Science.gov

Sample records for histamine releasing factor

  1. Comparative effect of recombinant IL-1, -2, -3, -4, and -6, IFN-gamma, granulocyte-macrophage-colony-stimulating factor, tumor necrosis factor-alpha, and histamine-releasing factors on the secretion of histamine from basophils

    SciTech Connect

    Alam, R.; Welter, J.B.; Forsythe, P.A.; Lett-Brown, M.A.; Grant, J.A. )

    1989-05-15

    Most cytokines possess multiple biologic activities. This study was undertaken to investigate the effect of rIL-1 beta, -2, -3, -4 and -6, IFN-gamma, TNF-alpha, and granulocyte-macrophage (GM)-CSF on basophils from 16 donors and the amount of histamine released was compared with that by partially purified mononuclear cell-derived histamine-releasing factor (HRF) and anti-IgE. We found that only IL-3 and GM-CSF at relatively high doses (50 to 500 ng/ml) released small amounts of histamine (3 to 14%) from two allergic donors. In contrast, both HRF and anti-IgE released significant amounts of histamine from all donors. Other cytokines did not release any measurable quantity of histamine. Simultaneous addition of several cytokines to the basophils also failed to release histamine. IL-3, GM-CSF, and IL-1 can also release histamine at lower concentrations (less than 5 ng/ml) when incubated with basophils in the presence of D{sub 2}O. Basophils from 6 out of 13 allergic donors released histamine in response to IL-3, whereas three donors responded to IL-1 beta and two responded to GM-CSF. The results of this study demonstrated that although IL-3 and GM-CSF release small amounts of histamine only from a select group of allergic patients, mononuclear cell-derived HRF is more potent in their action and release histamine from normals as well as allergic patients.

  2. Immune mimicry in malaria: Plasmodium falciparum secretes a functional histamine-releasing factor homolog in vitro and in vivo

    PubMed Central

    MacDonald, Susan M.; Bhisutthibhan, Jamaree; Shapiro, Theresa A.; Rogerson, Stephen J.; Taylor, Terrie E.; Tembo, Madalitso; Langdon, Jacqueline M.; Meshnick, Steven R.

    2001-01-01

    The Plasmodium falciparum translationally controlled tumor protein (TCTP) is a homolog of the mammalian histamine-releasing factor (HRF), which causes histamine release from human basophils and IL-8 secretion from eosinophils. Histamine, IL-8, and eosinophils have been reported to be elevated in patients with malaria. This study was undertaken to determine whether malarial TCTP is found in the plasma of malaria-infected patients and to determine whether it has HRF biologic activity. Malarial TCTP was found in lightly infected human volunteers and in heavily infected Malawian children, but not in uninfected patients. Recombinant malarial TCTP, like HRF, stimulated histamine release from basophils and IL-8 secretion from eosinophils in vitro. Whereas malarial TCTP was less active than HRF, the concentrations that were effective in vitro could be achievable in vivo. These data suggest that malarial TCTP, present in human plasma during a malarial illness, may affect host immune responses in vivo. PMID:11535839

  3. Stem cell factor potentiates histamine secretion by multiple mechanisms, but does not affect tumour necrosis factor-alpha release from rat mast cells.

    PubMed Central

    Lin, T J; Bissonnette, E Y; Hirsh, A; Befus, A D

    1996-01-01

    The effect of stem cell factor (SCF) on histamine and tumour necrosis factor-alpha (TNF-alpha) release from rat peritoneal mast cells (PMC) was determined and the intracellular pathways involved in the potentiation of histamine secretion were investigated. The effects of SCF (2-100 ng/ml) were examined following both short-term (0 and 20 min) and long-term (up to 24hr) preincubations with SCF. Pretreatment of PMC with SCF for 0 min (concurrent) or 20 min did not induce histamine secretion directly, but significantly increased antigen (Ag)-induced histamine secretion. SCF potentiated Ag-induced intracellular Ca2+ increase and calcium ionophore A23187-induced histamine secretion. Pertussis toxin (PT) inhibited SCF-induced potentiation of IgE-dependent histamine secretion, indicating that PT-sensitive G-proteins are involved in the immediate effects of SCF. In long-term incubation experiments, SCF pretreatment for 18-24 hr significantly enhanced Ag-induced histamine secretion, but did not affect Ag-induced intracellular Ca2+ levels. The effects of long-term incubation with SCF, but not the short-term effects, were blocked by cycloheximide. Interestingly, spontaneous and Ag-induced TNF-alpha release from rat PMC were not affected by pretreatment with SCF (2-500 ng/ml) for 1 to 24 hr. Thus, through immediate and delayed mechanisms, SCF potentiates histamine release from PMC, but has not effect on TNF-alpha release. The regulation of MC by SCF may be important in allergic and other inflammatory diseases. PMID:8943730

  4. Tick Histamine Release Factor Is Critical for Ixodes scapularis Engorgement and Transmission of the Lyme Disease Agent

    PubMed Central

    Dai, Jianfeng; Narasimhan, Sukanya; Zhang, Lili; Liu, Lei; Wang, Penghua; Fikrig, Erol

    2010-01-01

    Ticks are distributed worldwide and affect human and animal health by transmitting diverse infectious agents. Effective vaccines against most tick-borne pathogens are not currently available. In this study, we characterized a tick histamine release factor (tHRF) from Ixodes scapularis and addressed the vaccine potential of this antigen in the context of tick engorgement and B. burgdorferi transmission. Results from western blotting and quantitative Reverse Transcription-PCR showed that tHRF is secreted in tick saliva, and upregulated in Borrelia burgdorferi-infected ticks. Further, the expression of tHRF was coincident with the rapid feeding phase of the tick, suggesting a role for tHRF in tick engorgement and concomitantly, for efficient B. burgdorferi transmission. Silencing tHRF by RNA interference (RNAi) significantly impaired tick feeding and decreased B. burgdorferi burden in mice. Interfering with tHRF by actively immunizing mice with recombinant tHRF, or passively transferring tHRF antiserum, also markedly reduced the efficiency of tick feeding and B. burgdorferi burden in mice. Recombinant tHRF was able to bind to host basophils and stimulate histamine release. Therefore, we speculate that tHRF might function in vivo to modulate vascular permeability and increase blood flow to the tick bite-site, facilitating tick engorgement. These findings suggest that blocking tHRF might offer a viable strategy to complement ongoing efforts to develop vaccines to block tick feeding and transmission of tick-borne pathogens. PMID:21124826

  5. Tick histamine release factor is critical for Ixodes scapularis engorgement and transmission of the lyme disease agent.

    PubMed

    Dai, Jianfeng; Narasimhan, Sukanya; Zhang, Lili; Liu, Lei; Wang, Penghua; Fikrig, Erol

    2010-11-24

    Ticks are distributed worldwide and affect human and animal health by transmitting diverse infectious agents. Effective vaccines against most tick-borne pathogens are not currently available. In this study, we characterized a tick histamine release factor (tHRF) from Ixodes scapularis and addressed the vaccine potential of this antigen in the context of tick engorgement and B. burgdorferi transmission. Results from western blotting and quantitative Reverse Transcription-PCR showed that tHRF is secreted in tick saliva, and upregulated in Borrelia burgdorferi-infected ticks. Further, the expression of tHRF was coincident with the rapid feeding phase of the tick, suggesting a role for tHRF in tick engorgement and concomitantly, for efficient B. burgdorferi transmission. Silencing tHRF by RNA interference (RNAi) significantly impaired tick feeding and decreased B. burgdorferi burden in mice. Interfering with tHRF by actively immunizing mice with recombinant tHRF, or passively transferring tHRF antiserum, also markedly reduced the efficiency of tick feeding and B. burgdorferi burden in mice. Recombinant tHRF was able to bind to host basophils and stimulate histamine release. Therefore, we speculate that tHRF might function in vivo to modulate vascular permeability and increase blood flow to the tick bite-site, facilitating tick engorgement. These findings suggest that blocking tHRF might offer a viable strategy to complement ongoing efforts to develop vaccines to block tick feeding and transmission of tick-borne pathogens.

  6. Histamine release factor from Dermanyssus gallinae (De Geer): characterization and in vitro assessment as a protective antigen.

    PubMed

    Bartley, Kathryn; Nisbet, Alasdair J; Offer, Jill E; Sparks, Nicholas H C; Wright, Harry W; Huntley, John F

    2009-03-01

    A cDNA encoding a 174-amino-acid orthologue of a tick histamine release factor (HRF) was identified from the haematophagous poultry red mite Dermanyssus gallinae. The predicted D. gallinae HRF protein (Dg-HRF-1) sequence is highly conserved with the tick HRFs (identity 52-54%) and to a lesser degree with translationally controlled tumour proteins (TCTP) from mammals and other invertebrates (range 38-47%). Phylogenetically, Dg-HRF-1 partitions with the tick HRF clade suggesting a shared linage and potentially similar function(s). A recombinant Dg-HRF-1 protein (rDg-HRF-1) was produced and shown to induce degranulation of rat peritoneal mast cells in vitro, confirming conservation of the histamine-releasing function in D. gallinae. Polyclonal antibodies were generated in rabbits and hens to rDg-HRF-1. Western blotting demonstrated that native Dg-HRF is a soluble protein and immunohistochemical staining of mite sections revealed that the distribution of Dg-HRF, although ubiquitous, is more common in mite reproductive, digestive and synganglion tissues. A survey of hens housed continuously in a mite-infested commercial poultry unit failed to identify IgY specific for recombinant or native Dg-HRF, indicating that Dg-HRF is not exposed to the host during infestation/feeding and may therefore have potential as a vaccine using the concealed antigen approach. To test the protective capability of rDg-HRF-1, fresh heparinised chicken blood was enriched with yolk-derived anti-Dg-HRF IgY antibodies and fed to semi-starved mites using an in vitro feeding system. A statistically significant increase in mortality was shown (P=0.004) in mites fed with anti-Dg-HRF IgY after just one blood meal. The work presented here demonstrates, to our knowledge for the first time, the feasibility of vaccinating hens with recombinant D. gallinae antigens to control mite infestation and the potential of rDg-HRF-1 as a vaccine antigen.

  7. Release of platelet-activating factor (PAF) and histamine. II. The cellular origin of human PAF: monocytes, polymorphonuclear neutrophils and basophils.

    PubMed Central

    Camussi, G; Aglietta, M; Coda, R; Bussolino, F; Piacibello, W; Tetta, C

    1981-01-01

    The origin of platelet activating factor (PAF) from human leucocytes was investigated. Purified monocytes release PAF passively at pH 10.6, when challenged with Ionophore A 23187 or under phagocytic stimuli. Pure preparations of polymorphonuclear neutrophils liberate PAF passively, when challenged with C5a, neutrophil cationic proteins (CP), their carboxypeptidase B derived products (C5a des Arg, CP des Arg) or under phagocytic stimuli. Basophil rich buffy coat cells release PAF when challenged with C5a, CP, anti-IgE (in low amount) or Synacthen concomitantly with basophil degranulation and histamine release. Electron microscopy studies, carried out on Synacthen-stimulated basophil rich buffy coat, provide morphological evidence for platelet-basophil interaction. In conclusion our data demonstrate that PAF can be released from different leucocyte populations. However, the stimuli able to trigger such release appear to have some specificity for the cell target. Images Figure 5 PMID:6161885

  8. Histamine release inhibition activity of bisbenzylisoquinoline alkaloids.

    PubMed

    Nakamura, K; Tsuchiya, S; Sugimoto, Y; Sugimura, Y; Yamada, Y

    1992-12-01

    Eleven examples of bisbenzylisoquinoline alkaloids (head-to-head; 10, head-to-tail; 1) and one half molecule type (N-methylcoclaurine), were tested by in vitro histamine release inhibition assay. The order of the potency of the inhibitory effect was ranked thus: homoaromoline, aromoline, isotetrandrine, cepharanthine, fangchinoline, obaberine, and tetrandrine. The following substances, cepharanoline, berbamine, oxyacanthine, and cycleanine (head-to-tail structure) had no inhibitory effect. N-Methylcoclaurine showed an inhibitory effect comparable to that of fangchinoline. PMID:1484888

  9. Modafinil increases histamine release in the anterior hypothalamus of rats.

    PubMed

    Ishizuka, Tomoko; Sakamoto, Yasuhiko; Sakurai, Toshimi; Yamatodani, Atsushi

    2003-03-20

    Modafinil, (RS)-2-(Diphenylmethylsulfinyl)acetamide, is a well known wake promoting drug used for the treatment of narcolepsy. We investigated the effect of modafinil on the hypothalamic histamine release in the anesthetized rat using in vivo microdialysis. Modafinil (150 mg/kg, i.p.) increased histamine release by 150% of the basal release. The intracerebroventricular (i.c.v.) injection of modafinil (1 nmol) also increased histamine release, however, when modafinil (1 nmol) was injected directly into the tuberomammillary nucleus, a limited region where cell bodies of the histaminergic neurons are located, histamine release was not altered. These observations suggest that modafinil may promote waking via the activation of the histaminergic system, although it does not appear to be a direct pharmacological target of modafinil.

  10. Infralimbic cortex activation and motivated arousal induce histamine release

    PubMed Central

    Forray, María Inés; Torrealba, Fernando

    2015-01-01

    Appetitive behaviours occur in a state of behavioural and physiological activation that allows the optimal performance of these goal-directed behaviours. Here, we tested the hypothesis that histamine neurons under the command of the infralimbic cortex are important to provide behavioural activation. Extracellular histamine and serotonin were measured by microdialysis of the medial prefrontal cortex in behaving rats in parallel with a picrotoxin microinjection into the infralimbic cortex. The injection aroused the rats behaviourally, increased histamine release and decreased serotonin levels. Inhibition of the infralimbic cortex with muscimol produced the opposite effects on neurotransmitter release. The behavioural activation induced by motivating hungry rats with caged food was paralleled by an immediate histamine release, whereas awakening induced by tapping their microdialysis bowl increased serotonin, but not histamine levels. In conclusion, picrotoxin injection into the infralimbic cortex produces behavioural activation together with histamine release; in a similar manner, induction of an appetitive state produced histamine release, likely related to increased behavioural activation characteristic of an appetitive behaviour. PMID:25746330

  11. Histamine-releasing activity and bronchoconstricting effects of sisal

    PubMed Central

    Nicholls, P. J.; Evans, Elizabeth; Valić, F.; Žuškin, Eugenija

    1973-01-01

    Nicholls, P. J., Evans, E., Valić, F., and Žuškin, E. (1973).British Journal of Industrial Medicine,30, 142-145. Histamine-releasing activity and bronchoconstricting effects of sisal. Extracts of dry and oiled sisal released histamine from pig and human but not from rat lung tissue. A suspension in Tyrode solution of the oil used for softening the sisal fibres had a pH of 8·1 and also released histamine from pig and human lung. The releasing activity was abolished when the pH of this suspension was adjusted to pH 7·4. As all the sisal extracts were adjusted to pH 7·4 for incubation with lung tissue, the histamine-releasing activity of sisal in vitro is unrelated to the presence of the oil. Significant (P < 0·01) mean reductions over the work shift of ventilatory capacity (PEF and FEV1·0) were recorded in all the workers exposed to airborne sisal dust. These reductions were greater in combers than in drawers and spinners. Sisal collected from combing machines possessed more histamine-releasing activity than material from drawing and spinning machines. These results indicate that histamine release by sisal may be the cause of acute ventilatory capacity changes in sisal exposure. PMID:4122162

  12. Influence of nitrovasodilators on bovine pulmonary histamine release.

    PubMed

    Valentovic, M A; Ball, J G; Morenas, M; Szarek, J L; Gruetter, C A

    1992-06-01

    The organic nitrates and related nitrovasodilators are relaxants of vascular and airway smooth muscle. Very little information is currently available regarding the influence of nitrates and related nitrovasodilators on pulmonary autacoid release. This study examined the influence of glyceryl trinitrate, isosorbide dinitrate and sodium nitroprusside on histamine release from bovine lung mince. Spontaneous histamine release from bovine lung mince was not altered by 0.1 nM to 1 microM glyceryl trinitrate, isosorbide dinitrate or sodium nitroprusside. Glyceryl trinitrate, isosorbide dinitrate and sodium nitroprusside produced a concentration-dependent decrease in A23187 (10 microM) stimulated histamine release. Glyceryl trinitrate also inhibited histamine liberation following the addition of compound 48/80. Further studies indicated that the inhibitory action of glyceryl trinitrate was reversed by coincubation with the guanylate cyclase inhibitor, methylene blue (10 microM). These findings indicate that glyceryl trinitrate, sodium nitroprusside and isosorbide dinitrate inhibit non-immunologically stimulated pulmonary histamine release and suggest that alterations in guanylate cyclase activity may influence pulmonary histamine release.

  13. Histamine release by Western red cedar (Thuja plicata) from lung tissue in vitro

    PubMed Central

    Evans, Elizabeth; Nicholls, P. J.

    1974-01-01

    Evans, Elizabeth and Nicholls, P. J. (1974).British Journal of Industrial Medicine,31, 28-30. Histamine release by Western red cedar(Thuja plicata)from lung tissue in vitro. Various respiratory symptoms have previously been observed in workers exposed to dust from Western red cedar (Thuja plicata). Although an allergic basis for these effects has been proposed, the possibility that the dust may contain a pharmacologically active agent was investigated. Aqueous extracts of two samples of red cedar released significant amounts of histamine from pig and human lung in vitro. For one of these samples, using pig lung, a dose-response relation was found over a narrow range of concentrations. These dusts possessed the same order of histamine-releasing activity as a sample of cotton dust. Potassium cyanide reduced the release of histamine caused by low concentrations of Western red cedar. Similar effects of cyanide on the histamine-releasing activity of cotton dust and compound 48/80 were observed. It is possible that release of histamine in the lungs and upper respiratory tract occurs on inhalation of dust from Western red cedar and this may be a contributory factor to the development of respiratory symptoms in workers exposed to the dust of this wood. PMID:4132384

  14. Blood histamine release: A new allergy blood test

    SciTech Connect

    Faraj, B.A.; Gottlieb, G.R.; Camp, V.M.; Lollies, P.

    1985-05-01

    Allergen-mediated histamine release from human leukocytes represents an important model for in vitro studies of allergic reactions. The purpose of this study was to determine whether the measurement of histamine released in allergic patients (pts) by radioenzymatic assay following mixing of their blood with common allergens represents a reliable index for diagnosis of atopic allergy. Three categories of allergies were used: (1) housedust and mite; (2) cat and dog dander; (3) trees and grasses and ragweed mixture. The presence of allergy was established by intradermal skin testing in the study group of 82 pts. Significant atopy was defined as greater than or equal to 3+ (overall range 0-4 +, negative to maximum) on skin testing. The test was carried out in tubes with 0.5 ml heparinized blood, 0.5 ml tris albumin buffer, and one of the allergens (60-100 PNU/ml). In 20 controls without allergy, there always was less than or equal to 4% histamine release (normal response). A significant allergen-mediated histamine release, ranging from 12 to 30% of the total blood histamine content, was observed in 96% of the pts with skin test sensitivity of greater than or equal to 3+. There was good agreement between skin testing and histamine release in terms of the allergen causing the response. Thus, measurement of histamine release in blood in response to allergen challenge represents a clinically useful in vitro test for the diagnosis of atopic allergy. Because data can be obtained from a single sample and are highly quantitative, this new method should have application to the longitudinal study of allergic pts and to the assessment of interventions.

