in detail.\\u000a Behavior therapy techniques evaluated on the basis of their

Joseph Wolpe

1968-01-01

240

Method for inhibiting corrosion  

SciTech Connect

A composition comprising the reaction adduct or neutralized product resulting from the reaction of a maleic anhydride and an oil containing a polynuclear aromatic compound is provided which, when applied to a metal surface, forms a corrosion-inhibiting film thereon. The composition is particularly useful in the treatment of down-hole metal surfaces in oil and gas wells to inhibit the corrosion of the metal.

Wu, Y.; Stapp, P. R.

1985-12-03

241

Inhibition in multiclass classification.  

PubMed

The role of inhibition is investigated in a multiclass support vector machine formalism inspired by the brain structure of insects. The so-called mushroom bodies have a set of output neurons, or classification functions, that compete with each other to encode a particular input. Strongly active output neurons depress or inhibit the remaining outputs without knowing which is correct or incorrect. Accordingly, we propose to use a classification function that embodies unselective inhibition and train it in the large margin classifier framework. Inhibition leads to more robust classifiers in the sense that they perform better on larger areas of appropriate hyperparameters when assessed with leave-one-out strategies. We also show that the classifier with inhibition is a tight bound to probabilistic exponential models and is Bayes consistent for 3-class problems. These properties make this approach useful for data sets with a limited number of labeled examples. For larger data sets, there is no significant comparative advantage to other multiclass SVM approaches. PMID:22594829

Huerta, Ramón; Vembu, Shankar; Amigó, José M; Nowotny, Thomas; Elkan, Charles

2012-09-01

242

The Aspergillus fumigatus toxin fumagillin suppresses the immune response of Galleria mellonella larvae by inhibiting the action of haemocytes.  

PubMed

Larvae of Galleria mellonella are widely used to evaluate microbial virulence and to assess the in vivo efficacy of antimicrobial agents. The aim of this work was to examine the ability of an Aspergillus fumigatus toxin, fumagillin, to suppress the immune response of larvae. Administration of fumagillin to larvae increased their susceptibility to subsequent infection with A. fumigatus conidia (P?=?0.0052). It was demonstrated that a dose of 2 µg fumagillin ml?¹ reduced the ability of insect immune cells (haemocytes) to kill opsonized cells of Candida albicans (P?=?0.039) and to phagocytose A. fumigatus conidia (P?=?0.016). Fumagillin reduced the oxygen uptake of haemocytes and decreased the translocation of a p47 protein which is homologous to p47(phox), a protein essential for the formation of a functional NADPH oxidase complex required for superoxide production. In addition, toxin-treated haemocytes showed reduced levels of degranulation as measured by the release of a protein showing reactivity to an anti-myeloperoxidase antibody (P<0.049) that was subsequently identified by liquid chromatography-MS analysis as prophenoloxidase. This work demonstrates that fumagillin suppresses the immune response of G. mellonella larvae by inhibiting the action of haemocytes and thus renders the larvae susceptible to infection. During growth of the fungus in the larvae, this toxin, along with others, may facilitate growth by suppressing the cellular immune response. PMID:21349977

Fallon, John P; Reeves, Emer P; Kavanagh, Kevin

2011-05-01

243

Derivative of wheat germ agglutinin specifically inhibits formyl-peptide-induced polymorphonuclear leukocyte chemotaxis by blocking re-expression (or recycling) of receptors  

SciTech Connect

The mechanism of action of a derivative of wheat germ agglutinin (WGA-D) which specifically and irreversibly inhibits N-formyl-methionyl-leucyl-phenylalanine (FMLP)-induced polymorphonuclear leukocyte (PMN) chemotaxis was examined. At a concentration that completely inhibited PMN chemotaxis, WGA-D had no effect on either the uptake or release of (/sup 3/H)-FMLP by PMN. Similarly, WGA-D did not affect either the short-term binding to, or internalization by, PMN of a fluoresceinated FMLP analog. WGA-D did interfere, however, with the re-expression (or recycling) of FMLP receptors by PMN that had been preincubated with 1 ..mu..M FMLP for 10 min at 4/sup 0/C. This effect was specific for WGA-D, because it was not observed when concanavalin A was used. Scatchard plot analysis of FMLP binding to PMN after receptor re-expression demonstrated that WGA-D-treated PMN had a significant diminution in the number of high affinity receptors. WGA-D-mediated inhibition of FMLP receptor re-expression was associated with inhibition of FMLP-induced PMN chemotaxis, but had no effect on either FMLP-induced PMN superoxide anion generation or degranulation. Studies using (/sup 12/%I)-WGA-D demonstrated that PMN did not internalize WGA-D spontaneously. The data indicate that WGA-D perhaps by binding to the FMLP receptor, inhibits FMLP-induced PMN chemotaxis by blocking the re-expression (or recycling) of a population of receptors required for continuous migration.

Perez, H.D.; Elfman, F.; Lobo, E.; Sklar, L.; Chenoweth, D.; Hooper, C.

1986-03-01

244

Innovative Therapy of CTCL: Beyond PUVA and Nitrogen Mustard  

PubMed Central

Synopsis Cutaneous T Cell Lymphoma is a malignancy of skin homing T cells. This unique population of lymphocytes requires alternative therapies than those used in nodal lymphomas. Although phototherapy and nitrogen mustard have been standard treatments for decades, newer therapies have been arriving with increased frequency. Moreover some therapies, currently used to treat other disease, have been used in CTCL with good effect. These innovative therapies in CTCL are discussed, with review of current data and examples of how these therapies may be utilized today.

Heald, Peter

2010-01-01

245

Method for decreasing radiation load in puva therapy  

SciTech Connect

An improved method is described for treating a psoriatic subject undergoing treatment with a psoralen in conjection with ultraviolet A radiation of from wavelength of 3200 to 4000 angstroms. The improved method comprises prior to initiation of the treatment, pretreating the subject for a period of from 4 to 10 days with an effective amount of an anti-psoriatic polyene compound, and thereafter initiating the treatment with a psoralen in conjunction with ultraviolet A radiation and continuing the treatment concurrently with the administration of the anti-psoriatic polyene compound.

Wolff, K.

1987-02-10

246

Specific Inhibition of Obligate Anaerobes  

Microsoft Academic Search

MANY drugs are known which optimally inhibit single groups of micro-organisms (bacteria, fungi, or protozoa), or which inhibit specific types within one of these groups (Gram-positive or Gram-negative bacteria, pathogenic or non-pathogenic fungi). For example, certain antibiotics only inhibit bacteria; the polyene antibiotics only inhibit fungi; fumagillin inhibits protozoa1. This list can be extended to include compounds other than antibiotics:

Herbert N. Prince

1960-01-01

247

The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells  

PubMed Central

Introduction The aim was to determine the effect of the Bruton tyrosine kinase (Btk)-selective inhibitor PCI-32765, currently in Phase I/II studies in lymphoma trials, in arthritis and immune-complex (IC) based animal models and describe the underlying cellular mechanisms. Methods PCI-32765 was administered in a series of murine IC disease models including collagen-induced arthritis (CIA), collagen antibody-induced arthritis (CAIA), reversed passive anaphylactic reaction (RPA), and passive cutaneous anaphylaxis (PCA). Clinical and pathologic features characteristic of each model were examined following treatment. PCI-32765 was then examined in assays using immune cells relevant to the pathogenesis of arthritis, and where Btk is thought to play a functional role. These included proliferation and calcium mobilization in B cells, cytokine and chemokine production in monocytes/macrophages, degranulation of mast cells and its subsequent cytokine/chemokine production. Results PCI-32765 dose-dependently and potently reversed arthritic inflammation in a therapeutic CIA model with an ED50 of 2.6 mg/kg/day. PCI-32765 also prevented clinical arthritis in CAIA models. In both models, infiltration of monocytes and macrophages into the synovium was completely inhibited and importantly, the bone and cartilage integrity of the joints were preserved. PCI-32765 reduced inflammation in the Arthus and PCA assays. In vitro, PCI-32765 inhibited BCR-activated primary B cell proliferation (IC50 = 8 nM). Following Fc?R stimulation, PCI-32765 inhibited TNF?, IL-1? and IL-6 production in primary monocytes (IC50 = 2.6, 0.5, 3.9 nM, respectively). Following Fc?RI stimulation of cultured human mast cells, PCI-32765 inhibited release of histamine, PGD2, TNF-?, IL-8 and MCP-1. Conclusions PCI-32765 is efficacious in CIA, and in IC models that do not depend upon autoantibody production from B cells. Thus PCI-32765 targets not only B lymphocytes but also monocytes, macrophages and mast cells, which are important Btk-expressing effector cells in arthritis.

2011-01-01

248

Mechanisms of Inhibitive Chromate Primers.  

National Technical Information Service (NTIS)

This program continued the studies of chromate primer corrosion inhibition mechanisms and investigated other materials as inhibitive pigments. It was determined that failure occurred by destruction of the protective aluminum oxide layer at cathodic areas ...

D. B. Boies W. P. McDonald

1968-01-01

249

4-Chlorotetrazolo[1,5-a]quinoxaline inhibits activation of Syk kinase to suppress mast cells in vitro and mast cell-mediated passive cutaneous anaphylaxis in mice  

SciTech Connect

4-Chlorotetrazolo[1,5-a]quinoxaline is a quinoxaline derivative. We aimed to study the effects of 4-chlorotetrazolo[1,5-a]quinoxaline on activation of mast cells in vitro and in mice. 4-Chlorotetrazolo[1,5-a]quinoxaline reversibly inhibited degranulation of mast cells in a dose-dependent manner, and also suppressed the expression and secretion of TNF-{alpha} and IL-4 in mast cells. Mechanistically, 4-chlorotetrazolo[1,5-a]quinoxaline inhibited activating phosphorylation of Syk and LAT, which are crucial for early Fc{epsilon}RI-mediated signaling events, as well as Akt and MAP kinases, which play essential roles in the production of various pro-inflammatory cytokines in mast cells. Notably, although 4-chlorotetrazolo[1,5-a]quinoxaline inhibited the activation of Fyn and Syk, minimal inhibition was observed in mast cells in the case of Lyn. Furthermore, consistent with its in vitro activity, 4-chlorotetrazolo[1,5-a]quinoxaline significantly suppressed mast cell-mediated passive cutaneous anaphylaxis in mice. In summary, the results from this study demonstrate that 4-chlorotetrazolo[1,5-a]quinoxaline shows an inhibitory effect on mast cells in vitro and in vivo, and that this is mediated by inhibiting the activation of Syk in mast cells. Therefore, 4-chlorotetrazolo[1,5-a]quinoxaline could be useful in the treatment of mast cell-mediated allergic diseases. -- Highlights: Black-Right-Pointing-Pointer 4-chlorotetrazolo[1,5-a]quinoxaline is a quinoxaline derivative. Black-Right-Pointing-Pointer The effect of 4-chlorotetrazolo[1,5-a]quinoxaline on mast cells was investigated. Black-Right-Pointing-Pointer 4-chlorotetrazolo[1,5-a]quinoxaline reversibly inhibited Syk activation. Black-Right-Pointing-Pointer 4-chlorotetrazolo[1,5-a]quinoxaline could be useful for IgE-mediated allergy.

Park, Kui Lea [Center for Drug Development Assistance, National Institute of Food Drug Safety Evaluation (NIFDS), KFDA, Cheongwon-gun (Korea, Republic of)] [Center for Drug Development Assistance, National Institute of Food Drug Safety Evaluation (NIFDS), KFDA, Cheongwon-gun (Korea, Republic of); Ko, Na Young; Lee, Jun Ho; Kim, Do Kyun; Kim, Hyuk Soon; Kim, A-Ram; Her, Erk; Kim, Bokyung [Department of Immunology and physiology, College of Medicine, Konkuk University, Chungju (Korea, Republic of)] [Department of Immunology and physiology, College of Medicine, Konkuk University, Chungju (Korea, Republic of); Kim, Hyung Sik [College of Pharmacy, Pusan National University, Busan (Korea, Republic of)] [College of Pharmacy, Pusan National University, Busan (Korea, Republic of); Moon, Eun-Yi [Department of Bioscience and Biotechnology, College of Biological Science, Sejong University, Seoul (Korea, Republic of)] [Department of Bioscience and Biotechnology, College of Biological Science, Sejong University, Seoul (Korea, Republic of); Kim, Young Mi [College of Pharmacy, Duksung Women's University, Seoul (Korea, Republic of)] [College of Pharmacy, Duksung Women's University, Seoul (Korea, Republic of); Kim, Hang-Rae, E-mail: hangrae2@snu.ac.kr [Department of Anatomy, Seoul National University College of Medicine, Seoul (Korea, Republic of)] [Department of Anatomy, Seoul National University College of Medicine, Seoul (Korea, Republic of); Choi, Wahn Soo, E-mail: wahnchoi@kku.ac.kr [Department of Immunology and physiology, College of Medicine, Konkuk University, Chungju (Korea, Republic of)

2011-12-15

250

Changes in cell ultrastructure and inhibition of JAK1/STAT3 signaling pathway in CBRH-7919 cells with astaxanthin.  

PubMed

Astaxanthin (AST), a xanthophylls carotenoid, possesses significant anticancer effects. However, to date, the molecular mechanism of anticancer remains unclear. In the present research, we studied the anticancer mechanism of AST, including the changes in cell ultrastructure, such as the mitochondrion, rough endoplasmic reticulum (RER), Golgi complex, and cytoskeleton, the inhibition of Janus kinase 1(JAK1)/transduction and the activators of the transcription-3 (STAT3) signaling pathway using rat hepatocellular carcinoma CBRH-7919 cells. Cell apoptosis was evaluated and the expressions of JAK1, STAT3, non-metastasis23-1 (nm23-1), and apoptotic gene like B-cell lymphoma/leukemia-2 (bcl-2), B-cell lymphoma-extra large (bcl-xl), proto-oncogene proteins c myc (c-myc) and bcl-2- associated X (bax) were also examined. The results showed that AST could induce cancer cell apoptosis. Under transmission electron microscope, the ultrastructure of treated cells were not clearly distinguishable, the membranes of the mitochondrion, RER, Golgi complex were broken or loosened, and the endoplasmic reticulum (ER) was degranulated. Cytoskeleton depolymerization of the microtubule system led to the collapse of extended vimentin intermediate filament bundles into short agglomerations with disordered distributions. AST inhibited the expression of STAT3, its upstream activator JAK1, and the STAT3 target antiapoptotic genes bcl-2, bcl-xl, and c-myc. Conversely, AST enhanced the expressions of nm23-1 and bax. Overall, our findings demonstrate that AST could induce the apoptosis of CBRH-7919 cells, which are involved in cell ultrastructure and the JAK1/STAT3 signaling pathway. PMID:22889354

Song, Xiaodong; Wang, Meirong; Zhang, Lixia; Zhang, Jinjin; Wang, Xiuwen; Liu, Wenbo; Gu, Xinbin; Lv, Changjun

2012-11-01

251

Inhibition and brain work.  

PubMed

The major part of the brain's energy budget ( approximately 60%-80%) is devoted to its communication activities. While inhibition is critical to brain function, relatively little attention has been paid to its metabolic costs. Understanding how inhibitory interneurons contribute to brain energy consumption (brain work) is not only of interest in understanding a fundamental aspect of brain function but also in understanding functional brain imaging techniques which rely on measurements related to blood flow and metabolism. Herein we examine issues relevant to an assessment of the work performed by inhibitory interneurons in the service of brain function. PMID:18054855

Buzsáki, György; Kaila, Kai; Raichle, Marcus

2007-12-01

252

Wortmannin blocks lipid and protein kinase activities associated with PI 3-kinase and inhibits a subset of responses induced by Fc epsilon R1 cross-linking.  

PubMed Central

We have investigated the effects of wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase), on antigen-mediated signaling in the RBL-2H3 mast cell model. In RBL-2H3 cells, the cross-linking of high affinity IgE receptors (Fc epsilon R1) activates at least two cytoplasmic protein tyrosine kinases, Lyn and Syk, and stimulates secretion, membrane ruffling, spreading, pinocytosis, and the formation of actin plaques implicated in increased cell-substrate adhesion. In addition, Fc epsilon R1 cross-linking activates PI 3-kinase. It was previously shown that wortmannin causes a dose-dependent inhibition of PI 3-kinase activity and also inhibits antigen-stimulated degranulation. We report that the antigen-induced synthesis of inositol(1,4,5)P3 is also markedly inhibited by wortmannin. Consistent with evidence in other cell systems implicating phosphatidylinositol(3,4,5)P3 in ruffling, pretreatment of RBL-2H3 cells with wortmannin inhibits membrane ruffling and fluid pinocytosis in response to Fc epsilon R1 cross-linking. However, wortmannin does not inhibit antigen-induced actin polymerization, receptor internalization, or the actin-dependent processes of spreading and adhesion plaque formation that follow antigen stimulation in adherent cells. Wortmannin also fails to inhibit either of the Fc epsilon R1-coupled tyrosine kinases, Lyn or Syk, or the activation of mitogen-activated protein kinase as measured by in vitro kinase assays. Strikingly, there is substantial in vitro serine/threonine kinase activity in immunoprecipitates prepared from Fc epsilon R1-activated cells using antisera to the p85 subunit of PI 3-kinase. This activity is inhibited by pretreatment of the cells with wortmannin or by the direct addition of wortmannin to the kinase assay, suggesting that PI 3-kinase itself is capable of acting as a protein kinase. We conclude that Fc epsilon R1 cross-linking activates both lipid and protein kinase activities of PI 3-kinase and that inhibiting these activities with wortmannin results in the selective block of a subset of Fc epsilon R1-mediated signaling responses. Images

Barker, S A; Caldwell, K K; Hall, A; Martinez, A M; Pfeiffer, J R; Oliver, J M; Wilson, B S

1995-01-01

253

Inhibition of fibroblast attachment.  

PubMed

Reattachment is at present an ephemeral goal. There is, therefore, much interest in clarifying the events which determine patterns of cellular repopulation of denuded cementum during periodontal healing, and thus determine the outcome of reattachment surgery. It has previously been reported that human saliva inhibits the initial attachment or subsequent locomotion of human gingival fibroblast-like cells on plastic substrata in vitro, and that this property is a function of a high molecular weight sulphated glycoprotein in saliva. Recent work reported here shows that saliva in vitro also inhibits attachment to human cementum in serum-free medium. This effect can be reversed by superficial citric acid (pH 1.0) demineralisation of saliva-treated cementum. However, demineralisation itself does not augment cell attachment to either saliva-coated or normal cementum compared with controls. It is postulated that adsorption of saliva on cementum in vivo may lead to periodontal wound healing by repair (long junctional epithelium) rather than by regeneration of ligament and cementum; a novel explanation for the previously reported efficacy of citric acid in wound healing might be related to its ability to remove adsorbed saliva from the root surface and thus permit early root colonisation by connective tissue cells. PMID:3466910

Heaney, T G

1986-11-01

254

Oxazolidinones Inhibit Cellular Proliferation via Inhibition of Mitochondrial Protein Synthesis  

Microsoft Academic Search

bacterial protein synthesis. The oxazolidinones inhibit mitochondrial protein synthesis, as shown by (35S)me- thionine incorporation into intact rat heart mitochondria. Treatment of K562 human erythroleukemia cells with the oxazolidinone eperezolid resulted in a time- and concentration-dependent inhibition of cell prolifer- ation. The cells remained viable, but an increase in doubling time was observed with eperezolid treatment. Inhibition was reversible, since

Eva E. Nagiec; Luping Wu; Steve M. Swaney; John G. Chosay; Daniel E. Ross; Joan K. Brieland; Karen L. Leach

2005-01-01

255

Inhibition of human cord blood-derived mast cell responses by anti-Fc epsilon RI mAb 15/1 versus anti-IgE Omalizumab.  

PubMed

Aggregation of the alpha-chain of the high affinity IgE receptor (Fc epsilon RI alpha) on mast cells or basophils after cross-linking of receptor-bound IgE by its antigen or an anti-IgE antibody results in cell activation and release of inflammatory mediators. Omalizumab (Xolair), Novartis Pharmaceuticals; Genentech Inc.) is a recombinant humanized anti-IgE mAb developed for the treatment of severe allergic asthma. It complexes with free serum IgE, which prevents its binding to Fc epsilon RI and thereby interrupts the allergic cascade. Administration of an inhibitory anti-Fc epsilon RI alpha mAb may represent an alternative strategy to neutralize IgE-mediated receptor activation. In the present report, for the first time, we have performed direct side of side comparison between the inhibitory anti-Fc epsilon RI alpha mAb designated 15/1 and Omalizumab for their effects on human cord blood-derived mast cells. We provide the first evidence that both 15/1 mAb and Omalizumab efficiently inhibit Fc epsilon RI-mediated human mast cell responses in vitro (degranulation, activation, release of IL-8 and IL-13, phosphorylation of Akt) and that mAb 15/1 is a non-anaphylactogenic antibody, which compared to Omalizumab, displays markedly higher inhibitory potency in the presence of high IgE levels. PMID:17368811

Mirkina, Irina; Schweighoffer, Tamás; Kricek, Franz

2007-04-15

256

Pharmacological blockade of the DP2 receptor inhibits cigarette smoke-induced inflammation, mucus cell metaplasia, and epithelial hyperplasia in the mouse lung.  

PubMed

Prostaglandin D(2) (PGD(2)) is one of a family of biologically active lipids derived from arachidonic acid via the action of COX-1 and COX-2. PGD(2) is released from mast cells and binds primarily to two G protein-coupled receptors, namely DP1 and DP2, the latter also known as chemoattractant receptor-homologous molecule expressed on Th2 cells. DP2 is predominantly expressed on eosinophils, Th2 cells, and basophils, but it is also expressed to a lesser extent on monocytes, mast cells, and epithelial cells. Interaction of PGD(2) and its active metabolites with DP2 results in cellular chemotaxis, degranulation, up-regulation of adhesion molecules, and cytokine production. Chronic obstructive pulmonary disease (COPD) is a chronic progressive inflammatory disease characterized by elevated lung neutrophils, macrophages, and CD8+ T lymphocytes and mucus hypersecretion. Cigarette smoke contributes to the etiology of COPD and was used here as a provoking agent in a murine model of COPD. In an acute model, {2'-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4'-trifluoro-methyl-biphenyl-3-yl}-acetic acid, sodium salt (AM156) and (5-{2-[(benzoyloxycarbonyl-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid, sodium salt) (AM206), potent DP2 receptor antagonists, dose-dependently inhibited influx of neutrophils and lymphocytes to smoke-exposed airways. In a subchronic model, AM156 and AM206 inhibited neutrophil and lymphocyte trafficking to the airways. Furthermore, AM156 and AM206 treatment inhibited mucus cell metaplasia and prevented the thickening of the airway epithelial layer induced by cigarette smoke. These data suggest that DP2 receptor antagonism may represent a novel therapy for COPD or other conditions characterized by neutrophil influx, mucus hypersecretion, and airway remodeling. PMID:19996299

Stebbins, Karin J; Broadhead, Alex R; Baccei, Christopher S; Scott, Jill M; Truong, Yen P; Coate, Heather; Stock, Nicholas S; Santini, Angelina M; Fagan, Patrick; Prodanovich, Patricia; Bain, Gretchen; Stearns, Brian A; King, Christopher D; Hutchinson, John H; Prasit, Peppi; Evans, Jilly F; Lorrain, Daniel S

2010-03-01

257

Inhibition of erythrocyte invasion and Plasmodium falciparum merozoite surface protein 1 processing by human immunoglobulin G1 (IgG1) and IgG3 antibodies.  

