UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methoctramine, a selective M2 muscarinic cholinergic receptor antagonist, has been reported to activate phosphoinositide breakdown at high concentrations. Its polyamine structure suggests a putative activation of guanine nucleotide-binding proteins (G proteins). Incubation of methoctramine with rat peritoneal mast cells resulted in a dose-dependent noncytotoxic histamine release, with an EC50 of 20 microM and a maximum effect at 1 mM. Atropine, pirenzepine and HHSiD neither inhibited methoctramine-induced histamine release nor stimulated histamine release. Histamine release and inositol phosphates generation induced by methoctramine were both inhibited by pertussis toxin pretreatment. Benzalkonium chloride, a selective inhibitor of histamine secretion induced by basic secretagogues, inhibited the secretory response to methoctramine. [p-Glu5, D-Trp7,9,l0]-SPs5-11 (GPAnt-2), a well-characterized antagonist of G proteins, blocked the methoctramine-induced histamine release when the antagonist was allowed to reach its intracellular target by streptolysin O-permeabilization. The response to methoctramine was prevented by the hydrolysis of sialic acid residues of the cell surface by neuraminidase. The response of mast cells was restored by permeabilization of the plasma membrane. These results demonstrate that methoctramine, following its entry into the cell and the involvement of pertussis toxin-sensitive G proteins, activates phosphoinositide hydrolysis leading to mast cell exocytosis.
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PMID:The M2 muscarinic receptor antagonist methoctramine activates mast cells via pertussis toxin-sensitive G proteins. 960 19

Defensins are endogenous antimicrobial peptides stored in neutrophil granules. Here we report that a panel of defensins from human, rat, guinea pig, and rabbit neutrophils all have histamine-releasing activity, degranulating rat peritoneal mast cells with EC50 ranging from 70 to 2500 nM, and between 45 and 60% of the total histamine released. The EC50 for defensin-induced histamine secretion correlates with their net basic charge at neutral pH. There is no correlation between histamine release and antimicrobial potency. Degranulation induced by defensins has characteristics similar to those of activation by substance P. The maximum percent histamine release is achieved in <10 s, and it can be markedly inhibited by pertussis toxin (100 ng/ml) and by pretreatment of mast cells with neuraminidase. These properties differ from those for degranulation induced by IgE-dependent Ag stimulation and by the calcium ionophore A23187. GTPase activity, a measure of G protein activation, was induced in a membrane fraction from mast cells following treatment with defensin. Thus, neutrophil defensins are potent mast cell secretagogues that act in a manner similar to substance P and 48/80, through a rapid G protein-dependent response that is mechanistically distinct from Ag/IgE-dependent mast cell activation. Defensins may provide important pathways for communication between neutrophils and mast cells in defenses against microbial agents and in acute inflammatory responses.
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PMID:Neutrophil defensins induce histamine secretion from mast cells: mechanisms of action. 1039 91

Natural polyamines have been proposed to induce histamine release from mast cells through a direct interaction with G proteins. Alternatively, the polyamine binding site of ionotropic N-methyl-D-aspartate (NMDA) receptors has been suggested as a target for spermine on mast cells. We reexamined both hypotheses. Incubation of rat peritoneal mast cells with spermine resulted in a concentration-dependent histamine release (EC50 270 microM). Incubation with NMDA receptor agonists, glutamate or NMDA, associated to the co-agonist glycine, did not induce secretion. Western blot experiments did not reveal NMDA R1, R2a, R2b or R2c subunit expression in rat peritoneal mast cell membranes. The NMDA receptor antagonist at the glycine site, L-689,560, did not modify, at relevant concentrations, the spermine-induced secretion. The NMDA receptor antagonists, ifenprodil and LY 235959, and the NMDA channel blocker, MK801, slightly inhibited, at high concentrations, the secretory effect of spermine. The polyamine arcaine, an antagonist of the NMDA receptor polyamine binding site, induced histamine secretion (EC50 350 microM). Both spermine- and arcaine-induced effects were independent upon extracellular calcium and were largely inhibited by treatment of mast cells with pertussis toxin or benzalkonium chloride. The response to spermine and arcaine was prevented by the hydrolysis of sialic acid residues of the cell surface by neuraminidase, and was restored by permeabilization of the plasma membrane with streptolysine-O, indicating that polyamines act intracellularly. These results confirm the involvement of pertussis toxin-sensitive G proteins in the secretory effect of polyamines and demonstrate the absence of NMDA receptors on rat peritoneal mast cells. Nonselective effects of some NMDA receptor ligands on mast cells cannot be excluded.
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PMID:Effect of NMDA receptor ligands on mast cell histamine release, a reappraisal. 1043 64