  15. Enhanced Basophil Reactivities during Severe Malaria and Their Relationship with the Plasmodium falciparum Histamine-Releasing Factor Translationally Controlled Tumor Protein

    PubMed Central

    Pelleau, Stéphane; Diop, Sylvie; Dia Badiane, Méry; Vitte, Joana; Beguin, Pierre; Nato, Farida; Diop, Bernard M.; Bongrand, Pierre; Parzy, Daniel

    2012-01-01

    Recent studies suggest shared pathogenic pathways during malaria and allergy. Indeed, IgE, histamine, and the parasite-derived Plasmodium falciparum histamine-releasing factor translationally controlled tumor protein (PfTCTP) can be found at high levels in serum from patients experiencing malaria, but their relationship with basophil activation remains unknown. We recruited P. falciparum-infected patients in Senegal with mild malaria (MM; n = 19) or severe malaria (SM; n = 9) symptoms and healthy controls (HC; n = 38). Levels of serum IgE, PfTCTP, and IgG antibodies against PfTCTP were determined by enzyme-linked immunosorbent assays (ELISA). Basophil reactivities to IgE-dependent and -independent stimulations were measured ex vivo using fresh blood by looking at the expression level of the basophil activation marker CD203c with flow cytometry. Unstimulated basophils from MM had significantly lower levels of CD203c expression compared to those from HC and SM. After normalization on this baseline level, basophils from SM showed an enhanced reactivity to calcimycin (A23187) and hemozoin. Although SM reached higher median levels of activation after anti-IgE stimulation, great interindividual differences did not allow the results to reach statistical significance. When primed with recombinant TCTP before anti-IgE, qualitative differences in terms of a better ability to control excessive activation could be described for SM. IgE levels were very high in malaria patients, but concentrations in MM and SM were similar and were not associated with basophil responses, which demonstrates that the presence of IgE alone cannot explain the various basophil reactivities. Indeed, PfTCTP could be detected in 32% of patients, with higher concentrations for SM. These PfTCTP-positive patients displayed significantly higher basophil reactivities to any stimulus. Moreover, the absence of anti-PfTCTP IgG was associated with higher responses in SM but not MM. Our results show an

  16. Enhanced basophil reactivities during severe malaria and their relationship with the Plasmodium falciparum histamine-releasing factor translationally controlled tumor protein.

    PubMed

    Pelleau, Stéphane; Diop, Sylvie; Dia Badiane, Méry; Vitte, Joana; Beguin, Pierre; Nato, Farida; Diop, Bernard M; Bongrand, Pierre; Parzy, Daniel; Jambou, Ronan

    2012-08-01

    Recent studies suggest shared pathogenic pathways during malaria and allergy. Indeed, IgE, histamine, and the parasite-derived Plasmodium falciparum histamine-releasing factor translationally controlled tumor protein (PfTCTP) can be found at high levels in serum from patients experiencing malaria, but their relationship with basophil activation remains unknown. We recruited P. falciparum-infected patients in Senegal with mild malaria (MM; n = 19) or severe malaria (SM; n = 9) symptoms and healthy controls (HC; n = 38). Levels of serum IgE, PfTCTP, and IgG antibodies against PfTCTP were determined by enzyme-linked immunosorbent assays (ELISA). Basophil reactivities to IgE-dependent and -independent stimulations were measured ex vivo using fresh blood by looking at the expression level of the basophil activation marker CD203c with flow cytometry. Unstimulated basophils from MM had significantly lower levels of CD203c expression compared to those from HC and SM. After normalization on this baseline level, basophils from SM showed an enhanced reactivity to calcimycin (A23187) and hemozoin. Although SM reached higher median levels of activation after anti-IgE stimulation, great interindividual differences did not allow the results to reach statistical significance. When primed with recombinant TCTP before anti-IgE, qualitative differences in terms of a better ability to control excessive activation could be described for SM. IgE levels were very high in malaria patients, but concentrations in MM and SM were similar and were not associated with basophil responses, which demonstrates that the presence of IgE alone cannot explain the various basophil reactivities. Indeed, PfTCTP could be detected in 32% of patients, with higher concentrations for SM. These PfTCTP-positive patients displayed significantly higher basophil reactivities to any stimulus. Moreover, the absence of anti-PfTCTP IgG was associated with higher responses in SM but not MM. Our results show an

  17. In vivo modulation of rat hypothalamic histamine release by the histamine H3 receptor ligands, immepip and clobenpropit. Effects of intrahypothalamic and peripheral application.

    PubMed

    Jansen, F P; Mochizuki, T; Yamamoto, Y; Timmerman, H; Yamatodani, A

    1998-12-01

    We investigated the effect of the new potent and selective histamine H3 receptor agonist, immepip, and the histamine H3 receptor antagonist, clobenpropit, on in vivo neuronal histamine release from the anterior hypothalamic area of urethane-anesthetized rats, using microdialysis. Intrahypothalamic perfusion with immepip at concentrations of 1 and 10 nM reduced histamine release to 75% and 35% of its basal level, respectively. Peripheral injection of immepip (5 mg/kg) caused a sustained decrease in histamine release of 50%. Clobenpropit potently increased histamine release after intrahypothalamic perfusion. The maximal increase in histamine release was 2-fold, observed at a concentration of 10 nM clobenpropit. Peripheral injection of clobenpropit (5-15 mg/kg) increased histamine release to about 150% of the basal value. A more marked increase in histamine release was found after injection of the histamine H3 receptor antagonist, thioperamide (5 mg/kg). In conclusion, intrahypothalamic perfusion of the histamine H3 receptor agonist, immepip and the histamine H3 receptor antagonist, clobenpropit, potently and oppositely modulated in vivo histamine release from the anterior hypothalamic area. The decreased histamine release after peripheral injection of immepip indicates that this novel agonist readily crosses the blood-brain barrier, making it a potential candidate for in vivo histamine H3 receptor studies. The differential increase in histamine release after peripheral injection of clobenpropit and thioperamide is discussed.

  18. Mechanisms of histamine release by compound 48/80

    PubMed Central

    Rothschild, A. M.

    1970-01-01

    1. Rat and guinea-pig lung tissues were incubated for 20 min at 37° C in Krebs-Ringer phosphate buffer at pH 7·4, or in Tyrode-Tris buffer at pH 8·2, and the release of histamine produced by adding different concentrations of compound 48/80 to the incubation medium was determined. 2. At pH 7·4, increasing concentrations of 48/80 increased the release of histamine from the rat lung, with a tendency towards a maximum. No release of histamine from guinea-pig lung was observed at this pH. At pH 8·2, histamine release occurred both from rat and guinea-pig lung, and was proportional to the logarithm of the concentration of compound 48/80. 3. Histamine release from rat lung by 20 μg/ml. of 48/80 decreased when the pH was raised from 7·4 to 8·2; but the release caused by 1 mg/ml. of 48/80 increased both in rat and guinea-pig lung as the pH was raised. 4. 2-4-Dinitrophenol (DNP) inhibited the release of histamine from rat lung by a concentration of 20 μg/ml. of 48/80; the inhibition was prevented by glucose. DNP did not affect histamine release from rat or guinea-pig lung by a concentration of 1 mg/ml. of 48/80 and enhanced the release when the pH was raised from 7·4 to 8·2. 5. 1 mg/ml. of 48/80 did not inhibit the enhanced oxygen consumption produced by DNP in the isolated rat diaphragm. 6. Iodoacetic acid (IAA) or a Ca/Mg-free medium inhibited the release of histamine by 20 μg/ml. of 48/80 from rat lung but not the release produced by 1 mg/ml. in either rat or guinea-pig lung. 7. The degranulation of rat mesentery mast cells caused by 20 μg/ml. of compound 48/80 was inhibited by DNP. The degranulation evoked by 1 mg/ml. of 48/80 was also sensitive to this inhibitor; in this instance, however, the metachromatic staining reaction of the mesentery mast cells was greatly diminished. 8. It is concluded that two processes of histamine release by compound 48/80 occur in rat lung. One, dependent on cell metabolism, involves, mast cell granule secretion. The other

  19. Inhibition of tryptase release from human colon mast cells by histamine receptor antagonists.

    PubMed

    He, Shao-Heng; Xie, Hua; Fu, Yi-Ling

    2005-03-01

    The main objective of this study was to investigate the ability of histamine receptor antagonists to modulate tryptase release from human colon mast cells induced by histamine. Enzymatically dispersed cells from human colon were challenged with histamine in the absence or presence of the histamine receptor antagonists, and the tryptase release was determined. It was found that histamine induced tryptase release from colon mast cells was inhibited by up to approximately 61.5% and 24% by the H1 histamine receptor antagonist terfenadine and the H2 histamine receptor antagonist cimetidine, respectively, when histamine and its antagonists were added to cells at the same time. The H3 histamine receptor antagonist clobenpropit had no effect on histamine induced tryptase release from colon mast cells at all concentrations tested. Preincubation of terfenadine, cimetidine or clobenpropit with cells for 20 minutes before challenging with histamine did not enhance the ability of these antihistamines to inhibit histamine induced tryptase release. Apart from terfenadine at 100 microg/ml, the antagonists themselves did not stimulate tryptase release from colon mast cells following both 15 minutes and 35 minutes incubation periods. It was concluded that H1 and H2 histamine receptor antagonists were able to inhibit histamine induced tryptase release from colon mast cells. This not only added some new data to our hypothesis of self-amplification mechanisms of mast cell degranulation, but also suggested that combining these two types of antihistamine drugs could be useful for the treatment of inflammatory bowel disease (IBD).

  20. The fate of released histamine: reception, response and termination.

    PubMed Central

    Rangachari, P. K.

    1998-01-01

    Histamine released from ECL cells elicits responses from a variety of cellular targets in the vicinity. Three sets of receptors are involved (H1, H2 and H3). Receptor occupation is promptly transduced into cellular responses. The responses, in turn, are terminated by diverse mechanisms: enzymatic inactivation, cellular uptake and desensitization at the receptor level. Under specific pathological conditions, histamine effects could be exaggerated by the presence of derivatives that may be of marginal relevance under physiological conditions. Images Figure 2 PMID:10461350

  1. Caffeine promotes glutamate and histamine release in the posterior hypothalamus

    PubMed Central

    Kodama, Tohru; Siegel, Jerome M.

    2014-01-01

    Histamine neurons are active during waking and largely inactive during sleep, with minimal activity during rapid-eye movement (REM) sleep. Caffeine, the most widely used stimulant, causes a significant increase of sleep onset latency in rats and humans. We hypothesized that caffeine increases glutamate release in the posterior hypothalamus (PH) and produces increased activity of wake-active histamine neurons. Using in vivo microdialysis, we collected samples from the PH after caffeine administration in freely behaving rats. HPLC analysis and biosensor measurements showed a significant increase in glutamate levels beginning 30 min after caffeine administration. Glutamate levels remained elevated for at least 140 min. GABA levels did not significantly change over the same time period. Histamine level significantly increased beginning 30 min after caffeine administration and remained elevated for at least 140 min. Immunostaining showed a significantly elevated number of c-Fos-labeled histamine neurons in caffeine-treated rats compared with saline-treated animals. We conclude that increased glutamate levels in the PH activate histamine neurons and contribute to caffeine-induced waking and alertness. PMID:25031227

  2. Lymphatic diamine oxidase secretion stimulated by fat absorption is linked with histamine release

    PubMed Central

    Sakata, Yasuhisa; Li, Xiaoming; Zhang, Chao; Yang, Qing; Xu, Min; Wollin, Armin; Langhans, Wolfgang; Tso, Patrick

    2013-01-01

    Diamine oxidase (DAO) is abundantly expressed in mammalian small intestine catalyzing the oxidative breakdown of polyamines and histamine. The aim of this study was to determine the relationship between stimulation of intestinal diamine oxidase secretion with intestinal fat absorption and histamine release. Conscious intestinal lymph fistula rats were used. The mesenteric lymph ducts were cannulated and intraduodenal tubes were installed for the infusion of Liposyn II 20% (an intralipid emulsion). Lymphatic DAO activity and protein secretion were analyzed by radiometric assay and Western blot, respectively. Lymphatic histamine concentration was measured by ELISA. Infusion of Liposyn II (4.43 kcal/3 ml) resulted in a ∼3.5-fold increase in lymphatic DAO protein secretion and DAO activity, peaking at 1 h and lasting for 3 h. Liposyn II infusion also increased the lymphatic histamine release, a substrate for DAO. To determine the relationship of DAO release with histamine release, histamine was administered intraperitoneally (10 mg/kg) in fasting rats and resulted in a significant doubling in lymphatic DAO activity, supporting a link between histamine and DAO. In addition, ip administration of the histamine H4 receptor antagonist JNJ7777120 significantly reduced the Liposyn II-induced DAO output by 65.9%, whereas H1 (pyrilamine maleate), H2 (ranitidine), and H3 (thioperamide maleate) receptor antagonists had little effect. We conclude that DAO secretion may contribute to the catabolism of histamine released during fat absorption and this is probably mediated through the histamine H4 receptor. PMID:23413254

  3. Histamine H3 receptors regulate acetylcholine release from the guinea pig ileum myenteric plexus

    SciTech Connect

    Poli, E.; Coruzzi, G.; Bertaccini, G. )

    1991-01-01

    The effect of selective histamine H3-receptor agonists and antagonists on the acetylcholine release from peripheral nerves was evaluated in the guinea pig longitudinal muscle-myenteric plexus preparations, preloaded with ({sup 3}H)choline. In the presence of H1 and H2 blockade, histamine and (R)-{alpha}-methylhistamine inhibited the electrically-evoked acetylcholine release, being (R)-{alpha}-methylhistamine more active than histamine, but behaving as a partial agonist. The effect of histamine was completely reversed by selective H3-blocking drugs, thioperamide and impromidine, while only submaximal doses of (R)-{alpha}-methylhistamine were antagonized. Furthermore, thioperamide and impromidine enhanced the electrically-evoked acetylcholine release. On the contrary, the new H3-blocker, HST-7, was found substantially ineffective, both as histamine antagonist and as acetylcholine overflow enhancer. These data suggest that histamine exerts an inhibitory control on the acetylcholine release from intestinal cholinergic nerves through the activation of H3 receptors.

  4. Neurotensin stimulates histamine release from the isolated, spontaneously beating heart of rats.

    PubMed

    Rioux, F; Kérouac, R; St-Pierre, S

    1984-07-23

    Neurotensin (NT) evoked a transient, dose-dependent histamine release (ED50 170 ng ml-1) from the rat perfused heart. Histamine release by NT occurred within seconds and lasted less than 2 min. The histamine releasing effect of NT was followed by a dose-dependent increase of the perfusion pressure and a slight tachycardia. The histamine releasing effect of NT was completely abolished in hearts derived from rats pretreated for 3 days with high doses of compound 48/80. The coronary vasoconstrictor effect of NT was increased in hearts derived from compound 48/80-pretreated rats. The mast cell inhibitor cromoglycate markedly inhibited NT-induced histamine release without affecting the coronary vasoconstrictor effect of NT. The histamine releasing effect of NT was inhibited, while its coronary vasoconstrictor effect was markedly potentiated, in hearts derived from rats pretreated with the antiallergic and antiinflammatory steroid dexamethasone. The increase of perfusion pressure evoked by NT was not modified by antihistamine drugs. Infusions of exogenous histamine (10(-6)-10(-5) g ml-1) caused a dose-dependent coronary vasodilation in the rat perfused heart. The results suggest that NT stimulates histamine release from cardiac mast cells. These results together with those obtained in previous studies suggest that mast cell mediators (particularly histamine and serotonin) are unlikely to be responsible for the coronary vasoconstrictor effect of NT in the rat perfused heart.

  5. Histamine release inhibitory activity of Piper nigrum leaf.

    PubMed

    Hirata, Noriko; Naruto, Shunsuke; Inaba, Kazunori; Itoh, Kimihisa; Tokunaga, Masashi; Iinuma, Munekazu; Matsuda, Hideaki

    2008-10-01

    Oral administration of a methanolic extract of Piper nigrum leaf (PN-ext, 50, 200 and 500 mg/kg) showed a potent dose-dependent inhibition of dinitrofluorobenzene (DNFB)-induced cutaneous reaction at 1 h [immediate phase response (IPR)] after and 24 h [late phase response (LPR)] after DNFB challenge in mice which were passively sensitized with anti-dinitrophenyl (DNP) IgE antibody. Ear swelling inhibitory effect of PN-ext (50, 200 and 500 mg/kg, per os (p.o.)) on very late phase response (vLPR) in the model mice was significant but weaker than that on IPR. Oral administration of PN-ext (50, 200 and 500 mg/kg for 7 d) inhibited picryl chloride (PC)-induced ear swelling in PC sensitized mice. PN-ext exhibited in vitro inhibitory effect on compound 48/80-induced histamine release from rat peritoneal mast cells. Two lignans of PN-ext, (-)-cubebin (1) and (-)-3,4-dimethoxy-3,4-desmethylenedioxycubebin (2), were identified as major active principles having histamine release inhibitory activity.

  6. The suppression of IgE-mediated histamine release from mast cells following exocytic exclusion of biodegradable polymeric nanoparticles.

    PubMed

    Tahara, Kohei; Tadokoro, Satoshi; Yamamoto, Hiromitsu; Kawashima, Yoshiaki; Hirashima, Naohide

    2012-01-01

    The objective of this study is to evaluate the effect of polymeric nanoparticles (NPs) on the allergic response of mast cells that release inflammatory mediators such as histamine through exocytosis. Submicron-sized biodegradable poly(DL-lactide-co-glycolide) (PLGA) NPs were prepared by the emulsion solvent diffusion method. Here, we examined the interactions of the mast cells with two types of PLGA NPs, unmodified NPs and NPs modified with chitosan (CS), a biodegradable cationic polymer. The cellular uptake of NPs increased by CS modification due to electrostatic interactions with the plasma membrane. NPs were taken up by mast cells through an endocytic pathway (endocytic phase) and then the cellular uptake was saturated and maintained plateau level by the exclusion of NPs through exocytosis (exocytic phase). Antigen-induced histamine release from mast cells was inhibited during the exocytic phase. The extent of histamine release inhibition was related to the amount of excluded NPs. Exocytic exclusion of NPs competitively antagonize the antigen-induced exocytotic release of histamine by highjacking exocytosis machinery such as SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, since histamine release was recovered in mast cells that overexpress SNAP-23. The inhibitory effect of the allergic response by PLGA NPs was also evaluated in vivo using the mouse model for systemic anaphylaxis. The administration of NPs suppressed the antigen-induced systemic allergic response in vivo. In conclusion, PLGA NP itself has actions to inhibit the allergic responses mediated by mast cells.

  7. Histamine release by neurotensin in the rat hindquarter: structure-activity studies.

    PubMed

    Kerouac, R; St-Pierre, S; Rioux, F

    1984-01-01

    Histamine releasing effects of neurotensin (NT) and several NT fragments and structural analogues were measured in the rat perfused hindquarter. The results show that the chemical groups responsible for histamine release are located in the C-terminal sequence Arg9-Pro10-Tyr11-Ile12-Leu13-OH. Both the spatial configuration and positive charge of Arg8 and Arg9 appear to contribute to the histamine releasing effect of NT. Optimization of the histamine releasing effect of NT requires both a free C-terminal carboxyl group and the presence in position 11 of NT of an aromatic residue, with the L-configuration, bearing an heteroatom capable of hydrogen bonding with the receptor. The results indicate that the structural requirements of NT to induce histamine release from the rat perfused hindquarter are similar to those involved in other peripheral biological actions of NT.

  8. Luminal Nalpha-methyl histamine stimulates gastric acid secretion in duodenal ulcer patients via releasing gastrin.

    PubMed

    Konturek, P C; Konturek, S J; Sito, E; Kwiecien, N; Obtulowicz, W; Bielanski, W; Hahn, E G

    2001-01-26

    Nalpha-methyl histamine is an unusual histamine metabolite which is produced in the stomach infected by Helicobacter pylori and which was shown in animals to stimulate gastric acid secretion and to release gastrin in vitro isolated G-cells, but no information is available regarding its influence on gastric secretion and gastrin release in duodenal ulcer patients before and after H. pylori eradication. In this study, we compared the effects of intragastric administration of single or graded doses of Nalpha-methyl histamine on gastric acid secretion and plasma gastrin levels in 16 male duodenal ulcer patients (aging from 35 to 48 years and weighing 65-82 kg) before and after the eradication of H. pylori. Furthermore, the gastric luminal histamine and gastrin contents were determined before and after H. pylori eradication. In H. pylori-infected duodenal ulcer patients, the intragastric application of Nalpha-methyl histamine failed to affect gastric acid secretion or plasma gastrin levels. Following eradication of H. pylori, gastric luminal histamine and gastrin, and both basal gastric acid secretion and plasma gastrin levels, were significantly reduced. Nalpha-methyl histamine given intragastrically in graded doses to such H. pylori-eradicated duodenal ulcer patients was found to increase dose-dependently gastric acid output reaching at a dose of 5 mg, about 80% of histamine maximum induced by i.v. infusion of 25 microg/kg h of histamine dihydrochloride. We conclude that Nalpha-methyl histamine is a potent luminally active stimulant of gastrin release and gastric acid secretion in H. pylori-eradicated patients when luminal histamine is low but is not effective in H. pylori infected patients when luminal histamine is enhanced, possibly due to desensitization of gastrin (G-cells) and acid-producing (parietal) cells by Nalpha-methyl histamine produced excessively in H. pylori-infected stomach.