PubMed

Antigen-specific antibodies (Abs) to the 19-kDa carboxy-terminal region of Plasmodium falciparum merozoite surface protein 1 (MSP1(19)) play an important role in protective immunity to malaria. Mouse monoclonal Abs (MAbs) 12.10 and 12.8 recognizing MSP1(19) can inhibit red cell invasion by interfering with MSP1 processing on the merozoite surface. We show here that this ability is dependent on the intact Ab since Fab and F(ab')(2) fragments derived from MAb 12.10, although capable of binding MSP1 with high affinity and competing with the intact antibody for binding to MSP1, were unable to inhibit erythrocyte invasion or MSP1 processing. The DNA sequences of the variable (V) regions of both MAbs 12.8 and 12.10 were obtained, and partial amino acid sequences of the same regions were confirmed by mass spectrometry. Human chimeric Abs constructed by using these sequences, which combine the original mouse V regions with human gamma1 and gamma3 constant regions, retain the ability to bind to both parasites and recombinant MSP1(19), and both chimeric human immunoglobulin G1s (IgG1s) were at least as good at inhibiting erythrocyte invasion as the parental murine MAbs 12.8 and 12.10. Furthermore, the human chimeric Abs of the IgG1 class (but not the corresponding human IgG3), induced significant NADPH-mediated oxidative bursts and degranulation from human neutrophils. These chimeric human Abs will enable investigators to examine the role of human Fcgamma receptors in immunity to malaria using a transgenic parasite and mouse model and may prove useful in humans for neutralizing parasites as an adjunct to antimalarial drug therapy. PMID:19805526

Lazarou, Maria; Guevara Patiño, José A; Jennings, Richard M; McIntosh, Richard S; Shi, Jianguo; Howell, Steven; Cullen, Eilish; Jones, Tarran; Adame-Gallegos, Jaime R; Chappel, Jonathan A; McBride, Jana S; Blackman, Michael J; Holder, Anthony A; Pleass, Richard J

2009-12-01

258

SPIRULINA PLATENSIS INHIBITS ANAPHYLACTIC REACTION  

Microsoft Academic Search

We investigated the effects of the powders of Spirulina platensis (SPP) on anaphylactic reactions. SPP inhibited compound 4880-induced anaphylactic shock 100% with doses of 0.5, and 1.0 mg\\/g body weight (BW). SPP significantly inhibited serum histamine levels induced by compound 4880 in rats. SPP (0.5 mg\\/g BW) inhibited to 68.7% passive cutaneous anaphylaxis activated by antidinitrophenyl (DNP) IgE. SPP dose-dependently

Huh-Nam Yang; Eun-Hee Lee; Hyung-Min Kim

1997-01-01

259

Inhibition of Glioma Cell Lysosome Exocytosis Inhibits Glioma Invasion  

PubMed Central

Cancer cells invade by secreting enzymes that degrade the extracellular matrix and these are sequestered in lysosomal vesicles. In this study, the effects of the selective lysosome lysing drug GPN and the lysosome exocytosis inhibitor vacuolin-1 on lysosome exocytosis were studied to determine their effect on glioma cell migration and invasion. Both GPN and vacuolin-1 evidently inhibited migration and invasion in transwell experiments and scratch experiments. There are more lysosomes located on the cell membrane of glioma cells than of astrocytes. GPN decreased the lysosome number on the cell membrane. We found that rab27A was expressed in glioma cells, and colocalized with cathepsin D in lysosome. RNAi-Rab27A inhibited lysosome cathepsin D exocytosis and glioma cell invasion in an in vitro assay. Inhibition of cathepsin D inhibited glioma cell migration. The data suggest that the inhibition of lysosome exocytosis from glioma cells plays an important modulatory role in their migration and invasion.

Zhu, Keqing

2012-01-01

260

Behavioral Inhibition in Young Children.  

ERIC Educational Resources Information Center

Study of children aged 21 to 31 months tentatively concludes: (1)behavioral tendency to be inhibited or uninhibited with unfamiliar people or during unfamiliar events is moderately stable across time and context; and (2)moderately negative relationship exists between behavioral inhibition and heart rate variability, and positive relationship…

Garcia Coll, Cynthia; And Others

1984-01-01

261

Inhibition of lipases by  -polylysine  

Microsoft Academic Search

Oral administration of ? -polylysine to rats re- duced the peak plasma triacylglycerol concentration. In vitro, ? -polylysine and polylysine strongly inhibited the hy- drolysis, by either pancreatic lipase or carboxylester lipase, of trioleoylglycerol (TO) emulsified with phosphatidylcho- line (PC) and taurocholate. The ? -polylysine concentration required for complete inhibition of pancreatic lipase, 10 ? g\\/ml, is 1,000 times lower

Takahiro Tsujita; Maho Sumiyoshi; Takeshi Takaku; William E. Momsen; Mark E. Lowe; Howard L. Brockman

2003-01-01

262

Naming and inhibition in aphasia  

Microsoft Academic Search

Lexical retrieval models illustrate both activation and inhibition between concepts, words, and phonemes. When semantic activation spreads from one concept to its related concepts, inhibition is recruited so that competition between related concepts can be overcome and a target production achieved. Persons with aphasia often exhibit difficulty with producing the desired response, which could be the result of inadequate inhibitory

Lori R Bartels-Tobin

2007-01-01

263

Propolis inhibits osteoclast maturation.  

PubMed

Propolis, a natural product produced by the honey bee, has been successfully used in medicine as an anti-inflammatory and antimicrobial agent. Traumatic injuries to the teeth, especially avulsion injuries, present a challenging situation for the clinician because of post-treatment complications, such as inflammatory and/or replacement resorption. Agents that reduce osteoclast numbers and activity may be useful in the treatment of traumatic injuries to the teeth. In this study, we evaluated propolis as an anti-resorptive agent. Calcitriol-stimulated mouse marrow cultures, which contain both osteoclasts and osteoblasts, were exposed to the ethanol extracts of propolis or vehicle control and stained for tartrate-resistant acid phosphatase (TRAP)-activity to identify osteoclasts. A significant, dose-dependent reduction in multinuclear TRAP+ cells was demonstrated, although the propolis treatment accommodated cell growth and survival (P < 0.05). Propolis also reduced the formation of actin rings in pure cultures of RAW 264.7 osteoclast-like cells, suggesting that it exerts direct actions on osteoclast maturation. In summary, our data suggest that propolis inhibits late stages of osteoclast maturation including fusion of osteoclasts precursors to form giant cells and formation of actin rings. This supports the hypothesis that it may prove useful as a medicament to reduce resorption associated with traumatic injuries to the teeth. PMID:19843135

Pileggi, Roberta; Antony, Kathryn; Johnson, Kristie; Zuo, Jian; Shannon Holliday, L

2009-12-01

264

Absence of Fc epsilonRI alpha chain results in upregulation of Fc gammaRIII-dependent mast cell degranulation and anaphylaxis. Evidence of competition between Fc epsilonRI and Fc gammaRIII for limiting amounts of FcR beta and gamma chains.  

PubMed Central

In mouse mast cells, both Fc epsilonRI and Fc gammaRIII are alpha beta gamma2 tetrameric complexes in which different alpha chains confer IgE or IgG ligand recognition while the signaling FcR beta and gamma chains are identical. We used primarily noninvasive techniques (changes in body temperature, dye extravasation) to assess systemic anaphylactic responses in nonanesthetized wild-type, Fc epsilonRI alpha chain -/- and FcR gamma chain -/- mice. We confirm that systemic anaphylaxis in mice can be mediated largely through IgG1 and Fc gammaRIII and we provide direct evidence that these responses reflect activation of Fc gammaRIII rather than Fc gammaRI. Furthermore, we show that Fc gammaRIII-dependent responses are more intense in normal than in congenic mast cell-deficient KitW/KitW-v mice, indicating that Fc gammaRIII responses have mast cell-dependent and -independent components. Finally, we demonstrate that the upregulation of cell surface expression of Fc gammaRIII seen in Fc epsilonRI alpha chain -/- mice corresponds to an increased association of Fc gammaRIII alpha chains with FcR beta and gamma chains and is associated with enhanced Fc gammaRIII-dependent mast cell degranulation and systemic anaphylactic responses. Therefore, the phenotype of the Fc epsilonRI alpha chain -/- mice suggests that expression of Fc epsilonRI and Fc gammaRIII is limited by availability of the FcR beta and gamma chains and that, in normal mice, changes in the expression of one receptor (Fc epsilonRI) may influence the expression of functional responses dependent on the other (Fc gammaRIII).

Dombrowicz, D; Flamand, V; Miyajima, I; Ravetch, J V; Galli, S J; Kinet, J P

1997-01-01

265

Fc receptor-? subunits with both polar or non-polar amino acids at position of T22 are capable of restoring surface expression of the high-affinity IgE receptor and degranulation in ? subunit-deficient rat basophilic leukemia cells.  

PubMed

The high-affinity IgE receptor (Fc?RI) is formed by the IgE-binding ? subunit, ? subunit and ? subunits homodimer. All three subunits are required for proper expression of the receptor on the plasma membrane of mast cells and basophils. However, the exact molecular mechanism of inter-subunit interactions required for correct expression and function of the Fc?RI complex remains to be identified. A recent study suggested that polar aspartate at position 194 within the transmembrane domain of the ? subunit could interact by hydrogen bonding with polar threonine at position 22 in the transmembrane domains of the ? subunits. To verify this, we used previously isolated rat basophilic leukemia (RBL)-2H3 variant cells deficient in the expression of the Fc?RI-? subunit (FcR-?), and transfected them with DNA vectors coding for FcR-? of the wild-type or mutants in which T22 was substituted for nonpolar alanine (T22A mutant) or polar serine (T22S mutant). Analysis of the transfectants showed that both T22A and T22S mutants were capable to restore surface expression of the Fc?RI similar to wild-type FcR-?. Furthermore, cells transfected with wild-type, T22A or T22S FcR-? showed comparably enhanced Fc?RI-mediated degranulation. Our data indicate that substitution of FcR-? T22 with non-polar amino acid does not interfere with surface expression of the Fc?RI and its signaling capacity. PMID:22964482

Rashid, Amir; Housden, Jonathan E M; Helm, Birgit A; Draber, Petr

2013-03-01

266

Biology of TACE inhibition  

PubMed Central

Studies conducted over the past decade have demonstrated a central role for tumour necrosis factor ? (TNF?) in inflammatory diseases. As a result of this work, a number of biological agents that neutralise the activity of this cytokine have entered the clinic. The recent clinical data obtained with etanercept and infliximab highlight the relevance of this strategy. TNF? converting enzyme (TACE) is the metalloproteinase that processes the 26 kDa membrane bound precursor of TNF? (proTNF?) to the 17 kDa soluble component. Although a number of proteases have been shown to process proTNF?, none do so with the efficiency of TACE. A series of orally bioavailable, selective, and potent TACE inhibitors are currently in clinical development. These inhibitors effectively block TACE mediated processing of proTNF? and can reduce TNF production by lipopolysaccharide stimulated whole blood by >95%. Through a series of studies it is shown here that >80% of the unprocessed proTNF? is degraded intracellularly. The remainder appears to be transiently expressed on the cell surface. Although, in vitro, TACE inhibition has also been implicated in shedding of p55 and p75 surface TNF? receptors, the in vivo data cast doubt on the consequences of this finding. In a mouse model of collagen-induced arthritis, the inhibitors are efficacious both prophylactically and therapeutically. The efficacy seen is equivalent to strategies that neutralise TNF?. In many studies greater efficacy is observed with the TACE inhibitors, presumably owing to greater penetration to the site of TNF? production.??

Newton, R; Solomon, K; Covington, M; Decicco, C; Haley, P; Friedman, S; Vaddi, K

2001-01-01

267

Inhibition of glycogen synthase kinase-3 increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: role of STAT3.  

PubMed

Engagement of NKG2D and DNAX accessory molecule-1 (DNAM-1) receptors on lymphocytes plays an important role for anticancer response and represents an interesting therapeutic target for pharmacological modulation. In this study, we investigated the effect of inhibitors targeting the glycogen synthase kinase-3 (GSK3) on the expression of NKG2D and DNAM-1 ligands in multiple myeloma (MM) cells. GSK3 is a pleiotropic serine-threonine kinase point of convergence of numerous cell-signaling pathways, able to regulate the proliferation and survival of cancer cells, including MM. We found that inhibition of GSK3 upregulates both MICA protein surface and mRNA expression in MM cells, with little or no effects on the basal expression of the MICB and DNAM-1 ligand poliovirus receptor/CD155. Moreover, exposure to GSK3 inhibitors renders myeloma cells more efficient to activate NK cell degranulation and to enhance the ability of myeloma cells to trigger NK cell-mediated cytotoxicity. We could exclude that increased expression of ?-catenin or activation of the heat shock factor-1 (transcription factors inhibited by active GSK3) is involved in the upregulation of MICA expression, by using RNA interference or viral transduction of constitutive active forms. On the contrary, inhibition of GSK3 correlated with a downregulation of STAT3 activation, a negative regulator of MICA transcription. Both Tyr(705) phosphorylation and binding of STAT3 on MICA promoter are reduced by GSK3 inhibitors; in addition, overexpression of a constitutively active form of STAT3 significantly inhibits MICA upregulation. Thus, we provide evidence that regulation of the NKG2D-ligand MICA expression may represent an additional immune-mediated mechanism supporting the antimyeloma activity of GSK3 inhibitors. PMID:23686482

Fionda, Cinzia; Malgarini, Giulia; Soriani, Alessandra; Zingoni, Alessandra; Cecere, Francesca; Iannitto, Maria Luisa; Ricciardi, Maria Rosaria; Federico, Vincenzo; Petrucci, Maria Teresa; Santoni, Angela; Cippitelli, Marco

2013-06-15

268

5-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3,7-dimethoxy-4H-chromen-4-one (MSF-2) suppresses fMLP-mediated respiratory burst in human neutrophils by inhibiting phosphatidylinositol 3-kinase activity.  

PubMed

Respiratory burst mediates crucial bactericidal mechanism in neutrophils. However, undesirable respiratory burst leads to pathological inflammation and tissue damage. This study investigates the effect and the underlying mechanism of 5-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3,7-dimethoxy-4H-chromen-4-one (MSF-2), a lignan extracted from the fruit of Melicope Semecarprifolia, on fMLP-induced respiratory burst in human neutrophils and suggests a possible therapeutic approach to ameliorate disease associated with neutrophil hyperactivation. MSF-2 inhibited fMLP-induced neutrophil superoxide anion production, cathepsin G release and migration in human neutrophils isolated from healthy volunteers, reflecting inhibition of phosphatidylinositol 3-kinase (PI3K) activation. Specifically, PI3K/AKT activation results in migration, degranulation and superoxide anion production in neutrophils. MSF-2 suppresses PI3K activation and phosphatidylinositol (3,4,5)-trisphosphate (PIP3) production, and consequently inhibits downstream activation of PDK1 and AKT. Further, PI3K also stimulates respiratory burst via PLC-dependent elevation of intracellular calcium. MSF-2 reduces fMLP-mediated PLC?2 activation and intracellular calcium accumulation notably through extracellular calcium influx in a PI3K and PLC-dependent manner. However, MSF-2 is not a competitive or allosteric antagonist of fMLP. Additionally, in an in vivo study, MSF-2 prevents fMLP-induced neutrophil infiltration and inflammation in mice. In conclusion, MSF-2 opposes fMLP-mediated neutrophil activation and inflammation by inhibiting PI3K activation and subsequent activation of AKT and PLC?2. PMID:20945388

Liao, Chang-Hui; Chen, Jih-Jung; Lin, Jieru Egeria; Liu, Chia-Hsin; Tseng, Ching-Ping; Day, Yuan-Ji

2011-06-01

269

1,25(OH)2 vitamin D3-dependent inhibition of platelet Ca2+ signaling and thrombus formation in klotho-deficient mice.  

PubMed

Platelets are activated by increased cytosolic Ca(2+) concentration ([Ca(2+)]i) following store-operated calcium entry (SOCE) accomplished by calcium-release-activated calcium (CRAC) channel moiety Orai1 and its regulator STIM1. In other cells, Ca(2+) transport is regulated by 1,25(OH)2 vitamin D3 [1,25(OH)2D3]. 1,25(OH)2D3 formation is inhibited by klotho and excessive in klotho-deficient mice (kl/kl). The present study explored the effect of klotho deficiency on platelet Ca(2+) signaling and activation. Platelets and megakaryocytes isolated from WT and kl/kl-mice were analyzed by RT-PCR, Western blotting, confocal microscopy, Fura-2-fluorescence, patch clamp, flow cytometry, aggregometry, and flow chamber. STIM1/Orai1 transcript and protein levels, SOCE, agonist-induced [Ca(2+)]i increase, activation-dependent degranulation, integrin ?IIb?3 activation and aggregation, and thrombus formation were significantly blunted in kl/kl platelets (by 27-90%). STIM1/Orai1 transcript and protein levels, as well as CRAC currents, were significantly reduced in kl/kl megakaryocytes (by 38-73%) and 1,25(OH)2D3-treated WT megakaryocytes. Nuclear NF-?B subunit p50/p65 abundance was significantly reduced in kl/kl-megakaryocytes (by 51-76%). Transfection with p50/p65 significantly increased STIM1/Orai1 transcript and protein levels in megakaryocytic MEG-01 cells (by 46-97%). Low-vitamin D diet (LVD) of kl/kl mice normalized plasma 1,25(OH)2D3 concentration and function of platelets and megakaryocytes. Klotho deficiency inhibits platelet Ca(2+) signaling and activation, an effect at least partially due to 1,25(OH)2D3-dependent down-regulation of NF-?B activity and STIM1/Orai1 expression in megakaryocytes. PMID:24522202

Borst, Oliver; Münzer, Patrick; Schmid, Evi; Schmidt, Eva-Maria; Russo, Antonella; Walker, Britta; Yang, Wenting; Leibrock, Christina; Szteyn, Kalina; Schmidt, Sebastian; Elvers, Margitta; Faggio, Caterina; Shumilina, Ekaterina; Kuro-o, Makoto; Gawaz, Meinrad; Lang, Florian

2014-05-01

270

Aluminum inhibits erythropoiesis in vitro.  

PubMed Central

Anemia has been associated with aluminum intoxication in patients on chronic dialysis and in animals. In studies presented here, in vitro human erythroid culture was used to delineate the effects of aluminum on normal hematopoiesis. Aluminum by itself in routine culture, even at very high levels (1,035 ng/ml), did not significantly affect erythroid colony growth. The addition of human transferrin to the culture, however, resulted in a marked dose-dependent inhibition of erythroid, but not myeloid colony growth. At all doses, CFU-E progenitors showed greater inhibition than burst-forming units (BFU-E). Aluminum inhibition was not overcome by increasing the dose of erythropoietin or adding additional burst-promoting activity to the culture. Inhibition by aluminum was directly related to the number of binding sites on transferrin in the culture, and was not observed in the presence of fully iron-saturated transferrin. Images

Mladenovic, J

1988-01-01

271

Method for inhibiting nematocyst discharge  

US Patent & Trademark Office Database

Compositions for inhibiting nematocyst or polar capsule discharge are provided in the form of an effective amount of antihistamine, an effective amount of antihistamine and an effective amount of at least one cation, or an effective amount of at least one cation. The compositions can be in the form of ointments or can be added to the environment surrounding the nematocysts or polar capsules. Methods of inhibiting nematocyst or polar capsule discharge using the compositions of the invention are also provided.

2002-06-18

272

Inhibition of Microbiologically Induced Corrosion  

Microsoft Academic Search

\\u000a Chemicals of systematically changed structures were synthesized in order to inhibit the activity of aerobic and\\/or anaerobic\\u000a bacteria and to inhibit metal corrosion. Their efficiency on the microbiologically influenced corrosion (MIC) was monitored\\u000a by different techniques (gravimetric measurements, light microscopy, microbiological methods). The morphological changes due\\u000a to the MIC were demonstrated by atomic force microscope (AFM). Three environmentally acceptable chemicals

J. Telegdi; J. Beczner; Zs. Keresztes; F. H. Karman; E. Kalman

273

Direct renin inhibition: clinical pharmacology  

Microsoft Academic Search

Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modeling and X-ray crystallography\\u000a of the active site of renin have led to the development of new orally active renin inhibitors such as aliskiren. Aliskiren\\u000a has a low bioavailality (2.6% to 5%) compensated by its high potency to inhibit renin and a long plasma half-life (24 to 40 h),

Michel Azizi

2008-01-01

274

Inhibition of phospholipase D by agents that inhibit cell growth.  

PubMed

The phospholipases are an important class of enzymes for growth factor and oncogene intracellular signalling. The anti-tumor drug suramin was found to inhibit phosphatidylcholine hydrolysis and trans-phosphatidylation by solubilized rat brain phospholipase D (PLD) with an IC50 of 15 microM. An azo analogue of suramin, which is a considerably more potent inhibitor of phosphatidylinositol phospholipase C (PIPLC) than suramin, inhibited PLD with and IC50 of 58 microM. D-609, a xanthogenate compound with in vitro antitumor activity, inhibited PLD with an IC50 of 820 microM. The cytotoxic aminosteroid compound U-73, 122 was a weaker inhibitor of PLD with an IC50 of 78 microM. However, U-73, 122 was a more potent inhibitor of PLD in fibroblast membranes with an IC50 of 25 microM, while suramin was less active with an IC50 of 4.2 mM. The antitumor ether lipid drug ET-18-OCH3 did not inhibit solubilized or membrane PLD although it is a potent inhibitor of PIPLC. The results of the study show that the compounds tested have different abilities to inhibit PIPLC and PLD. Access of hydrophilic drugs to membrane PLD may be a limiting factor to their inhibitory activity. PMID:8352550

Gratas, C; Powis, G

1993-01-01

275

Behavioral inhibition and childhood stuttering  

PubMed Central

Purpose The purpose of this study was to assess the relation of behavioral inhibition to stuttering and speech/language output in preschool-age children who do (CWS) and do not stutter (CWNS). Method Participants were preschool-age (ages 36 to 68 months), including 26 CWS (22 males) and 28 CWNS (13 males). Participants’ behavioral inhibition (BI) was assessed by measuring the latency to their sixth spontaneous comment during conversation with an unfamiliar experimenter, using methodology developed by Kagan, Reznick, and Gibbons (1989). In addition to these measures of BI, each participant’s stuttered and non-stuttered disfluencies and mean length of utterance (in morphemes) were assessed. Results Among the more salient findings, it was found that (1) there was no significant difference in BI between preschool-age CWS and CWNS as a group, (2) when extremely high versus low inhibited children were selected, there were more CWS with higher BI and fewer CWS with lower BI when compared to their CWNS peers, and (3) more behaviorally inhibited CWS, when compared to less behaviorally inhibited CWS, exhibited more stuttering. Conclusions Findings are taken to suggest that one aspect of temperament (i.e., behavioral inhibition) is exhibited by some preschool-age CWS and that these children stutter more than CWS with lower behavioral inhibition. The present results seem to support continued study of the association between young children’s temperamental characteristics and stuttering, the diagnostic entity (i.e., CWS versus CWNS), as well as stuttering, the behavior (e.g., frequency of stuttered disfluencies).