The present study was designed to clarify the mechanism of histamine release caused by levofloxacin, a fluoroquinolone antibacterial agent, using rat peritoneal mast cells. Levofloxacin induced a concentration-dependent histamine secretion from 300 microg/ml without lactate dehydrogenase leakage, and the release was rapidly completed within 30 s. This action was dependent on temperature, energy, pH and intracellular Ca(2+), similarly to the effect of compound 48/80, a basic compound. Unlike that with the calcium ionophore A23187, histamine secretion due to levofloxacin or compound 48/80 was prevented by pretreatment with either pertussis toxin or benzalkonium chloride, a selective inhibitor of G proteins of G(i) subtypes. Moreover, the histamine release elicited by levofloxacin or compound 48/80 was suppressed by hydrolysis of sialic acid residues on the cell surface brought about by neuraminidase. These results demonstrate that the mechanism by which levofloxacin exerts histamine release may be closely linked to activation of pertussis toxin-sensitive G proteins.
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PMID:Mechanism of histamine release induced by levofloxacin, a fluoroquinolone antibacterial agent. 1077 Oct 34

We examined agmatine and imidazoline derivatives as putative ligands of trimeric G protein in rat peritoneal mast cells. Agmatine induced a concentration-dependent and pertussis toxin-sensitive secretion of histamine (exocytosis) and arachidonate. Clonidine and idazoxan had no effect. Blockage of Gbetagamma dimers by a specific anti-Gbeta antibody inhibited exocytosis elicited by agmatine and mastoparan. The G protein antagonist [p-Glu(5),D-Trp(7,9,10)]substance P-(5-11) prevented both mastoparan- and agmatine-induced exocytosis when it was allowed to reach its intracellular targets by streptolysin-O permeabilisation. In intact cells, this response was prevented by both the removal of sialic acid residues by neuraminidase and by [D-Pro(4),D-Trp(7,9,10)]substance P-(4-11) acting at the mast cell surface. Exocytosis was restored by permeabilisation of the plasma membrane with streptolysin-O. These results suggest that agmatine might have several molecular targets, exerting its neurotransmitter function at low concentrations (i.e., with high affinity) through membrane receptors and at high concentrations (i.e., with weak affinity) through direct G protein activation.
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PMID:Agmatine: a mastoparan-like activity related to direct activation of heterotrimeric G proteins. 1179 Mar 74

Mast cells' hyperplasia and activation are prominent features in Trichinella spiralis infection. Recently, it was shown that TSL-1 antigens from T. spiralis muscle larvae induce IL-4 and TNF release by unsensitized, normal mast cells (MC) involving an Ig-independent mechanism. In this study, we characterized histamine secretion induced by TSL-1 antigens from normal, unsensitized rat peritoneal MC. Maximum histamine secretion (30+/-5.3% SEM, n=13) was achieved with 30 ng/mL TSL-1 antigens. However, TSL-1 did not induce an increase in beta-hexosaminidase release or NADPH oxidase activity by MC. Interestingly, histamine secretion by TSL-1 was completed at 10s, and was inhibited by both Bordetella pertussis toxin and neuraminidase V, characteristics similar to those involved in substance P-induced histamine secretion. However, in contrast to substance P, TSL-1 induced histamine secretion in the absence of detectable changes in intracellular Ca(2+). We are investigating the molecular pathways involved in MC activation by TSL-1.
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PMID:Trichinella spiralis: histamine secretion induced by TSL-1 antigens from unsensitized mast cells. 1660 Feb 18