  9. The response of a human bronchial epithelial cell line to histamine: Intracellular calcium changes and extracellular release of inflammatory mediators

    SciTech Connect

    Noah, T.L.; Paradiso, A.M.; Madden, M.C.; McKinnon, K.P.; Devlin, R.B. )

    1991-11-01

    Epithelial cells are likely to modulate inflammation and tissue repair in the airways, but the factors responsible for these processes remain unclear. Because human airway epithelia are infrequently available for in vitro studies, transformed epithelial cell lines are of interest as models. The authors therefore investigated the response of an SV-40/adenovirus-transformed human bronchial epithelial cell line (BEAS-2B) to histamine, a mediator with relevance for airway diseases. The intracellular calcium response to histamine (10(-4) M) was measured, using Fura-2 and microspectrofluorimetry. Histamine induced a transient increase in intracellular calcium that originated from intracellular sources; this effect was inhibited by the H1 receptor antagonist diphenhydramine, suggesting that BEAS cells retain functioning histamine receptors. BEAS cells were grown to confluence on microporous, collagen-coated filters, allowing measurement of vectorial release of soluble mediators. Monolayers exposed to histamine for 30 min released interleukin-6 and fibronectin in the apical direction, in a dose-dependent manner. Little eicosanoid production was induced by histamine, either in the apical or the basolateral direction, although BEAS cells constitutively produced small amounts of prostaglandin E2 and 15-HETE. However, these cells formed large amounts of eicosanoids in response to ozone exposure as a positive control. Comparison of their data with published reports for human airway epithelia in primary culture suggests that the BEAS cell line is, in a number of respects, a relevant model for the study of airway epithelial responses to a variety of stimuli.

  10. Agarwood Inhibits Histamine Release from Rat Mast Cells and Reduces Scratching Behavior in Mice

    PubMed Central

    Inoue, Eiji; Shimizu, Yasuharu; Masui, Ryo; Tsubonoya, Tomoe; Hayakawa, Tomomi; Sudoh, Keiichi

    2016-01-01

    Objectives: This study was conducted to clarify the effects of agarwood on histamine release from mast cells in rats and on the scratching behaviors in mice. Methods: Histamine release from rat mast cells induced by compound 48/80 or concanavalin A (Con A) and compound 48/80-induced scratching behavior in mice were examined to investigate the effects of agarwood. The hyaluronidase activity and the 3’,5’-cyclic adenosine monophosphate (cAMP) levels in mast cells were examined to investigate the mechanisms for the inhibition of histamine release. The correlation between the inhibitory effects of agarwood on histamine release and the content of its typical ingredients, a 2-(2-phenylethyl)chromone derivatives, was analyzed using thin-layer chromatography. Results: Agarwood showed an inhibitory effect on mast-cell histamine release induced by compound 48/80 or Con A without any effect on hyaluronidase activity; this effect involves an increase in the cAMP levels in mast cells. Oral administration of agarwood showed an inhibitory effect on compound 48/80-induced scratching behavior in mice. The inhibitory effects of agarwood on histamine release were quite different, depending on the area where the agarwood was produced, its quality, and its market price. No correlation was found between the inhibitory effects of agarwood on histamine release and the typical ingredients of agarwood, which are 2-(2-phenylethyl)chromone derivatives. Conclusion: These results show that agarwood inhibits histamine release from mast cells partially through an increase in the cAMP levels in cells. We suggest that some active ingredients of agarwood must be effective on oral intake and that agarwood can be used to treat patients with a number of conditions, including urticaria, atopic dermatitis, and bronchial asthma, in which an increase in histamine release occurs. Differences in the pharmacological effects of this crude drug among markets may provide important information for the quality

  11. Agarwood Inhibits Histamine Release from Rat Mast Cells and Reduces Scratching Behavior in Mice

    PubMed Central

    Inoue, Eiji; Shimizu, Yasuharu; Masui, Ryo; Tsubonoya, Tomoe; Hayakawa, Tomomi; Sudoh, Keiichi

    2016-01-01

    Objectives: This study was conducted to clarify the effects of agarwood on histamine release from mast cells in rats and on the scratching behaviors in mice. Methods: Histamine release from rat mast cells induced by compound 48/80 or concanavalin A (Con A) and compound 48/80-induced scratching behavior in mice were examined to investigate the effects of agarwood. The hyaluronidase activity and the 3’,5’-cyclic adenosine monophosphate (cAMP) levels in mast cells were examined to investigate the mechanisms for the inhibition of histamine release. The correlation between the inhibitory effects of agarwood on histamine release and the content of its typical ingredients, a 2-(2-phenylethyl)chromone derivatives, was analyzed using thin-layer chromatography. Results: Agarwood showed an inhibitory effect on mast-cell histamine release induced by compound 48/80 or Con A without any effect on hyaluronidase activity; this effect involves an increase in the cAMP levels in mast cells. Oral administration of agarwood showed an inhibitory effect on compound 48/80-induced scratching behavior in mice. The inhibitory effects of agarwood on histamine release were quite different, depending on the area where the agarwood was produced, its quality, and its market price. No correlation was found between the inhibitory effects of agarwood on histamine release and the typical ingredients of agarwood, which are 2-(2-phenylethyl)chromone derivatives. Conclusion: These results show that agarwood inhibits histamine release from mast cells partially through an increase in the cAMP levels in cells. We suggest that some active ingredients of agarwood must be effective on oral intake and that agarwood can be used to treat patients with a number of conditions, including urticaria, atopic dermatitis, and bronchial asthma, in which an increase in histamine release occurs. Differences in the pharmacological effects of this crude drug among markets may provide important information for the quality

  12. Forskolin inhibits histamine release by neurotensin in the rat perfused hind limb.

    PubMed

    Kérouac, R; St-Pierre, S; Rioux, F

    1984-08-01

    We have assessed the influence of forskolin, a potent activator of adenylate cyclase, on histamine release by neurotensin (NT) in the rat perfused hind limb. The results indicate that forskolin, in concentrations known to increase the cyclic AMP content of various tissues, markedly inhibits the histamine releasing effect of NT. The inhibitory action of forskolin was mimicked by a synthetic cyclic AMP derivative and by 3-isobutyl-1-methyl-xanthine (IBMX), a potent phosphodiesterase inhibitor. Our results suggest that the inhibitory action of forskolin toward histamine release by NT in the rat hind limb mast cells results from the activation of a cyclic AMP-generating system in mast cells.

  13. Characterization of the histamine releasing effect of neurotensin in the rat heart.

    PubMed

    Rioux, F; Kérouac, R; St-Pierre, S

    1985-01-01

    Bolus injections of neurotensin (NT) in the rat perfused heart elicited a transient, dose-dependent histamine release. The histamine releasing effect of NT appears to be independent of the heart rate and coronary perfusion pressure and it was not influenced by atropine, propanolol, prazosin, methysergide, ketanserin, indomethacin, morphine, lidocaine or by removal of the atria. However, it was potentiated by adenosine, inhibited by sub-stimulatory concentrations of NT and the mast cell membrane stabilizing drug cromoglycate but was unaltered by the calcium antagonist verapamil. The absence of calcium in the heart perfusate suppressed the histamine releasing effect of NT. These results suggest that the histamine releasing effect of NT in the rat heart results from a direct effect on ventricular mast cells and is calcium-dependent.

  14. Enhanced histamine release from lung mast cells of guinea pigs exposed to sulfuric acid aerosols

    SciTech Connect

    Fujimaki, Hidekazu ); Katayama, Noboru; Wakamori, Kazuo )

    1992-06-01

    To clarify the relationship between air pollution and mast cell response, the effects of sulfuric acid aerosols on histamine release from lung mast cells of guinea pigs were investigated. Guinea pigs were exposed to 0.3, 1.0 and 3.2 mg/m{sup 3} sulfuric acid (H{sub 2}SO{sub 4}) aerosols or 4 ppm nitrogen dioxide (NO{sub 2}) for 2 and 4 weeks. After the exposure, lung mast cell suspensions were isolated by collagenase treatment and antigen- or A23187-induced histamine release was measured. Antigen-induced histamine release from mast cells was significantly enhanced by the exposure to 1.0 and 3.2 mg/m{sup 3} H{sub 2}SO{sub 4} for 2 weeks, but exposure to H{sub 2}SO{sub 4} for 4 weeks did not show the enhancement of antigen-induced histamine release. A23187-induced histamine release was significantly enhanced by the exposure to 1.0 mg/m{sup 3} H{sub 2}SO{sub 4} or 4 ppm NO{sub 2} for 2 weeks, but suppression of histamine release from lung mast cells stimulated with A23187 was observed by the exposure to 3.2 mg/m{sup 3} H{sub 2}So{sub 4} for 4 weeks. The exposure to 0.3 mg/m{sup 3} H{sub 2}So{sub 4} showed no changes in antigen- and A23187-induced histamine release. The combination of 1.0 mg/m{sup 3} H{sub 2}So{sub 4} with 4 ppm NO{sub 2} for 2 weeks resulted in no changes in antigen- and A23187-induced histamine release. These results suggested that functional properties of lung mast cells may be altered by a low concentration of H{sub 2}So{sub 4} aerosol exposure.

  15. Modulation of histamine release from human basophils in vitro by physiological concentrations of zinc

    SciTech Connect

    Marone, G.; Findlay, S.R.; Lichtenstein, L.M.

    1981-05-01

    Zinc, at physiologic concentrations, inhibits in vitro histamine release from human basophils induced by several immunologic (i.e., antigen and anti-immunoglobulin E (IgE) and nonimmunologic (Ca/sup + +/ ionophore A23187 and formylated tripeptide formyl-methionyl-leucyl-phenylalanine (f-met peptide)) stimuli in a dose-dependent manner. Inhibition begins at about 10(-6) (ionophore A23187, anti-IgE and antigen) or 10(-5) M (f-met peptide) and is maximum at 10(-4) M (80--100% inhibition of histamine release). The activity of zinc is about 25-fold greater with respect to ionophore A23187 (ID50 . 1.1 x 10(-6) M) than to f-met peptide-induced (ID50 . 4 x 10(-5) M) histamine release. Its activity on IgE-mediated histamine release is intermediate between these two extremes (ID50 . 9.7 x 10(-6) M). Zinc does not affect the first stage of histamine release but acts on the calcium-dependent second stage. It is a competitive antagonist of the action of Ca/sup + +/ in histamine secretion induced by antigen, anti-IgE and f-met peptide (but not by A23187) with a dissociation constant of about 1.2 x 10(-5) M. The addition of colchicine with zinc fails to increase the inhibition caused by the ion alone, suggesting the two compounds work via a common mechanism of action. Deuterium oxide reversed, in a dose-dependent manner, the inhibition of histamine release caused by zinc. These results suggest that the effect of zinc on histamine release from human basophils may be related to its influence on the microtubule system, directly or via its interaction with calcium.

  16. Potentiation of NF-κB-dependent transcription and inflammatory mediator release by histamine in human airway epithelial cells

    PubMed Central

    Holden, N S; Gong, W; King, E M; Kaur, M; Giembycz, M A; Newton, R

    2007-01-01

    Background and purpose: In asthma, histamine contributes to bronchoconstriction, vasodilatation and oedema, and is associated with the late phase response. The current study investigates possible inflammatory effects of histamine acting on nuclear factor κB (NF-κB)-dependent transcription and cytokine release. Experimental approach: Using BEAS-2B bronchial epithelial cells, NF-κB-dependent transcription and both release and mRNA expression of IL-6 and IL-8 were examined by reporter assay, ELISA and quantitative RT-PCR. Histamine receptors were detected using qualitative RT-PCR and function examined using selective agonists and antagonists. Key results: Addition of histamine to TNFα-stimulated BEAS-2B cells maximally potentiated NF-κB-dependent transcription 1.8 fold, whereas IL-6 and IL-8 protein release were enhanced 7.3- and 2.7-fold respectively. These responses were, in part, NF-κB-dependent and were associated with 2.6- and 1.7-fold enhancements of IL-6 and IL-8 mRNA expression. The H1 receptor antagonist, mepyramine, caused a rightward shift in the concentration-response curves of TNFα-induced NF-κB-dependent transcription (pA2=9.91) and release of IL-6 (pA2=8.78) and IL-8 (pA2=8.99). Antagonists of histamine H2, H3 and H4 receptors were without effect. Similarly, H3 and H4 receptor agonists did not affect TNFα-induced NF-κB-dependent transcription, or IL-6 and IL-8 release at concentrations below 10 μM. The anti-inflammatory glucocorticoid, dexamethasone, inhibited the histamine enhanced NF-κB-dependent transcription and IL-6 and IL-8 release. Conclusions and implications: Potentiation of NF-κB-dependent transcription and inflammatory cytokine release by histamine predominantly involves receptors of the H1 receptor subtype. These data support an anti-inflammatory role for H1 receptor antagonists by preventing the transcription and release of pro-inflammatory cytokines. PMID:17891168

  17. Inhibition of anaphylactic histamine release by Forssman antiserum. I. Characteristics of the reaction and inhibitor.

    PubMed Central

    Duravetz, J; Baumal, R; Broder, I

    1976-01-01

    Forssman antiserum produced in rabbits immunized with sheep erythrocyte stromata was found to contain an IgG antibody which inhibited both passive anaphylactic sensitization of guinea-pig lung and also histamine-releasing activity of soluble immune complexes. This Forssman antibody did not itself cause histamine release or depletion of lung histamine stores. The IgM haemolysin component of the Forssman antiserum was not associated with inhibitory activity. The inhibition by the IgG Forssman antibody differed from that of normal rabbit gammaglobulin both in its irreversible character and in being absorbed by sheep erythrocytes. The inhibitory antibody had no effect on the histamine-releasing activity of compound 48/80, anaphylatoxin or reversed anaphylaxis. It was concluded that IgG Forssman antibody probably blocks the tissue receptor(s) for anaphylactic antibody in guinea-pig lung. PMID:55380

  18. Inhaled nedocromil sodium reduces histamine release from isolated large airway segments of asthmatic subjects in vivo.

    PubMed

    Maxwell, D L; Hawksworth, R J; Lee, T H

    1993-09-01

    Placement of an intrabronchial single balloon catheter provides the possibility of measuring histamine release in isolated large airway segments in vivo. We wanted to assess the protective effect of nedocromil sodium on intrabronchial histamine release after hyperosmolar challenge. Six mild asthmatics were bronchoscoped 30 min after inhalation of 4 mg nedocromil sodium or placebo, given via a metered dose inhaler in a randomized, double-blind, cross-over study. Lavage of the left main bronchus was carried out proximal to a balloon catheter inflated at its bifurcation, and specimens were assayed for histamine and prostaglandin D2 (PGD2) by radioimmunoassay. The rise in histamine concentration in bronchial epithelial fluid following hyperosmolar saline challenge was significantly greater following placebo than following nedocromil sodium (mean +/- SEM prechallenge histamine concentration on placebo day 6.9 +/- 2.9 nM; post-challenge: 25.3 +/- 8.0 nM; mean +/- SEM prechallenge histamine concentration on the day nedocromil sodium was given: 3.7 +/- 0.7 nM; post-challenge 5.8 +/- 1.7 nM). Changes in PGD2 levels reflected the changes in histamine, but the variability of response was large, and there were no significant differences between the effects of placebo and nedocromil sodium. The procedure caused significantly greater falls in peak expiratory flow rates following placebo (mean +/- SEM percentage fall 20.2 +/- 4.4%) than following nedocromil sodium (0.9 +/- 5.8%, p < 0.02). We conclude that there is tonic basal histamine release within asthmatic airways, and that nedocromil sodium inhibits histamine release from mediator cells in vivo.

  19. Thioperamide, a histamine H3 receptor antagonist, increases GABA release from the rat hypothalamus.

    PubMed

    Yamamoto, Y; Mochizuki, T; Okakura-Mochizuki, K; Uno, A; Yamatodani, A

    1997-06-01

    Using a microdialysis method and a new high performance liquid chromatography (HPLC)-fluorometric method for the detection of gamma-aminobutyric acid (GABA), we investigated the effect of thioperamide, an H3 receptor antagonist, on the GABA content in the dialysate from the anterior hypothalamic area of rats anesthetized with urethane. The addition of thioperamide to the perfusion fluid increased the release of GABA and histamine. Depleting neuronal histamine with alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, and the administration of immepip, an H3 agonist, had no effect on basal- and thioperamide-induced GABA release. In addition, an infusion of clobenpropit, the most specific H3 receptor antagonist available, did not alter the basal release of GABA. On the other hand, histamine release was decreased by immepip and increased by thioperamide and clobenpropit. Removing Ca2+ from the perfusion fluid did not alter the effect of thioperamide on the GABA release, whereas that on histamine release was abrogated. These results suggest that the effect of thioperamide on GABA release is not mediated by histamine H3 receptors and that thioperamide acts on the transporter to cause an efflux of GABA from neurons and/or glia. Thioperamide is a popular H3 receptor antagonist which has been used applied to many studies. However, results using this compound should be interpreted in consideration of its effects on GABA release.

  20. Calcium influx and release mechanism(s) in histamine-induced myometrial contraction in buffaloes.

    PubMed

    Sharma, Abhishek; Choudhury, Soumen; Nakade, Udayraj P; Yadav, Rajkumar Singh; Garg, Satish Kumar

    2014-05-01

    The present study was undertaken to characterize the presence of histamine H1R using molecular biology tools and unravel the influx and release mechanism(s) involved in calcium signalling cascades in histamine-induced myometrial contraction in buffaloes. The presence of H1R mRNA transcript and immunoreactive membrane protein in buffalo myometrium was confirmed by RT-PCR and Western blot analysis. Further, histamine produced concentration-dependent (1nM-10μM) contraction in buffalo myometrium with a potency of 7.13±0.11. When myometrial strips were pre-incubated either with Ca(2+) free solution or with nifedipine, a L-type Ca(2+) channel blocker, dose response curve (DRC) of histamine was significantly (P<0.05) shifted towards right with decline in maximal contraction (Emax). Reduction in Emax of histamine in the presence of nifedipine (55.75±3.10%) was significantly (P<0.001) greater than that in the presence of ruthenium red (93.61±3.43%), a blocker of IP3-gated and RyR-sensitive Ca(2+) channels. Moreover, histamine produced only 26.87±1.99% of the maximum contraction in the presence of both nifedipine and CPA (blocker of sarco-endoplasmic reticulum Ca(2+)-ATPase). Interestingly, following concurrent exposure to U-73122 (a PL-C inhibitor) and nifedipine, the DRC of histamine was significantly (P<0.05) shifted towards left with increase in maximal contraction (126.30±3.36%). Our findings in buffalo uterus thus suggest that influx of extracellular calcium plays a major role in histamine-induced myometrial contraction, while release of intracellular calcium through calcium-release channels of sarcoplasmic reticulum has a minor role. A possible involvement of non-selective cation channels in histamine-induced myometrial contraction cannot be ruled out, and therefore requires further investigations. PMID:24631173

  1. Calcium influx and release mechanism(s) in histamine-induced myometrial contraction in buffaloes.

    PubMed

    Sharma, Abhishek; Choudhury, Soumen; Nakade, Udayraj P; Yadav, Rajkumar Singh; Garg, Satish Kumar

    2014-05-01

    The present study was undertaken to characterize the presence of histamine H1R using molecular biology tools and unravel the influx and release mechanism(s) involved in calcium signalling cascades in histamine-induced myometrial contraction in buffaloes. The presence of H1R mRNA transcript and immunoreactive membrane protein in buffalo myometrium was confirmed by RT-PCR and Western blot analysis. Further, histamine produced concentration-dependent (1nM-10μM) contraction in buffalo myometrium with a potency of 7.13±0.11. When myometrial strips were pre-incubated either with Ca(2+) free solution or with nifedipine, a L-type Ca(2+) channel blocker, dose response curve (DRC) of histamine was significantly (P<0.05) shifted towards right with decline in maximal contraction (Emax). Reduction in Emax of histamine in the presence of nifedipine (55.75±3.10%) was significantly (P<0.001) greater than that in the presence of ruthenium red (93.61±3.43%), a blocker of IP3-gated and RyR-sensitive Ca(2+) channels. Moreover, histamine produced only 26.87±1.99% of the maximum contraction in the presence of both nifedipine and CPA (blocker of sarco-endoplasmic reticulum Ca(2+)-ATPase). Interestingly, following concurrent exposure to U-73122 (a PL-C inhibitor) and nifedipine, the DRC of histamine was significantly (P<0.05) shifted towards left with increase in maximal contraction (126.30±3.36%). Our findings in buffalo uterus thus suggest that influx of extracellular calcium plays a major role in histamine-induced myometrial contraction, while release of intracellular calcium through calcium-release channels of sarcoplasmic reticulum has a minor role. A possible involvement of non-selective cation channels in histamine-induced myometrial contraction cannot be ruled out, and therefore requires further investigations.