Choi, Dahye; Conture, Edward G.; Walden, Tedra A.; Lambert, Warren E.; Tumanova, Victoria

2013-01-01

276

Inhibition of allergen-induced wheal and flare reactions by levocetirizine and desloratadine  

PubMed Central

Aims To evaluate the inhibitory activity of the new-generation antihistamines levocetirizine and desloratadine at their therapeutic doses on the allergen-induced wheal and flare reaction at 1.5 h, 4 h, 7 h, 12 h and 24 h postdose, and to measure their plasma and skin concentrations. Methods A double-blind, randomized, cross-over, placebo-controlled study in 18 allergic subjects was carried out. The time–response of the wheal and flare reaction areas under the curve (AUC) were compared by anova. Results Both antihistamines significantly (P < 0.001) inhibited the allergen-induced wheal and flare reactions compared with placebo. Levocetirizine was significantly more potent than desloratadine. Mean ± SEM wheal AUC(0–24 h) was 506.4 ± 81.0 with levocetirizine and 995.5 ± 81.0 mm2 h with desloratadine as compared with placebo (1318.5 ± 361.0 mm2 h). Flare AUC(0–24 h) was 5927.3 ± 1686.5 and 15838.2 ± 1686.5 mm2 h, respectively [P < 0.001 for both compared with placebo (22508.2 ± 7437.1 mm2 h)]. Levocetirizine showed significant inhibition of wheal and flare already at 1.5 h postdose compared with placebo (P ? 0.001); desloratadine achieved a significant effect only after 4 h. The mean total plasma concentration at 12 h and 24 h after intake was higher for levocetirizine (58.1 ± 13.4 and 20.0 ± 8.1 ng ml?1, respectively) as compared with desloratadine (0.82 ± 0.24 and 0.45 ± 0.16 ng ml?1). Similarly, higher mean unbound skin concentrations were observed for levocetirizine 24 h after intake (1.80 ng g?1) than for desloratadine (0.07 ng g?1). This was associated with greater receptor occupancy for levocetirizine (54%) than desloratadine (34%) at 24 h. Conclusions Levocetirizine suppressed the cutaneous allergic reactions with a higher potency than desloratadine, which correlated with its high receptor occupancy. Receptor occupancy rather than drug affinity or plasma half-life is more representative of antihistamine potency. What is already known about this subject The reproducible and standardized histamine-induced wheal and flare model helps identify the objective effectiveness of antihistamines in humans, as well as their differences in onset and duration of action.Some of the newest antihistamines have already been compared in a head-to-head setting using this model. However, their objective action at inhibiting the allergen-induced wheal and flare response has not been reported yet. What this study adds The time–response study presented here shows the objective activity of two of the newest generation of antihistamines, levocetirizine and desloratadine, at inhibiting the allergen-induced wheal and flare response in a randomized, cross over, placebo-controlled trial.This model is interesting to the clinical setting since allergic subjects are recruited, and the response to allergen involves mast cell degranulation and release of numerous vasoactive and pro-inflammatory mediators additionally to histamine.In addition, this study reports receptor occupancy for both antihistamines at therapeutic dosage, leading to analysis of potential differences in activity.This study clearly shows the potential anti-inflammatory properties of desloratadine and levocetirizine in their skin activity when allergen is the challenging agent as occurs in the clinical situation.

Frossard, Nelly; Strolin-Benedetti, Margherita; Purohit, Ashok; Pauli, Gabrielle

2008-01-01

277

Type A behavior pattern, inhibited power motivation, and activity inhibition.  

PubMed

The constructs of the Type A behavior pattern and the Inhibited Power Motive Syndrome (IPMS) have many features in common. The empirical relation between the two constructs was investigated in this study with 45 employed, male medical and surgical patients. Four different measures of the Type A pattern were examined. Results showed that, of the four measures, the Structured Interview and the Hostility Scale were related significantly to the IPMS. Systolic blood pressure reactivity was also related significantly to the IPMS. These relations could be ascribed largely to activity inhibition alone. The contribution of activity inhibition to an understanding of the biological and psychological substrates of the Type A behavior pattern is discussed. PMID:3820069

Fontana, A F; Rosenberg, R L; Marcus, J L; Kerns, R D

1987-01-01

278

Presynaptic inhibition of elicited neurotransmitter release  

Microsoft Academic Search

Activation of presynaptic receptors for a variety of neurotransmitters and neuromodulators inhibits transmitter release at many synapses. Such presynaptic inhibition might serve as a means of adjusting synaptic strength or preventing excessive transmitter release, or both. Previous evidence showed that presynaptic modulators inhibit Ca2+ channels and activate K+ channels at neuronal somata. These modulators also inhibit spontaneous transmitter release by

Ling-Gang Wu; Peter Saggau

1997-01-01

279

Post-Stop-Signal Adjustments: Inhibition Improves Subsequent Inhibition  

ERIC Educational Resources Information Center

Performance in the stop-signal paradigm involves a balance between going and stopping, and one way that this balance is struck is through shifting priority away from the go task, slowing responses after a stop signal, and improving the probability of inhibition. In 6 experiments, the authors tested whether there is a corresponding shift in…

Bissett, Patrick G.; Logan, Gordon D.

2012-01-01

280

Enzyme inhibiting compounds and methods  

US Patent & Trademark Office Database

The invention provides compounds, compositions, and methods for studying the Rohmer pathway and for treating bacterial infections or parasitic infections. The parasitic infection can be a protozoan infection, such as malaria. The compounds and compositions can also be used as antibiotics, for example, to kill bacteria or parasites, or to inhibit bacterial or parasite growth. The invention further provides inhibitors of isoprenoid biosynthesis enzymes, and methods of inhibiting the activity of isoprenoid biosynthesis enzymes. The compounds can be, for example, alkynes or allenes that bind to a unique Fe of an Fe4S4 cluster of an isoprenoid biosynthesis enzyme.

2013-12-17

281

Action spectra for photosynthetic inhibition  

NASA Technical Reports Server (NTRS)

The ultraviolet action spectrum for photosynthesis inhibition was determined to fall between that of the general DNA action spectrum and the generalized plant action spectrum. The characteristics of this action spectrum suggest that a combination of pronounced increase in effectiveness with decreasing wavelength, substantial specificity for the UV-B waveband, and very diminished response in the UV-A waveband result in large radiation amplification factors when the action spectra are used as weighting functions. Attempted determination of dose/response relationships for leaf disc inhibition provided inconclusive data from which to deconvolute an action spectrum.

Caldwell, M. M.; Flint, S.; Camp, L. B.

1981-01-01

282

Mast cell degranulation activates a pain pathway underlying migraine headache  

Microsoft Academic Search

Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonged activation of meningeal nociceptors but the mechanisms responsible for such nociceptor activation are poorly understood. In this study, we examined the hypothesis that meningeal nociceptors can be activated locally through a neuroimmune interaction with resident mast cells, granulated immune cells that densely populate the dura

Dan Levy; Rami Burstein; Vanessa Kainz; Moshe Jakubowski; Andrew M. Strassman

2007-01-01

283

Chorein sensitivity of cytoskeletal organization and degranulation of platelets.  

PubMed

Chorea-acanthocytosis (ChAc), a lethal disease caused by defective chorein, is characterized by neurodegeneration and erythrocyte acanthocytosis. The functional significance of chorein in other cell types remained ill-defined. The present study revealed chorein expression in blood platelets. As compared to platelets from healthy volunteers, platelets from patients with ChAc displayed a 47% increased globular/filamentous actin ratio, indicating actin depolymerization. Moreover, phosphoinositide-3-kinase subunit p85 phosphorylation, p21 protein-activated kinase (PAK1) phosphorylation, as well as vesicle-associated membrane protein 8 (VAMP8) expression were significantly reduced in platelets from patients with ChAc (by 17, 22, and 39%, respectively) and in megakaryocytic (MEG-01) cells following chorein silencing (by 16, 54, and 11%, respectively). Activation-induced platelet secretion from dense granules (ATP release) and ? granules (P-selectin exposure) were significantly less (by 55% after stimulation with 1 ?g/ml CRP and by 33% after stimulation with 5 ?M TRAP, respectively) in ChAc platelets than in control platelets. Furthermore, platelet aggregation following stimulation with different platelet agonists was significantly impaired. These observations reveal a completely novel function of chorein, i.e., regulation of secretion and aggregation of blood platelets. PMID:23568775

Schmidt, Eva-Maria; Schmid, Evi; Münzer, Patrick; Hermann, Andreas; Eyrich, Ann-Kathrin; Russo, Antonella; Walker, Britta; Gu, Shuchen; vom Hagen, Jennifer Müller; Faggio, Caterina; Schaller, Martin; Föller, Michael; Schöls, Ludger; Gawaz, Meinrad; Borst, Oliver; Storch, Alexander; Stournaras, Christos; Lang, Florian

2013-07-01

284

Azide inhibition of urate oxidase.  

PubMed

The inhibition of urate oxidase (UOX) by azide was investigated by X-ray diffraction techniques and compared with cyanide inhibition. Two well characterized sites for reagents are present in the enzyme: the dioxygen site and the substrate-binding site. To examine the selectivity of these sites towards azide inhibition, several crystallization conditions were developed. UOX was co-crystallized with azide (N3) in the presence or absence of either uric acid (UA, the natural substrate) or 8-azaxanthine (8AZA, a competitive inhibitor). In a second set of experiments, previously grown orthorhombic crystals of the UOX-UA or UOX-8AZA complexes were soaked in sodium azide solutions. In a third set of experiments, orthorhombic crystals of UOX with the exchangeable ligand 8-nitroxanthine (8NXN) were soaked in a solution containing uric acid and azide simultaneously (competitive soaking). In all assays, the soaking periods were either short (a few hours) or long (one or two months). These different experimental conditions showed that one or other of the sites, or the two sites together, could be inhibited. This also demonstrated that azide not only competes with dioxygen as cyanide does but also competes with the substrate for its enzymatic site. A model in agreement with experimental data would be an azide in equilibrium between two sites, kinetically in favour of the dioxygen site and thermodynamically in favour of the substrate-binding site. PMID:25005084

Gabison, Laure; Colloc'h, Nathalie; Prangé, Thierry

2014-07-01

285

Presynaptic inhibition of acetylcholine release.  

PubMed

High potassium (51 mM) has been shown to evoke release of acetylcholine ([3H]ACh and endogenous ACh) from cholinergic nerves in rat bronchial smooth muscle. The release of [3H]ACh was reduced by 85% when the Ca2+ concentration was changed from 2 to 0.1 mM. The veratridine-induced release was completely inhibited by tetrodotoxin, but tetrodotoxin did not reduce the potassium-evoked release. The muscarinic agonist, oxotremorine, reduced the potassium stimulated release of [3H]ACh, without affecting the basal release. In contrast, scopolamine substantially potentiated the potassium-evoked release. Adenosine had a dual effect in the rat bronchi. Adenosine inhibited the potassium-evoked release of [3H]ACh and this presynaptic effect of adenosine was antagonized by 8-phenyltheophylline. Adenosine also induced contraction of the bronchial smooth muscle and there was potentiation by adenosine of the ACh-induced contraction. The results indicate that cholinergic nerve terminals in the rat bronchi possess muscarinic receptors which inhibit the release of ACh. Adenosine may have analogous effects, e.g. presynaptic inhibition of transmitter release in addition to postsynaptic enhancement of bronchial smooth muscle contraction. PMID:3019084

Aas, P; Fonnum, F

1986-07-01

286

Subliminal priming of intentional inhibition.  

PubMed

Intentional choice is an important process underlying human behaviour. Intentional inhibition refers to the capacity to endogenously cancel an about-to-be-executed action at the last moment. Previous research suggested that such intentional inhibitory control requires conscious effort and awareness. Here we show that intentional decisions to inhibit are nevertheless influenced by unconscious processing. In a novel version of the Go/No-Go task, participants made speeded keypress actions to a Go target, or withheld responses to a No-Go target, or made free, spontaneous choices whether to execute or inhibit a keypress when presented with a free-choice target. Prior to each target, subliminal masked prime arrows were presented. Primes could be congruent with the Go or No-Go arrows, or neutral. Response times and proportion of action choices were measured. Primes were presented at latencies that would give either positive or negative compatibility effects (PCE, Experiment 1, and NCE, Experiment 2, respectively), based on previous literature. Go-primes at positive-compatibility latencies facilitated speeded response times as expected, but did not influence number of choices to act on free-choice trials. However, when Go primes were presented at negative-compatibility latencies, "free" decisions to inhibit were significantly increased. Decisions to act or not can be unconsciously manipulated, at least by inhibitory mechanisms. The cognitive mechanisms for intentionally withholding an action can be influenced by unconscious processing. We discuss possible moral and legal implications of these findings. PMID:24334316

Parkinson, Jim; Haggard, Patrick

2014-02-01

287

Islam Does Not Inhibit Science.  

ERIC Educational Resources Information Center

Compares the science/religion relationship in both Christian and Islamic countries. Presents Muslim scholars' ideas about the presence of humans on earth. Presents ideas on active nature, Noah's curse, and the age of the universe. Refutes the notion that Islam inhibited science and advocates the belief that Islam promoted science. (YDS)

Shanavas, T. O.

1999-01-01

288

Behavioral Inhibition to the Unfamiliar.  

ERIC Educational Resources Information Center

A group of 43 children classified as either behaviorally inhibited or uninhibited at 21 months were observed at four years of age in situations designed to evaluate behavior with an unfamiliar peer, heart rate and heart rate variability to cognitively challenging tasks, reluctance to answer difficult questions, and differential fixation of an…

Kagan, Jerome; And Others

1984-01-01

289

Calcergy inhibited by calciphylactic challengers.  

PubMed

The subcutaneous calcification effected in the rat at sites directly treated with calcergens, such as lead acetate, CeCl(3), CaCl(2), and KMnO(4), is inhibited by simultaneous local application of various calciphylactic challengers, but not by many other compounds. PMID:5644264

Selye, H; Somogyi, A; Mécs, I

1968-03-22

290

Infant Predictors of Behavioural Inhibition  

ERIC Educational Resources Information Center

Behavioural inhibition in the second year of life is a hypothesized predictor for shyness, social anxiety and depression in later childhood, adolescence and even adulthood. To search for the earliest indicators of this fundamental temperamental trait, this study examined whether behavioural characteristics in early infancy can predict behavioural…

Moehler, Eva; Kagan, Jerome; Oelkers-Ax, Rieke; Brunner, Romuald; Poustka, Luise; Haffner, Johann; Resch, Franz

2008-01-01

291

Paramyosin inhibits complement C1.  

PubMed

We report here the results of studies showing that inhibition of C is a property of several invertebrate paramyosins. Paramyosins from Taenia solium, Schistosoma mansoni, and the mussel Mytilus edulis bind polymeric collagen and can be isolated from crude extracts of tissues by collagen affinity. These paramyosins inhibit C1 function whether the C1 is isolated or present in C2-deficient serum. Because T. solium paramyosin was the best inhibitor, we concentrated further studies on this molecule. T. solium paramyosin binds purified C1q in solution with a dose/response similar to C1r2S2. Further studies of the C1-paramyosin interaction indicate that: 1) C4 is not activated, 2) C4b2a decay is not affected, and 3) there is no effect on the efficiency of C3-9, as provided in EDTA-chelated guinea pig serum, in lysing SRBC. Thus, paramyosin inhibition is directed at the initiation of the classical pathway. The results suggest that paramyosins of helminthic parasites may have a role as modulators of the host immune response through C inhibition at C1. PMID:1727860

Laclette, J P; Shoemaker, C B; Richter, D; Arcos, L; Pante, N; Cohen, C; Bing, D; Nicholson-Weller, A

1992-01-01

292

Iodoacetate Inhibition of Galactoside Transport.  

National Technical Information Service (NTIS)

Iodoacetic acid (IAA) was shown to inhibit the in vivo hydrolysis of o-nitro-phenyl-beta-D-galactopyranoside by E. coli K12. Because other work has shown the rate of this hydrolysis to be minimally energy dependent, the IAA effect evidently occurs directl...

E. Spoerl W. S. Pfeiffer

1966-01-01

293

Inhibition among olfactory receptor neurons  

PubMed Central

Often assumed to be epiphenomena of a cell’s activity, extracellular currents and resulting potential changes are increasingly recognized to influence the function of other cells in the vicinity. Experimental evidence shows that even small electric fields can modulate spike timing in neurons. Moreover, when neurons are brought close together experimentally or in pathological conditions, activity in one neuron can excite its neighbors. Inhibitory ephaptic mechanisms, however, may depend on more specialized coupling among cells. Recent studies in the Drosophila olfactory system have shown that excitation of a sensory neuron can inhibit its neighbor, and it was speculated that this interaction was ephaptic. Here we give an overview of ephaptic interactions that effect changes in spike timing, excitation or inhibition in diverse systems with potential relevance to human neuroscience. We examine the mechanism of the inhibitory interaction in the Drosophila system and that of the well-studied ephaptic inhibition of the Mauthner cell in more detail. We note that both current towards and current away from the local extracellular environment of a neuron can inhibit it, but the mechanism depends on the specific architecture of each system.

Van der Goes van Naters, Wynand

2013-01-01

294

Prasugrel Metabolites Inhibit Neutrophil Functions  

PubMed Central

Clopidogrel and prasugrel belong to a thienopyridine class of oral antiplatelet drugs that, after having been metabolized in the liver, can inhibit platelet function by irreversibly antagonizing the P2Y12 receptor. Furthermore, thienopyridines influence numerous inflammatory conditions, but their effects on neutrophils have not been evaluated, despite the important role of these cells in inflammation. Therefore, we investigated the effect of prasugrel metabolites on neutrophils to further clarify the role of thienopyridines in inflammation. Interestingly, a prasugrel metabolite mixture, produced in vitro using rat liver microsomes, significantly inhibited N-formyl-methionyl-leucyl-phenylalanine (fMLP)- and platelet-activating factor (PAF)-induced neutrophil activation. More specifically, prasugrel metabolites inhibited neutrophil transmigration, CD16 surface expression, and neutrophil-platelet aggregation. Moreover, prasugrel metabolite pretreatment also significantly decreased fMLP- or PAF-induced extracellular-signal–regulated kinase phosphorylation as well as calcium mobilization. To determine the target of prasugrel in neutrophils, the role of both P2Y12 and P2Y13 receptors was studied using specific reversible antagonists, AR-C69931MX and MRS2211, respectively. Neither antagonist had any direct effect on the agonist-induced neutrophil functional responses. Our findings indicate that prasugrel metabolites may directly target neutrophils and inhibit their activation, suggesting a possible explanation for their anti-inflammatory effects previously observed. However, these metabolites do not act through either the P2Y12 or P2Y13 receptor in neutrophils.

Rico, Mario C.; Garcia, Analia E.; Kilpatrick, Laurie E.; Kunapuli, Satya P.

2013-01-01

295

Visual-tactile saccadic inhibition  

Microsoft Academic Search

In an eye movement countermanding paradigm it is demonstrated for the first time that a tactile stimulus can be an effective stop signal when human participants are to inhibit saccades to a visual target. Estimated stop signal processing times were 90–140 ms, comparable to results with auditory stop signals, but shorter than those commonly found for manual responses. Two of the

Annika Åkerfelt; Hans Colonius; Adele Diederich

2006-01-01

296

Strigolactone inhibition of shoot branching  

Microsoft Academic Search

A carotenoid-derived hormonal signal that inhibits shoot branching in plants has long escaped identification. Strigolactones are compounds thought to be derived from carotenoids and are known to trigger the germination of parasitic plant seeds and stimulate symbiotic fungi. Here we present evidence that carotenoid cleavage dioxygenase 8 shoot branching mutants of pea are strigolactone deficient and that strigolactone application restores

Victoria Gomez-Roldan; Soraya Fermas; Philip B. Brewer; Virginie Puech-Pagès; Elizabeth A. Dun; Jean-Paul Pillot; Fabien Letisse; Radoslava Matusova; Saida Danoun; Jean-Charles Portais; Harro Bouwmeester; Guillaume Bécard; Christine A. Beveridge; Catherine Rameau; Soizic F. Rochange

2008-01-01

297

Methanogenic Inhibition by Arsenic Compounds  

PubMed Central

The acute acetoclastic methanogenic inhibition of several inorganic and organic arsenicals was assayed. Trivalent species, i.e., methylarsonous acid and arsenite, were highly inhibitory, with 50% inhibitory concentrations of 9.1 and 15.0 ?M, respectively, whereas pentavalent species were generally nontoxic. The nitrophenylarsonate derivate, roxarsone, displayed moderate toxicity.

Sierra-Alvarez, Reyes; Cortinas, Irail; Yenal, Umur; Field, Jim A.

2004-01-01

298

Vasopeptidase inhibition: a double-edged sword?  

PubMed

The enormous benefits of inhibition of ACE demonstrate that manipulation of the metabolism of peptide hormones is a valuable therapeutic strategy for cardiovascular disease. Recent attempts to expand these benefits have combined ACE inhibition with inhibition of other peptidases such as neutral endopeptidase (NEP) in a single molecule, a strategy known as vasopeptidase inhibition. NEP metabolizes natriuretic peptides, and NEP inhibition offers the prospect of combining the benefits of increased natriuretic peptide levels with those of ACE inhibition. However, peptidases such as ACE and NEP have many different substrates, and there are complex interactions between ACE inhibition and NEP inhibition. Both ACE and NEP metabolize the kinin peptides bradykinin and kallidin, and NEP also converts angiotensin (Ang) I to Ang-(1-7) and metabolizes Ang II and endothelin. Addition of NEP inhibition to ACE inhibition potentiates the ACE inhibitor-induced increase in kinin levels, increases Ang II levels, reduces Ang-(1-7) levels, and may increase endothelin levels. These additional consequences of combined ACE/NEP inhibition increase the risk of angioedema and may counteract any benefit of ACE inhibition that depends on reduced Ang II levels and increased Ang-(1-7) levels. Further considerations are that the ratio of ACE and NEP inhibition is fixed for vasopeptidase inhibitors, and there is uncertainty how these drugs should be compared with ACE inhibitors. Vasopeptidase inhibitors will therefore require careful evaluation before they are introduced to patient care. PMID:12623931

Campbell, Duncan John

2003-03-01

299

Myc inhibition impairs autophagosome formation  

PubMed Central

Autophagy, a major clearance route for many long-lived proteins and organelles, has long been implicated in cancer development. Myc is a proto-oncogene often found to be deregulated in many cancers, and thus is an attractive target for design of cancer therapy. Therefore, understanding the relationship between anti-Myc strategies and autophagy will be important for development of effective therapy. Here, we show that Myc depletion inhibits autophagosome formation and impairs clearance of autophagy substrates. Myc suppression has an inhibitory effect on autophagy via reduction of c-Jun N-terminal kinase 1 (JNK1) and B-cell lymphoma 2 (Bcl2) phosphorylation. Additionally, the decrease in JNK1 phosphorylation observed with Myc knockdown is associated with a reduction in ROS production. Our data suggest that targeting Myc in cancer therapy might have the additional benefit of inhibiting autophagy in the case of therapy resistance associated with chemotherapy-induced autophagy.