The common structural feature of LK direct thrombin inhibitors is a strong basic group attached to the azaphenylalanine scaffold, which is important for the appropriate interaction at the thrombin active site. Our previous results have shown that this basic group could be responsible for a reduction of tracheal air flow and a fall of mean arterial pressure in anaesthetized rats, an undesired effect of direct thrombin inhibitors which correlated with their ability to release histamine from mast cells. In the present study, we investigated the mechanism of LK direct thrombin inhibitors-induced histamine release from rat peritoneal mast cells. We demonstrated that thrombin inhibitors with basic character (LK-732, LK-639 and LK-6063) provoked release of histamine from mast cells, while less basic analogs (LK-658, LK-633 and LK-6062) had no effect. Histamine released by LK-732 and LK-639 was suppressed by removal of sialic acid residues by neuraminidase and by pertussis toxin, an inhibitor of G(i) protein activity. Additional demonstration that G proteins are the targets of LK-732 and LK-639 was provided by the increase of GTPgammaS binding rate to G proteins in rat brain cortical membranes. Our results indicate that basic direct thrombin inhibitors LK-732 and LK-639 provoke release of histamine from mast cells by direct activation of G(i) proteins through the similar biochemical pathway as basic secretagogues.
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PMID:Histamine release, an undesired effect of thrombin inhibitors with basic character, is mediated through direct activation of G(i) proteins. 1665 Apr 5

The pediatric population experiences preventable hospitalizations and serves as a reservoir for influenza and its transmission to other children as well as adults. As a consequence, the Advisory Committee on Immunization Practices has recommended initiating influenza immunization of children as young as 6 months of age through 23 months of age and, recently, up to 5 years of age. However, immunization of older children has not yet become a priority of the US Public Health Service. As a consequence, the importance of antiviral agents, particularly neuraminidase (NA) inhibitors, cannot be overemphasized. From an epidemiological perspective, influenza resulted in higher childhood mortality than did Bordetella pertussis infection in 2003-2004. During that season, 153 children died of influenza, and two-thirds were <5 years of age. Importantly, nearly 50% of these children were previously healthy, with no underlying illness. Currently, 2 NA inhibitors are approved for the treatment of influenza in children. Zanamivir is approved for children >7 years of age, and oseltamivir is approved for children >1 year of age. Arguably, the younger children are at particular risk for influenza complications and hospitalization. In placebo-controlled studies in children >1 year of age, oseltamivir therapy accelerated resolution of clinical illness and defervescence and decreased both the incidence of otitis media and the concomitant use of antibiotics. However, oseltamivir is not currently approved for children <1 year of age. Three clinical toxicology studies identified neurotoxicity in newborn rats administered this medication. In these preclinical toxicology studies, the dose of oseltamivir exceeded that which would be used in humans. In addition, the metabolism of oseltamivir is different in rats than in humans. A key component of influenza therapy is the possibility for development of resistance. Although in studies performed in North America, resistance was not a frequent event, it has been documented in Japanese children treated with this medication; the adequacy of the dose used has been questioned. Children represent only one unique study population among others. Individuals who are at increased risk for influenza infection include the elderly, the immunocompromised, and pregnant women. Collectively, antiviral medications must be evaluated in populations in which they have not yet been assessed. The development of additional antiviral drugs is an important recommendation for the future, so that antiviral resistance can be circumvented. Similarly, availability of drugs for children <1 year of age is mandatory.
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PMID:Prevention and treatment of influenza in high-risk groups: children, pregnant women, immunocompromised hosts, and nursing home residents. 1716 86