  2. Involvement of histamine released from mast cells in acute radiation dermatitis in mice.

    PubMed

    Moriyasu, Saiko; Yamamoto, Kouichi; Kureyama, Naoko; Okamura, Keita; Ikeda, Toshiji; Yamatodani, Atsushi

    2007-06-01

    A possible involvement of histamine in acute radiation dermatitis in mice was investigated. The dose of 40 Gy of gamma irradiation induced erythema and edema in C57BL/6 mice treated with vehicle. However, in C57BL/6 mice treated with chlorpheniramine and WBB6F1-W/Wv mice, erythema and edema were not observed. In all of these mice, epilation and dry desquamation were induced, but bepotastine significantly reduced the extent of these areas. These results suggest that gamma irradiation-induced erythema and edema were caused by histamine released from mast cells via histamine H1 receptor, and epilation was induced by other inflammatory mediators.

  3. The effect of hardness of food on amygdalar histamine release in rats.

    PubMed

    Ishizuka, Tomoko; Sako, Noritaka; Murotani, Tomotaka; Morimoto, Aya; Yamatodani, Atsushi; Ohura, Kiyoshi

    2010-02-01

    When animals eat food, the oral cavity receives a variety of sensory information from food. The hardness of food, which elicits somatic sensation, is thought to affect feeding behavior, however, the details of neuronal mechanism are unclear. The histaminergic system is known to be involved in feeding behavior, and our previous studies indicated that gustatory information activates the histaminergic system, and that palatability of tastants influences its activity. From these findings, we hypothesized that the hardness of food may affect the histaminergic system. Thus, in the present study, we examined the effect of the hardness of food on histamine release in the central nucleus of amygdala when rats consumed either of two types of pellets composed of similar ingredients but having different degrees of hardness: hard and soft pellets. Histamine release was significantly increased in the rat fed with hard pellets. By contrast, histamine release was not enhanced in soft pellets-fed rats. There were no significant differences between the hard and soft pellet intakes during the experimental period. When rats acquired a conditioned aversion to soft pellets, histamine release was increased during feeding, in sharp contrast to no change of histamine release pattern seen during unconditioned soft pellet intake. These observations indicate that the amygdalar histaminergic system is modulated by oral somatic sensation from food, and by palatability of food texture.

  4. Modulations of histamine release from mast cells by interleukin-2 is affected by nedocromil sodium.

    PubMed

    Rubinchik, E; Norris, A; Levi-Schaffer, F

    1995-07-01

    We have previously demonstrated that histamine release from immunologically activated mast cells (MC) is enhanced by their preincubation (1 h) with interleukin-2(IL-2), and that IL-2 induces slow-chronic histamine release by MC in long-term cultures (6 days). In the present study we assessed whether nedocromil sodium can interfere with IL-2 modulation of MC histamine release. IL-2 enhancing effects nedocromil sodium activity were studied in cocultures of rat peritoneal MC with 3T3 fibroblasts (MC/3T3). MC/3T3 were preincubated for 1 h with IL-2 (50 micrograms/ml) and activated with either rabbit anti-rat IgE or compound 48/80. In chronic experiments MC/3T3 were long-term (5-6 days) incubated with IL-2 (50 micrograms/ml). Nedocromil sodium was used at 10(-5) M. MC activation both when added during the preincubation period (no tachyphylaxis was present) and when added together with the MC activators (30-50% inhibition). Washing out IL-2 before addition of the anti-IgE antibodies did not affect its histamine-release enhancing activity. Removal of nedocromil sodium before addition of the stimulus completely abrogated its effect. Continuous presence of IL-2 in the culture medium enhanced spontaneous histamine release by 37% and this effect was completely abolished in the presence of nedocromil sodium. Furthermore, nedocromil sodium decreased MC basal histamine release by 23% in long-term cocultures. Since IL-2 is known to be elevated in some pathological conditions, our results show that nedocromil sodium inhibits MC activation in an in vitro system which may represent a close resemblance to the in vivo allergic response.

  5. Centrally injected histamine increases posterior hypothalamic acetylcholine release in hemorrhage-hypotensive rats.

    PubMed

    Altinbas, Burcin; Yilmaz, Mustafa S; Savci, Vahide; Jochem, Jerzy; Yalcin, Murat

    2015-01-01

    Histamine, acting centrally as a neurotransmitter, evokes a reversal of hemorrhagic hypotension in rats due to the activation of the sympathetic and the renin-angiotensin systems as well as the release of arginine vasopressin and proopiomelanocortin-derived peptides. We demonstrated previously that central nicotinic cholinergic receptors are involved in the pressor effect of histamine. The aim of the present study was to examine influences of centrally administrated histamine on acetylcholine (ACh) release at the posterior hypothalamus-a region characterized by location of histaminergic and cholinergic neurons involved in the regulation of the sympathetic activity in the cardiovascular system-in hemorrhage-hypotensive anesthetized rats. Hemodynamic and microdialysis studies were carried out in Sprague-Dawley rats. Hemorrhagic hypotension was induced by withdrawal of a volume of 1.5 ml blood/100 g body weight over a period of 10 min. Acute hemorrhage led to a severe and long-lasting decrease in mean arterial pressure (MAP), heart rate (HR), and an increase in extracellular posterior hypothalamic ACh and choline (Ch) levels by 56% and 59%, respectively. Intracerebroventricularly (i.c.v.) administered histamine (50, 100, and 200 nmol) dose- and time-dependently increased MAP and HR and caused an additional rise in extracellular posterior hypothalamic ACh and Ch levels at the most by 102%, as compared to the control saline-treated group. Histamine H1 receptor antagonist chlorpheniramine (50 nmol; i.c.v.) completely blocked histamine-evoked hemodynamic and extracellular posterior hypothalamic ACh and Ch changes, whereas H2 and H3/H4 receptor blockers ranitidine (50 nmol; i.c.v.) and thioperamide (50 nmol; i.c.v.) had no effect. In conclusion, centrally administered histamine, acting via H1 receptors, increases ACh release at the posterior hypothalamus and causes a pressor and tachycardic response in hemorrhage-hypotensive anesthetized rats.

  6. [Medicinal foodstuffs. XI. Histamine release inhibitors from wax gourd, the fruits of Benincasa hispida Cogn].

    PubMed

    Yoshizumi, S; Murakami, T; Kadoya, M; Matsuda, H; Yamahara, J; Yoshikawa, M

    1998-05-01

    The methanol extract of wax gourd (Japanese name "Tougan"), the fruits of Benincasa hispida COGN. (Cucurbitaceae), was found to show inhibitory activity on the histamine release from rat exudate cells induced by antigen-antibody reaction. Through bioassay-guided separation, four known triterpenes and two known sterols were isolated as active components together with a flavonoid C-glycoside, an acylated glucose, and a benzyl glycoside. Among the active triterpenes and sterols, two triterpenes, alnusenol and multiflorenol, were found to potently inhibit the histamine release. PMID:9612135

  7. Enhancement of mite antigen-induced histamine release by deuterium oxide from leucocytes of chronic urticarial patients

    SciTech Connect

    Numata, T.; Yamamoto, S.; Yamura, T.

    1981-09-01

    The mite antigen-induced histamine release from leucocytes of chronic urticarial patients was enhanced in the presence of deuterium oxide, which stabilizes microtubules. This enhancing effect of deuterium oxide on the histamine release from leucocytes may provide a useful means for the detection of allergens in vitro in chronic urticaria.

  8. Optogenetic-mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal.

    PubMed

    Williams, Rhannan H; Chee, Melissa J S; Kroeger, Daniel; Ferrari, Loris L; Maratos-Flier, Eleftheria; Scammell, Thomas E; Arrigoni, Elda

    2014-04-23

    Histaminergic neurons in the tuberomammillary nucleus (TMN) are an important component of the ascending arousal system and may form part of a "flip-flop switch" hypothesized to regulate sleep and wakefulness. Anatomical studies have shown that the wake-active TMN and sleep-active ventrolateral preoptic nucleus (VLPO) are reciprocally connected, suggesting that each region can inhibit its counterpart when active. In this study, we determined how histamine affects the two branches of this circuit. We selectively expressed channelrhodopsin-2 (ChR2) in TMN neurons and used patch-clamp recordings in mouse brain slices to examine the effects of photo-evoked histamine release in the ventrolateral TMN and VLPO. Photostimulation decreased inhibitory GABAergic inputs to the ventrolateral TMN neurons but produced a membrane hyperpolarization and increased inhibitory synaptic input to the VLPO neurons. We found that in VLPO the response to histamine was indirect, most likely via a GABAergic interneuron. Our experiments demonstrate that release of histamine from TMN neurons can disinhibit the TMN and suppresses the activity of sleep-active VLPO neurons to promote TMN neuronal firing. This further supports the sleep-wake "flip-flop switch" hypothesis and a role for histamine in stabilizing the switch to favor wake states.

  9. Histamine and FLRFamide regulate acetylcholine release at an identified synapse in Aplysia in opposite ways.

    PubMed Central

    Baux, G; Fossier, P; Tauc, L

    1990-01-01

    1. The effects of histamine and FLRFamide (Phe-Leu-Arg-Phe-NH2) on acetylcholine (ACh) release were studied in the buccal ganglion of Aplysia californica on an identified synapse (buccal ganglion inhibitory synapse, BGIS) involved in a small neuronal circuit controlling the feeding behaviour. The inhibitory postsynaptic current (IPSC) evoked by a presynaptic spike in the voltage-clamped postsynaptic neurone was decreased by histamine and increased by FLRFamide. 2. Histamine and FLRFamide modified the amplitude of the presynaptic spike. To test if these drugs acted directly on presynaptic calcium influx, we evoked transmitter release by 3 s depolarizations of the presynaptic neurone (to +10 mV) under voltage clamp to avoid modifications of presynaptic membrane polarization induced by changes in presynaptic voltage-dependent K+ and/or Na+ conductances. 3. Statistical analysis of this evoked long-duration (3 s) induced postsynaptic current (LDIPSC) allowed us to calculate the amplitude and the decay time of the miniature postsynaptic current and consequently the number of quanta released by the presynaptic terminal. 4. The amplitude of the LDIPSC decreased during the 3 s presynaptic depolarization. This was not due to a lack of available transmitter, since LDIPSC amplitude could be maintained constant by a 'clamp of the release of ACh' which adequately depolarized the presynaptic neurone, but rather to changes in the calcium influx into the presynaptic neurone. 5. FLRFamide increased more the initial portions of the LDIPSC than the final portions. This effect of FLRFamide was only reduced and delayed by atropine or curare, antagonists of muscarinic-like and nicotinic-like autoreceptors previously demonstrated to be present at the same terminal. Activation of the nicotinic-like receptors, which also increased transmitter release, induced a modification of the shape of the LDIPSC which was completely different from that due to FLRFamide. 6. Histamine decreased the

  10. Histamine release and fibrinogen adsorption mediate acute inflammatory responses to biomaterial implants in humans

    PubMed Central

    Zdolsek, Johann; Eaton, John W; Tang, Liping

    2007-01-01

    Background Medical implants often fail as a result of so-called foreign body reactions during which inflammatory cells are recruited to implant surfaces. Despite the clinical importance of this phenomenon, the mechanisms involved in these reactions to biomedical implants in humans are not well understood. The results from animal studies suggest that both fibrinogen adsorption to the implant surface and histamine release by local mast cells are involved in biomaterial-mediated acute inflammatory responses. The purpose of this study was to test this hypothesis in humans. Methods Thirteen male medical student volunteers (Caucasian, 21–30 years of age) were employed for this study. To assess the importance of fibrinogen adsorption, six volunteers were implanted with polyethylene teraphthalate disks pre-coated with their own (fibrinogen-containing) plasma or (fibrinogen-free) serum. To evaluate the importance of histamine, seven volunteers were implanted with uncoated disks with or without prior oral administration of histamine receptor antagonists. The acute inflammatory response was estimated 24 hours later by measuring the activities of implant-associated phagocyte-specific enzymes. Results Plasma coated implants accumulated significantly more phagocytes than did serum coated implants and the recruited cells were predominantly macrophage/monocytes. Administration of both H1 and H2 histamine receptor antagonists greatly reduced the recruitment of macrophages/monocytes and neutrophils on implant surfaces. Conclusion In humans – as in rodents – biomaterial-mediated inflammatory responses involve at least two crucial events: histamine-mediated phagocyte recruitment and phagocyte accumulation on implant surfaces engendered by spontaneously adsorbed host fibrinogen. Based on these results, we conclude that reducing fibrinogen:surface interactions should enhance biocompatibility and that administration of histamine receptor antagonists prior to, and shortly after

  11. Mosla punctulata Inhibits Mast Cell-mediated Allergic Reactions Through the Inhibition of Histamine Release and Inflammatory Cytokine Production

    PubMed Central

    Je, I. G.; Shin, T. Y.; Kim, S. H.

    2013-01-01

    Allergic inflammatory diseases such as food allergy, asthma, sinusitis and atopic dermatitis are increasing worldwide. This study examined the effects of aqueous extract of Mosla punctulata on mast cell-mediated allergic inflammation and studied the possible mechanism of action. Aqueous extract of Mosla punctulata inhibited compound 48/80-induced systemic and immunoglobulin E-mediated local anaphylaxis and it also reduced intracellular calcium level and down-streamed histamine release from mast cells. In addition, aqueous extract of Mosla punctulata decreased gene expression and secretion of tumour necrosis factor alpha, an important proinflammatory cytokine, in mast cells. The inhibitory effect on tumour necrosis factor alpha expression was nuclear factor kappa B dependent. The results indicate that aqueous extract of Mosla punctulata inhibited mast cell-mediated allergic inflammatory reaction by suppressing histamine release and expression of tumour necrosis factor alpha, and involvement of calcium and nuclear factor kappa B in these effects. Hence it can be concluded that, the aqueous extract of Mosla punctulata might be a possible therapeutic candidate for allergic inflammatory disorders. PMID:24591741

  12. The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception.

    PubMed

    Parada, C A; Tambeli, C H; Cunha, F Q; Ferreira, S H

    2001-01-01

    Formalin injected subcutaneously into the paw is a widely used model of pain. This procedure evokes a short-lasting period of flinching (phase 1) and a long-lasting period of intense flinching (phase 2) following a very short period of quiescence. Phase 2 has been extensively used to support the involvement of central (spinal cord) sensitization in inflammatory hyperalgesia. The present study evaluated the contribution of stimulation of peripheral nociceptors by the release of endogenous mediators at the site of lesion. The participation of histamine and 5-hydroxytryptamine was demonstrated by the treatment of the rat hindpaws with selective histamine H1 (pyrilamine and meclizine) and histamine H2 (cimetidine) receptor antagonists or selective 5-hydroxytryptamine(1A) (WAY100,135) and 5-hydroxytryptamine(4/3) (tropisetron) receptor antagonists. The co-administration of pyrilamine or meclizine with formalin (1%) significantly reduced phases 1 and 2, while cimetidine had no effect. Pyrilamine administration during the period of quiescence (10min after formalin administration) caused strong dose-related inhibition of phase 2. The co-administration of tropisetron with formalin caused a blockade of both phases, while with WAY100,135 caused only inhibition of the phase 2. In contrast, tropisetron administrated during the period of quiescence did not cause antinociception. Histamine and 5-hydroxytryptamine receptors could be strongly activated in naïve animals by administration of a mixture of both agonists or compound 48/80 (2microg/paw) which is known to release both mediators from mast cells. Pretreatment of the paws with a mast cell stabilizer, sodium cromoglycate, significantly reduced the second phase of the formalin injection model. From these results we suggest that phases 1 and 2 of the formalin test are dependent upon the ongoing afferent input. Furthermore, while histamine H1 participates in both phases, 5-hydroxytryptamine(4/3) participates in phase 1 and 5

  13. Constituents in watercress: inhibitors of histamine release from RBL-2H3 cells induced by antigen stimulation.

    PubMed

    Goda, Y; Hoshino, K; Akiyama, H; Ishikawa, T; Abe, Y; Nakamura, T; Otsuka, H; Takeda, Y; Tanimura, A; Toyoda, M

    1999-12-01

    Histamine release inhibitors in watercress (Nasturtium officinale) were isolated using a monitoring system with antigen-stimulated RBL-2H3 cells. Of the 15 compounds isolated, flavonols and megastigmanes significantly inhibited histamine release. Two flavonols, 3-O-sophorosides of rhamnetin and rhamnazin, were new compounds. To investigate the inhibitory mechanism, the effects of rhamnetin, rhamnetin 3-O-sophoroside and an isolated megastigmane glucoside on the increase in the intracellular free calcium concentration were examined at a concentration providing 60% inhibition of histamine release. The results suggest that these compounds did not affect the calcium influx at that concentration. The structure-activity relationships of the megastigmanes on histamine release were also investigated.

  14. Sensitization and histamine release by cells of the sand dollar, Mellita quinquiesperforata.

    PubMed

    Smith, S L; Smith, A C

    1985-01-01

    The coelomic fluid of the sand dollar, Mellita quinquiesperforata, contains cells (coelomocytes) that release red granules when the animal is stressed. Preliminary evidence suggests that the red pigment is protective, but its release from the coelomocytes is similar to that of allergy-inducing mediators from mammalian basophils and mast cells. The present study revealed further links with allergy, e.g., the coelomocytes can be sensitized to foreign proteins and release histamine on challenge. These and other findings suggest that the coelomocyte stress response may be an evolutionary precursor to the mammalian allergic response. PMID:2417896

  15. Nesfatin-1, corticotropin-releasing hormone, thyrotropin-releasing hormone, and neuronal histamine interact in the hypothalamus to regulate feeding behavior.

    PubMed

    Gotoh, Koro; Masaki, Takayuki; Chiba, Seiichi; Ando, Hisae; Shimasaki, Takanobu; Mitsutomi, Kimihiko; Fujiwara, Kansuke; Katsuragi, Isao; Kakuma, Tetsuya; Sakata, Toshiie; Yoshimatsu, Hironobu

    2013-01-01

    Nesfatin-1, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and hypothalamic neuronal histamine act as anorexigenics in the hypothalamus. We examined interactions among nesfatin-1, CRH, TRH, and histamine in the regulation of feeding behavior in rodents. We investigated whether the anorectic effect of nesfatin-1, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), a CRH antagonist, or anti-TRH antibody affects the anorectic effect of nesfatin-1, whether nesfatin-1 increases CRH and TRH contents and histamine turnover in the hypothalamus, and whether histamine increases nesfatin-1 content in the hypothalamus. We also investigated whether nesfatin-1 decreases food intake in mice with targeted disruption of the histamine H1 receptor (H1KO mice) and if the H1 receptor (H1-R) co-localizes in nesfatin-1 neurons. Nesfatin-1-suppressed feeding was partially attenuated in rats administered with FMH, a CRH antagonist, or anti-TRH antibody, and in H1KO mice. Nesfatin-1 increased CRH and TRH levels and histamine turnover, whereas histamine increased nesfatin-1 in the hypothalamus. Immunohistochemical analysis revealed H1-R expression on nesfatin-1 neurons in the paraventricular nucleus of the hypothalamus. These results indicate that CRH, TRH, and hypothalamic neuronal histamine mediate the suppressive effects of nesfatin-1 on feeding behavior.