Toh, Pearl P. C.; Luo, Shouqing; Menzies, Fiona M.; Rasko, Tamas; Wanker, Erich E.; Rubinsztein, David C.

2013-01-01

300

Orlistat Inhibits Dietary Cholesterol Absorption  

Microsoft Academic Search

Objective: Orlistat decreases the absorption of dietary triglycerides by inhibiting intestinal lipases. Orlistat therapy is associated with a greater decline in plasma low-density lipoprotein-cholesterol concentrations than that expected from weight loss alone. Therefore, we evaluated the effect of orlistat treatment on dietary cholesterol absorption as a possible mechanism for the independent effect of orlistat on plasma cholesterol concentration.Research Methods and

Bettina Mittendorfer; Richard E. Ostlund; Bruce W. Patterson; Samuel Klein

2001-01-01

301

Inhibition in Prolonged Work Tasks  

Microsoft Academic Search

A new model is presented that explains reaction time fluctuations in prolonged work tasks. The model extends the so-called Poisson-Erlang model and can account for long-term trend effects in the reaction time curve. The model is consistent with Spearman's hy pothesis that inhibition increases during work and de creases during rest. Predictions concerning the long- term trend were tested against

J. C. Smit; R. W. T. L. Jansen

1989-01-01

302

Inhibition of Hendra Virus Fusion  

PubMed Central

Hendra virus (HeV) is a recently identified paramyxovirus that is fatal in humans and could be used as an agent of bioterrorism. The HeV receptor-binding protein (G) is required in order for the fusion protein (F) to mediate fusion, and analysis of the triggering/activation of HeV F by G should lead to strategies for interfering with this key step in viral entry. HeV F, once triggered by the receptor-bound G, by analogy with other paramyxovirus F proteins, undergoes multistep conformational changes leading to a six-helix bundle (6HB) structure that accomplishes fusion of the viral and cellular membranes. The ectodomain of paramyxovirus F proteins contains two conserved heptad repeat regions (HRN and HRC) near the fusion peptide and the transmembrane domains, respectively. Peptides derived from the HRN and HRC regions of F are proposed to inhibit fusion by preventing F, after the initial triggering step, from forming the 6HB structure that is required for fusion. HeV peptides have previously been found to be effective at inhibiting HeV fusion. However, we found that a human parainfluenza virus 3 F-peptide is more effective at inhibiting HeV fusion than the comparable HeV-derived peptide.

Porotto, M.; Doctor, L.; Carta, P.; Fornabaio, M.; Greengard, O.; Kellogg, G. E.; Moscona, A.

2006-01-01

303

Retroactive Inhibition, Hypnosis, and Hypnotic Amnesia.  

National Technical Information Service (NTIS)

An experiment was performed to investigate the relationship of hypnosis and posthypnotic amnesia to retroactive inhibition. Four groups of 10 Ss each learned lists of adjectives in a retroactive inhibition paradigm. Two of the groups learned the interveni...

K. R. Graham A. Patton

1967-01-01

304

Inhibition of Cell Motility by Interferon  

Microsoft Academic Search

Interferon derived from human leukocytes, human fibroblasts, and mouse fibroblasts was found to inhibit the motility of cultured cells. It inhibits the tumor-induced motility of capillary endothelial cells as well as the spontaneous migration of other cell types. The ability of a given preparation of interferon to inhibit the motility of a given cell type is proportional to its antiviral

Daniele Brouty-Boye; Bruce R. Zetter

1980-01-01

305

Effect of Spice Extract on Fungal Inhibition  

Microsoft Academic Search

Spices, namely chilli, coriander, pepper, cumin and asafoetida were examined in their capacity to inhibit the growth of food spoilage fungi. Among the spices tested, asafoetida showed promising results by inhibiting growth both in paper disc assay and agitated liquid culture assay.Asafoetida was fractionated by extraction method to obtain an ethanolic fraction and an aqueous fraction. Inhibition was noticed in

Nagappa Thyagaraja; Akiyoshi Hosono

1996-01-01

306

Photo-Activated Psoralen Binds the ErbB2 Catalytic Kinase Domain, Blocking ErbB2 Signaling and Triggering Tumor Cell Apoptosis  

PubMed Central

Photo-activation of psoralen with UVA irradiation, referred to as PUVA, is used in the treatment of proliferative skin disorders. The anti-proliferative effects of PUVA have been largely attributed to psoralen intercalation of DNA, which upon UV treatment, triggers the formation of interstrand DNA crosslinks (ICL) that inhibit transcription and DNA replication. Here, we show that PUVA exerts antitumor effects in models of human breast cancer that overexpress the ErbB2 receptor tyrosine kinase oncogene, through a new mechanism. Independent of ICL formation, the antitumor effects of PUVA in ErbB2+ breast cancer models can instead be mediated through inhibition of ErbB2 activation and signaling. Using a mass spectroscopy-based approach, we show for the first time that photo-activated 8MOP (8-methoxypsoralen) interacts with the ErbB2 catalytic autokinase domain. Furthermore, PUVA can reverse therapeutic resistance to lapatinib and other ErbB2 targeted therapies, including resistance mediated via expression of a phosphorylated, truncated form of ErbB2 (p85ErbB2) that is preferentially expressed in tumor cell nuclei. Current ErbB2 targeted therapies, small molecule kinase inhibitors or antibodies, do not block the phosphorylated, activated state of p85ErbB2. Here we show that PUVA reduced p85ErbB2 phosphorylation leading to tumor cell apoptosis. Thus, in addition to its effects on DNA and the formation of ICL, PUVA represents a novel ErbB2 targeted therapy for the treatment of ErbB2+ breast cancers, including those that have developed resistance to other ErbB2 targeted therapies.

Xia, Wenle; Gooden, David; Liu, Leihua; Zhao, Sumin; Soderblom, Erik J.; Toone, Eric J.; Beyer, Wayne F.; Walder, Harold; Spector, Neil L.

2014-01-01

307

Graphene: corrosion-inhibiting coating.  

PubMed

We report the use of atomically thin layers of graphene as a protective coating that inhibits corrosion of underlying metals. Here, we employ electrochemical methods to study the corrosion inhibition of copper and nickel by either growing graphene on these metals, or by mechanically transferring multilayer graphene onto them. Cyclic voltammetry measurements reveal that the graphene coating effectively suppresses metal oxidation and oxygen reduction. Electrochemical impedance spectroscopy measurements suggest that while graphene itself is not damaged, the metal under it is corroded at cracks in the graphene film. Finally, we use Tafel analysis to quantify the corrosion rates of samples with and without graphene coatings. These results indicate that copper films coated with graphene grown via chemical vapor deposition are corroded 7 times slower in an aerated Na(2)SO(4) solution as compared to the corrosion rate of bare copper. Tafel analysis reveals that nickel with a multilayer graphene film grown on it corrodes 20 times slower while nickel surfaces coated with four layers of mechanically transferred graphene corrode 4 times slower than bare nickel. These findings establish graphene as the thinnest known corrosion-protecting coating. PMID:22299572

Prasai, Dhiraj; Tuberquia, Juan Carlos; Harl, Robert R; Jennings, G Kane; Rogers, Bridget R; Bolotin, Kirill I

2012-02-28

308

Inhibition of Adipogenesis by Ghrelin  

PubMed Central

Ghrelin, a novel gastric hormone, regulates food intake and energy metabolism via central mechanisms. The peripheral effect of ghrelin on adiposity is poorly understood. We established a stable 3T3-L1 cell line expressing ghrelin to study the direct effect of ghrelin on adipogenesis. Cells overexpressing ghrelin demonstrate significantly attenuated differentiation of preadipocytes into adipocytes. Expression of peroxisome proliferator-activator receptor-? is significantly inhibited as demonstrated by decrease of peroxisome proliferator-activator receptor-? mRNA and protein. Both ghrelin overexpression and exogenous ghrelin stimulate cell proliferation. Phosphorylation of mitogen-activated protein kinase is increased after treatment of cells with ghrelin. Ghrelin binding activity is demonstrated in both native and ghrelin-overexpressing 3T3-L1 cells by radiolabeled ghrelin, although reverse transcription-polymerase chain reaction with the primer sequence of the previously identified ghrelin receptor subtypes detected no signal. Our results demonstrate that ghrelin inhibits adipogenesis by stimulation of cell proliferation via the mediation of a ghrelin receptor, likely a novel unidentified subtype.

Zhang, Weizhen; Zhao, Lili; Lin, Theodore R.; Chai, Biaoxin; Fan, Yongyi; Gantz, Ira; Mulholland, Michael W.

2004-01-01

309

Magnetic catalysis versus magnetic inhibition.  

PubMed

We discuss the fate of chiral symmetry in an extremely strong magnetic field B. We investigate not only quark fluctuations but also neutral meson effects. The former enhances the chiral-symmetry breaking at finite B according to the magnetic catalysis, while the latter suppresses the chiral condensate once B exceeds the scale of the hadron structure. Using a chiral model, we demonstrate how neutral mesons are subject to the dimensional reduction and the low dimensionality favors the chiral-symmetric phase. We point out that this effect, the magnetic inhibition, can be a feasible explanation for recent lattice-QCD data indicating the decreasing behavior of the chiral-restoration temperature with increasing B. PMID:23373911

Fukushima, Kenji; Hidaka, Yoshimasa

2013-01-18

310

Inhibition of vection by red.  

PubMed

We investigated the effects of colors on vection induction. Expanding optical flows during one's forward self-motion were simulated by moving dots. The dots and the background were painted in equiluminant red and green. Experiments 1 and 2 showed that vection was weaker when the background was red than when the background was green. In addition, Experiment 3 showed that vection was weaker when the moving dots were red than when the dots were green. Experiment 4 demonstrated that red dots on a red background induced very weak vection, as compared with green dots on a green background. In Experiments 5 and 6, we showed that the present results could not be explained by a luminance artifact. Furthermore, Experiment 7 showed that a moving red grating induced weaker vection than did a green one. We concluded that a red visual stimulus inhibits vection. PMID:20675807

Seno, Takeharu; Sunaga, Shoji; Ito, Hiroyuki

2010-08-01

311

Suramin inhibits EV71 infection.  

PubMed

Enterovirus-71 (EV71) is one of the major causative reagents for hand-foot-and-mouth disease. In particular, EV71 causes severe central nervous system infections and leads to numerous dead cases. Although several inactivated whole-virus vaccines have entered in clinical trials, no antiviral agent has been provided for clinical therapy. In the present work, we screened our compound library and identified that suramin, which has been clinically used to treat variable diseases, could inhibit EV71 proliferation with an IC50 value of 40 ?M. We further revealed that suramin could block the attachment of EV71 to host cells to regulate the early stage of EV71 infection, as well as affected other steps of EV71 life cycle. Our results are helpful to understand the mechanism for EV71 life cycle and provide a potential for the usage of an approved drug, suramin, as the antiviral against EV71 infection. PMID:24374150

Wang, Yaxin; Qing, Jie; Sun, Yuna; Rao, Zihe

2014-03-01

312

Corrosion inhibition using mercury intensifiers  

SciTech Connect

This patent describes an intensified corrosion inhibitor composition for inhibiting the corrosion of steel in the presence of an acidic medium. It comprises: an effective amount of an acid soluble mercury metal intensifier; and a corrosion inhibitor. This patent also describes a method of treating a subterranean well for enhancement of production within the well, comprising the steps of introducing and positioning within the well a high alloy stec surface exposable to a treatment fluid therewith; introducing into the well and contacting the surface with a treatment fluid comprising an acidic injection medium, an acid corrosion inhibitor, and an intensifier for deposition on or effective treatment contact with the surface, the intensifier comprising an acid soluble mercury metal site circulating the fluid into the well for contact with at least one production zone within the well.

Cizek, A.

1990-03-05

313

Tetrahydrocannabinol inhibition of macrophage nitric oxide production  

Microsoft Academic Search

?9-Tetrahydrocannabinol (THC) inhibited nitric oxide (NO.) production by mouse peritoneal macrophages activated by bacterial endotoxin lipopolysaccharide (LPS) and interferon-? (IFN)-?). Inhibition of NO. production was noted at THC concentrations as low as 0.5 ?g\\/mL, and was nearly total at 7 ?g\\/mL. Inhibition was greatest if THC was added 1–4 hr before induction of nitric oxide synthase (NOS) by LPS and

Ronald G. Coffey; Yoshimasa Yamamoto; Elizabeth Snella; Susan Pross

1996-01-01

314

Enantioselective inhibition of dichlorprop on catalase.  

PubMed

The enantioselectivity interaction of 2,4-dichlorprop (DCPP) and catalase were studied, and it was further evaluated with the presence of humus. Both of rac-DCPP and R-DCPP can inhibit the activity of catalase with the concentrations of 0.05-80 mg L(-1), the inhibitory type of rac-DCPP was uncompetitive, and of R-DCPP was complex. The presence of humic acid has changed the inhibitory ability of DCPP on catalase, the inhibition of rac-DCPP disappeared and the inhibition type of R-DCPP mainly became uncompetitive. These results suggest that inhibition of chiral DCPP on catalase is enantioselective. PMID:22961377

Ma, Yun; Jiang, Jihong; Xu, Chao; Lu, Xianting

2012-11-01

315

Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth.  

PubMed

Genomic aberrations of key regulators of the apoptotic pathway have hardly been identified in neuroblastoma. We detected high BCL2 mRNA and protein levels in the majority of neuroblastoma tumours by Affymetrix expression profiling and Tissue Micro Array analysis. This BCL2 mRNA expression is strongly elevated compared to normal tissues and other malignancies. Most neuroblastoma cell lines lack this high BCL2 expression. Only two neuroblastoma cell lines (KCNR and SJNB12) show BCL2 expression levels representative for neuroblastoma tumours. To validate BCL2 as a therapeutic target in neuroblastoma we employed lentivirally mediated shRNA. Silencing of BCL2 in KCNR and SJNB12 resulted in massive apoptosis, while cell lines with low BCL2 expression were insensitive. Identical results were obtained by treatment of the neuroblastoma cell lines with the small molecule BCL2 inhibitor ABT263, which is currently being clinically evaluated. Combination assays of ABT263 with most classical cytostatics showed strong synergistic responses. Subcutaneous xenografts of a neuroblastoma cell line with high BCL2 expression in NMRI nu/nu mice showed a strong response to ABT263. These findings establish BCL2 as a promising drug target in neuroblastoma and warrant further evaluation of ABT263 and other BCL2 inhibiting drugs. PMID:22366560

Lamers, Fieke; Schild, Linda; den Hartog, Ilona J M; Ebus, Marli E; Westerhout, Ellen M; Ora, Ingrid; Koster, Jan; Versteeg, Rogier; Caron, Huib N; Molenaar, Jan J

2012-11-01

316

Inhibition in Autism: Children with Autism Have Difficulty Inhibiting Irrelevant Distractors but Not Prepotent Responses  

ERIC Educational Resources Information Center

Resistance to distractor inhibition tasks have previously revealed impairments in children with autism. However, on the classic Stroop task and other prepotent response tasks, children with autism show intact inhibition. These data may reflect a distinction between prepotent response and resistance to distractor inhibition. The current study…

Adams, Nena C.; Jarrold, Christopher

2012-01-01

317

RNA III Inhibiting Peptide Inhibits In Vivo Biofilm Formation by Drug-Resistant Staphylococcus aureus  

Microsoft Academic Search

Staphylococcus aureus is a prevalent cause of bacterial infections associated with indwelling medical devices. RNA III inhibiting peptide (RIP) is known to inhibit S. aureus pathogenesis by disrupting quorum-sensing mechanisms. RIP was tested in the present study for its ability to inhibit S. aureus biofilm formation in a rat Dacron graft model. The activity of RIP was synergistic with those

Andrea Giacometti; Oscar Cirioni; Yael Gov; Roberto Ghiselli; Maria Simona Del Prete; Federico Mocchegiani; Vittorio Saba; Fiorenza Orlando; Giorgio Scalise; Naomi Balaban; Giorgio Dell' Acqua

2003-01-01

318

Preparing for selective inhibition within frontostriatal loops.  

PubMed

Action inhibition can globally prevent all motor output or selectively cancel specific actions during concurrent motor output. Here we examine the behavioral and neural basis of selective inhibition focusing on the role of preparation. In 18 healthy human participants we manipulated the extent to which they could prepare for selective inhibition by providing or withholding information on what actions might need to be stopped. We show that, on average, information improves both speed and selectivity of inhibition. Functional magnetic resonance imaging data show that preparation for selective inhibition engages the inferior frontal gyrus, supplementary motor area, and striatum. Examining interindividual differences, we find the benefit of proactive control to speed and selectivity of inhibition trade off against each other, such that an improvement in stopping speed leads to a deterioration of selectivity of inhibition, and vice versa. This trade-off is implemented through engagement of the dorsolateral prefrontal cortex and putamen. Our results suggest proactive selective inhibition is implemented within frontostriatal structures, and we provide evidence that a speed-selectivity trade-off might underlie a range of findings reported previously. PMID:24227719

Smittenaar, Peter; Guitart-Masip, Marc; Lutti, Antoine; Dolan, Raymond J

2013-11-13

319

A Qualitative Approach to Enzyme Inhibition  

ERIC Educational Resources Information Center

Most general biochemistry textbooks present enzyme inhibition by showing how the basic Michaelis-Menten parameters K[subscript m] and V[subscript max] are affected mathematically by a particular type of inhibitor. This approach, while mathematically rigorous, does not lend itself to understanding how inhibition patterns are used to determine the…

Waldrop, Grover L.

2009-01-01

320

Preparing for Selective Inhibition within Frontostriatal Loops  

PubMed Central

Action inhibition can globally prevent all motor output or selectively cancel specific actions during concurrent motor output. Here we examine the behavioral and neural basis of selective inhibition focusing on the role of preparation. In 18 healthy human participants we manipulated the extent to which they could prepare for selective inhibition by providing or withholding information on what actions might need to be stopped. We show that, on average, information improves both speed and selectivity of inhibition. Functional magnetic resonance imaging data show that preparation for selective inhibition engages the inferior frontal gyrus, supplementary motor area, and striatum. Examining interindividual differences, we find the benefit of proactive control to speed and selectivity of inhibition trade off against each other, such that an improvement in stopping speed leads to a deterioration of selectivity of inhibition, and vice versa. This trade-off is implemented through engagement of the dorsolateral prefrontal cortex and putamen. Our results suggest proactive selective inhibition is implemented within frontostriatal structures, and we provide evidence that a speed-selectivity trade-off might underlie a range of findings reported previously.

Guitart-Masip, Marc; Lutti, Antoine; Dolan, Raymond J.

2013-01-01

321

Central and peripheral inhibition of milk ejection  

Microsoft Academic Search

Milk ejection can be inhibited as a result of a lack of release of oxytocin (OT) from the pituitary gland, or, when OT is released normally, as a lack of effect on the mammary gland. The former can be overcome by administration of exogenous OT, whereas the latter cannot. Central inhibition of OT release can be caused by several factors,

Olga Wellnitz; Rupert M. Bruckmaier

2001-01-01

322

Substrate inhibition kinetics of phenol biodegradation  

SciTech Connect

Phenol biodegradation was studied in batch experiments using an acclimated inoculum and initial phenol concentrations ranging from 0.1 to 1.3 g/L. Phenol depletion an associated microbial growth were monitored over time to provide information that was used to estimate the kinetics of phenol biodegradation. Phenol inhibited biodegradation at high concentrations, and a generalized substrate inhibition model based on statistical thermodynamics was used to describe the dynamics of microbial growth in phenol. For experimental data obtained in this study, the generalized substrate inhibition model reduced to a form that is analogous to the Andrews equation, and the biokinetic parameters {micro}{sub max}, maximum specific growth; K{sub s}, saturation constant; and K{sub i}, inhibition constant were estimated as 0.251 h{sup {minus}1}, 0.011 g/L, and 0.348 g/L, respectively, using a nonlinear least squares technique. Given the wide variability in substrate inhibition models used to describe phenol biodegradation, an attempt was made to justify selection of particular model based on theoretical considerations. Phenol biodegradation data from nine previously published studies were used in the generalized substrate inhibition model to determine the appropriate form of the substrate inhibition model. In all nine cases, the generalized substrate inhibition model reduced to a form analogous to the Andrews equation suggesting the suitability of the Andrews equation to describe phenol biodegradation data.

Goudar, C.T.; Ganji, S.H.; Pujar, B.G.; Strevett, K.A.

2000-02-01

323

Inhibition of lipase activities by basic polysaccharide.  

PubMed

Basic polysaccharide strongly inhibited the hydrolysis of trioleoylglycerol (TO) emulsified with phosphatidylcholine and taurocholate by either pancreatic lipase or carboxylester lipase. DEAE-Sephadex dose-dependently inhibited the hydrolysis of TO by pancreatic lipase and carboxylester lipase; however, carboxymethyl-Sephadex and Sephadex G-50 did not inhibit the hydrolysis. Polydextrose (PD), a soluble polysaccharide, was a very weak inhibitor of pancreatic lipase. However, when a basic group, a DEAE group, was attached to PD, lipase inhibition by DEAE-PD was increased, and this was dependent on the substitution ratio of DEAE groups. The number of positive charges per PD molecule is important in lipase inhibition. Similar substitution effects were observed with other basic groups, such as piperidinoethyl and 3-triethylamino-2-hydroxypropyl. The natural basic polysaccharide, chitosan, also inhibited pancreatic lipase activity. Gel-filtration experiments suggested that DEAE-PD did not bind strongly to pancreatic lipase. The effect of DEAE-PD on TO hydrolysis by pancreatic lipase was studied using various emulsifiers: DEAE-PD (50 microg/ml) did not inhibit the hydrolysis of TO emulsified with arabic gum, phosphatidylserine, or phosphatidic acid. In vivo, oral administration of DEAE-PD to rats reduced the peak plasma triacylglycerol concentration and increased fecal lipid excretion. These results suggest that basic polysaccharide is able to suppress dietary fat absorption from the small intestine by inhibiting pancreatic lipase activity. PMID:17093292

Tsujita, Takahiro; Takaichi, Hiroe; Takaku, Takeshi; Sawai, Toshiya; Yoshida, Naoyuki; Hiraki, Jun

2007-02-01

324

Inhibition and Attention Deficit Hyperactivity Disorder  

Microsoft Academic Search

This paper updates the author's earlier hypothesis that Attention Deficit Hyperactivity Disorder (ADHD) reflects underactivity in Gray's Behavioral Inhibition System. Five areas of research are reviewed: (1) studies using the stop-signal task, (2) studies of errors of commission, (3) a study of inhibition indexed by eye movements, (4) a neuroimaging study of the corpus callosum, and (5) a study on

Herbert C. Quay

1997-01-01

325

Inhibition and Facilitation of Nucleic Acid Amplification  

Microsoft Academic Search

Factors that inhibit the amplification of nucleic acids by PCR are present with target DNAs from many sources. The inhib- itors generally act at one or more of three essential points in the reaction in the following ways: they interfere with the cell lysis necessary for extraction of DNA, they interfere by nucleic acid degradation or capture, and they inhibit

IAN G. WILSON

1997-01-01

326

Progress with proton pump inhibition.  