Anti-inflammatory activities of thymoquinone (TQ) have been demonstrated in in vitro and in vivo studies. However, the precise mechanism(s) of TQ in these anti-inflammatory activities is not well understood. Using a newly developed assay to detect sialidase activity in live macrophage cells (Glycoconj J doi: 10.1007/s10719-009-9239-8 ), here we show that TQ has no inhibitory effect on endotoxin lipopolysaccharide (LPS) induced sialidase activity in live BMC-2 macrophage cells. In contrast, the parent black seed oil (BSO) and another constituent of BSO para-cymene (p-CY) completely block LPS induced sialidase activity. All of these compounds had no effect on cell viability. On the other hand, TQ induces a vigorous sialidase activity in live BMC-2 macrophage cells in a dose dependent manner as well in live DC-2.4 dendritic cells, HEK-TLR4/MD2, HEK293, SP1 mammary adenocarcinoma cells, human WT and 1140F01 and WG0544 type I sialidosis fibroblast cells. Tamiflu (oseltamivir phosphate) inhibits TQ-induced sialidase activity in live BMC-2 cells with an IC(50) of 0.0194 microM compared to an IC(50) of 19.1 microM for neuraminidase inhibitor DANA (2-deoxy-2,3-dehydro-N-acetylneuraminic acid). Anti-Neu1, -2 and -3 antibodies have no inhibition of TQ-induced sialidase activity in live BMC-2 and human THP-1 macrophage cells but anti-Neu4 antibodies completely block this activity. There is a vigorous sialidase activity associated with TQ treated live primary bone marrow (BM) macrophage cells derived from WT and hypomorphic cathepsin A mice with a secondary Neu1 deficiency (NeuI KD), but not from Neu4 knockout (Neu4 KO) mice. Pertussis toxin (PTX), a specific inhibitor of Galphai proteins of G-protein coupled receptor (GPCR) and the broad range inhibitors of matrix metalloproteinase (MMP) galardin and piperazine applied to live BMC-2, THP-1 and primary BM macrophage cells completely block TQ-induced sialidase activity. These same inhibitory effects are not observed with the GM1 ganglioside specific cholera toxin subunit B (CTXB) as well as with CTX, tyrosine kinase inhibitor K252a, and the broad range GPCR inhibitor suramin. The specific inhibitor of MMP-9, anti-MMP-9 antibody and anti-Neu4 antibody, but not the specific inhibitor of MMP-3 completely block TQ-induced sialidase activity in live THP-1 cells, which express Neu4 and MMP-9 on the cell surface. Neu4 sialidase activity in cell lysates from TQ-treated live THP-1 cells desialylates natural gangliosides and mucin substrates. RT-PCR and western blot analyses reveal no correlation between mRNA and protein values for Neu3 and Neu4 in human monocytic THP-1 cells, suggesting for the first time a varied post-transcriptional mechanism for these two mammalian sialidases independent of TQ activation. Our findings establish an unprecedented activation of Neu4 sialidase on the cell surface by thymoquinone, which is derived from the nutraceutical black cumin oil. The potentiation of GPCR-signaling by TQ via membrane targeting of Galphai subunit proteins and matrix metalloproteinase-9 activation may be involved in the activation process of Neu4 sialidase on the cell surface.
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PMID:Thymoquinone from nutraceutical black cumin oil activates Neu4 sialidase in live macrophage, dendritic, and normal and type I sialidosis human fibroblast cells via GPCR Galphai proteins and matrix metalloproteinase-9. 2021 45

Original antigenic sin is a phenomenon wherein sequential exposure to closely related influenza virus variants reduces antibody (Ab) response to novel antigenic determinants in the second strain and, consequently, impairs the development of immune memory. This could pose a risk to the development of immune memory in persons previously infected with or vaccinated against influenza. Here, we explored strategies to overcome original antigenic sin responses in mice sequentially exposed to two closely related hemagglutinin 1 neuraminidase 1 (H1N1) influenza strains A/PR/8/34 and A/FM/1/47. We found that dendritic cell-activating adjuvants [Bordetella pertussis toxin (PT) or CpG ODN or a squalene-based oil-in-water nanoemulsion (NE)], upon administration during the second viral exposure, completely protected mice from a lethal challenge and enhanced neutralizing-Ab titers against the second virus. Interestingly, PT and NE adjuvants when administered during the first immunization even prevented original antigenic sin in subsequent immunization without any adjuvants. As an alternative to using adjuvants, we also found that repeated immunization with the second viral strain relieved the effects of original antigenic sin. Taken together, our studies provide at least three ways of overcoming original antigenic sin.
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PMID:Strategies to alleviate original antigenic sin responses to influenza viruses. 2286 31

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