  16. Evidence for lipoxygenase activity in induction of histamine release from rat peritoneal mast cells by chelated iron.

    PubMed Central

    Magro, A M; Brai, M

    1983-01-01

    The ferric iron-desferrioxamine B chelate effectively induced histamine release from rat peritoneal mast cells. The release was maximum at exogenous ferric iron concentrations of 10-100 microM, and the chelate was non-toxic, as determined by trypan blue uptake. In many aspects the chelate-induced histamine release paralleled IgE-mediated release. The kinetics, temperature, and Ca2+ dependence resembled antigen-induced release. Phosphatidylserine potentiated the release in Wistar rats but not in fawn-hooded rats, a strain which does not respond to phosphatidylserine potentiation. The chelate-induced histamine release was blocked by the metabolic inhibitors dinitrophenol, potassium cyanide, 2-deoxyglucose, and antimycin A. Lipoxygenase inhibitors also effectively blocked release, indicating an involvement of fatty acid metabolism via the lipoxygenase pathway. Free radical scavengers and antioxidants antagonistic to lipid peroxidation also inhibited the chelate-induced histamine release. Overall the data raise the possibility that endogenous cellular iron may be involved in the generation of free radicals and lipid peroxidation and that these may be early events in IgE-mediated release of histamine. PMID:6188682

  17. Effects of shear stress on intracellular calcium change and histamine release in rat basophilic leukemia (RBL-2H3) cells.

    PubMed

    Yang, Wenzhong; Chen, Jiyao; Zhou, Luwei

    2009-01-01

    Massage, one form of physical therapy, is widely used for a large number of musculoskeletal disorders, but its exact mechanism still remains to be elucidated. One hypothesis is that the shear stress caused by massage may induce cutaneous mast cells to release histamine, thereby improving the local tissue microcirculation of blood. In the present work, a mast cell line (rat basophilic leukemia cells, RBL-2H3) was used in vitro to study cellular responses to the stimulus of shear stress generated by a rotating rotor in a cell dish. The intracellular calcium ([Ca2+]c) was studied by confocal fluorescence microscopy with Fluo-3/AM staining and the released histamine was measured with a fluorescence spectrometer using o-phthalaldehyde (OPA) staining. An elevation of [Ca2+]c occurred immediately after the shear stress, followed by histamine release. However, both [Ca2+]c increase and histamine release disappeared when a Ca2+-free saline was used, indicating that the rise in the [Ca2+]c is due to a Ca2+ influx from the extracellular buffer. Furthermore, Ruthenium red, a transient receptor potential vanilloid (TRPV) inhibitor, could effectively block the shear stressinduced histamine release, suggesting that TRPV membrane proteins are the likely targets of the shear stress. Because histamine is a well-known mediator of microvascular tissue dilation, these results may have an important impact on understanding the mechanism involved in massage therapy. PMID:19888909

  18. Effects of methyl p-hydroxybenzoate (methyl paraben) on Ca2+ concentration and histamine release in rat peritoneal mast cells

    PubMed Central

    Fukugasako, Sanae; Ito, Shinichi; Ikemoto, Yoshimi

    2003-01-01

    Mechanisms of methyl p-hydroxybenzoate (methyl paraben) action in allergic reactions were investigated by measuring the intracellular Ca2+ concentration ([Ca2+]i) and histamine release in rat peritoneal mast cells (RPMCs). In the presence or absence of extracellular Ca2+, methyl paraben (0.1–10 mM) increased [Ca2+]i, in a concentration-dependent manner. Under both the conditions, methyl paraben alone did not evoke histamine release. In RPMCs pretreated with a protein kinase C (PKC) activator (phorbol 12-myristate 13-acetate (PMA) 3 and 10 nM), methyl paraben (0.3–3 mM) induced histamine release. However, a high concentration (10 mM) of the agent did not increase the histamine release. U73122 (0.1 and 0.5 μM), an inhibitor of phospholipase C (PLC), significantly inhibited the methyl paraben-induced histamine release in PMA-pretreated RPMCs. U73343 (0.5 μM), an inactive analogue of U73122, did not inhibit the histamine release caused by methyl paraben. In Ca2+-free solution, PLC inhibitors (U73122 0.1 and 0.5 μM, D609 1–10 μM) inhibited the methyl paraben-induced increase in [Ca2+]i, whereas U73343 (0.5 μM) did not. Xestospongin C (2–20 μM) and 2 aminoethoxydiphenyl borate (30 and 100 μM), blockers of the inositol 1,4,5-trisphosphate (IP3) receptor, inhibited the methyl paraben-induced increase in [Ca2+]i in Ca2+-free solution. In conclusion, methyl paraben causes an increase in [Ca2+]i, which may be due to release of Ca2+ from storage sites by IP3 via activation of PLC in RPMCs. In addition, methyl paraben possibly has some inhibitory effects on histamine release via unknown mechanisms. PMID:12770943

  19. Pre-synaptic histamine H3 receptors regulate glutamate, but not GABA release in rat thalamus.

    PubMed

    Garduño-Torres, Belén; Treviño, Mario; Gutiérrez, Rafael; Arias-Montaño, José-Antonio

    2007-02-01

    We have investigated the presence of histamine H(3) receptors (H(3)Rs) on rat thalamic isolated nerve terminals (synaptosomes) and the effect of their activation on glutamate and GABA release. N-alpha-[methyl-(3)H]histamine ([(3)H]-NMHA) bound specifically to synaptosomal membranes with dissociation constant (K(d)) 0.78+/-0.20 nM and maximum binding (B(max)) 141+/-12fmol/mg protein. Inhibition of [(3)H]-NMHA binding by histamine and the H(3)R agonist immepip fit better to a two-site model, whereas for the H(3)R antagonist clobenpropit the best fit was to the one-site model. GTPgammaS (30 microM) decreased [(3)H]-NMHA binding by 55+/-4% and made the histamine inhibition fit better to the one-site model. Immepip (30 nM) induced a modest, but significant increase (113+/-2% of basal) in [(35)S]-GTPgammaS binding to synaptosomal membranes, an effect prevented by clobenpropit (1 microM) and by pre-treatment with pertussis toxin. In thalamus synaptosomes depolarisation-induced, Ca(2+)-dependent glutamate release was inhibited by histamine (1 microM, 25+/-4% inhibition) and immepip (30 nM, 38+/-5% reduction). These effects were reversed by clobenpropit (1microM). Conversely, immepip (up to 1 microM) had no effect on depolarisation-evoked [(3)H]-GABA release. Extracellular synaptic responses were recorded in the thalamus ventrobasal complex by stimulating corticothalamic afferents. H(3)R activation reduced by 38+/-7% the glutamate receptor-mediated field potentials (FPs), but increased the FP2/FP1 ratio (from 0.86+/-0.03 to 1.38+/-0.05) in a paired-pulse paradigm. Taken together, our results confirm the presence of H(3)Rs on thalamic nerve terminals and show that their activation modulates pre-synaptically glutamatergic, but not GABAergic neurotransmission.

  20. The effects of a chactoid scorpion venom and its purified toxins on rat blood pressure and mast cells histamine release.

    PubMed

    Ettinger, Keren; Cohen, Gadi; Momic, Tatjana; Lazarovici, Philip

    2013-07-29

    The effect of the venom of the Chactoid family of scorpions on blood pressure was scantly investigated and was addressed in the present study using the venom of the Israeli scorpion, Scorpio maurus palmatus. Blood pressure in rats was monitored via cannulated femoral artery, while venom and toxins were introduced into femoral vein. Venom injection elicited a biphasic effect, expressed first by a fast and transient hypotensive response, which lasted up to 10 min, followed by a hypertensive response, which lasted up to one hour. It was found that these effects resulted from different venom components. Phospholipase A₂ produced the hypotensive effect, while a non-enzymatic neurotoxic polypeptide fraction produced the hypertensive effect. Surprisingly, the main neurotoxic polypeptide to mice had no effect on blood pressure. In vitro experiments indicated that the hypertensive factors caused histamine release from the peritoneal mast cells, but this effect is assumed to be not relevant to their in vivo effect. In spite of the cytotoxic activity of phospholipase A₂, it did not release histamine. These findings suggest that the effects of venom and isolated fractions on blood pressure parameters are mediated by different mechanisms, which deserve further pharmacological investigation.

  1. Histamine Induces ATP Release from Human Subcutaneous Fibroblasts, via Pannexin-1 Hemichannels, Leading to Ca2+ Mobilization and Cell Proliferation*

    PubMed Central

    Pinheiro, Ana Rita; Paramos-de-Carvalho, Diogo; Certal, Mariana; Costa, Maria Adelina; Costa, Cristina; Magalhães-Cardoso, Maria Teresa; Ferreirinha, Fátima; Sévigny, Jean; Correia-de-Sá, Paulo

    2013-01-01

    Changes in the regulation of connective tissue ATP-mediated mechano-transduction and remodeling may be an important link to the pathogenesis of chronic pain. It has been demonstrated that mast cell-derived histamine plays an important role in painful fibrotic diseases. Here we analyzed the involvement of ATP in the response of human subcutaneous fibroblasts to histamine. Acute histamine application caused a rise in intracellular Ca2+ ([Ca2+]i) and ATP release from human subcutaneous fibroblasts via H1 receptor activation. Histamine-induced [Ca2+]i rise was partially attenuated by apyrase, an enzyme that inactivates extracellular ATP, and by blocking P2 purinoceptors with pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) tetrasodium salt and reactive blue 2. [Ca2+]i accumulation caused by histamine was also reduced upon blocking pannexin-1 hemichannels with 10Panx, probenecid, or carbenoxolone but not when connexin hemichannels were inhibited with mefloquine or 2-octanol. Brefeldin A, an inhibitor of vesicular exocytosis, also did not block histamine-induced [Ca2+]i mobilization. Prolonged exposure of human subcutaneous fibroblast cultures to histamine favored cell growth and type I collagen synthesis via the activation of H1 receptor. This effect was mimicked by ATP and its metabolite, ADP, whereas the selective P2Y1 receptor antagonist, MRS2179, partially attenuated histamine-induced cell growth and type I collagen production. Expression of pannexin-1 and ADP-sensitive P2Y1 receptor on human subcutaneous fibroblasts was confirmed by immunofluorescence confocal microscopy and Western blot analysis. In conclusion, histamine induces ATP release from human subcutaneous fibroblasts, via pannexin-1 hemichannels, leading to [Ca2+]i mobilization and cell growth through the cooperation of H1 and P2 (probably P2Y1) receptors. PMID:23918924

  2. Characteristics of histamine release from rat mast cells in relation to the valency of the stimulating ligand.

    PubMed Central

    Healicon, R M; Foreman, J C

    1986-01-01

    The relationship between the valency of a ligand and the subsequent characteristics of histamine release was investigated in rat peritoneal mast cells. The cells were passively sensitized to the DNP hapten and a series of DNP-human serum albumin conjugates of known valency were used to induce histamine release. The rate of release of histamine induced by these conjugates was independent of the DNP/HSA ratio when the ratio was between 71.3 and 7.2. Marked slowing of the release occurred as the ratio was reduced below 7.2. The rate of desensitization of the cells slowed as a continuous function as the DNP/HSA ratio was reduced. 45Calcium uptake measurements showed that the changes in histamine release were paralleled by changes in the membrane permeability to calcium. The rate of release of histamine from mast cells and the rate of desensitization of the cells are discussed in terms of the size of IgE receptor complexes on the cell membrane. PMID:2420710

  3. Differential effect of cannabinoid agonists and endocannabinoids on histamine release from distinct regions of the rat brain

    PubMed Central

    Cenni, Gabriele; Blandina, Patrizio; Mackie, Ken; Nosi, Daniele; Formigli, Lucia; Giannoni, Patrizia; Ballini, Chiara; Corte, Laura Della; Mannaioni, Pier Francesco; Passani, M. Beatrice

    2006-01-01

    Cannabinoids exert complex actions on neurotransmitter systems involved in cognition, locomotion, appetite, but no information was available so far on the interactions between the endocannabinoid system and histaminergic neurons that command several, similar behavioural states and memory. In this study, we investigated the effect of cannabimimetic compounds on histamine release using the microdialysis technique in the brain of freely moving rats. We found that systemic administration of the cannabinoid receptors 1 (CB1-r) agonist arachidonyl-2′chloroethylamide/N-(2chloroethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (ACEA; 3 mg/kg) increased histamine release from the posterior hypothalamus, where the histaminergic tuberomamillary nuclei (TMN) are located. Local infusions of ACEA (150 nM) or R(+)-methanandamide (mAEA; 1μM), another CB1-r agonist, in the TMN augmented histamine release from the TMN, as well as from two histaminergic projection areas, the nucleus basalis magnocellularis and the dorsal striatum. When the endocannabinoid uptake inhibitor AM404 was infused into the TMN, however, increased histamine release was observed only in the TMN. The cannabinoid-induced effects on histamine release were blocked by co-administrations with the CB1-r antagonist AM251. Using double-immunofluorescence labelling and confocal laser-scanning microscopy, CB1-r immunostaining was found in the hypothalamus, but was not localized onto histaminergic cells. The modulatory effect of cannabimimetic compounds on histamine release apparently did not involve inhibition of γ-aminobutyric acid (GABA)ergic neurotransmission, which provides the main inhibitory input to the histaminergic neurons in the hypothalamus, as local infusions of ACEA did not modify GABA release from the TMN. These profound effects of cannabinoids on histaminergic neurotransmission may partially underlie some of the behavioural changes observed following exposure to cannabinoid-based drugs. PMID:17004927

  4. SG-HQ2 inhibits mast cell-mediated allergic inflammation through suppression of histamine release and pro-inflammatory cytokines.

    PubMed

    Je, In-Gyu; Kim, Hui-Hun; Park, Pil-Hoon; Kwon, Taeg Kyu; Seo, Seung-Yong; Shin, Tae-Yong; Kim, Sang-Hyun

    2015-05-01

    In this study, we investigated the effect of 3,4,5-trihydroxy-N-(8-hydroxyquinolin-2-yl)benzamide) (SG-HQ2), a synthetic analogue of gallic acid (3,4,5-trihydroxybenzoic acid), on the mast cell-mediated allergic inflammation and the possible mechanism of action. Mast cells play major roles in immunoglobulin E-mediated allergic responses by the release of histamine, lipid-derived mediators, and pro-inflammatory cytokines. We previously reported the potential effects of gallic acid using allergic inflammation models. For incremental research, we synthesized the SG-HQ2 by the modification of functional groups from gallic acid. SG-HQ2 attenuated histamine release by the reduction of intracellular calcium in human mast cells and primary peritoneal mast cells. The inhibitory efficacy of SG-HQ2 was similar with gallic acid. Enhanced expression of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, interleukin-4, and interleukin-6 in activated mast cells was significantly diminished by SG-HQ2 100 times lower concentration of gallic acid. This inhibitory effect was mediated by the reduction of nuclear factor-κB. In animal models, SG-HQ2 inhibited compound 48/80-induced serum histamine release and immunoglobulin E-mediated local allergic reaction, passive cutaneous anaphylaxis. Our results indicate that SG-HQ2, an analogue of gallic acid, might be a possible therapeutic candidate for mast cell-mediated allergic inflammatory diseases through suppression of histamine release and pro-inflammatory cytokines.

  5. SG-HQ2 inhibits mast cell-mediated allergic inflammation through suppression of histamine release and pro-inflammatory cytokines

    PubMed Central

    Je, In-Gyu; Kim, Hui-Hun; Park, Pil-Hoon; Kwon, Taeg Kyu

    2015-01-01

    In this study, we investigated the effect of 3,4,5-trihydroxy-N-(8-hydroxyquinolin-2-yl)benzamide) (SG-HQ2), a synthetic analogue of gallic acid (3,4,5-trihydroxybenzoic acid), on the mast cell-mediated allergic inflammation and the possible mechanism of action. Mast cells play major roles in immunoglobulin E-mediated allergic responses by the release of histamine, lipid-derived mediators, and pro-inflammatory cytokines. We previously reported the potential effects of gallic acid using allergic inflammation models. For incremental research, we synthesized the SG-HQ2 by the modification of functional groups from gallic acid. SG-HQ2 attenuated histamine release by the reduction of intracellular calcium in human mast cells and primary peritoneal mast cells. The inhibitory efficacy of SG-HQ2 was similar with gallic acid. Enhanced expression of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, interleukin-4, and interleukin-6 in activated mast cells was significantly diminished by SG-HQ2 100 times lower concentration of gallic acid. This inhibitory effect was mediated by the reduction of nuclear factor-κB. In animal models, SG-HQ2 inhibited compound 48/80-induced serum histamine release and immunoglobulin E-mediated local allergic reaction, passive cutaneous anaphylaxis. Our results indicate that SG-HQ2, an analogue of gallic acid, might be a possible therapeutic candidate for mast cell-mediated allergic inflammatory diseases through suppression of histamine release and pro-inflammatory cytokines. PMID:25349218

  6. The effects of thermal stimuli on intracellular calcium change and histamine releases in rat basophilic leukemia mast cells

    NASA Astrophysics Data System (ADS)

    Wu, Zu-Hui; Zhu, Dan; Chen, Ji-Yao; Zhou, Lu-Wei

    2012-05-01

    The effects of thermal stimuli on rat basophilic leukemia mast cells were studied. The cells in calcium-contained or calcium-free buffers were thermally stimulated in the temperature range of 25-60 °C. The corresponding calcium ion concentration in cells [Ca2+]i as well as the released histamine from cells was measured with fluorescence staining methods. The ruthenium red (RR), a block of membrane calcium channels (transient receptor potential family V (TRPV)), was used in experiments. Under the stimulus of 25-50 °C, no significant difference on [Ca2+]i was found between these three groups of the cells in calcium-contained buffer without or with RR and cells in calcium-free saline, indicating that the increased calcium in cytosol did not result from the extracellular buffer but came from the intracellular calcium stores. The [Ca2+]i continuously increased under the temperature of 50-60 °C, but the RR and calcium-free saline can obviously diminish the [Ca2+]i increase at these high temperatures, reflecting that the opening of the TRPV2 channels leads to a calcium influx resulting in the [Ca2+]i increment. The histamine release also became significant in these cases. Since the released histamine is a well-known mediator for the microcirculation promotion, the histamine release from mast cells could be one of the mechanisms of thermal therapy.

  7. Effect of picumast on histamine release from rat cardiac and peritoneal mast cells.

    PubMed

    Wan, B Y; Peh, K H; Assem, E S

    1991-05-01

    Compound 48/80-induced histamine release (HR) from the isolated perfused rat heart was markedly and significantly inhibited by picumast (PIC), possibly by acting as a calmodulin antagonist (CMA) or membrane stabilizer. Trifluoperazine (TFP, another CMA in clinical use) had a similar effect. However, an action as CMA being the basis of inhibition of HR could not be confirmed in another 'allergy' model, namely HR from rat peritoneal mast cells (RPMC). PIC, TFP and two other CMA, W7 and N-(4-aminobutyl)-5-chloro-1-naphthalenesulfonamide) failed consistently to inhibit 48/80-induced HR from RPMC, and when used on their own at high concentration these compounds caused HR. PIC and TFP also potentiated the heat-induced haemolysis of rat erythrocytes, i.e. lacked membrane stabilizing effect in this model.