PubMed Central

The proton pump, a H+/K(+)-ATPase located on the secretory canalicular membrane of the parietal cell, forms the final pathway for gastric acid secretion. Omeprazole is concentrated in the secretory canaliculus, where it is converted to its active form, which binds covalently with the H+/K(+)-ATPase, thus inhibiting acid secretion arising from any stimulus. Meta-analysis has defined the primary determinants for peptic ulcer healing as the degree of acid suppression, the duration of suppression over 24 hours, and the length of treatment. The longer duration of acid suppression with omeprazole, particularly during the day, when food is ingested and H2-receptor antagonists are less effective, is reflected in the clinical superiority for symptom relief and ulcer healing and especially for the treatment of erosive esophagitis. Extensive clinical experience has proved omeprazole to be safe, and concerns over hypergastrinemia, ECL-cell hyperplasia, and carcinoid formation have not been substantiated in humans. Recent evidence has shown that omeprazole suppresses Helicobacter pylori and, in combination with antibiotics, can eradicate this organism in a substantial proportion of patients. This effect may result from enhancement of antibiotic bioavailability and optimizing host defense mechanisms.

Bell, N. J.; Hunt, R. H.

1992-01-01

327

STUDIES ON PNEUMOCOCCUS GROWTH INHIBITION  

PubMed Central

A simplified and compact agitator for growth inhibition tests with serum-leucocyte mixtures has been described. Several modifications have been made as well in the technique of the test, which have eliminated occasional irregularities that necessitated discarding the results of the individual experiment. Such irregularities were found to be due chiefly to injury of the pneumococci brought about by prolonged suspension in gelatin-Locke's solution which resulted in failure of the organisms to grow in the control serum-leucocyte tubes. This deterioration of the pneumococcus suspension may be greatly lessened or entirely prevented by the addition of a small quantity of a balanced phosphate mixture to the gelatin-Locke's solution. The use of small tubes made of Pyrex glass has also eliminated the former, not infrequent, occurrence of early hemolysis which was sometimes intense enough to disturb the results of the test. It has been found that washed rabbit leucocytes, suspended in their homologous serum, may be kept in the ice box for as long a period as 2 days without showing any apparent diminution of their functional activity in the serum-leucocyte test.

Robertson, Oswald H.; Woo, Shutai T.; Cheer, Sheo Nan

1924-01-01

328

Analgesia by inhibiting tetrahydrobiopterin synthesis.  

PubMed

Physiological control of the co-factor tetrahydrobiopterin (BH4) is tight in normal circumstances but levels increase pathologically in the injured somatosensory system. BH4 is an essential co-factor in the production of serotonin, dopamine, epinephrine, norepinephrine and nitric oxide. Excess BH4 levels cause pain, likely through excess production of one or more of these neurotransmitters or signaling molecules. The rate limiting step for BH4 production is GTP Cyclohydrolase 1 (GCH1). A human GCH1 gene haplotype exists that leads to less GCH1 transcription, translation, and therefore enzyme activity, following cellular stress. Carriers of this haplotype produce less BH4 and therefore feel less pain, especially following nerve injury where BH4 production is pathologically augmented. Sulfasalazine (SSZ) an FDA approved anti-inflammatory agent of unknown mechanism of action, has recently been shown to be a sepiapterin reductase (SPR) inhibitor. SPR is part of the BH4 synthesis cascade and is also upregulated by nerve injury. Inhibiting SPR will reduce BH4 levels and therefore should act as an analgesic. We propose SSZ as a novel anti-neuropathic pain medicine. PMID:22178186

Costigan, Michael; Latremoliere, Alban; Woolf, Clifford J

2012-02-01

329

Caffeine inhibits suicidal erythrocyte death.  

PubMed

Eryptosis, the suicidal death of erythrocytes, is characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine exposure at the erythrocyte surface. Eryptosis is triggered by several stress conditions including isotonic cell shrinkage (Cl(-) removal) and energy depletion (glucose removal). Both are effective through an increase in the cytosolic Ca(2+) concentration. Phosphatidylserine-exposing erythrocytes are cleared from circulating blood. Enhanced eryptosis thus leads to anemia. Accordingly, drugs interfering with eryptosis may prove useful in the treatment of anemia. The present study explored, whether caffeine interferes with eryptosis. Erythrocyte phosphatidylserine exposure was estimated from annexin V-binding, cell volume from forward scatter and cytosolic Ca(2+) activity from Fluo3 fluorescence. Under control conditions, eryptosis affected less than 5% of the erythrocytes and was not significantly modified by the presence of caffeine (50-500 microM). Glucose depletion (for 48 hours) significantly increased Fluo3 fluorescence and annexin V-binding and decreased forward scatter, effects partially reversed by caffeine (500 microM). Low Cl(-) solution (Cl(-) exchanged by gluconate for 48 hours) similarly increased annexin V-binding and decreased forward scatter, effects again reversed by caffeine (50-500 microM). In conclusion, caffeine inhibits Ca(2+) entry following glucose depletion and thus counteracts eryptosis during isotonic cell shrinkage and energy depletion. PMID:18769052

Floride, Elisa; Föller, Michael; Ritter, Markus; Lang, Florian

2008-01-01

330

Copolymer 1 inhibits experimental autoimmune uveoretinitis.  

PubMed

Copolymer 1 (Cop 1) inhibits experimental allergic encephalomyelitis induced by a variety of myelin proteins, but has been found ineffective so far in inhibiting other experimental autoimmune diseases such as diabetes or arthritis. Here, we report for the first time that Cop I inhibits the development of experimental autoimmune uveoretinitis, induced in mice by interphotoreceptor retinoid-binding protein (IRBP). Pooled data of three experiments showed that treatment with Cop 1, at 0.5 mg/mouse, reduced the disease severity by 53% ( p = 0.0002). Cop 1 treatment also inhibited the proliferation and the production of cytokines by lymph node cells in response to IRBP and moderately reduced the antibody response to this antigen. The possible mechanisms of EAU inhibition by Cop 1 are discussed. PMID:10696914

Zhang, M; Chan, C C; Vistica, B; Hung, V; Wiggert, B; Gery, I

2000-03-01

331

Inhibition Phenomenon of Staphylococci by Bacteriophages  

PubMed Central

In the study of the relationship between bacteriophage and strains of staphylococci showing inhibition, slight differences were observed in the ability to adsorb phage between staphylococci of full phage sensitivity and those showing inhibition by phage. Only a few plaques were produced by inhibitory phages adsorbed on strains showing inhibition, whereas almost all of the phages adsorbed on corresponding phage-propagating strains produced plaques. Some strains showing inhibition were converted to full sensitivity to certain phages by heat shock or trypaflavine treatment. Treated strains adsorbed inhibitory phages to almost the same degree as nontreated strains, but most of the phages adsorbed on treated strains produced plaques. Killing was not always observed in cells adsorbing inhibitory phages. These results suggest that inhibition is not due to low adsorption rates, but rather to plaque formation by a small number of the sensitive fraction of the population and overgrowth by nonlysed cells.

Chun, Doki; Chung, Jae Kyu

1970-01-01

332

Inhibition phenomenon of staphylococci by bacteriophages.  

PubMed

In the study of the relationship between bacteriophage and strains of staphylococci showing inhibition, slight differences were observed in the ability to adsorb phage between staphylococci of full phage sensitivity and those showing inhibition by phage. Only a few plaques were produced by inhibitory phages adsorbed on strains showing inhibition, whereas almost all of the phages adsorbed on corresponding phage-propagating strains produced plaques. Some strains showing inhibition were converted to full sensitivity to certain phages by heat shock or trypaflavine treatment. Treated strains adsorbed inhibitory phages to almost the same degree as nontreated strains, but most of the phages adsorbed on treated strains produced plaques. Killing was not always observed in cells adsorbing inhibitory phages. These results suggest that inhibition is not due to low adsorption rates, but rather to plaque formation by a small number of the sensitive fraction of the population and overgrowth by nonlysed cells. PMID:4246881

Chun, D; Chung, J K

1970-06-01

333

Role of mutual inhibition in binocular rivalry  

PubMed Central

Binocular rivalry is a phenomenon that occurs when a different image is presented to each eye. The observer generally perceives just one image at a time, with perceptual switches occurring every few seconds. A natural assumption is that this perceptual mutual exclusivity is achieved via mutual inhibition between populations of neurons that encode for either percept. Theoretical models that incorporate mutual inhibition have been largely successful at capturing experimental features of rivalry, including Levelt's propositions, which characterize perceptual dominance durations as a function of image contrasts. However, basic mutual inhibition models do not fully comply with Levelt's fourth proposition, which states that percepts alternate faster as the stimulus contrasts to both eyes are increased simultaneously. This theory-experiment discrepancy has been taken as evidence against the role of mutual inhibition for binocular rivalry. Here, we show how various biophysically plausible modifications to mutual inhibition models can resolve this problem.

Seely, Jeffrey

2011-01-01

334

Lysophospholipase inhibition by organophosphorus toxicants.  

PubMed

Lysophospholipases (LysoPLAs) are a large family of enzymes for removing lysophospholipids from cell membranes. Potent inhibitors are needed to define the importance of LysoPLAs as targets for toxicants and potential therapeutics. This study considers organophosphorus (OP) inhibitors with emphasis on mouse brain total LysoPLA activity relative to the mipafox-sensitive neuropathy target esterase (NTE)-LysoPLA recently established as 17% of the total activity and important in the action of OP delayed toxicants. The most potent inhibitors of total LysoPLA in mouse brain are isopropyl dodecylphosphonofluoridate (also for LysoPLA of Vibrio bacteria), ethyl octylphosphonofluoridate (EOPF), and two alkyl-benzodioxaphosphorin 2-oxides (BDPOs)[(S)-octyl and dodecyl] (IC50 2-8 nM). OP inhibitors acting in vitro and in vivo differentiate a more sensitive portion but not a distinct NTE-LysoPLA compared with total LysoPLA activity. For 10 active inhibitors, NTE-LysoPLA is 17-fold more sensitive than total LysoPLA, but structure-activity comparisons give a good correlation (r(2) = 0.94) of IC50 values, suggesting active site structural similarity or identity. In mice 4 h after intraperitoneal treatment with discriminating doses, EOPF, tribufos (a plant defoliant), and dodecanesulfonyl fluoride inhibit 41-57% of the total brain LysoPLA and 85-99% of the NTE-LysoPLA activity. Total LysoPLA as well as NTE-LysoPLA is decreased in activity in Nte(+/-)-haploinsufficient mice compared to their Nte(+/+) littermates. The lysolecithin level of spinal cord but not brain is elevated significantly following EOPF treatment (3 mg/kg), thereby focusing attention on localized rather than general alterations in lysophospholipid metabolism in OP-induced hyperactivity and toxicity. PMID:15094302

Quistad, Gary B; Casida, John E

2004-05-01

335

Inhibition of Clostridium botulinum by 5-Nitrothiazoles  

PubMed Central

A number of 5-nitrothiazoles with various substituents in the 2-position were tested for inhibition of Clostridium botulinum in a culture medium. Thiazole itself or 2-bromo- or 2-methylthiazole at 30 ?g/ml did not inhibit the organism. An amino group in the 2-position of thiazole inhibited at 10 ?g/ml. Substitution of a nitro group in the 5-position of 2-aminothiazole increased the inhibitory level to 0.12 ?g/ml; acetyl-, propionyl-, or butyroyl-2-amino-5-nitrothiazole inhibited at 0.04 ?g/ml. Benzoyl-2-amino-5-nitrothiazole inhibited at 0.16 ?g/ml; this increased to 0.01 ?g/ml when the benzoyl group carried a nitro group in the m- or p-position; a nitro group in the o-position, on the other hand, inhibited at 0.04 ?g/ml. Unsaturated aliphatic acyls decreased inhibition. The greatest activity was exhibited by 2-nonanoyl- and 2-lauroylamides, with minimum inhibitory concentrations of 0.005 and 0.0025 ?g/ml, respectively.

Dymicky, M.; Huhtanen, C. N.; Wasserman, A. E.

1977-01-01

336

Tetherin inhibits prototypic foamy virus release  

PubMed Central

Background Tetherin (also known as BST-2, CD317, and HM1.24) is an interferon- induced protein that blocks the release of a variety of enveloped viruses, such as retroviruses, filoviruses and herpesviruses. However, the relationship between tetherin and foamy viruses has not been clearly demonstrated. Results In this study, we found that tetherin of human, simian, bovine or canine origin inhibits the production of infectious prototypic foamy virus (PFV). The inhibition of PFV by human tetherin is counteracted by human immunodeficiency virus type 1 (HIV-1) Vpu. Furthermore, we generated human tetherin transmembrane domain deletion mutant (delTM), glycosyl phosphatidylinositol (GPI) anchor deletion mutant (delGPI), and dimerization and glycosylation deficient mutants. Compared with wild type tetherin, the delTM and delGPI mutants only moderately inhibited PFV production. In contrast, the dimerization and glycosylation deficient mutants inhibit PFV production as efficiently as the wild type tetherin. Conclusions These results demonstrate that tetherin inhibits the release and infectivity of PFV, and this inhibition is antagonized by HIV-1 Vpu. Both the transmembrane domain and the GPI anchor of tetherin are important for the inhibition of PFV, whereas the dimerization and the glycosylation of tetherin are dispensable.

2011-01-01

337

Regulation of Spatial Selectivity by Crossover Inhibition  

PubMed Central

Signals throughout the nervous system diverge into parallel excitatory and inhibitory pathways that later converge on downstream neurons to control their spike output. Converging excitatory and inhibitory synaptic inputs can exhibit a variety of temporal relationships. A common motif is feedforward inhibition, in which an increase (decrease) in excitatory input precedes a corresponding increase (decrease) in inhibitory input. The delay of inhibitory input relative to excitatory input originates from an extra synapse in the circuit shaping inhibitory input. Another common motif is push-pull or “crossover” inhibition, in which increases (decreases) in excitatory input occur together with decreases (increases) in inhibitory input. Primate On midget ganglion cells receive primarily feedforward inhibition and On parasol cells receive primarily crossover inhibition; this difference provides an opportunity to study how each motif shapes the light responses of cell types that play a key role in visual perception. For full-field stimuli, feedforward inhibition abbreviated and attenuated responses of On midget cells, while crossover inhibition, though plentiful, had surprisingly little impact on the responses of On parasol cells. Spatially structured stimuli, however, could cause excitatory and inhibitory inputs to On parasol cells to increase together, adopting a temporal relation very much like that for feedforward inhibition. In this case, inhibitory inputs substantially abbreviated a cell’s spike output. Thus inhibitory input shapes the temporal stimulus selectivity of both midget and parasol ganglion cells, but its impact on responses of parasol cells depends strongly on the spatial structure of the light inputs.

Cafaro, Jon; Rieke, Fred

2013-01-01

338

Connexin-43 hemichannels opened by metabolic inhibition.  

PubMed

The cause of altered ionic homeostasis leading to cell death during ischemia and metabolic inhibition is unclear. Hemichannels, which are precursors to gap junctions, are nonselective ion channels that are permeable to molecules of less than Mr 1000. We show that hemichannels open upon exposure to calcium-free solutions when they are either heterologously overexpressed in HEK293 cells or endogenously expressed in cardiac ventricular myocytes. In the presence of normal extracellular calcium, hemichannels open during metabolic inhibition. During ischemia and other forms of metabolic inhibition, activation of relatively few hemichannels will seriously compromise the cell's ability to maintain ionic homeostasis, which is an essential step promoting cell death. PMID:9867835

John, S A; Kondo, R; Wang, S Y; Goldhaber, J I; Weiss, J N

1999-01-01

339

Acetylcholinesterase inhibition by pitofenone: a spasmolytic compound.  

PubMed

Pitofenone, a spasmolytic compound, inhibited the acetylcholinesterase activity from bovine erythrocytes and from electric eel. It is a potent inhibitor of this enzyme from the two sources, with Ki values of 36 and 45 microM, respectively. Of the five compounds structurally related to pitofenone, only those containing a piperidine moiety show acetylcholinesterase inhibition. All these inhibitions are reversible, linear, and noncompetitive in nature. A qualitative correlation between the anticholinesterase and the corresponding antimuscarinic activity for some of these compounds was apparent. Good separation of these two effects would be a desirable feature for newer muscarinic antagonists. PMID:1777122

Punekar, N S; Kulkarni, A V

1991-12-01

340

Inhibition of Threonine Dehydratase Is Herbicidal.  

PubMed Central

Threonine dehydratase, the first enzyme in isoleucine biosynthesis, catalyzes deamination and dehydration of threonine to produce 2-ketobutyrate and ammonia. An antimetabolite, 2-(1-cyclohexen-3(R)-yl)-S-glycine (CHG), inhibits the plant enzyme. CHG inhibits the growth of Black Mexican Sweet corn (Zea mays) cells and of Arabidopsis thaliana plants. The herbicidal effects of CHG can be reversed by 2-ketobutyrate, other intermediates of isoleucine biosynthesis, and by isoleucine itself. These results suggest that the herbicidal effects observed with CHG are a consequence of inhibition of threonine dehydratase. The enzyme could be a potential target site for an herbicide screening program.

Szamosi, I. T.; Shaner, D. L.; Singh, B. K.

1994-01-01

341

Methods for Inhibiting Cutaneous Inflammation and Hyperpigmentation.  

National Technical Information Service (NTIS)

This invention provides a method of preventing or treating in a subject contact dermatitis which comprises administering to the subject an amount of a compound capable of inhibiting the stem cell factor signaling pathway effective to prevent or treat cont...

B. J. Longley

2005-01-01

342

Dissolution Inhibition in Positive Novolak Resists.  

National Technical Information Service (NTIS)

The inhibition of novolak dissolution by various light-sensitive compounds is the basis of the most important imaging materials of the semiconductor device industry. A formidable amount of empirical information on these systems is available in the literat...

K. J. Wynne

1992-01-01

343

EEG Correlates of Reinforced Behavioral Inhibition.  

National Technical Information Service (NTIS)

Three cats, bearing chronically implanted cortical electrodes, were trained in an instrumental vigilance situation to inhibit licking a foodcup for 15 - 25 sec prior to the onset of a stimulus signalling availability of a milk reward. Electrocortical acti...

N. Weinberger L. Yeudall D. B. Lindsley

1968-01-01

344

Neurophysiology of Dystonia: The Role of Inhibition  

PubMed Central

The pathophysiology of dystonia has been best studied in patients with focal hand dystonia. A loss of inhibitory function has been demonstrated at spinal, brainstem and cortical levels. Many cortical circuits seem to be involved. One consequence of the loss of inhibition is a failure of surround inhibition, and this appears to directly lead to overflow and unwanted muscle spasms. There are mild sensory abnormalities and deficits in sensorimotor integration; these also might be explained by a loss of inhibition. Increasing inhibition may be therapeutic. A possible hypothesis is that there is a genetic loss of inhibitory interneurons in dystonia and that this deficit is a substrate on which other factors can act to produce dystonia.

Hallett, Mark

2010-01-01

345

Methods and Compositions to Inhibit Lipid Oxidation.  

National Technical Information Service (NTIS)

The invention relates to methods and compositions for the inhibition of lipid oxidation in food products susceptible to lipid oxidation. The invention provides natural lipophilic antioxidant compositions extracted from fruit used for use in a variety of p...

M. P. Richards C. H. Lee J. D. Reed

2004-01-01

346

Inhibition of human intestinal ?-glucosidases by calystegines.  

PubMed

Calystegines are polyhydroxylated nortropane alkaloids found in Convolvulaceae, Solanaceae, and other plant families. These plants produce common fruits and vegetables. The calystegine structures resemble sugars and suggest interaction with enzymes of carbohydrate metabolism. Maltase and sucrase are ?-glucosidases contributing to human carbohydrate degradation in the small intestine. Inhibition of these enzymes by orally administered drugs is one option for treatment of diabetes mellitus type 2. In this study, inhibition of maltase and sucrase by calystegines A3 and B2 purified from potatoes was investigated. In silico docking studies confirmed binding of both calystegines to the active sites of the enzymes. Calystegine A3 showed low in vitro enzyme inhibition; calystegine B2 inhibited mainly sucrose activity. Both compounds were not transported by Caco-2 cells indicating low systemic availability. Vegetables rich in calystegine B2 should be further investigated as possible components of a diet preventing a steep increase in blood glucose after a carbohydrate-rich meal. PMID:23697377

Jockovi?, Nebojša; Fischer, Wiebke; Brandsch, Matthias; Brandt, Wolfgang; Dräger, Birgit

2013-06-12

347

Method of Cell Growth Inhibition with Agnoprotein.  

National Technical Information Service (NTIS)

The growth of normal and abnormally proliferating cells can be inhibited by the introduction of agnoprotein, or biologically active fragments or derivatives of agnoprotein, into the cell in the absence of any other polyoma virus protein or viral replicati...

K. Khalili

2003-01-01

348

Quinoline hydrodenitrogenation kinetics and reaction inhibition  

Microsoft Academic Search

Quinoline hydrodenitrogenation kinetics and reaction inhibition are studied in a unique high-pressure liquid-phase flow microreactor and in a batch autoclave at 350°C and 34 atm over presulfided commercial nickel-molybdenum\\/..gamma..-alumina catalysts. Hydrodenitrogenation of quinoline and its methyl-substituted derivatives involved hydrogenation of the nitrogen-containing ring followed by carbon-nitrogen bond scission. Methyl substitution had only secondary effects on the hydrodenitrogenation kinetics. Quinoline inhibited

Bhinde

1979-01-01

349

Corrosion inhibition of steel by bacteria  

SciTech Connect

Mild steel was exposed to Pseudomonas sp. S9 or Serratia marcescens in synthetic seawater. An increase in corrosion resistance over that i natural seawater was monitored by electrochemical techniques. Biological analyses were performed to characterize the system. The inhibition effect also was observed when mild steel was coated with bacteria and then immersed in synthetic seawater. When specimens coated with bacteria were transferred to a natural seawater flow system, the inhibition effect disappeared during the first 2 weeks.

Hernandez, G.; Kucera, V.; Thierry, D.; Pedersen, A. (Swedish Corrosion Inst., Stockholm (Sweden)); Hermansson, M. (Univ. of Gothenburg (Sweden). Dept. of General and Marine Microbiology)

1994-08-01

350

CANNABINOIDS INHIBIT CALCIUM UPTAKE BY BRAIN SYNAPTOSOMES  

Microsoft Academic Search

The depolarization-dependent uptake of calcium was studied in synaptosomes isolated from whole mouse brain and regions of rat brain. In vitro addition of A'-tetrahydrocannabinol (THC) inhibited calcium uptake. The brainstem was most sensitive to this effect-a lo-@ M THC concentration was sufficient to inhibit uptake by synaptosomes from this region. Cannabidiol produced effects similar to those of THC. Cannabinol was

R. ADRON HARRIS; JAMES A. STOKES

351

Current Understanding of Mullerian-Inhibiting Substance  

Microsoft Academic Search

\\u000a In the ovary, Mullerian-Inhibiting Substance (MIS) is produced by the granulosa cells of early developing follicles and inhibits\\u000a the transition from the primordial to the primary follicular stage. MIS levels can be measured in serum and have been shown\\u000a to be proportional to the number of small antral follicles. In women, serum MIS levels decrease with age and are undetectable

Antonio La Marca; Giovanna Sighinolfi; Annibale Volpe

352

Inhibited solid propellant composition containing beryllium hydride  

NASA Technical Reports Server (NTRS)

An object of this invention is to provide a composition of beryllium hydride and carboxy-terminated polybutadiene which is stable. Another object of this invention is to provide a method for inhibiting the reactivity of beryllium hydride toward carboxy-terminated polybutadiene. It was found that a small amount of lecithin inhibits the reaction of beryllium hydride with the acid groups in carboxy terminated polybutadiene.

Thompson, W. W. (inventor)

1978-01-01

353

Matrix metalloproteinase inhibition by green tea catechins  

Microsoft Academic Search

We have investigated the effects of different biologically active components from natural products, including green tea polyphenols (GTP), resveratrol, genistein and organosulfur compounds from garlic, on matrix metalloproteinase (MMP)-2, MMP-9 and MMP-12 activities. GTP caused the strongest inhibition of the three enzymes, as measured by fluorescence assays using gelatin or elastin as substrates. The inhibition of MMP-2 and MMP-9 caused

Michel Demeule; Mathieu Brossard; Martine Pagé; Denis Gingras; Richard Béliveau

2000-01-01

354

Tryptophan Inhibits Biofilm Formation by Pseudomonas aeruginosa  

PubMed Central

Biofilm formation by Pseudomonas aeruginosa has been implicated in the pathology of chronic wounds. Both the d and l isoforms of tryptophan inhibited P. aeruginosa biofilm formation on tissue culture plates, with an equimolar ratio of d and l isoforms producing the greatest inhibitory effect. Addition of d-/l-tryptophan to existing biofilms inhibited further biofilm growth and caused partial biofilm disassembly. Tryptophan significantly increased swimming motility, which may be responsible in part for diminished biofilm formation by P. aeruginosa.

Brandenburg, Kenneth S.; Rodriguez, Karien J.; McAnulty, Jonathan F.; Murphy, Christopher J.; Abbott, Nicholas L.; Schurr, Michael J.

2013-01-01

355

Solar Urticaria Inhibited by Visible Light  

Microsoft Academic Search

A 25-year-old man with solar urticaria is described. The action spectrum ranged from 400 to 500 nm. An inhibition spectrum was found to be in the visible light range above 660 nm. Simultaneous or alternate exposure to ‘blue-violet light’ and ‘red light’ mostly inhibited weal formation. The urticarial reaction was not blocked by local injection of antihistamines and not prevented

Wakio Torinuki; Norio Kumai; Takashi Miura

1983-01-01

356

Human milk glycoconjugates that inhibit pathogens.  

PubMed

Breast-fed infants have lower incidence of diarrhea, respiratory disease, and otitis media. The protection by human milk has long been attributed to the presence of secretory IgA. However, human milk contains large numbers and amounts of complex carbohydrates, including glycoproteins, glycolipids, glycosaminoglycans, mucins, and especially oligosaccharides. The oligosaccharides comprise the third most abundant solid constituent of human milk, and contain a myriad of structures. Complex carbohydrate moieties of glycoconjugates and oligosaccharides are synthesized by the many glycosyltransferases in the mammary gland; those with homology to cell surface glycoconjugate pathogen receptors may inhibit pathogen binding, thereby protecting the nursing infant. Several examples are reviewed: A fucosyloligosaccharide inhibits the diarrheagenic effect of stable toxin of Escherichia coli. A different fucosyloligosaccharide inhibits infection by Campylobacter jejuni. Binding of Streptococcus pneumoniae and of enteropathogenic E. coli to their respective receptors is inhibited by human milk oligosaccharides. The 46-kD glycoprotein, lactadherin, inhibits rotavirus binding and infectivity. Low levels of lactadherin in human milk are associated with a higher incidence of symptomatic rotavirus in breast-fed infants. A mannosylated glycopeptide inhibits binding by enterohemorrhagic E. coli. A glycosaminoglycan inhibits binding of gp120 to CD4, the first step in HIV infection. Human milk mucin inhibits binding by S-fimbriated E. coli. The ganglioside, GM1, reduces diarrhea production by cholera toxin and labile toxin of E. coli. The neutral glycosphingolipid, Gb3, binds to Shigatoxin. Thus, many complex carbohydrates of human milk may be novel antipathogenic agents, and the milk glycoconjugates and oligosaccharides may be a major source of protection for breastfeeding infants. PMID:9927761

Newburg, D S

1999-02-01

357

Inhibition of Heme Peroxidases by Melamine  

PubMed Central

In 2008 melamine-contaminated infant formula and dairy products in China led to over 50,000 hospitalizations of children due to renal injuries. In North America during 2007 and in Asia during 2004, melamine-contaminated pet food products resulted in numerous pet deaths due to renal failure. Animal studies have confirmed the potent renal toxicity of melamine combined with cyanuric acid. We showed previously that the solubility of melamine cyanurate is low at physiologic pH and ionic strength, provoking us to speculate how toxic levels of these compounds could be transported through the circulation without crystallizing until passing into the renal filtrate. We hypothesized that melamine might be sequestered by heme proteins, which could interfere with heme enzyme activity. Four heme peroxidase enzymes were selected for study: horseradish peroxidase (HRP), lactoperoxidase (LPO), and cyclooxygenase-1 and -2 (COX-1 and -2). Melamine exhibited noncompetitive inhibition of HRP (Ki??9.5 ± 0.7?mM), and LPO showed a mixed model of inhibition (Ki??14.5 ± 4.7?mM). The inhibition of HRP and LPO was confirmed using a chemiluminescent peroxidase assay. Melamine also exhibited COX-1 inhibition, but inhibition of COX-2 was not detected. Thus, our results demonstrate that melamine inhibits the activity of three heme peroxidases.

Vanachayangkul, Pattaraporn; Tolleson, William H.

2012-01-01

358

Activin inhibits telomerase activity in cancer  

SciTech Connect

Activin is a pleiotropic cytokine with broad tissue distributions. Recent studies demonstrate that activin-A inhibits cancer cell proliferation with unknown mechanisms. In this report, we demonstrate that recombinant activin-A induces telomerase inhibition in cancer cells. In breast and cervical cancer cells, activin-A resulted in telomerase activity in a concentration-dependent manner. Significant inhibition was observed at 10 ng/ml of activin-A, with a near complete inhibition at 80 ng/ml. Consistently, activin-A induced repression of the telomerase reverse transcriptase (hTERT) gene, with the hTERT gene to be suppressed by 60-80% within 24 h. In addition, activin-A induced a concomitant increase in Smad3 signaling and decrease of the hTERT gene promoter activity in a concentration-dependent fashion. These data suggest that activin-A triggered telomerase inhibition by down-regulating hTERT gene expression is involved in activin-A-induced inhibition of cancer cell proliferation.

Katik, Indzi; Mackenzie-Kludas, Charley; Nicholls, Craig [Department of Immunology, Monash University, Melbourne (Australia)] [Department of Immunology, Monash University, Melbourne (Australia); Jiang, Fang-Xu [Centre for Diabetes Research, Western Australian Institute for Medical Research and The University of Western Australia, Perth (Australia)] [Centre for Diabetes Research, Western Australian Institute for Medical Research and The University of Western Australia, Perth (Australia); Zhou, Shufeng [School of Health Sciences, RMIT University, Melbourne (Australia)] [School of Health Sciences, RMIT University, Melbourne (Australia); Li, He [Department of Immunology, Monash University, Melbourne (Australia)] [Department of Immunology, Monash University, Melbourne (Australia); Liu, Jun-Ping, E-mail: jun-ping.liu@med.monash.edu.au [Department of Immunology, Monash University, Melbourne (Australia)] [Department of Immunology, Monash University, Melbourne (Australia)

2009-11-27

359

Dipyridamole Reversibly Inhibits Mengovirus RNA Replication  

PubMed Central

Dipyridamole is an effective inhibitor of cardiovirus growth in cell culture. The effects of dipyridamole on mengovirus replication in vivo and in vitro were examined in the hope the drug could be used as an experimental analog of the poliovirus inhibitor guanidine. Guanidine selectively inhibits poliovirus RNA synthesis but not RNA translation, and as such, has been a valuable research tool. Although guanidine does not inhibit cardiovirus infection, a compound with similar discriminatory characteristics would be experimentally useful for parallel work with these viruses. We found that mengovirus plaque formation in HeLa or L cells was inhibited nearly 100% by the presence of 80 ?M dipyridamole. The inhibitory effect was reversible and targeted an early step in the replication cycle. Studies with luciferase-expressing mengovirus replicons showed that viral protein synthesis was unaffected by dipyridamole, and rather, RNA synthesis was the step targeted by the drug. This assessment was confirmed by direct analyses of viral translation and RNA synthesis activities in a Krebs-2-derived in vitro system that supported complete, infectious cardiovirus replication. In Krebs extracts, dipyridamole specifically inhibited viral RNA synthesis to more than 95%, with no concomitant effect on viral protein translation or polyprotein processing. The observed inhibition reversibly affected an early step in both minus-strand and plus-strand RNA synthesis, although inhibition of plus-strand synthesis was more profound than that of minus-strand synthesis. We conclude that dipyridamole is a potent experimental tool that readily distinguishes between cardiovirus translation and RNA replication functions.

Fata-Hartley, Cori L.; Palmenberg, Ann C.

2005-01-01

360

Piperine, a dietary phytochemical, inhibits angiogenesis  

PubMed Central

Angiogenesis plays an important role in tumor progression. Piperine, a major alkaloid constituent of black pepper, has diverse physiological actions including killing of cancer cells; however, the effect of piperine on angiogenesis is not known. Here we show that piperine inhibited the proliferation and G1/S transition of human umbilical vein endothelial cells (HUVECs) without causing cell death. Piperine also inhibited HUVEC migration and tubule formation in vitro, as well as collagen-induced angiogenic activity by rat aorta explants and breast cancer cell-induced angiogenesis in chick embryos. Although piperine binds to and activates the cation channel transient receptor potential vanilloid 1 (TRPV1), its effects on endothelial cells did not involve TRPV1 since the antiproliferative effect of piperine was not affected by TRPV1-selective antagonists, nor did HUVECs express detectable TRPV1 mRNA. Importantly, piperine inhibited phosphorylation of Ser 473 and Thr 308 residues of Akt (protein kinase B), which is a key regulator of endothelial cell function and angiogenesis. Consistent with Akt inhibition as the basis of piperine’s action on HUVECs, inhibition of the phosphoinositide-3 kinase/Akt signaling pathway with LY-294002 also inhibited HUVEC proliferation and collagen-induced angiogenesis. Taken together, these data support the further investigation of piperine as an angiogenesis inhibitor for use in cancer treatment.

Doucette, Carolyn D.; Hilchie, Ashley L.; Liwski, Robert; Hoskin, David W.

2012-01-01

361

Grape seed extracts inhibit platelet aggregation by inhibiting protein tyrosine phosphatase.  

PubMed

Platelets play an important role in various thrombotic diseases, including myocardial infarction. Because red wine consumption is inversely associated with death due to ischemic heart diseases, the effects of grape components on platelet function have been extensively investigated. Grape seed extracts (GSEs) reportedly inhibit platelet aggregation; however, the underlying mechanism has not been elucidated. We discovered that GSEs inhibit platelet aggregation induced by collagen and thrombin-receptor agonist peptide and increase basal levels of tyrosine phosphorylation, which was also observed in the presence of a protein tyrosine phosphatase (PTP) inhibitor. An in vitro phosphatase assay indicated that GSE dose dependently inhibited PTP-1B and Src homology 2 domain-containing phosphatase-1 activity, which positively regulates platelet aggregation. We propose that GSEs inhibit platelet aggregation by inhibiting tyrosine phosphatase activity. Moreover, we showed that GSE ingestion inhibited platelet aggregation in mice without enhancing tail bleeding, implying that GSE supplementation might be beneficial to prevention of thrombotic diseases. PMID:23478570

Jin, Joseph Wuxun; Inoue, Osamu; Suzuki-Inoue, Katsue; Nishikawa, Go; Kawakami, Yoshinori; Hisamoto, Masashi; Okuda, Tohru; Ozaki, Yukio

2014-04-01

362

Clearance of generalized papular umbilicated granuloma annulare in a child with bath PUVA therapy.  

PubMed

Papular umbilicated granuloma annulare is usually localized and is relatively asymptomatic. The generalized condition is rarely reported in children and tends to respond less well to treatment than the localized form. We report the first instance of generalized papular umbilicated granuloma annulare in an 11-year-old boy, which cleared following bath psoralen plus ultraviolet A therapy. PMID:16445418

Batchelor, Rebecca; Clark, Sheila

2006-01-01

363

Relationships between inhibition constants, inhibitor concentrations for 50% inhibition and types of inhibition: new ways of analysing data.  

PubMed Central

The concentration of an inhibitor that decreases the rate of an enzyme-catalysed reaction by 50%, symbolized i(0.5), is often used in pharmacological studies to characterize inhibitors. It can be estimated from the common inhibition plots used in biochemistry by means of the fact that the extrapolated inhibitor concentration at which the rate becomes infinite is equal to -i(0.5). This method is, in principle, more accurate than comparing the rates at various different inhibitor concentrations, and inferring the value of i(0.5) by interpolation. Its reciprocal, 1/i(0.5), is linearly dependent on v(0)/V, the uninhibited rate divided by the limiting rate, and the extrapolated value of v(0)/V at which 1/i(0.5) is zero allows the type of inhibition to be characterized: this value is 1 if the inhibition is strictly competitive; greater than 1 if the inhibition is mixed with a predominantly competitive component; infinite (i.e. 1/i(0.5) does not vary with v(0)/V) if the inhibition is pure non-competitive (i.e. mixed with competitive and uncompetitive components equal); negative if the inhibition is mixed with a predominantly uncompetitive component; and zero if it is strictly uncompetitive. The type of analysis proposed has been tested experimentally by examining inhibition of lactate dehydrogenase by oxalate (an uncompetitive inhibitor with respect to pyruvate) and oxamate (a competitive inhibitor with respect to pyruvate), and of cytosolic malate dehydrogenase by hydroxymalonate (a mixed inhibitor with respect to oxaloacetate). In all cases there is excellent agreement between theory and experiment.

Cortes, A; Cascante, M; Cardenas, M L; Cornish-Bowden, A

2001-01-01

364

Cis-inhibition of Notch by endogenous Delta biases the outcome of lateral inhibition  

PubMed Central

Summary Lateral inhibition mediated by Delta/Notch (Dl/N) signaling is used throughout development to limit the number of initially equivalent cells that adopt a particular fate [1], [2] and [3]. While adjacent cells express both Dl ligand and N receptor, signaling between them ultimately occurs in only one direction. Classically this has been explained entirely by feedback: activated N can downregulate Dl, amplifying even slight asymmetries in the Dl or N activities of adjacent cells [1], [2], [3], [4] and [5]. Here, however, we present an example of lateral inhibition in which unidirectional signaling depends instead on Dl’s ability to inhibit N within the same cell, a phenomenon known as “cis-inhibition” [6], [7], [8], [9], [10] and [11]. By genetically manipulating individual R1/R6/R7 photoreceptor precursors in the Drosophila eye, we show that in the absence of Dl-mediated cis-inhibition, the normal direction of lateral signaling is reversed. Based on our finding that Dl in R1/R6s requires endocytosis to trans-activate but not to cis-inhibit N, we reexamine previously published data from other examples of lateral inhibition. We conclude that cis-inhibition generally influences the direction of Dl/N signaling and should therefore be included in standard models of lateral inhibition.

Miller, Adam C.; Lyons, Eric L.; Herman, Tory G.

2009-01-01

365

Inhibition of Shigella flexneri by the normal intestinal flora. I. Mechanisms of inhibition by Klebsiella.  

PubMed

Growth curves were plotted for Shigella flexneri and Klebsiella (Aerobacter aerogenes) multiplying in pure and mixed culture. In mixed culture, Klebsiella inhibited Shigella. Exponential growth was interrupted and Shigella entered into a logarithmic death phase. An analysis of cultures at the time inhibition occurred revealed that formic and acetic acids produced by Klebsiella were responsible for the inhibition of Shigella. Klebsiella strongly reduced the culture medium. The volatile fatty acids, operating under reduced conditions, exerted a bactericidal effect on Shigella. Results are discussed with reference to the possible role of volatile fatty acids as factors responsible for Shigella inhibition in vivo. PMID:6032512

Hentges, D J

1967-04-01

366

Increased in vivo inhibition of gene expression by combining RNA interference and U1 inhibition  

PubMed Central

Inhibition of gene expression can be achieved with RNA interference (RNAi) or U1 small nuclear RNA—snRNA—interference (U1i). U1i is based on U1 inhibitors (U1in), U1 snRNA molecules modified to inhibit polyadenylation of a target pre-mRNA. In culture, we have shown that the combination of RNAi and U1i results in stronger inhibition of reporter or endogenous genes than that obtained using either of the techniques alone. We have now used these techniques to inhibit gene expression in mice. We show that U1ins can induce strong inhibition of the expression of target genes in vivo. Furthermore, combining U1i and RNAi results in synergistic inhibitions also in mice. This is shown for the inhibition of hepatitis B virus (HBV) sequences or endogenous Notch1. Surprisingly, inhibition obtained by combining a U1in and a RNAi mediator is higher than that obtained by combining two U1ins or two RNAi mediators. Our results suggest that RNAi and U1i cooperate by unknown mechanisms to result in synergistic inhibitions. Analysis of toxicity and specificity indicates that expression of U1i inhibitors is safe. Therefore, we believe that the combination of RNAi and U1i will be a good option to block damaging endogenous genes, HBV and other infectious agents in vivo.

Blazquez, Lorea; Gonzalez-Rojas, Sandra Jovanna; Abad, Amaya; Razquin, Nerea; Abad, Xabier; Fortes, Puri

2012-01-01

367

Chemical inhibition of nitrification in activated sludge.  

PubMed

Conventional aerobic nitrification was adversely affected by single pulse inputs of six different classes of industrially relevant chemical toxins: an electrophilic solvent (1-chloro-2,4-dinitrobenzene, CDNB), a heavy metal (cadmium), a hydrophobic chemical (1-octanol), an uncoupling agent (2,4-dinitrophenol, DNP), alkaline pH, and cyanide in its weak metal complexed form. The concentrations of each chemical source that caused 1 5, 25, and 50% respiratory inhibition of a nitrifying mixed liquor during a short-term assay were used to shock sequencing batch reactors containing nitrifying conventional activated sludge. The reactors were monitored for recovery over a period of 30 days or less. All shock conditions inhibited nitrification, but to different degrees. The nitrate generation rate (NGR) of the shocked reactors recovered overtime to control reactor levels and showed that it was a more sensitive indicator of nitrification inhibition than both initial respirometric tests conducted on unexposed biomass and effluent nitrogen species analyses. CDNB had the most severe impact on nitrification, followed by alkaline pH 11, cadmium, cyanide, octanol, and DNP. Based on effluent data, cadmium and octanol primarily inhibited ammonia-oxidizing bacteria (AOB) while CDNB, pH 11,and cyanide inhibited both AOB and nitrite-oxidizing bacteria (NOB). DNP initially inhibited nitrification but quickly increased the NGR relative to the control and stimulated nitrification after several days in a manner reflective of oxidative uncoupling. The shocked mixed liquor showed trends toward recovery from inhibition for all chemicals tested, but in some cases this reversion was slow. These results contribute to our broader effort to identify relationships between chemical sources and the process effects they induce in activated sludge treatment systems. PMID:14966810

Kelly, R T; Henriques, I D S; Love, N G

2004-03-20

368

Impaired interhemispheric inhibition in writer's cramp  

PubMed Central

Objectives: Reduced cortical inhibition is a feature of focal hand dystonia and this likely contributes to excessive muscle contractions. Inhibition from the opposite hemisphere, known as interhemispheric inhibition (IHI), was studied bidirectionally in 7 right-handed patients with writer's cramp (WC) and age-matched healthy controls in a cross-sectional physiologic study. Methods: IHI was measured with paired transcranial magnetic stimulation with the conditioning stimulus applied to the motor cortex and the test stimulus applied to the contralateral motor cortex. Surface EMG was measured in right and left first dorsal interosseous muscles during rest, and while holding a pen between the thumb and index finger at 20% maximum voluntary contraction with the right dystonia-affected hand. The time course and magnitude of IHI was studied at interstimulus intervals of 6, 8, 10, 12, 30, 40, and 50 msec between the conditioning stimulus and test stimulus. Results: In WC at rest, IHI was significantly reduced in the dystonia-affected right hand (IHI from right to left motor cortex) at both short (SIHI, 10–12 msec) and long (LIHI, 30–40 msec) intervals compared to the unaffected hand. Compared to controls, SIHI and LIHI were reduced in the dystonia-affected hand only. There was no difference in IHI between controls and WC during the task of holding a pen. Conclusions: In WC, both SIHI and LIHI are reduced in the dystonia-affected hand compared to the unaffected hand and to healthy controls. Impaired IHI may contribute to excessive muscle contraction in WC. GLOSSARY ANOVA = analysis of variance; CS = conditioning stimulus; FDI = first dorsal interosseous; FHD = focal hand dystonia; GABA = gamma-aminobutyric acid; IHI = interhemispheric inhibition; ISI = interstimulus interval; LIHI = long interhemispheric inhibition; MEP = motor evoked potential; MVC = maximum voluntary contraction; SICI = short-interval intracortical inhibition; SIHI = short interhemispheric inhibition; TMS = transcranial magnetic stimulation; TS = test stimulus; WC = writer's cramp.

Nelson, A.J.; Hoque, T.; Gunraj, C.; Ni, Z.; Chen, R.

2010-01-01

369

IGF-1 receptor antagonism inhibits autophagy  

PubMed Central

Inhibition of the insulin/insulin-like growth factor signalling pathway increases lifespan and protects against neurodegeneration in model organisms, and has been considered as a potential therapeutic target. This pathway is upstream of mTORC1, a negative regulator of autophagy. Thus, we expected autophagy to be activated by insulin-like growth factor-1 (IGF-1) inhibition, which could account for many of its beneficial effects. Paradoxically, we found that IGF-1 inhibition attenuates autophagosome formation. The reduced amount of autophagosomes present in IGF-1R depleted cells can be, at least in part, explained by a reduced formation of autophagosomal precursors at the plasma membrane. In particular, IGF-1R depletion inhibits mTORC2, which, in turn, reduces the activity of protein kinase C (PKC?/?). This perturbs the actin cytoskeleton dynamics and decreases the rate of clathrin-dependent endocytosis, which impacts autophagosome precursor formation. Finally, with important implications for human diseases, we demonstrate that pharmacological inhibition of the IGF-1R signalling cascade reduces autophagy also in zebrafish and mice models. The novel link we describe here has important consequences for the interpretation of genetic experiments in mammalian systems and for evaluating the potential of targeting the IGF-1R receptor or modulating its signalling through the downstream pathway for therapeutic purposes under clinically relevant conditions, such as neurodegenerative diseases, where autophagy stimulation is considered beneficial.

Renna, Maurizio; Bento, Carla F.; Fleming, Angeleen; Menzies, Fiona M.; Siddiqi, Farah H.; Ravikumar, Brinda; Puri, Claudia; Garcia-Arencibia, Moises; Sadiq, Oana; Corrochano, Silvia; Carter, Sarah; Brown, Steve D.M.; Acevedo-Arozena, Abraham; Rubinsztein, David C.