  8. The diagnostic value of the histamine release test in food allergy.

    PubMed

    Oehling, A; Ona, J; Trento, H; Sanz, M L; Domínguez, M A

    1984-01-01

    One hundred and nine patients were selected in this study. All had food allergies (Urticaria, Quincke's Oedema and Bronchial Asthma) diagnosed by either clinical history or skin test results later confirmed by oral challenge. Since many of these patients had multiple sensitivities to various food allergens, the study was performed on 175 blood samples classifying the results according to personal history and results of the skin test. The diagnostic value of histamine release in whole blood of a patient suffering from food allergy is optimally reliable. The study is complemented by providing a better understanding of the dynamics involved in the hypersensitivity response. The results from this comparative study with RAST, once again demonstrate the uselessness in using this technique in food allergy since the existence of other cytotropic antibodies, IgG4 capable of provoking the basophil to produce a clearly detectable and significant histamine release has been well demonstrated. Once again the importance of other antibodies which are not exactly cytotropic or anaphylactic (IgG, IgM, etc.) in nature in hypersensitivity response is brought to light. These are readily detected with a great degree of reliability (78%) using hemagglutination. This method is highly sensitive and is strongly recommended in the diagnoses of allergy because of its simplicity and affordability. The study of the parameters studied shows us once again that there are several mechanisms involved in the hypersensitivity response as well as a variation from one individual to another depending, of course on the class of antigen. Finally we must keep in mind the complexity of the antigen involved in food allergies which in many cases are haptenic.

  9. The mast cell stabilizer sodium cromoglycate reduces histamine release and status epilepticus-induced neuronal damage in the rat hippocampus.

    PubMed

    Valle-Dorado, María Guadalupe; Santana-Gómez, César Emmanuel; Orozco-Suárez, Sandra Adela; Rocha, Luisa

    2015-05-01

    Experiments were designed to evaluate changes in the histamine release, mast cell number and neuronal damage in hippocampus induced by status epilepticus. We also evaluated if sodium cromoglycate, a stabilizer of mast cells with a possible stabilizing effect on the membrane of neurons, was able to prevent the release of histamine, γ-aminobutyric acid (GABA) and glutamate during the status epilepticus. During microdialysis experiments, rats were treated with saline (SS-SE) or sodium cromoglycate (CG-SE) and 30 min later received the administration of pilocarpine to induce status epilepticus. Twenty-four hours after the status epilepticus, the brains were used to determine the neuronal damage and the number of mast cells in hippocampus. During the status epilepticus, SS-SE group showed an enhanced release of histamine (138.5%, p = 0.005), GABA (331 ± 91%, p ≤ 0.001) and glutamate (467%, p ≤ 0.001), even after diazepam administration. One day after the status epilepticus, SS-SE group demonstrated increased number of mast cells in Stratum pyramidale of CA1 (88%, p < 0.001) and neuronal damage in dentate gyrus, CA1 and CA3. In contrast to SS-SE group, rats from the CG-SE group showed increased latency to the establishment of the status epilepticus (p = 0.048), absence of wet-dog shakes, reduced histamine (but not GABA and glutamate) release, lower number of mast cells (p = 0.008) and reduced neuronal damage in hippocampus. Our data revealed that histamine, possibly from mast cells, is released in hippocampus during the status epilepticus. This effect may be involved in the subsequent neuronal damage and is diminished with sodium cromoglycate pretreatment.

  10. Histamine released from epidermal keratinocytes plays a role in α-melanocyte-stimulating hormone-induced itching in mice.

    PubMed

    Shimizu, Kyoko; Andoh, Tsugunobu; Yoshihisa, Yoko; Shimizu, Tadamichi

    2015-11-01

    Sunburn, wound repair, and chronic renal failure with hemodialysis are usually accompanied by both pigmentation and itching. Proopiomelanocortin-derived α-melanocyte-stimulating hormone (α-MSH) is produced in response to external stimuli, such as UV irradiation, and is involved in cutaneous pigmentation. However, it is unclear whether α-MSH is also involved in the itching. We therefore investigated whether α-MSH elicited itch-related responses in mice. We found that an intradermal injection of α-MSH induced hind-paw scratching, an itch-related response, in mice. The α-MSH-induced scratching was inhibited by the μ-opioid receptor antagonist naltrexone and the H1 histamine receptor antagonist terfenadine. In mast cell-deficient mice, α-MSH also elicited scratching, which was inhibited by terfenadine. The immunoreactivity for l-histidine decarboxylase, a key enzyme required for the production of histamine, histamine, and the melanocortin 1 and 5 receptors were shown in not only mast cells but also keratinocytes in murine skin. In addition to the expression of l-histidine decarboxylase and melanocortin 1 and 5 receptors, the mouse keratinocyte cell lines (Pam212) also showed immunoreactivity for l-histidine decarboxylase, histamine, and melanocortin 1 and 5 receptors. The application of α-MSH induced the release of histamine from Pam212 cells. These findings indicate that α-MSH may play an important role in the itching associated with pigmented cutaneous lesions and that the histamine released from keratinocytes is involved in this α-MSH-induced itching. PMID:26358220

  11. Histamine released from epidermal keratinocytes plays a role in α-melanocyte-stimulating hormone-induced itching in mice.

    PubMed

    Shimizu, Kyoko; Andoh, Tsugunobu; Yoshihisa, Yoko; Shimizu, Tadamichi

    2015-11-01

    Sunburn, wound repair, and chronic renal failure with hemodialysis are usually accompanied by both pigmentation and itching. Proopiomelanocortin-derived α-melanocyte-stimulating hormone (α-MSH) is produced in response to external stimuli, such as UV irradiation, and is involved in cutaneous pigmentation. However, it is unclear whether α-MSH is also involved in the itching. We therefore investigated whether α-MSH elicited itch-related responses in mice. We found that an intradermal injection of α-MSH induced hind-paw scratching, an itch-related response, in mice. The α-MSH-induced scratching was inhibited by the μ-opioid receptor antagonist naltrexone and the H1 histamine receptor antagonist terfenadine. In mast cell-deficient mice, α-MSH also elicited scratching, which was inhibited by terfenadine. The immunoreactivity for l-histidine decarboxylase, a key enzyme required for the production of histamine, histamine, and the melanocortin 1 and 5 receptors were shown in not only mast cells but also keratinocytes in murine skin. In addition to the expression of l-histidine decarboxylase and melanocortin 1 and 5 receptors, the mouse keratinocyte cell lines (Pam212) also showed immunoreactivity for l-histidine decarboxylase, histamine, and melanocortin 1 and 5 receptors. The application of α-MSH induced the release of histamine from Pam212 cells. These findings indicate that α-MSH may play an important role in the itching associated with pigmented cutaneous lesions and that the histamine released from keratinocytes is involved in this α-MSH-induced itching.

  12. Histamine and chondroitin sulfate E proteoglycan released by cultured human colonic mucosa: indication for possible presence of E mast cells

    SciTech Connect

    Eliakim, R.; Gilead, L.; Ligumsky, M; Okon, E.; Rachmilewitz, D.; Razin, E.

    1986-01-01

    An association between the release of histamine and chondroitin sulfate E proteoglycan (PG) was demonstrates in human colonic mucosa (HCM). Colonic biopsy samples incorporated (/sup 35/S)sulfate into PG, which was partially released into the culture medium during the incubation period. Ascending thin-layer chromatography of the released /sup 35/S-labeled PG after its digestion by chondroitin ABC lyase (chondroitinase, EC 4.2.2.4) followed by autoradiography yielded three products that migrated in the position of monosulfated disaccharides of N-acetylgalactosamine 4-sulfate and N-acetylgalactosoamine 6-sulfate and of an oversulfated disaccharide possessing N-acetylgalatosamine 4,6-disulfate. Cultured colonic mucosa released 23.6 +/- 3.7ng of histamine per mg of wet tissue without any special trigger. Comparison by linear regression analysis of the release of histamine and chondroitin (/sup 35/S)sulfate E PG revealed a correlation coefficient (r) of 0.7. Histological examination of the colonic biopsies revealed the presence of many mast cells in various degrees of degranulation in the mucosa and submucosa. The above correlation, the observation that most of the mast cells showed various degrees of degranulation, and the lack of heparin synthesis as opposed to the synthesis and immunological release of chondroitin sulfate E strongly suggest that the E mast cell exists in the human colon.

  13. The Effects of Electrical Stimuli on Calcium Change and Histamine Release in Rat Basophilic Leukemia Mast Cells

    NASA Astrophysics Data System (ADS)

    Zhu, Dan; Wu, Zu-Hui; Chen, Ji-Yao; Zhou, Lu-Wei

    2013-06-01

    We apply electric fields at different frequencies of 0.1, 1, 10 and 100 kHz to the rat basophilic leukemia (RBL) mast cells in calcium-containing or calcium-free buffers. The stimuli cause changes of the intracellular calcium ion concentration [Ca2+]i as well as the histamine. The [Ca2+]i increases when the frequency of the external electric field increases from 100 Hz to 10 kHz, and then decreases when the frequency further increases from 10 kHz to 100 kHz, showing a peak at 100 kHz. A similar frequency dependence of the histamine release is also found. The [Ca2+]i and the histamine releases at 100 Hz are about the same as the values of the control group with no electrical stimulation. The ruthenium red (RR), an inhibitor to the TRPV (transient receptor potential (TRP) family V) channels across the cell membrane, is used in the experiment to check whether the electric field stimuli act on the TRPV channels. Under an electric field of 10 kHz, the [Ca2+]i in a calcium-concentration buffer is about 3.5 times as much as that of the control group with no electric stimulation, while the [Ca2+]i in a calcium-free buffer is only about 2.2 times. Similar behavior is also found for the histamine release. RR blockage effect on the [Ca2+]i decrease is statistically significant (~75%) when mast cells in the buffer with calcium are stimulated with a 10 kHz electric field in comparison with the result without the RR treatment. This proves that TRPVs are the channels that calcium ions inflow through from the extracellular environment under electrical stimuli. Under this condition, the histamine is also released following a similar way. We suggest that, as far as an electric stimulation is concerned, an application of ac electric field of 10 kHz is better than other frequencies to open TRPV channels in mast cells, and this would cause a significant calcium influx resulting in a significant histamine release, which could be one of the mechanisms for electric therapy.

  14. Screening of several Indonesian medicinal plants for their inhibitory effect on histamine release from RBL-2H3 cells.

    PubMed

    Ikawati, Z; Wahyuono, S; Maeyama, K

    2001-05-01

    Twelve alcoholic extracts and 12 hexane extracts of plant materials selected on the basis of medicinal folklore for asthma treatment in Indonesia were studied for their activity in inhibiting histamine release from RBL-2H3 cells (rat basophilic leukemia cell line), a tumor analog of mast cells. The results of screening indicated that five alcoholic extracts (Plantago major leaves, Eucalyptus globulus leaves and fruit, Cinnamomum massoiae cortex, Vitex trifolia leaves) and two hexane extracts (Eucalyptus globulus leaves, Vitex trifolia leaves) inhibited IgE-dependent histamine release from RBL-2H3 cells. The inhibitory effects were found to be more than 80% for extract concentrations of 0.5 mg/ml. The results indicate that the extracts contain active compounds that inhibit mast-cell degranulation, and provide insight into the development of new drugs for treating asthma and/or allergic disease. PMID:11297859

  15. Suppressed histamine release from rat peritoneal mast cells by ultraviolet B irradiation: decreased diacylglycerol formation as a possible mechanism

    SciTech Connect

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

    1988-06-01

    This study was designed to investigate the effect of ultraviolet B (UVB) irradiation on mast cell functions. Purified mast cells obtained from rat peritoneal cavity were irradiated with UVB and subsequently exposed to a degranulator, compound 48/80, or the calcium ionophore A-23187. The amount of histamine released from mast cells measured by the enzyme isotopic assay was significantly decreased by UVB irradiation (100-400 mJ/cm2). Within this dose range, UVB alone was not cytotoxic to the cells because it did not induce histamine release. The suppression was observed when mast cells were subjected to degranulation without intervals after UVB irradiation, and even after 5 h postirradiation. The wavelength of 300 nm from a monochromatic light source showed the maximum effect. When mast cells prelabeled with (/sup 3/H)arachidonate were irradiated and challenged by compound 48/80, label accumulation in diacylglycerol produced by the phosphatidylinositol cycle was considerably decreased by UVB irradiation. From these results, we hypothesize that, within an adequate irradiation dose, UVB irradiation suppresses histamine release from mast cells, probably by causing noncytotoxic damage to the membrane phospholipid metabolism, which is tied to the degranulation mechanisms.

  16. Histamine induces activation of protein kinase D that mediates tissue factor expression and activity in human aortic smooth muscle cells.

    PubMed

    Hao, Feng; Wu, Daniel Dongwei; Xu, Xuemin; Cui, Mei-Zhen

    2012-12-01

    Histamine, an inflammatory mediator, has been shown to influence the pathogenesis of vascular wall cells. However, the molecular basis of its influence is not well understood. Our data reveal that histamine markedly induces protein kinase D (PKD) activation in human aortic smooth muscle cells. PKD belongs to a family of serine/threonine protein kinases, and its function in vascular disease is largely unknown. Our data show that histamine-induced PKD phosphorylation is dependent on the activation of histamine receptor 1 and protein kinase C (PKC). To determine the role of PKD in the histamine pathway, we employed a small-interfering RNA approach to downregulate PKD expression and found that PKD1 and PKD2 are key mediators for expression of tissue factor (TF), which is the key initiator of blood coagulation and is important for thrombosis. Our results show that PKD2 predominantly mediates histamine-induced TF expression via the p38 mitogen-activated protein kinase (MAPK) pathway, whereas PKD1 mediates histamine-induced TF expression through a p38 MAPK-independent pathway. We demonstrate that histamine induces TF expression via the PKC-dependent PKD activation. Our data provide the first evidence that PKD is a new component in histamine signaling in live cells and that PKD has a novel function in the histamine signaling pathway leading to gene expression, as evidenced by TF expression. Importantly, our data reveal a regulatory link from histamine to PKD and TF, providing new insights into the mechanisms of coagulation and the development of atherothrombosis.

  17. Mosla dianthera inhibits mast cell-mediated allergic reactions through the inhibition of histamine release and inflammatory cytokine production

    SciTech Connect

    Lee, Dong-Hee; Kim, Sang-Hyun . E-mail: shkim72@knu.ac.kr; Eun, Jae-Soon; Shin, Tae-Yong . E-mail: tyshin@woosuk.ac.kr

    2006-11-01

    In this study, we investigated the effect of the aqueous extract of Mosla dianthera (Maxim.) (AEMD) on the mast cell-mediated allergy model and studied the possible mechanism of action. Mast cell-mediated allergic disease is involved in many diseases such as asthma, sinusitis and rheumatoid arthritis. The discovery of drugs for the treatment of allergic disease is an important subject in human health. AEMD inhibited compound 48/80-induced systemic reactions in mice. AEMD decreased immunoglobulin E-mediated local allergic reactions, passive cutaneous anaphylaxis. AEMD attenuated intracellular calcium level and release of histamine from rat peritoneal mast cells activated by compound 48/80. Furthermore, AEMD attenuated the phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187-stimulated TNF-{alpha}, IL-8 and IL-6 secretion in human mast cells. The inhibitory effect of AEMD on the pro-inflammatory cytokines was nuclear factor-{kappa}B (NF-{kappa}B) dependent. AEMD decreased PMA and A23187-induced degradation of I{kappa}B{alpha} and nuclear translocation of NF-{kappa}B. Our findings provide evidence that AEMD inhibits mast cell-derived immediate-type allergic reactions and involvement of pro-inflammatory cytokines and NF-{kappa}B in these effects.

  18. Histamine release and pseudoallergic reactions induced by radiographic contrast media: comparison of Angiographin, Hexabrix and Telebrix using an in vivo canine model.

    PubMed

    Ennis, M; Lorenz, W; Schmal, A; Dombrowski, H

    1990-04-01

    Radiographic contrast media (RCM) in clinical use cause unwanted allergic/pseudoallergic reactions of all grades of severity. They also induce histamine release from a variety of mast cell populations, the extent of the histamine release reaction depending on both the organ and species. In this study 3 RCM, which had been previously shown to be effective histamine releasing agents with canine liver cells, were investigated using an in vivo canine model based on the clinical situation. The dogs (n = 36) were randomly allocated to one of 3 treatment groups and received a bolus injection (2 ml/kg body weight) of either Angiographin, Hexabrix or Telebrix. Blood pressure was monitored continuously and blood sampling, for plasma histamine measurements, was performed before and 1, 5, 10, 20 and 30 min after RCM injection. All 3 RCM caused elevated plasma histamine levels in some animals: Angiographin 9 of 12 dogs, 0.40 ng/ml, (0-1.9 ng/ml) median (range); Hexabrix 11/12, 0.5 ng/ml (0-3.8 ng/ml); Telebrix 7/12, 0.4 ng/ml (0-2.0 ng/ml). Cardiovascular reactions were observed in most animals. The hypotensive reactions occurred with a maximum 30 sec after RCM application and recovery was normally observed after 1-1.5 min. The response after Angiographin or Telebrix was significantly greater than after Hexabrix. Hypertensive reactions occurred later (15 min (5-25 min)) and did not differ between the groups. All 3 agents tested were able to elicit histamine release and cardiovascular reactions. In comparison to histamine release occurring after intravenous administration of other agents, such as hypnotics, the degree of histamine release was small.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1695468

  19. Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia.

    PubMed

    Hatta, E; Yasuda, K; Levi, R

    1997-11-01

    During protracted myocardial ischemia, ATP depletion promotes Na+ accumulation in sympathetic terminals and prevents vesicular storage of norepinephrine (NE). This forces the reversal of the neuronal uptake1 transporter, and NE is massively released (carrier-mediated release). We had shown that histamine H3 receptors (H3Rs) modulate ischemic NE release in animals. We have now used a human model of protracted myocardial ischemia to investigate whether H3Rs may control carrier-mediated NE release. Surgical specimens of human atrium were incubated in anoxic conditions. NE release increased approximately 7-fold within 70 min of anoxia. This release was carrier mediated because it was Ca++ independent and inhibited by the uptake1 inhibitor desipramine. Furthermore, the Na+/H+ exchanger (NHE) inhibitors ethyl-isopropyl-amiloride and HOE 642, and the Na+ channel blocker tetrodotoxin inhibited NE release, whereas the Na+ channel activator aconitine potentiated it. The selective H3R agonist imetit decreased NE release, an effect that was blocked by each of the H3R antagonists thioperamide and clobenpropit. Notably, imetit acted synergistically with ethyl-isopropyl-amiloride, HOE 642 and tetrodotoxin to reduce anoxic NE release. Thus, activation of H3R appears to result in an inhibition of both NHE- and voltage-dependent Na+ channels. Most importantly, endogenous histamine was released from the anoxic human heart, and thioperamide and clobenpropit each alone increased NE release, indicating that H3R become activated in myocardial ischemia. Our findings indicate that H3Rs are likely to mitigate sympathetic overactivity in the ischemic human heart and suggest new therapeutic strategies to alleviate dysfunctions associated with myocardial ischemia.

  20. Exocytotic and cytolytic release of histamine from mast cells treated with Portuguese man-of-war (Physalia physalis) venom.