2013-01-01

370

ROCK Inhibition Activates MCF-7 Cells  

PubMed Central

Dormant carcinoma cancer cells showing epithelial characteristics can be activated to dissipate into the surrounding tissue or organs through epithelial-mesenchymal transition (EMT). However, the molecular details underlying the activation of dormant cancer cells have been less explored. In this study, we examined the molecular pathway to activate dormant breast cancer cells. Rho-associated kinase (ROCK) inhibition disrupted cell junction, promoted cell proliferation and migration / invasion in both two-dimensional and three-dimensional substrates. The disintegration of cell junction upon ROCK inhibition, coupled with the loss of E-cadherin and b-catenin from the cell membrane, was associated with the activation of Rac1 upon ROCK inhibition. Migration / invasion also increased upon ROCK inhibition. However, the activation of MCF-7 cells upon ROCK inhibition was not associated with the up-regulation of typical EMT markers, such as snail and slug. Based on these results, we suggest the potential risk for dormant cancer cells to dissipate through non-typical EMT when ROCK activity is down-regulated.

Yang, Seungwon; Kim, Hyun-Man

2014-01-01

371

Rosette nanotubes inhibit bovine neutrophil chemotaxis  

PubMed Central

Migration of activated neutrophils that have prolonged lifespan into inflamed organs is an important component of host defense but also contributes to tissue damage and mortality. In this report, we used biologically-inspired RGD-tagged rosette nanotubes (RNT) to inhibit neutrophil chemotaxis. We hypothesize that RGD-RNT will block neutrophil migration through inhibition of MAPK. In this report, RNT conjugated to lysine (K–RNT) and arginine-glycine-aspartic acid-serine-lysine (RGDSK-RNT) were co-assembled in a molar ratio of 95/5. The effect of the resulting composite RNT (RGDSK/K–RNT) on neutrophil chemotaxis, cell signaling and apoptosis was then investigated. Exposure to RGDSK/K–RNT reduced bovine neutrophil migration when compared to the non-treated group (p < 0.001). Similar effect was seen following treatment with ERK1/2 or p38 MAPK inhibitors. Phosphorylation of the ERK1/2 and p38 MAPK was inhibited at 5 min by RGDSK/K–RNT (p < 0.05). The RGDSD/K-RNT did not affect the migration of neutrophils pre-treated with ?v?3 integrin antibody suggesting that both bind to the same receptor. RGDSK/K–RNT did not induce apoptosis in bovine neutrophils, which was suppressed by pre-exposing them to LPS (p < 0.001). We conclude that RGDSK/K–RNT inhibit phosphorylation of ERK1/2 and p38 MAPK and inhibit chemotaxis of bovine neutrophils.

Le, Minh Hong Anh; Suri, Sarabjeet Singh; Rakotondradany, Felaniaina; Fenniri, Hicham; Singh, Baljit

2010-01-01

372

Inhibition and Agglutination of Arthrobacters by Pseudomonads  

PubMed Central

The bacterial flora of water in Narragansett Bay, R.I., was observed semimonthly from 1962 to 1964. Dominant isolates were keyed to genus, and the isolates for each genus were expressed as percentage of total isolates. There was a consistent inverse relationship between arthrobacters and the dominant pseudomonads. Pseudomonad growth on agar plates markedly inhibited arthrobacter cross-streaks. Agar from inhibition zones as well as supernatant fluids from pseudomonad broth cultures inhibited arthrobacter motility and caused the cells to agglutinate. Gummy pseudomonad residues from vacuum-evaporated broth cultures readily passed a G-25 Sephadex column. This material agglutinated arthrobacter cells, but failed to cause arthrobacter inhibition in filter-pad assays. In contrast, sterile medium inside a dialysis sac, inoculated externally with a pseudomonad, was inhibitory to arthrobacters in pad assay but failed to agglutinate arthrobacter cells. Pseudomonad isolates from soil showed similar inhibiting and agglutinating activities for both soil and seawater arthrobacter isolates. The inhibitory and agglutinating activities of pseudomonad isolates appeared to diminish on prolonged laboratory cultivation. Images

Sieburth, John McN.

1967-01-01

373

Rapamycin inhibits vascular smooth muscle cell migration.  

PubMed Central

Abnormal vascular smooth muscle cell (SMC) proliferation and migration contribute to the development of restenosis after percutaneous transluminal coronary angioplasty and accelerated arteriopathy after cardiac transplantation. Previously, we reported that the macrolide antibiotic rapamycin, but not the related compound FK506, inhibits both human and rat aortic SMC proliferation in vitro by inhibiting cell cycle-dependent kinases and delaying phosphorylation of retinoblastoma protein (Marx, S.O., T. Jayaraman, L.O. Go, and A.R. Marks. 1995. Circ. Res. 362:801). In the present study the effects of rapamycin on SMC migration were assayed in vitro using a modified Boyden chamber and in vivo using a porcine aortic SMC explant model. Pretreatment with rapamycin (2 ng/ml) for 48 h inhibited PDGF-induced migration (PDGF BB homodimer; 20 ng/ml) in cultured rat and human SMC (n = 10; P < 0.0001), whereas FK506 had no significant effect on migration. Rapamycin administered orally (1 mg/kg per d for 7 d) significantly inhibited porcine aortic SMC migration compared with control (n = 15; P < 0.0001). Thus, in addition to being a potent immunosuppressant and antiproliferative, rapamycin also inhibits SMC migration.

Poon, M; Marx, S O; Gallo, R; Badimon, J J; Taubman, M B; Marks, A R

1996-01-01

374

Hypothalamic glucagon signaling inhibits hepatic glucose production.  

PubMed

Glucagon activates hepatic protein kinase A (PKA) to increase glucose production, but the gluco-stimulatory effect is transient even in the presence of continuous intravenous glucagon infusion. Continuous intravenous infusion of insulin, however, inhibits glucose production through its sustained actions in both the liver and the mediobasal hypothalamus (MBH). In a pancreatic clamp setting, MBH infusion with glucagon activated MBH PKA and inhibited hepatic glucose production (HGP) in rats, as did central glucagon infusion in mice. Inhibition of glucagon receptor-PKA signaling in the MBH and hepatic vagotomy each negated the effect of MBH glucagon in rats, whereas the central effect of glucagon was diminished in glucagon receptor knockout mice. A sustained rise in plasma glucagon concentrations transiently increased HGP, and this transiency was abolished in rats with negated MBH glucagon action. In a nonclamp setting, MBH glucagon infusion improved glucose tolerance, and inhibition of glucagon receptor-PKA signaling in the MBH enhanced the ability of intravenous glucagon injection to increase plasma glucose concentrations. We also detected a similar enhancement of glucose concentrations that was associated with a disruption in MBH glucagon signaling in rats fed a high-fat diet. We show that hypothalamic glucagon signaling inhibits HGP and suggest that hypothalamic glucagon resistance contributes to hyperglycemia in diabetes and obesity. PMID:23685839

Mighiu, Patricia I; Yue, Jessica T Y; Filippi, Beatrice M; Abraham, Mona A; Chari, Madhu; Lam, Carol K L; Yang, Clair S; Christian, Nikita R; Charron, Maureen J; Lam, Tony K T

2013-06-01

375

Response Inhibition in Motor Conversion Disorder  

PubMed Central

Conversion disorders (CDs) are unexplained neurological symptoms presumed to be related to a psychological issue. Studies focusing on conversion paralysis have suggested potential impairments in motor initiation or execution. Here we studied CD patients with aberrant or excessive motor movements and focused on motor response inhibition. We also assessed cognitive measures in multiple domains. We compared 30 CD patients and 30 age-, sex-, and education-matched healthy volunteers on a motor response inhibition task (go/no go), along with verbal motor response inhibition (color-word interference) and measures of attention, sustained attention, processing speed, language, memory, visuospatial processing, and executive function including planning and verbal fluency. CD patients had greater impairments in commission errors on the go/no go task (P <.001) compared with healthy volunteers, which remained significant after Bonferroni correction for multiple comparisons and after controlling for attention, sustained attention, depression, and anxiety. There were no significant differences in other cognitive measures. We highlight a specific deficit in motor response inhibition that may play a role in impaired inhibition of unwanted movement such as the excessive and aberrant movements seen in motor conversion. Patients with nonepileptic seizures, a different form of conversion disorder, are commonly reported to have lower IQ and multiple cognitive deficits. Our results point toward potential differences between conversion disorder subgroups.

Voon, Valerie; Ekanayake, Vindhya; Wiggs, Edythe; Kranick, Sarah; Ameli, Rezvan; Harrison, Neil A.; Hallett, Mark

2014-01-01

376

Levetiracetam inhibits neurotransmitter release associated with CICR.  

PubMed

To define the antiepileptic mechanisms of levetiracetam (LEV), the present study determined the concentration-dependent effects of locally perfused LEV on the releases of norepinephrine, dopamine, serotonin, l-glutamate and GABA induced by 50 mMK(+)-evoked stimulation and agonists of ryanodine receptor (RyR) and inositol-triphosphate receptor (IP3R) in the median prefrontal cortex (mPFC) using in vivo microdialysis. Local perfusion with LEV (10, 30 and 100 ?M) alone did not affect the extracellular levels of all neurotransmitters in the mPFC. The release of neurotransmitters induced by K(+)-evoked stimulation was inhibited by perfusion with LEV in a concentration-dependent manner, and those induced by agonists of RyR and IP3R were also inhibited by LEV. Specifically, the RyR-induced release was inhibited by 10 ?M LEV, whereas the IP3R-induced release was inhibited by 100 ?M LEV, but not by 10 or 30 ?M LEV. The above results suggest that LEV has little effect on the components of normal synaptic transmission but selectively inhibits transmission induced by neuronal hyperactivation. Thus, the mechanisms of the antiepileptic and neuroprotective actions of LEV seem to be mediated, at least in part, through the combination of these two inhibitory effects on depolarization-induced and CICR-associated neurotransmitter releases. PMID:22484014

Fukuyama, Kouji; Tanahashi, Shunsuke; Nakagawa, Masanori; Yamamura, Satoshi; Motomura, Eishi; Shiroyama, Takashi; Tanii, Hisashi; Okada, Motohiro

2012-06-19

377

Human Miillerian Inhibiting Substance Inhibits Tumor Growth in Vitro and in Vivo1  

Microsoft Academic Search

Mullerian inhibiting substance (MIS) causes regression of the miiller- ian duct in the male fetus. Bovine MIS has been reported to inhibit the growth of some gynecologicaltumors. Recombinant human MIS (rhMIS) produced in transfected Chinese hamster ovary cells has been highly purified by immunoaffinity chromatography. The introduction of a salt wash prior to elution of MIS from the affinity column

Taiwai Chin; Robert L. Parry; Patricia K. Donahoe

1991-01-01

378

Inhibition of Inhibition in Visual Cortex: The Logic of Connections Between Molecularly Distinct Interneurons  

PubMed Central

Cortical inhibitory neurons contact each other to form a network of inhibitory synaptic connections. Our knowledge of the connectivity pattern underlying this inhibitory network is, however, still incomplete. Here we discover a simple and complementary interaction scheme between three large molecularly distinct interneuron populations in mouse visual cortex: Parvalbumin expressing interneurons strongly inhibit one another but, surprisingly, provide little inhibition to other populations. In contrast, somatostatin expressing interneurons avoid inhibiting one another, yet strongly inhibit all other populations. Finally, vasoactive intestinal peptide expressing interneurons preferentially inhibit somatostatin interneurons. This scheme occurs in supra- and infra-granular layers, suggesting that inhibitory networks operate similarly at the input and output of visual cortex. Thus, as the specificity of connections between excitatory neurons forms the basis for the cortical canonical circuit, the scheme described here outlines a standard connectivity pattern among cortical inhibitory neurons.

Pfeffer, Carsten K.; Xue, Mingshan; He, Miao; Huang, Z. Josh; Scanziani, Massimo

2013-01-01

379

Selective Inhibition of Carotenoid Cleavage Dioxygenases  

PubMed Central

Members of the carotenoid cleavage dioxygenase family catalyze the oxidative cleavage of carotenoids at various chain positions, leading to the formation of a wide range of apocarotenoid signaling molecules. To explore the functions of this diverse enzyme family, we have used a chemical genetic approach to design selective inhibitors for different classes of carotenoid cleavage dioxygenase. A set of 18 arylalkyl-hydroxamic acids was synthesized in which the distance between an iron-chelating hydroxamic acid and an aromatic ring was varied; these compounds were screened as inhibitors of four different enzyme classes, either in vitro or in vivo. Potent inhibitors were found that selectively inhibited enzymes that cleave carotenoids at the 9,10 position; 50% inhibition was achieved at submicromolar concentrations. Application of certain inhibitors at 100 ?m to Arabidopsis node explants or whole plants led to increased shoot branching, consistent with inhibition of 9,10-cleavage.

Sergeant, Martin J.; Li, Jian-Jun; Fox, Christine; Brookbank, Nicola; Rea, Dean; Bugg, Timothy D. H.; Thompson, Andrew J.

2009-01-01

380

Black Tea Polyphenols Inhibit Tumor Proteasome Activity  

PubMed Central

Tea is a widely consumed beverage and its constituent polyphenols have been associated with potential health benefits. Although black tea polyphenols have been reported to possess potent anticancer activities, the effect of its polyphenols, theaflavins on the tumor’s cellular proteasome function, an important biological target in cancer prevention, has not been carefully studied. Here black tea extract (T5550) enriched in theaflavins inhibited the chymotrypsin-like (CT) activity of the proteasome and proliferation of human multiple myeloma cells in a dose-dependent manner. Also an isolated theaflavin (TF-1) can bind to, and inhibit the purified 20S proteasome, accompanied by suppression of tumor cell proliferation, suggesting that the tumor proteasome is an important target whose inhibition is at least partially responsible for the anti-cancer effects of black tea.

MUJTABA, TASKEEN; DOU, Q. PING

2012-01-01

381

Mapuche herbal medicine inhibits blood platelet aggregation.  

PubMed

12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0??M) and collagen- (2.0??g/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H(2)O), Amomyrtus luma (DCM?:?MeOH 1?:?1) and Cestrum parqui (DCM?:?MeOH 1?:?1). The platelet aggregating inhibitory effects of A. luma (DCM?:?MeOH 1?:?1), and L. apiculata (H(2)O) were substantial and confirmed by inhibition of platelet surface activation markers. PMID:22028732

Falkenberg, Susan Skanderup; Tarnow, Inge; Guzman, Alfonso; Mølgaard, Per; Simonsen, Henrik Toft

2012-01-01

382

Anticancer Alkaloid Lamellarins Inhibit Protein Kinases  

PubMed Central

Lamellarins, a family of hexacyclic pyrrole alkaloids originally isolated from marine invertebrates, display promising anti-tumor activity. They induce apoptotic cell death through multi-target mechanisms, including inhibition of topoisomerase I, interaction with DNA and direct effects on mitochondria. We here report that lamellarins inhibit several protein kinases relevant to cancer such as cyclin-dependent kinases, dual-specificity tyrosine phosphorylation activated kinase 1A, casein kinase 1, glycogen synthase kinase-3 and PIM-1. A good correlation is observed between the effects of lamellarins on protein kinases and their action on cell death, suggesting that inhibition of specific kinases may contribute to the cytotoxicity of lamellarins. Structure/activity relationship suggests several paths for the optimization of lamellarins as kinase inhibitors.

Baunbaek, Dianne; Trinkler, Nolwenn; Ferandin, Yoan; Lozach, Olivier; Ploypradith, Poonsakdi; Rucirawat, Somsak; Ishibashi, Fumito; Iwao, Masatomo; Meijer, Laurent

2008-01-01

383

Inhibition of alcohol dehydrogenase by bismuth.  

PubMed

Bismuth compounds have been widely used for the treatment of ulcers and Helicobacter pylori infection, and enzyme inhibition was thought to be crucial for bismuth anti-microbial activity. We have investigated the interaction of colloidal bismuth subcitrate (CBS) with alcohol dehydrogenase and our results demonstrate that bismuth can effectively inhibit the enzyme. Kinetic analysis revealed that CBS acted as a non-competitive inhibitor of yeast alcohol dehydrogenase. Both UV-vis and fluorescence data show that interaction of CBS with the enzyme exhibits biphasic processes. Bismuth can replace only half of Zn(II) from the enzyme (i.e., about one Zn(II) per monomer). Surprisingly, binding of CBS also induces the enzyme dissociation from its native form, tetramer into dimers. The inhibition of Bi(III) on the enzyme is probably due to its direct interference with the zinc sites. This study is likely to provide an insight into the mechanism of action of bismuth drugs. PMID:15271509

Jin, Lan; Szeto, Ka-Yee; Zhang, Li; Du, Weihong; Sun, Hongzhe

2004-08-01

384

Mapuche Herbal Medicine Inhibits Blood Platelet Aggregation  

PubMed Central

12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0??M) and collagen- (2.0??g/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H2O), Amomyrtus luma (DCM?:?MeOH 1?:?1) and Cestrum parqui (DCM?:?MeOH 1?:?1). The platelet aggregating inhibitory effects of A. luma (DCM?:?MeOH 1?:?1), and L. apiculata (H2O) were substantial and confirmed by inhibition of platelet surface activation markers.

Falkenberg, Susan Skanderup; Tarnow, Inge; Guzman, Alfonso; M?lgaard, Per; Simonsen, Henrik Toft

2012-01-01

385

Kinetics of ergothioneine inhibition of mushroom tyrosinase.  

PubMed

The native amino acid ergothioneine, a thiourea derivative of histidine, inhibits mushroom tyrosinase activity in a dose-dependent manner, with an IC(50) value of 1.025 mg/ml (4.47 mM). By contrast, histidine exhibited no inhibitory effect on mushroom tyrosinase activity. We characterized ergothioneine as a noncompetitive tyrosinase inhibitor using a Lineweaver-Burk plot of experimental kinetic data. The IC(50) value for ergothioneine scavenging of 2,2-diphenyl-1-picrylhydrazyl was 6.110?±?0.305 mg/ml, much higher than the IC(50) for inhibition of tyrosinase activity which indicating ergothioneine on tyrosinase shows a weak correlation to its antioxidative activity. The results demonstrated that ergothioneine has a potent inhibition effect on tyrosinase enzyme activity, resulting from the presence of the sulfur substituted imidazole ring in ergothioneine. PMID:22068690

Liao, Wayne C; Wu, Wen Hong; Tsai, Pei-Chuan; Wang, Hui-Feng; Liu, Yi-Hsin; Chan, Chin-Feng

2012-01-01

386

Complete corrosion inhibition through graphene defect passivation.  

PubMed

Graphene is expected to enable superior corrosion protection due to its impermeability and chemical inertness. Previous reports, however, demonstrate limited corrosion inhibition and even corrosion enhancement of graphene on metal surfaces. To enable the reliable and complete passivation, the origin of the low inhibition efficiency of graphene was investigated. Combining electrochemical and morphological characterization techniques, nanometer-sized structural defects in chemical vapor deposition grown graphene were found to be the cause for the limited passivation effect. Extremely fast mass transport on the order of meters per second both across and parallel to graphene layers results in an inhibition efficiency of only ?50% for Cu covered with up to three graphene layers. Through selective passivation of the defects by atomic layer deposition (ALD) an enhanced corrosion protection of more than 99% was achieved, which compares favorably with commercial corrosion protection methods. PMID:24359599

Hsieh, Ya-Ping; Hofmann, Mario; Chang, Kai-Wen; Jhu, Jian Gang; Li, Yuan-Yao; Chen, Kuang Yao; Yang, Chang Chung; Chang, Wen-Sheng; Chen, Li-Chyong

2014-01-28

387

The inhibition of monoamine oxidase by esomeprazole.  

PubMed

Virtual screening of a library of drugs has suggested that esomeprazole, the S-enantiomer of omeprazole, may possess binding affinities for the active sites of the monoamine oxidase (MAO) A and B enzymes. Based on this finding, the current study examines the MAO inhibitory properties of esomeprazole. Using recombinant human MAO-A and MAO-B, IC50 values for the inhibition of these enzymes by esomeprazole were experimentally determined. To examine the reversibility of MAO inhibition by esomeprazole, the recoveries of the enzymatic activities after dilution of the enzyme-inhibitor complexes were evaluated. In addition, reversibility of inhibition was also examined by measuring the recoveries of enzyme activities after dialysis of enzyme-inhibitor mixtures. Lineweaver-Burk plots were constructed to evaluate the mode of MAO inhibition and to measure Ki values. The results document that esomeprazole inhibits both MAO-A and MAO-B with IC50 values of 23 µM and 48 µM, respectively. The interactions of esomeprazole with MAO-A and MAO-B are reversible and most likely competitive with Ki values for the inhibition of the respective enzymes of 8.99 µM and 31.7 µM. Considering the available pharmacokinetic data and typical therapeutic doses of esomeprazole, these inhibitory potencies are unlikely to be of pharmacological relevance in humans. The MAO inhibitory effects of esomeprazole should however be taken into consideration when using this drug in animal experiments where higher doses are often administered. PMID:23677700

Petzer, A; Pienaar, A; Petzer, J P

2013-09-01

388

A qualitative approach to enzyme inhibition.  

PubMed

Most general biochemistry textbooks present enzyme inhibition by showing how the basic Michaelis-Menten parameters K(m) and V(max) are affected mathematically by a particular type of inhibitor. This approach, while mathematically rigorous, does not lend itself to understanding how inhibition patterns are used to determine the kinetic aspects of an enzyme. The discussion here describes a qualitative approach to teaching enzyme inhibition that allows for a physical or mechanistic understanding. This qualitative approach to enzyme inhibition starts by recognizing that the two fundamental kinetic parameters of an enzyme catalyzed reaction are V(max) and V(max) /K(m) , which correspond to the apparent rates of reaction at very high and very low concentrations of substrate, respectively. It just so happens that the reciprocals of V(max) and V(max) /K(m) correspond to the y-intercept and slope of the Lineweaver-Burk plot, respectively. Thus, an inhibitor that affects the y-intercept binds to the enzyme at very high substrate concentrations, and thus binds to the enzyme-substrate complex, while an inhibitor that affects the slope binds to the enzyme at very low substrate concentrations, and thus binds only to free enzyme. These simple precepts can be used to interpret the basic inhibition patterns, competitive, uncompetitive and noncompetitive, and more importantly, derive mechanistic information, especially in multisubstrate reactions. The application of these principles is illustrated by using an example from cancer chemotherapy, the inhibition of thymidylate synthase by 5-fluorouracil and leucovorin. PMID:21567682

Waldrop, Grover L

2009-01-01

389

Fluconazole inhibits human adrenocortical steroidogenesis in vitro.  