    PubMed

    Cormier, S M

    1984-07-01

    Electron microscopic observations suggest that venom from isolated nematocysts of the stinging tentacles of the Portuguese man-of-war, Physalia physalis, causes histamine release via a rapid, short-duration exocytosis of granules and a slower, long-duration lysis of mast cells. Fine structural changes in mast cells are concurrent with histamine release and are independent of the presence of leukocytes. Vesiculation of the plasma membrane and release of granules nearest the cell surface occur within 10 sec after exposure to 100 micrograms venom/10(5) cells. Released granules and granules retained in plasma membrane invaginations are fibrous and less electron opaque than more centrally located granules. Complex channels to the external medium continue to form, and within 1 min, characteristics of both degranulation and cytolysis are well advanced. Mitochondria are swollen or disrupted. Microridges are absent. Intracellular granules are significantly fewer in venom-treated mast cells, but are more widely separated than in controls. This suggests that degranulation occurs at early stages but is halted as cytolysis proceeds. PMID:6206195

  1. In Vivo Electrochemical Evidence for Simultaneous 5-HT and Histamine Release in the Rat Substantia Nigra pars Reticulata Following Medial Forebrain Bundle Stimulation

    PubMed Central

    Hashemi, Parastoo; Dankoski, Elyse C.; Wood, Kevin M.; Ambrose, R. Ellen; Wightman, R. Mark

    2011-01-01

    Exploring the mechanisms of serotonin (5-hydoxytryptophan (5-HT)) in the brain requires an in vivo method that combines fast temporal resolution with chemical selectivity. Fast-scan cyclic voltammetry (FSCV) is a technique with sufficient temporal and chemical resolution for probing dynamic 5-HT neurotransmission events; however, traditionally it has not been possible to probe in vivo 5-HT mechanisms. Recently, we optimized FSCV for measuring 5-HT release and uptake in vivo in the substantia nigra pars reticulata (SNR) with electrical stimulation of the dorsal raphe nucleus (DRN) in the rat brain. Here, we address technical challenges associated with rat DRN surgery by electrically stimulating 5-HT projections in the medial forebrain bundle (MFB), a more accessible anatomical location. MFB stimulation elicits 5-HT in the SNR; furthermore, we find simultaneous release of an additional species. We use electrochemical and pharmacological methods and describe physiological, anatomical and independent chemical analyses to identify this species as histamine. We also show pharmacologically that increasing the lifetime of extracellular histamine significantly decreases 5-HT release, most likely due to increased activation of histamine H-3 receptors that inhibit 5-HT release. Despite this, under physiological conditions, we find by kinetic comparisons of DRN and MFB stimulations that the simultaneous release of histamine does not interfere with the quantitative 5-HT concentration profile. We therefore present a novel and robust electrical stimulation of the MFB that is technically less challenging than DRN stimulation to study 5-HT and histamine release in the SNR. PMID:21682723

  2. Inhibition of IgE-dependent histamine release from human dispersed lung mast cells by anti-allergic drugs and salbutamol.

    PubMed Central

    Church, M. K.; Hiroi, J.

    1987-01-01

    The ability of the anti-allergic drugs, sodium cromoglycate (SCG), lodoxamide, traxanox, RU31156 and the beta-adrenoceptor agonist salbutamol to inhibit IgE-dependent histamine and prostaglandin D2 (PGD2) release was assessed using human dispersed lung mast cells. The anti-allergic drugs were weak inhibitors of histamine release, high concentrations (100-1000 microM) producing less than 35% inhibition. Salbutamol produced 39% inhibition at 10 microM. The efficacy of both SCG and salbutamol was inversely related to the concentration of anti-IgE used for challenge and to the degree of histamine release. Rapid tachyphylaxis was observed with all anti-allergic drugs but not with salbutamol. Cross-tachyphylaxis was observed between SCG and the other anti-allergic drugs, suggesting a common mechanism of action. No cross-tachyphylaxis was observed between SCG and salbutamol. SCG was significantly (P less than 0.001) more effective in inhibiting PGD2 than it was histamine release. Preferential inhibition of PGD2 compared with histamine release was less marked (P less than 0.05) with salbutamol and not significant with the other anti-allergic drugs. Mast cells dispersed by enzymatic digestion of human lung released more histamine on immunological challenge than mechanically dispersed cells obtained by fine chopping of tissue. Enzyme treatment of mechanically dispersed cells removed this difference. Enzymatically and mechanically dispersed cells responded similarly to the inhibitory effects of SCG and salbutamol. Our results suggest that salbutamol is a more effective inhibitor of mediator release from human lung mast cells than anti-allergic drugs. However, with the low levels of mediator release achieved during an allergic reaction in man in vivo, both salbutamol and SCG are likely to be effective inhibitors of both preformed and newly generated mediators. PMID:2435353

  3. Development and validation of a liquid-chromatography tandem mass spectrometry method to determine in vitro and in vivo histamine release.

    PubMed

    Chimalakonda, Krishna C; Pang, Eric; Weaver, James L; Howard, Kristina E; Patel, Vikram; Boyne, Michael T

    2015-01-01

    Histamine is an important biogenic amine involved in regulating numerous physiological and pathophysiological processes in humans and animals. To date, there have been very few studies focused on developing and validating sensitive liquid-chromatography-tandem mass spectrometric (LC-MS/MS) assays capable of quantitative trace level histamine analysis in biological matrices. In the present study, a rapid and sensitive LC-MS/MS assay, amenable to high throughput analysis was developed and validated to characterize in vitro and in vivo histamine release. The LC-MS/MS procedure incorporating deuterium labeled internal standards provides rapid resolution of histamine with excellent sensitivity, precision, and accuracy. Histamine eluted at 1.5 min and was well separated from endogenous plasma peaks. The total run time of the assay was 8.0 min. A linear (r(2) ≥ 0.99) instrument response over the entire concentration range of 1.0-1000 ng/mL was observed. Excellent accuracy (error ± 3.4%) and precision (CV ± 10%) of the assay was demonstrated, with the lower limit of quantitation (LLOQ) at 15.6 ng/mL. The validated LC-MS/MS assay was applied to determine histamine release in both in vitro and in vivo models. Peritoneal mast cells treated with prototypical degranulating agents (Compound 48/80 and Teicoplanin) showed that the two chemicals caused approximately 40% histamine release. In rats, using this assay, basal histamine plasma levels were typically under 100 ng/mL. Treatment with an agent suspected of causing anaphylactic type reactions resulted in plasma histamine levels to increase above 3000 ng/mL. The LC-MS/MS assay presented in this study can be applied to further characterize the physiological and pathophysiological role of histamine release in complex in vitro and in vivo models. Importantly, the LC-MS/MS assay may be useful in assessing active pharmaceutical ingredient-mediated degranulation and anaphylaxis as part of either a pre-market or a post

  4. [Histamine intolerance--possible dermatologic sequences].

    PubMed

    Lugović-Mihić, Liborija; Seserko, Ana; Duvancić, Tomislav; Situm, Mirna; Mihić, Josip

    2012-12-01

    Although histamine intolerance (HIT) is not very frequently encountered, it can have serious consequences. Food intolerance is a non allergic hypersensitivity to food that does not include the immune system even though the symptoms are similar to those of IgE-mediated allergic reactions. HIT apparently develops as a result of an impaired diamine oxidase (DAO) activity due to gastrointestinal disease or through DAO inhibition, as well as through a genetic predisposition which was proven in a number of patients. The intake of histamine-rich foods as well as alcohol or drugs which cause either the release of histamine or the blocking of DAO can lead to various disorders in many organs (gastrointestinal system, skin, lungs, cardiovascular system and brain), depending on the expression of histamine receptors. Dermatologic sequels can be rashes, itch, urticaria, angioedema, dermatitis, eczema and even acne, rosacea, psoriasis, and other. Recognizing the symptoms due to HIT is especially important in treating such patients. The significance of HIT in patients with atopic dermatitis in whom the benefit of a low histamine diet has been proven is becoming increasingly understood recently. Because of the possibility of symptoms affecting numerous organs, a detailed history of symptoms following the intake of histamine-rich foods or drugs that interfere with histamine metabolism is essential for making the diagnosis of HIT. Considering that such symptoms can be the result of multiple factors, the existence of HIT is usually underestimated, but considerable expectations are being made from future studies.

  5. Differential effects of the complement peptides, C5a and C5a des Arg on human basophil and lung mast cell histamine release.

    PubMed Central

    Schulman, E S; Post, T J; Henson, P M; Giclas, P C

    1988-01-01

    The ability of purified anaphylatoxins to induce human lung mast cell mediator release was investigated. In eight anti-IgE responsive (histamine release = 22 +/- 5%, mean +/- SEM) mast cell preparations of 1-96% purity, C5a and C5a des Arg (0.55 pg/ml to 55 micrograms/ml), failed to elicit or potentiate histamine release; lung fragments were similarly unresponsive. The related peptide C3a was also inactive. All anaphylatoxins failed to induce mast cell leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) release. LTC4 release was also negligible from basophils where C5a was a potent histamine release stimulus. Supernatants from C5a-challenged mast cells remained fully active on basophils, excluding carboxypeptidase inactivation of C5a as an explanation for the lung mast cell results. In contrast to lung, skin mast cells were C5a-responsive (histamine release = 8 +/- 1%, at 55 micrograms/ml, n = 2). We conclude that C5a, though devoid of activity on the human lung mast cell, is a human basophil and skin mast cell secretagogue. These findings demonstrate significant organ-specific heterogeneity in mast cell responsiveness. PMID:2449462

  6. Comparison of the effect of an H(3)-inverse agonist on energy intake and hypothalamic histamine release in normal mice and leptin resistant mice with high fat diet-induced obesity.

    PubMed

    Ishizuka, Tomoko; Hatano, Kouta; Murotani, Tomotaka; Yamatodani, Atsushi

    2008-04-01

    Leptin is a key signal linking peripheral adiposity levels to the regulation of energy homeostasis in the brain. The injection of leptin decreases body weight and food intake in lean rodents; however, in a rodent model of high fat diet-induced obesity (DIO), the exogenous leptin cannot improve adiposity. This ineffectiveness is known as leptin resistance, and the factors downstream of leptin signaling have received attention as viable targets in the treatment of obesity. We previously reported that the histaminergic system is one of the targets of leptin. In the present study, the effect of an H(3)-receptor inverse agonist on hypothalamic histamine release and energy intake was investigated in normal and DIO mice. Leptin (1.3 mg/kg, i.p.) significantly increased hypothalamic histamine release and reduced 12 h-energy intake in normal mice, but had no such effects in DIO mice. In contrast, clobenpropit (5 mg/kg, i.p.), an H(3)-inverse agonist, elicited a significant increase in histamine release in both types of mice. Clobenpropit did not reduce 12 h-energy intake; however, it decreased 3 h-energy intake in both types of mice. These results suggest that lack of the activation of the histaminergic system partly contributes to obesity in DIO mice and direct activation of the histaminergic system circumvents leptin resistance.

  7. Histamine H₃ receptors modulate depolarization-evoked [³H]-noradrenaline release from rat olfactory bulb slices.

    PubMed

    Aquino-Miranda, Guillermo; Osorio-Espinoza, Angélica; Escamilla-Sánchez, Juan; González-Pantoja, Raúl; Ortiz, Jordi; Arias-Montaño, José-Antonio

    2012-02-01

    We have studied the effect of histamine H(3) receptor (H(3)R) activation on the depolarization-evoked release of labeled neurotransmitters from slices of the rat olfactory bulb (rOB). The presence of pre-synaptic H(3)Rs was evidenced by the specific binding of the H(3)R ligand N-α-[methyl-(3)H]histamine to membranes from rOB synaptosomes (maximum binding, B(max), 106 ± 19 fmol/mg protein; dissociation constant, K(d), 0.68 ± 0.11 nM) which was inhibited by selective H(3)R ligands (immepip, (R)(-)-α-methylhistamine (RAMH) and clobenpropit) with affinities similar to those previously reported for H(3)Rs expressed in other rat brain areas. Perfusion of rOB slices with the selective H(3)R agonist RAMH (0.1 and 1 μM) had no effect on the release of [(3)H]-γ-aminobutyric acid ([(3)H]-GABA), [(3)H]-d-aspartate, [(3)H]-dopamine or [(3)H]-5-hydroxytryptamine ([(3)H]-5-HT) evoked by depolarization with high K(+) (20 or 40 mM). [(3)H]-Noradrenaline release induced by 20 mM K(+) was reduced in a modest but significant manner by RAMH (94.9 ± 1.7% and 83.1 ± 2.1% of control release at 0.1 and 1 μM, respectively). The effect of 1 μM RAMH was blocked by the selective H(3)R antagonist/inverse agonist clobenpropit (5 μM). When tested alone clobenpropit and a second H(3)R antagonist/inverse agonist, ciproxifan (both at 1 μM) significantly increased K(+)-evoked [(3)H]-noradrenaline release to 119.4 ± 4.2% and 120.0 ± 3.7% of K(+) alone, respectively. Ciproxifan (1 μM) had no effect on the depolarization-evoked release of the other labeled neurotransmitters. These data indicate that H(3)Rs with constitutive activity modulate noradrenaline release in rOB, presumably through a pre-synaptic action. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

  8. Synthesis of ε-Viniferin Glycosides by Glucosyltransferase from Phytolacca americana and their Inhibitory Activity on Histamine Release from Rat Peritoneal Mast Cells.

    PubMed

    Hamada, Hiroki; Hamada, Hatsuyuki; Shimoda, Kei

    2015-06-01

    Glycosylation of (+)-ε-viniferin was investigated using glucosyltransferase from Phytolacca americana (PaGT3) as a biocatalyst. (+)-ε-Viniferin was converted by PaGT3 into its 4b- and 13b-β-D-glucosides, the inhibitory activities on histamine release from rat peritoneal mast cells of which were higher than that of (+)-ε-viniferin.

  9. Analysis of the effect of a 60 Hz AC field on histamine release by rat peritoneal mast cells.

    PubMed

    Price, J A; Strattan, R D

    1998-01-01

    Reports have indicated effects of electromagnetic fields on inflammatory processes in vivo. To begin a systematic approach toward separating and examining the many components of such responses, we created and tested a temperature-controlled device to develop 5 mT 60 Hz magnetic fields for studies of the effects of fields on mast cells, a key component in acute inflammatory responses. Such fields have been reported to modulate cell activity, including changes in membrane function, in various systems. The magnetic field was generated using a solenoid and calibrated with an induction probe. Tests of mast cell function were determined by histamine release response to stimulation by compound 48/80, using both an "expose then test" and a "test during exposure" protocol. Aliquots not treated with 48/80 were used to evaluate field treatment effects on spontaneous histamine release. Freshly harvested rat peritoneal mast cells were exposed to the magnetic field for periods of 30 min to 2 h at 37 degrees C. They showed no significant degranulation during treatment, nor did they show reduced sensitivity to the degranulating agent 48/80. These observations are consistent with a model in which such processes are exclusively reflexive by the cells using field-independent membrane systems. This observation is very useful and was needed before examining longer term exposures in which gene expression in the cells might be influenced; this is the first such report of in vitro exposure of purified mast cells under these conditions and will further the study of the effects of electromagnetic fields on cell types active in acute inflammation.

  10. Natriuretic Peptide-Induced Catecholamine Release from Cardiac Sympathetic Neurons: Inhibition by Histamine H3 and H4 Receptor Activation

    PubMed Central

    Chan, Noel Yan-Ki; Robador, Pablo A.

    2012-01-01

    We reported previously that natriuretic peptides, including brain natriuretic peptide (BNP), promote norepinephrine release from cardiac sympathetic nerves and dopamine release from differentiated pheochromocytoma PC12 cells. These proexocytotic effects are mediated by an increase in intracellular calcium secondary to cAMP/protein kinase A (PKA) activation caused by a protein kinase G (PKG)-mediated inhibition of phosphodiesterase type 3 (PDE3). The purpose of the present study was to search for novel means to prevent the proadrenergic effects of natriuretic peptides. For this, we focused our attention on neuronal inhibitory Gαi/o-coupled histamine H3 and H4 receptors. Our findings show that activation of neuronal H3 and H4 receptors inhibits the release of catecholamines elicited by BNP in cardiac synaptosomes and differentiated PC12 cells. This effect results from a decrease in intracellular Ca2+ due to reduced intracellular cAMP/PKA activity, caused by H3 and H4 receptor-mediated PKG inhibition and consequent PDE3-induced increase in cAMP metabolism. Indeed, selective H3 and H4 receptor agonists each synergized with a PKG inhibitor and a PDE3 activator in attenuating BNP-induced norepinephrine release from cardiac sympathetic nerve endings. This indicates that PKG inhibition and PDE3 stimulation are pivotal for the H3 and H4 receptor-mediated attenuation of BNP-induced catecholamine release. Cardiac sympathetic overstimulation is characteristic of advanced heart failure, which was recently found not to be improved by the administration of recombinant BNP (nesiritide), despite the predicated beneficial effects of natriuretic peptides. Because excessive catecholamine release is likely to offset the desirable effects of natriuretic peptides, our findings suggest novel means to alleviate their adverse effects and improve their therapeutic potential. PMID:22923736

  11. Controlled-release formulation of antihistamine based on cetirizine zinc-layered hydroxide nanocomposites and its effect on histamine release from basophilic leukemia (RBL-2H3) cells

    PubMed Central

    Hasan, Samer; Ali, Hussein Al; Al-Qubaisi, Mothanna; Hussein, Mohd Zobir; Ismail, Maznah; Zainal, Zulkarnain; Hakim, Muhammad Nazrul

    2012-01-01

    A controlled-release formulation of an antihistamine, cetirizine, was synthesized using zinc-layered hydroxide as the host and cetirizine as the guest. The resulting well-ordered nanolayered structure, a cetirizine nanocomposite “CETN,” had a basal spacing of 33.9 Å, averaged from six harmonics observed from X-ray diffraction. The guest, cetirizine, was arranged in a horizontal bilayer between the zinc-layered hydroxide (ZLH) inorganic interlayers. Fourier transform infrared spectroscopy studies indicated that the intercalation takes place without major change in the structure of the guest and that the thermal stability of the guest in the nanocomposites is markedly enhanced. The loading of the guest in the nanocomposites was estimated to be about 49.4% (w/w). The release study showed that about 96% of the guest could be released in 80 hours by phosphate buffer solution at pH 7.4 compared with about 97% in 73 hours at pH 4.8. It was found that release was governed by pseudo-second order kinetics. Release of histamine from rat basophilic leukemia cells was found to be more sensitive to the intercalated cetirizine in the CETN compared with its free counterpart, with inhibition of 56% and 29%, respectively, at 62.5 ng/mL. The cytotoxicity assay toward Chang liver cells line show the IC50 for CETN and ZLH are 617 and 670 μg/mL, respectively. PMID:22848164

  12. Plasma histamine and tumour necrosis factor-alpha levels in Crohn's disease and ulcerative colitis at various stages of disease.

    PubMed

    Hagel, A F; de Rossi, T; Konturek, P C; Albrecht, H; Walker, S; Hahn, E G; Raithel, M

    2015-08-01

    Mast cells secrete numerous mediators and this study investigated plasma levels of histamine, and tumor necrosis factor alpha (TNF-α) in chronic inflammatory bowel disease (IBD). Plasma levels of histamine were determined in 68 patients with Crohn's disease (CD), 22 with ulcerative colitis (UC) and 13 controls. TNF-α levels were assessed in 29 CD patients, 11 UC patients, and in 11 controls. Plasma histamine levels in the control group were 0.25 ng (0.14 - 0.33) and showed no difference to CD (0.19 ng, 0.09 - 0.35) or UC (0.23 ng, 0.11 - 0.60). Significantly lower histamine levels were only found in CD patients on 5-aminosalicylic acid treatment (P ≤ 0.04). Plasma TNF-α levels in the control group were significantly lower 0.44 ml/m(2) (0 - 1.15) than in CD patients (4.62 ml/m(2), 1.82 - 9.22, P = 0.005) or UC (3.14 ml/m(2); 0.08 - 11.34, P = 0.01). In CD disease activity, fistula, and extraintestinal manifestations (EM) were associated with significantly higher plasma TNF-α values, but not the type of treatment. We concluded that in contrast to TNF-α, histamine levels were normal in CD and UC. There is no correlation with histamine and thus the proportion of TNF-α secreted from mast cells in the plasma in patients with IBD is less important.

  13. Histamine, histamine intoxication and intolerance.

    PubMed

    Kovacova-Hanuskova, E; Buday, T; Gavliakova, S; Plevkova, J

    2015-01-01

    Excessive accumulation of histamine in the body leads to miscellaneous symptoms mediated by its bond to corresponding receptors (H1-H4). Increased concentration of histamine in blood can occur in healthy individuals after ingestion of foods with high contents of histamine, leading to histamine intoxication. In individuals with histamine intolerance (HIT) ingestion of food with normal contents of histamine causes histamine-mediated symptoms. HIT is a pathological process, in which the enzymatic activity of histamine-degrading enzymes is decreased or inhibited and they are insufficient to inactivate histamine from food and to prevent its passage to blood-stream. Diagnosis of HIT is difficult. Multi-faced, non-specific clinical symptoms provoked by certain kinds of foods, beverages and drugs are often attributed to different diseases, such as allergy and food intolerance, mastocytosis, psychosomatic diseases, anorexia nervosa or adverse drug reactions. Correct diagnosis of HIT followed by therapy based on histamine-free diet and supplementation of diamine oxidase can improve patient's quality of life.