PubMed

The antifungal agent ketoconazole is often used to suppress cortisol production in patients with Cushing's syndrome (CS). However, ketoconazole has serious side effects and is hepatotoxic. Here, the in vitro effects of ketoconazole and fluconazole, which might be less toxic, on human adrenocortical steroidogenesis were compared. The effects on steroidogenesis were examined in primary cultures of nine human adrenocortical tissues and two human adrenocortical carcinoma cell lines. Moreover, the effects on mRNA expression levels of steroidogenic enzymes and cell growth were assessed. Ketoconazole significantly inhibited 11-deoxycortisol (H295R cells; maximum inhibition 99%; EC(50) 0.73??M) and cortisol production (HAC15 cells; 81%; EC(50) 0.26??M and primary cultures (mean EC(50) 0.75??M)). In cultures of normal adrenal cells, ketoconazole increased pregnenolone, progesterone, and deoxycorticosterone levels, while concentrations of 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, DHEA, and androstenedione decreased. Fluconazole also inhibited 11-deoxycortisol production in H295R cells (47%; only at 1?mM) and cortisol production in HAC15 cells (maximum inhibition 55%; EC(50) 35??M) and primary cultures (mean EC(50) 67.7??M). In the cultures of normal adrenals, fluconazole suppressed corticosterone, 17-hydroxypregnenolone, and androstenedione levels, whereas concentrations of progesterone, deoxycorticosterone, and 11-deoxycortisol increased. Fluconazole (1?mM) slightly increased STAR mRNA expression in both cell lines. Neither compound affected mRNA levels of other steroidogenic enzymes or cell number. In conclusion, by inhibiting 11?-hydroxylase and 17-hydroxylase activity, pharmacological concentrations of fluconazole dose dependently inhibit cortisol production in human adrenocortical cells in vitro. Although fluconazole seems less potent than ketoconazole, it might become an alternative for ketoconazole to control hypercortisolism in CS. Furthermore, patients receiving fluconazole because of mycosis might be at risk for developing adrenocortical insufficiency. PMID:23038793

van der Pas, R; Hofland, L J; Hofland, J; Taylor, A E; Arlt, W; Steenbergen, J; van Koetsveld, P M; de Herder, W W; de Jong, F H; Feelders, R A

2012-12-01

390

Human SRY inhibits ?-catenin-mediated transcription  

PubMed Central

In most mammals, sex is determined by the presence or absence of the SRY gene. SRY encodes a DNA binding HMG-box transcription factor which, during embryogenesis, is the initial trigger of testis differentiation from the bipotential gonad, yet its precise mode of function remains unclear. In ovarian development, R-spondin1 and Wnt4 act through the Wnt/?-catenin signaling pathway to regulate TCF-dependent expression of unknown target genes and repress testis development. Conversely, SRY may be necessary to prevent the development of ovaries by inhibiting the action of ovarian-determining genes. We hypothesize that SRY prevents Wnt/?-catenin signaling, thereby inhibiting ovarian development. In HEK293T cells, SRY repressed ?-catenin-mediated TCF-dependent gene activation in the presence of a specific GSK3? inhibitor or an activated ?-catenin mutant, suggesting that SRY inhibits Wnt signaling at the level of ?-catenin. Three SRY mutant proteins with nuclear localization defects, encoded by XY male-to-female patients, failed to inhibit ?-catenin; surprisingly four SRY sex reversed mutants with defective DNA binding activity showed near wild-type SRY inhibitory activity. Moreover the potent transactivator SRY-VP16 fusion protein also showed wild-type SRY inhibitory activity. Thus SRY inhibition of ?-catenin involves neither DNA binding nor transactivation functions of SRY. ?-catenin and SRY interact in-vitro and SRY expression triggered ?-catenin localization into specific nuclear bodies in NT2/D1 and Hela cells. We conclude that SRY inhibits ?-catenin-mediated Wnt signaling by a novel nuclear function of SRY that could be important in sex determination.

Bernard, Pascal; Sim, Helena; Knower, Kevin; Vilain, Eric; Harley, Vincent

2008-01-01

391

Bacterial contact-dependent growth inhibition.  

PubMed

Bacteria cooperate to form multicellular communities and compete against one another for environmental resources. Here, we review recent advances in the understanding of bacterial competition mediated by contact-dependent growth inhibition (CDI) systems. Different CDI+ bacteria deploy a variety of toxins to inhibit neighboring cells and protect themselves from autoinhibition by producing specific immunity proteins. The genes encoding CDI toxin-immunity protein pairs appear to be exchanged between cdi loci and are often associated with other toxin-delivery systems in diverse bacterial species. CDI also appears to facilitate cooperative behavior between kin, suggesting that these systems may have other roles beyond competition. PMID:23473845

Ruhe, Zachary C; Low, David A; Hayes, Christopher S

2013-05-01

392

Experimental studies of inhibited counterflow flames  

NASA Astrophysics Data System (ADS)

An experimental and numerical study was performed to investigate the fundamental mechanisms of chemical inhibition. The first part of this work examined the structure of non-premixed counterflow methane-air flames. Gas samples were taken with a quartz microprobe and analyzed using a gas chromatograph with a thermal conductivity detector. Experimental and detailed numerical results were obtained for an uninhibited flame and flames inhibited by 1.5% CF3Br and 1.5% CF3I added to the oxidizer, all with a strain rate of 150s-1. The experimental data showed a slight shift toward the oxidizer duct above the flame, but showed excellent agreement with the numerical results below the flame in all cases. The inhibiting effect of CF3Br on a non-premixed diluted hydrogen-air flame was also investigated in the counterflowing configuration. Extinction results were obtained for 15%H2/85%N2 and 16%H 2/84%N2 in the fuel stream. The experimental results supported the theory that carbon chemistry does not play a significant role in inhibition by CF3Br. These results were compared with two different numerical models with different inhibition mechanisms. The effect of partially premixing a methane-air counterflow flame on the extinction strain rate was also examined. Premixing the oxidizer flow had a stabilizing effect, premixing the fuel flow had a weak inhibiting effect, and premixing in both flows had a very weak stabilizing effect that was basically the average of the two individual cases. These results were compared with detailed calculations, asymptotic and one-step analysis. The detailed numerical calculations had excellent agreement with the experiments but the asymptotic and one-step analysis predicted incorrect trends for all cases. Tests were also performed to examine the inhibiting effectiveness of alkali metal salts. Experiments were performed with NaHCO3 and KHCO3 with particle sizes of <30 microns and <20 microns, NaBr and KBr with a particle size of 5--25 microns, and silica (SiO 2) with a particle size of 1--3 microns. Inhibiting effectiveness increased as the particle sized decreased for all powders. The KHCO3 was approximately twice as effective as the NaHCO3, NaBr and KBr for similar particle sizes. These powders were approximately 10 times more efficient than silica and CF3Br on a mass basis.

Truett, Leonard Franklin, III

393

Inhibition of the acetylcholine receptor by histrionicotoxin.  

PubMed Central

1 The action of C5-decahydrohistrionicotoxin (C5-HTX) has been investigated on the extrajunctional acetylcholine (ACh) receptors of denervated rat muscle. 2 C5-HTX causes both a rapid and slow reduction in amplitude of iontophoretic ACh potentials evoked at all frequencies from the extrajunctional receptors. 3 C5-HTX also causes a time-dependent inhibition of the iontophoretic potentials evoked at frequencies greater than 0.02 Hz. This inhibition was observed either alone or superimposed upon desensitization, and may be caused by a similar mechanism to desensitization.

Anwyl, R.; Narahashi, T.

1980-01-01

394

Peptide inhibition of human cytomegalovirus infection  

PubMed Central

Background Human cytomegalovirus (HCMV) is the most prevalent congenital viral infection in the United States and Europe causing significant morbidity and mortality to both mother and child. HCMV is also an opportunistic pathogen in immunocompromised individuals, including human immunodeficiency virus (HIV)- infected patients with AIDS, and solid organ and allogeneic stem cell transplantation recipients. Current treatments for HCMV-associated diseases are insufficient due to the emergence of drug-induced resistance and cytotoxicity, necessitating novel approaches to limit HCMV infection. The aim of this study was to develop therapeutic peptides targeting glycoprotein B (gB), a major glycoprotein of HCMV that is highly conserved across the Herpesviridae family, that specifically inhibit fusion of the viral envelope with the host cell membrane preventing HCMV entry and infection. Results Using the Wimley-White Interfacial Hydrophobicity Scale (WWIHS), several regions within gB were identified that display a high potential to interact with lipid bilayers of cell membranes and hydrophobic surfaces within proteins. The ability of synthetic peptides analogous to WWIHS-positive sequences of HCMV gB to inhibit viral infectivity was evaluated. Human foreskin fibroblasts (HFF) were infected with the Towne-GFP strain of HCMV (0.5 MOI), preincubated with peptides at a range of concentrations (78 nm to 100 ?M), and GFP-positive cells were visualized 48 hours post-infection by fluorescence microscopy and analyzed quantitatively by flow cytometry. Peptides that inhibited HCMV infection demonstrated different inhibitory concentration curves indicating that each peptide possesses distinct biophysical properties. Peptide 174-200 showed 80% inhibition of viral infection at a concentration of 100 ?M, and 51% and 62% inhibition at concentrations of 5 ?M and 2.5 ?M, respectively. Peptide 233-263 inhibited infection by 97% and 92% at concentrations of 100 ?M and 50 ?M, respectively, and 60% at a concentration of 2.5 ?M. While peptides 264-291 and 297-315, individually failed to inhibit viral infection, when combined, they showed 67% inhibition of HCMV infection at a concentration of 0.125 ?M each. Conclusions Peptides designed to target putative fusogenic domains of gB provide a basis for the development of novel therapeutics that prevent HCMV infection.

2011-01-01

395

Inhibition of glycosphingolipid biosynthesis induces cytokinesis failure  

PubMed Central

Although cells undergo dramatic shape changes during cytokinesis, the role of the plasma membrane and lipids is poorly understood. We report that inactivation of glucosyl ceramide synthase (GCS), either by RNAi or with the small molecule PPMP, causes failure of cleavage furrow ingression. Using mass spectrometry-based global lipid profiling, we identify individual lipids that are enhanced or depleted due to GCS inhibition. We show that GCS inhibition results in the mis-localization of actin and the ERM proteins, key cytoskeletal proteins that connect the plasma membrane to the actin cortex. Our data suggest that ceramides participate in mediating the interactions between the membrane and the cortex.

Atilla-Gokcumen, G. E.; Bedigian, A. V.; Sasse, S.; Eggert, U. S.

2011-01-01

396

Adaptive regulation of sparseness by feedforward inhibition  

PubMed Central

In the mushroom body of insects, odors are represented by very few spikes in a small number of neurons, a highly efficient strategy known as sparse coding. Physiological studies of these neurons have shown that sparseness is maintained across thousand-fold changes in odor concentration. Using a realistic computational model, we propose that sparseness in the olfactory system is regulated by adaptive feedforward inhibition. When odor concentration changes, feedforward inhibition modulates the duration of the temporal window over which the mushroom body neurons may integrate excitatory presynaptic input. This simple adaptive mechanism could maintain the sparseness of sensory representations across wide ranges of stimulus conditions.

Assisi, Collins; Stopfer, Mark; Laurent, Gilles; Bazhenov, Maxim

2014-01-01

397

Elucidating Influenza Inhibition Pathways via Network Reconstruction.  

PubMed

Abstract Viruses evade detection by the host immune system through the suppression of antiviral pathways. These pathways are thus obscured when measuring the host response to viral infection and cannot be inferred by current network reconstruction methodology. Here we aim to close this gap by providing a novel computational framework for the inference of such inhibited pathways as well as the proteins targeted by the virus to achieve this inhibition. We demonstrate the power of our method by testing it on the response to influenza infection in humans, with and without the viral inhibitory protein NS1, revealing its direct targets and their inhibitory effects. PMID:24450433

Mazza, Arnon; Gat-Viks, Irit; Sharan, Roded

2014-05-01

398

Bacterial contact-dependent growth inhibition (CDI)  

PubMed Central

Bacteria cooperate to form multicellular communities and compete against one another for environmental resources. Here, we review recent advances in our understanding of bacterial competition mediated by contact-dependent growth inhibition (CDI) systems. Different CDI+ bacteria deploy a variety of toxins to inhibit neighboring cells and protect themselves from autoinhibition by producing specific immunity proteins. The genes encoding CDI toxin–immunity pairs appear to be exchanged between cdi loci and are often associated with other toxin-delivery systems in diverse bacteria. CDI also appears to facilitate cooperative behavior between kin, suggesting that these systems may have other roles beyond competition.

Ruhe, Zachary C.; Low, David A.; Hayes, Christopher S.

2013-01-01

399

Inhibition of carotenoid synthesis in Micrococcus roseus.  

PubMed

Micrococcus roseus forms bicyclic keto-carotenoids. The effects of nicotine, piperonyl butoxide, and 2-(4-chlorophenylthio)-triethylamine hydrochloride (CPTA) were studied with regard to their ability to selectively inhibit carotenogenesis in the organism. Nicotine caused accumulation of beta-zeacarotene; piperonyl butoxide caused accumulation of phytoene and traces of phytofluene, zeta-carotene, and beta-zeacarotene. In both cases canthaxanthin biosynthesis was inhibited. CPTA inhibited canthaxanthin synthesis and caused accumulation of beta-zeacarotene and gamma-carotene and their mono- and di-hydroxy derivatives. Regardless of the inhibitor used, canthaxanthin was the major colored carotenoid biosynthesized. The expected precursors of carotenoid cyclization, neurosporene and (or) lycopene, were not detected in CPTA- or nicotine-inhibited cultures. Therefore, carotenoid cyclization in M. roseus does not involve neurosporene or lycopene and must occur early in carotene biosynthesis, prior to the formation of beta-zeacarotene, zeta-Carotene is proposed as the cyclization substrate and beta-zeacarotene as the substrate for oxygen insertion. PMID:7237286

Cooney, J J; Berry, R A

1981-04-01

400

Inhibition of the butyrylcholinesterase by ethidium bromide.  

PubMed

The effect of ethidium bromide (3,8-diamino-5-ethyl-6-phenyl-phenanthridinium bromide) on the activity of purified horse serum butyrylcholinesterase in vitro has been studied. Ethidium bromide is a middle reversible inhibitor with complex mixed competitive-noncompetitive inhibition kinetics. The inhibitor is bound to the anionic site of the enzyme surface. PMID:3446203

Patocka, J

1987-01-01

401

Chemical inhibition of epibiota by Australian seaweeds  

Microsoft Academic Search

Detailed, ecologically realistic studies of chemical inhibition of fouling (epibiosis) by marine organisms are rare. A first step in understanding chemical mediation of the interaction between epibionts and their hosts is to quantify potential inhibitory molecules on or near the surface of an alga (or other organisms) in the field. In situ quantification can be difficult, and measurements will be

Peter D Steinberg; Rocky de Nys; Staffan Kjelleberg

1998-01-01

402

Illustrating Enzyme Inhibition Using Gibbs Energy Profiles  

ERIC Educational Resources Information Center

Gibbs energy profiles have great utility as teaching and learning tools because they present students with a visual representation of the energy changes that occur during enzyme catalysis. Unfortunately, most textbooks divorce discussions of traditional kinetic topics, such as enzyme inhibition, from discussions of these same topics in terms of…

Bearne, Stephen L.

2012-01-01

403

INHIBITION AS A FUNCTION OF STIMULUS INTENSITY  

Microsoft Academic Search

The present experiment affords a situation in which the inhibitory action of the first stimulus (S?), of varying intensity, may be observed as it affects the amplitude and latency of a lid reflex (R?) to a second stimulus (S?) of constant intensity. This provides the possibility of noting quantitative variation in amount of inhibition of the second response incident to

Helen Peak

1936-01-01

404

Polyene antibiotic that inhibits membrane transport proteins.  

PubMed

The limited therapeutic arsenal and the increase in reports of fungal resistance to multiple antifungal agents have made fungal infections a major therapeutic challenge. The polyene antibiotics are the only group of antifungal antibiotics that directly target the plasma membrane via a specific interaction with the main fungal sterol, ergosterol, often resulting in membrane permeabilization. In contrast to other polyene antibiotics that form pores in the membrane, the mode of action of natamycin has remained obscure but is not related to membrane permeabilization. Here, we demonstrate that natamycin inhibits growth of yeasts and fungi via the immediate inhibition of amino acid and glucose transport across the plasma membrane. This is attributable to ergosterol-specific and reversible inhibition of membrane transport proteins. It is proposed that ergosterol-dependent inhibition of membrane proteins is a general mode of action of all the polyene antibiotics, of which some have been shown additionally to permeabilize the plasma membrane. Our results imply that sterol-protein interactions are fundamentally important for protein function even for those proteins that are not known to reside in sterol-rich domains. PMID:22733749

te Welscher, Yvonne Maria; van Leeuwen, Martin Richard; de Kruijff, Ben; Dijksterhuis, Jan; Breukink, Eefjan

2012-07-10

405

Polyene antibiotic that inhibits membrane transport proteins  

PubMed Central

The limited therapeutic arsenal and the increase in reports of fungal resistance to multiple antifungal agents have made fungal infections a major therapeutic challenge. The polyene antibiotics are the only group of antifungal antibiotics that directly target the plasma membrane via a specific interaction with the main fungal sterol, ergosterol, often resulting in membrane permeabilization. In contrast to other polyene antibiotics that form pores in the membrane, the mode of action of natamycin has remained obscure but is not related to membrane permeabilization. Here, we demonstrate that natamycin inhibits growth of yeasts and fungi via the immediate inhibition of amino acid and glucose transport across the plasma membrane. This is attributable to ergosterol-specific and reversible inhibition of membrane transport proteins. It is proposed that ergosterol-dependent inhibition of membrane proteins is a general mode of action of all the polyene antibiotics, of which some have been shown additionally to permeabilize the plasma membrane. Our results imply that sterol-protein interactions are fundamentally important for protein function even for those proteins that are not known to reside in sterol-rich domains.

te Welscher, Yvonne Maria; van Leeuwen, Martin Richard; de Kruijff, Ben; Dijksterhuis, Jan; Breukink, Eefjan

2012-01-01

406

Matrix metalloproteinase inhibition by green tea catechins.  

PubMed

We have investigated the effects of different biologically active components from natural products, including green tea polyphenols (GTP), resveratrol, genistein and organosulfur compounds from garlic, on matrix metalloproteinase (MMP)-2, MMP-9 and MMP-12 activities. GTP caused the strongest inhibition of the three enzymes, as measured by fluorescence assays using gelatin or elastin as substrates. The inhibition of MMP-2 and MMP-9 caused by GTP was confirmed by gelatin zymography and was observed for MMPs associated with both various rat tissues and human brain tumors (glioblastoma and pituitary tumors). The activities of MMPs were also measured in the presence of various catechins isolated from green tea including (-)-epigallocatechin gallate (EGCG), (-)-epicatechin gallate(ECG), (-)-epigallocatechin (EGC), (-)-epicatechin (EC) and (+)-catechin (C). The most potent inhibitors of these activities, as measured by fluorescence and by gelatin or casein zymography, were EGCG and ECG. GTP and the different catechins had no effect on pancreatic elastase, suggesting that the effects of these molecules on MMP activities are specific. Furthermore, in vitro activation of proMMP-2 secreted from the glioblastomas cell line U-87 by the lectin concanavalin A was completely inhibited by GTP and specifically by EGCG. These results indicate that catechins from green tea inhibit MMP activities and proMMP-2 activation. PMID:10719174

Demeule, M; Brossard, M; Pagé, M; Gingras, D; Béliveau, R

2000-03-16

407

Inhibition of deterioration of rubbers by hydroaromatics  

SciTech Connect

Based on the results obtained from previous works, which concluded that hydrogen donating hydroaromatics can be available as radical scavengers in inhibiting the deterioration of hydrocarbon products at lower oxygen partial pressure, a hydroaromatic type inhibitor which contains various hydroaromatics as its main components produced from coal tar fraction was examined by adding it to natural rubber (NR) and styrene-butadiene rubber (SBR). It was found that the inhibitor was as effective as the conventional amine-type inhibitor. From practical viewpoint, heavy hydroaromatics from petroleum (HHAP) was produced by the hydrogenation of the highly aromatic oil from the heavy fraction of petroleum to improve the physical properties of the previous inhibitor from coal tar fraction. From the deterioration tests for NR, SBR, and chloroprene (CR), the following results could be obtained: (1) HHAP showed excellent inhibiting abilities toward NR and CR, exceeding the conventional inhibitor; (2) inhibiting effect toward SBR could be recognized, viscosity and flex cracking were improved by the addition of HHAP. From these results, the hydrogen donation from hydroaromatic is considered to be effective in inhibiting the deterioration of rubbers.

Kubo, Junichi (Nippon Oil Co., Naka-ku (Japan))

1993-03-01

408

RGD-Tachyplesin Inhibits Tumor Growth1  

Microsoft Academic Search

Tachyplesin is an antimicrobial peptide present in leukocytes of the horseshoe crab (Tachypleus tridentatus). In this study, a synthetic tachyplesin conjugated to the integrin homing domain RGD was tested for antitumor activity. The in vitro results showed that RGD-tachyplesin inhibited the proliferation of both cultured tumor and endothelial cells and reduced the colony formation of TSU prostate cancer cells. Staining

Yixin Chen; Xueming Xu; Shuigen Hong; Jinguo Chen; Ningfei Liu; Charles B. Underhill; Karen Creswell; Lurong Zhang

2001-01-01

409

Temporal preparation, response inhibition and impulsivity.  

PubMed

Temporal preparation and impulsivity involve overlapping neural structures (prefrontal cortex) and cognitive functions (response inhibition and time perception), however, their interrelations had not been investigated. We studied such interrelations by comparing the performance of groups with low vs. high non-clinical trait impulsivity during a temporal preparation go no-go task. This task measured, in less than 10 min, how response inhibition was influenced both by temporal orienting of attention (guided by predictive temporal cues) and by sequential effects (produced by repetition/alternation of the duration of preparatory intervals in consecutive trials). The results showed that sequential effects produced dissociable patterns of temporal preparation as a function of impulsivity. Sequential effects facilitated both response speed (reaction times - RTs - to the go condition) and response inhibition (false alarms to the no-go condition) selectively in the low impulsivity group. In the high impulsivity group, in contrast, sequential effects only improved RTs but not response inhibition. We concluded that both excitatory and inhibitory processing may be enhanced concurrently by sequential effects, which enables the temporal preparation of fast and controlled responses. Impulsivity could hence be related to less efficient temporal preparation of that inhibitory processing. PMID:20566235

Correa, Angel; Triviño, Mónica; Pérez-Dueñas, Carolina; Acosta, Alberto; Lupiáñez, Juan

2010-08-01

410

Erotic stimuli and aggression: Facilitation or inhibition  

Microsoft Academic Search

Attempted to reconcile previous results on the relationship of erotic stimuli and aggression. 81 male undergraduates were either insulted or not insulted prior or subsequent to observing erotic stimuli of varying levels of arousal inducements. It was found, in support of prior research, that mildly erotic stimuli had an inhibiting effect on aggression when viewed subsequent to anger arousal, whereas

Edward Donnerstein; Marcia Donnerstein; Ronald Evans

1975-01-01

411

Inhibition of topoisomerase I by naphthoquinone derivatives  

Microsoft Academic Search

Alkannin and shikonin are naturally occurring naphthoquinones. We have tested several derivatives of the title compounds and we have found that naphthoquinones bearing at least one phenolic hydroxyl group are potent inhibitors of topoisomerase I. The ability of the tested compounds to complex Zn++ parallels with a few exceptions their topoisomerase I inhibition properties while their intercalation and redox properties

Zoi F. Plyta; Tianhu Li; Vassilios P. Papageorgiou; Antonios S. Mellidis; Andreana N. Assimopoulou; Emmanuel N. Pitsinos; Elias A. Couladouros

1998-01-01