  14. Equilibrium theory for the clustering of bivalent cell surface receptors by trivalent ligands: application to histamine release from basophils

    SciTech Connect

    Goldstein, B.; Perelson, A.S.

    1984-06-01

    For certain cell types, the cross-linking of bivalent cell surface receptors by multivalent ligands is an important biochemical step in the transmission of information across the cell's membrane to its interior. The formation of cell surface receptor-ligand aggregates has been shown to turn on and turn off particular cell responses. It has been hypothesized that very large aggregates generate signals that small aggregates cannot. This hypothesis has not been rigorously tested as yet, in part because of a lack of quantitative information about aggregate sizes. Here the authors develop a general equilibrium theory for the clustering of bivalent receptors by trivalent ligands. In addition to predicting the concentrations of receptor-ligand aggregates of all possible sizes, they show that a range of ligand concentrations exists at which extremely large aggregates, i.e., superaggregates, form on the cell surface. The formation of a superaggregate corresponds to a sol-gel phase transition, and this transition is studied in some detail. For the biologically interesting case of histamine release by basophils, it is shown, using realistic parameter values, that such transitions should occur when the cells are from highly allergic individuals. Experimental conditions are described in detail under which such transitions should occur. These conditions can be used as a guide to test whether or not large aggregates provide signals to cells that small aggregates do not.

  15. Interaction of lectins with human IgE: IgE-binding property and histamine-releasing activity of twelve plant lectins.

    PubMed

    Shibasaki, M; Sumazaki, R; Isoyama, S; Takita, H

    1992-01-01

    We examined the IgE-binding reaction and the histamine-releasing response of basophils to a panel of 12 lectins: concanavalin A (Con A), Lens culinaris hemagglutinin (LcH), Pisum sativum agglutinin (PSA), wheat germ agglutinin (WGA), soybean agglutinin (SBA), Bauhinia purpurea agglutinin (BPA), peanut agglutinin (PNA), Ricinus communis agglutinin I (RCA-I), Lotus tetragonolobus agglutinin (Lotus A), Ulex europeus agglutinin I (UEA-I), phytohemagglutinin E (PHA-E) and phytohemagglutinin L (PHA-L), IgE from allergic patients bound with high affinity to Con A, LcH, PSA, RCA-I and PHA-E, and with lower affinity to WGA, BPA, Lotus A and UEA-I, but they did not bind to SBA, PNA or PHA-L. There was no apparent individual difference in the reactivity of IgE to these lectins between 10 IgE preparations from allergic patients. The binding to these lectins, except Lotus A and UEA-I, were competitively inhibited by the lectin-specific sugars or glycopeptide. Upon stimulation by Con A, LcH, PSA, WGA, RCA-1 and PHA-E, leukocytes from allergic patients showed a significant release of histamine, but cells from IgE-deficient subjects did not respond to these lectins. The histamine-releasing responses by these lectins were also inhibited by specific sugars or glycopeptides.

  16. Structure-activity relationship of a series of 17 parabens and related compounds for histamine release in rat peritoneal mast cells and skin allergic reaction in guinea pigs.

    PubMed

    Uramaru, Naoto; Inoue, Toshio; Watanabe, Yoko; Shigematsu, Hidenari; Ohta, Shigeru; Kitamura, Shigeyuki

    2014-02-01

    Parabens, which are a homologous series of esters of p-hydroxybenzoic acid, have been used as preservatives in cosmetics, medicines and foods because of their antimicrobial activity. However, parabens in cosmetics have been suspected to cause allergic contact dermatitis. In this study, we examined paraben-induced histamine release from rat peritoneal mast cells and skin reaction in guinea pigs using a series of 17 parabens with different alcohol side chains, ranging from methylparaben to dodecylparaben. Octylparaben showed the greatest histamine release-inducing activity from mast cells, and the activity was decreased in shorter- and longer-side-chain parabens. Octyl benzoate, octyl o-hydroxybenzoate and phenyloctane caused no significant degranulation of mast cells, whereas octyl m-hydroxybenzoate, octyl p-hydroxybenzoate and octyl phenol induced concentration-related degranulation. Metabolites of these parabens (p-hydroxybenzoic acid and alcohols) did not show histamine release-inducing activity. In the guinea pig skin reaction test, heptylparaben induced a typical strong skin reaction, while butylparaben induced a typical weak skin reaction, and methylparaben and dodecylparaben were inactive. Metabolites of parabens (p-hydroxybenzoic acid and alcohols) were also inactive. These results indicate that interaction of parabens with rat mast cells requires a minimum length and adequate lipophilicity of the alkyl side chain. Since metabolites of parabens were inactive, parabens appear to be direct-acting allergens.

  17. Phenolic constituents of the Bangladeshi medicinal plant Pothos scandens and their anti-estrogenic, hyaluronidase inhibition, and histamine release inhibitory activities.

    PubMed

    Muhit, Md Abdul; Izumikawa, Masahiro; Umehara, Kaoru; Noguchi, Hiroshi

    2016-01-01

    Extracts from the stem and roots of the Bangladeshi medicinal plant Pothos scandens L. (Araceae) were isolated, and three hemiterpene glucoside aromatic esters, pothobanosides A (1), B (2), and C (3), and a phenylisobutanoid, pothobanol (4), along with 14 known compounds, were characterized. The isolates were tested for their estrogenic/anti-estrogenic activity using the estrogen-responsive human breast cancer cell lines MCF-7 and T47D, and syringoyl derivatives (2, 3, and canthoside B) showed strong inhibitory activity against both cell lines. Their less oxygenated analogs (1, and markhamioside F) were almost inactive. The isolates were also evaluated for hyaluronidase and histamine release inhibitory activities, and pothobanoside A (1) showed significant hyaluronidase inhibitory activity among the isolated compounds, which was similar to that of the positive control rosmarinic acid. Because hyaluronidase produces an angiogenic response that has been implicated in tumor invasiveness and metastasis, 1 could be valuable as an anti-tumor compound with a different mechanism of action from related compounds (2, 3). Pothobanoside C (3) and pothobanol (4) were also found to inhibit histamine release to a similar degree to the positive control epigallocatechin 3-O-(3"-O-methyl)-gallate. The histamine release inhibitory potency of these isolates may support the traditional uses of this plant in folk medicine. PMID:26542239

  18. Regional Differential Effects of the Novel Histamine H3 Receptor Antagonist 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) on Histamine Release in the Central Nervous System of Freely Moving Rats

    PubMed Central

    Giannoni, Patrizia; Medhurst, Andrew D.; Passani, Maria Beatrice; Giovannini, Maria Grazia; Ballini, Chiara; Corte, Laura Della

    2010-01-01

    After oral administration, the nonimidazole histamine H3 receptor antagonist, 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), increased histamine release from the tuberomammillary nucleus, where all histaminergic somata are localized, and from where their axons project to the entire brain. To further understand functional histaminergic circuitry in the brain, dual-probe microdialysis was used to pharmacologically block H3 receptors in the tuberomammillary nucleus, and monitor histamine release in projection areas. Perfusion of the tuberomammillary nucleus with GSK189254 increased histamine release from the tuberomammillary nucleus, nucleus basalis magnocellularis, and cortex, but not from the striatum or nucleus accumbens. Cortical acetylcholine (ACh) release was also increased, but striatal dopamine release was not affected. When administered locally, GSK189254 increased histamine release from the nucleus basalis magnocellularis, but not from the striatum. Thus, defined by their sensitivity to GSK189254, histaminergic neurons establish distinct pathways according to their terminal projections, and can differentially modulate neurotransmitter release in a brain region-specific manner. Consistent with its effects on cortical ACh release, systemic administration of GSK189254 antagonized the amnesic effects of scopolamine in the rat object recognition test, a cognition paradigm with important cortical components. PMID:19815811

  19. Regional differential effects of the novel histamine H3 receptor antagonist 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) on histamine release in the central nervous system of freely moving rats.

    PubMed

    Giannoni, Patrizia; Medhurst, Andrew D; Passani, Maria Beatrice; Giovannini, Maria Grazia; Ballini, Chiara; Corte, Laura Della; Blandina, Patrizio

    2010-01-01

    After oral administration, the nonimidazole histamine H(3) receptor antagonist, 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), increased histamine release from the tuberomammillary nucleus, where all histaminergic somata are localized, and from where their axons project to the entire brain. To further understand functional histaminergic circuitry in the brain, dual-probe microdialysis was used to pharmacologically block H(3) receptors in the tuberomammillary nucleus, and monitor histamine release in projection areas. Perfusion of the tuberomammillary nucleus with GSK189254 increased histamine release from the tuberomammillary nucleus, nucleus basalis magnocellularis, and cortex, but not from the striatum or nucleus accumbens. Cortical acetylcholine (ACh) release was also increased, but striatal dopamine release was not affected. When administered locally, GSK189254 increased histamine release from the nucleus basalis magnocellularis, but not from the striatum. Thus, defined by their sensitivity to GSK189254, histaminergic neurons establish distinct pathways according to their terminal projections, and can differentially modulate neurotransmitter release in a brain region-specific manner. Consistent with its effects on cortical ACh release, systemic administration of GSK189254 antagonized the amnesic effects of scopolamine in the rat object recognition test, a cognition paradigm with important cortical components.

  20. Diamine oxidase-gold ultrastructural localization of histamine in human skin biopsies containing mast cells stimulated to degranulate in vivo by exposure to recombinant human stem cell factor.

    PubMed

    Dvorak, A M; Costa, J J; Morgan, E S; Monahan-Earley, R A; Galli, S J

    1997-10-15

    Stem cell factor (SCF) has a major role in hematopoiesis and in the regulation of mast cell development and function. For example, recombinant human SCF (rhSCF) can induce the development of human mast cells from precursor cells in vitro, stimulate mediator release from human skin mast cells in vitro, and promote both the development and functional activation of human skin mast cells in vivo. In the present study, we used a new ultrastructural enzyme-affinity method, employing diamine oxidase (DAO)-conjugated gold particles (DAO-gold), to detect histamine in skin biopsies obtained from patients with breast carcinomas who were receiving daily subcutaneous (SC) injections of rhSCF in a phase I study of this cytokine. We examined control biopsies obtained at sites remote from rhSCF injection as well as biopsies of rhSCF-injected skin that were obtained within 2 hours and 30 minutes of the SC injection of rhSCF at that site. The rhSCF-injected sites (which clinically exhibited a wheal-and-flare response), but not the control sites, contained mast cells undergoing regulated secretion by granule extrusion. The DAO-gold-affinity method detected histamine in electron-dense granules of mast cells in control and injected skin biopsies; however, the altered matrix of membrane-free, extruded mast cell granules was largely unreactive with DAO-gold. Notably, DAO-gold bound strongly to fibrin deposits and collagen fibers that were adjacent to degranulated mast cells. These findings represent the first morphologic evidence of histamine secretion by classical granule exocytosis in human mast cells in vivo. PMID:9376568

  1. Histamine and substance P in synovial fluid of patients with temporomandibular disorders.

    PubMed

    Li, W; Long, X; Jiang, S; Li, Y; Fang, W

    2015-05-01

    Although psychosocial factors and malocclusion are regarded as potential causes of temporomandibular disorders (TMD), the underlying pathogenesis is poorly understood. Recent studies suggest that substance P (SP), which has been associated with both psychosocial factors and malocclusion, and histamine, whose release can be induced by SP, may be implicated in the pathogenetic process. This study was designed to measure the concentration of histamine and SP in synovial fluid (SF) of both 38 patients with TMD and 11 healthy controls, and analyse the correlation between histamine and SP. Patients with TMD were divided into three subgroups: displaced disc with reduction (DDR), displaced disc without reduction (DDNR) and osteoarthritis (OA), with 10, 13, 15 subjects in every subgroup, respectively. After collecting SF samples, histamine and SP levels were measured by enzyme-linked immunosorbent assay analysis (ELISA) and calibrated by bicinchoninic acid (BCA)-quantified protein level in the samples. The results suggest that OA group presented a significantly higher level of both histamine and SP than DDNR, DDR and healthy control groups. Histamine or SP in DDR and DDNR groups tend to be higher than control group, but no significance was found. Painful TMJs show higher histamine and SP than painless TMJs. Correlation analysis reveals a significant correlation between histamine and SP concentrations. Collectively, this study showed the changes of histamine and SP in the SF from different stages of TMD and found a significant correlation between the two substances, suggesting their potential implication in the pathogenesis of TMD.

  2. Histamine and histamine receptor regulation of gastrointestinal cancers

    PubMed Central

    Kennedy, Lindsey; Hodges, Kyle; Meng, Fanyin; Alpini, Gianfranco; Francis, Heather

    2012-01-01

    Histamine is a neurotransmitter released throughout the body that regulates multiple physiological responses. Primarily histamine is acknowledged for its role in inflammatory reactions to foreign pathogens that enter the body. Aside from inflammatory responses, histamine expression and synthesis has been detected in various cancer cell lines and multiple malignancies. Through experimentation histamine has demonstrated its ability to manage proliferation and angiogenesis in these cancerous cells, in either a positive or inhibitory manner. Regulation of angiogenesis and proliferation have been proven to be carried out by the stimulation or inhibition of numerous pathways and secondary response elements, such as VEGFA/C, IP3/Ca2+, G-proteins, cAMP, and many more. The activation of these different response pathways is linked to the binding of ligands to the histamine receptors H1-H4HR. These receptors exhibit various effects dependent on whether it binds an agonist, antagonist, or its specific ligand, histamine. In cancer cell lines and different tumor cells the binding of these different compounds has shown to be one of the main components in exerting proliferative or antiproliferative changes in the microenvironment. It is also known that the histamine receptors have varying degrees of expression in different forms of cancer, and this expression can impact the tumor in various ways. This clearly indicates the significance of histamine receptors in cancer formation, and one of the aims of this review is to cover this topic concisely and in depth. Histamine is produced from numerous cells such as basophils and mast cells and is synthesized from the enzyme histidine decarboxylase (HDC). In this review we will prominently discuss the function of mast cells and HDC in histamine expression in various gastrointestinal carcinomas. We also briefly discuss current studies to support these claims. In this review we hope to give the reader a clear and comprehensible overview of

  3. Histamine increases sickle erythrocyte adherence to endothelium.

    PubMed

    Wagner, Matthew C; Eckman, James R; Wick, Timothy M

    2006-02-01

    Complications of sickle cell anaemia include vascular occlusion triggered by the adherence of sickle erythrocytes to endothelium in the postcapillary venules. Adherence can be promoted by inflammatory mediators that induce endothelial cell adhesion molecule expression and arrest flowing erythrocytes. The present study characterised the effect of histamine stimulation on the kinetics of sickle cell adherence to large vessel and microvascular endothelium under physiological flow. Increased sickle cell adherence was observed within minutes of endothelial activation by histamine and reached a maximum value within 30 min. At steady state, sickle cell adherence to histamine-stimulated endothelium was 47 +/- 4 adherent cells/mm(2), 2.6-fold higher than sickle cell adherence to unstimulated endothelial cells. Histamine-induced sickle cell adherence occurred rapidly and transiently. Studies using histamine receptor agonists and antagonists suggest that histamine-induced sickle cell adhesion depends on simultaneous stimulation of the H(2) and H(4) histamine receptors and endothelial P-selectin expression. These data show that histamine release may promote sickle cell adherence and vaso-occlusion. In vivo histamine release should be studied to determine its role in sickle complications and whether blocking of specific histamine receptors may prevent clinical complications or adverse effects from histamine release stimulated by opiate analgesic treatment.

  4. Histamine H1-receptors mediate endothelium-dependent relaxation of rat isolated pulmonary arteries.

    PubMed

    Szarek, J L; Bailly, D A; Stewart, N L; Gruetter, C A

    1992-01-01

    Histamine has been reported to cause endothelium-dependent relaxation of vascular smooth muscle and vasodilation. This study was undertaken to examine the inhibitory effects of histamine on cylindrical segments of extrapulmonary arteries isolated from male Sprague Dawley rats. In arterial segments precontracted with phenylephrine (10 microM), histamine (0.1-100 microM) elicited concentration-dependent relaxation responses. Removal of the endothelium or pretreatment with methylene blue (10 microM) abolished relaxation responses to low concentrations of histamine and markedly inhibited those caused by histamine at concentrations greater than 1 microM. Incubation of endothelium-intact arterial segments with pyrilamine (1 microM) caused a significant rightward shift of the histamine concentration-response curves. Treatment of the segments with cimetidine (100 microM) or indomethacin (10 microM) only minimally antagonized histamine-induced relaxation in arteries with endothelium. Residual relaxation responses observed in arteries stripped of endothelium were unaffected by pretreatment with cimetidine, indomethacin, or pyrilamine. The results suggest that the inhibitory effect of histamine in rat pulmonary arteries is mediated predominantly by activation of H1-receptors on the endothelium and the subsequent release of endothelium-derived relaxing factor(s).

  5. The histamine H3 receptor antagonist clobenpropit enhances GABA release to protect against NMDA-induced excitotoxicity through the cAMP/protein kinase A pathway in cultured cortical neurons.

    PubMed

    Dai, Haibin; Fu, Qiuli; Shen, Yao; Hu, Weiwei; Zhang, Zhongmiao; Timmerman, Henk; Leurs, Rob; Chen, Zhong

    2007-06-01

    Using the histamine H3 receptor antagonist clobenpropit, the roles of histamine H3 receptors in NMDA-induced necrosis were investigated in rat cultured cortical neurons. Clobenpropit reversed the neurotoxicity in a concentration-dependent manner, and showed peak protection at a concentration of 10(-7) M. This protection was antagonized by the histamine H3 receptor agonist (R)-alpha-methylhistamine, but not by the histamine H1 receptor antagonist pyrilamine or the histamine H2 receptor antagonist cimetidine. In addition, the protection by clobenpropit was inhibited by the GABAA receptor antagonists picrotoxin and bicuculline. Further study demonstrated that the protection by clobenpropit was due to increased GABA release. The inducible GABA release was also inhibited by (R)-alpha-methylhistamine, but not by pyrilamine or cimetidine. Furthermore, both the adenylyl cyclase inhibitor SQ-22536 and the protein kinase A (PKA) inhibitor H-89 reversed the protection and the GABA release by clobenpropit. In addition, clobenpropit reversed the NMDA-induced increase in intracellular calcium level, which was antagonized by (R)-alpha-methylhistamine. These results indicate that clobenpropit enhanced GABA release to protect against NMDA-induced excitotoxicity, which was induced through the cAMP/PKA pathway, and reduction of intracellular calcium level may also be involved.

  6. Histamine h3 receptor antagonists potentiate methamphetamine self-administration and methamphetamine-induced accumbal dopamine release.

    PubMed

    Munzar, Patrik; Tanda, Gianluigi; Justinova, Zuzana; Goldberg, Steven R

    2004-04-01

    Methamphetamine administration increases brain levels of histamine and neuronal histamine attenuates several of methamphetamine's behavioral effects. The role of different subtypes of histamine receptors in this negative feedback, however, remains unclear. There is some evidence on possible involvement of histamine H3 receptors in these actions of methamphetamine. The aim of the present study was to evaluate the effects of two histamine H3 receptor antagonists, clobenpropit and thioperamide, on rewarding and neurochemical effects of methamphetamine utilizing three in vivo methodologies, drug self-administration, drug discrimination, and microdialysis in Sprague-Dawley rats. In rats self-administering methamphetamine intravenously under a fixed-ratio schedule, presession treatment with thioperamide (1.0-3.0 mg/kg, subcutaneous, s.c.) or clobenpropit (1.0-3.0 mg/kg, s.c.) potentiated the reinforcing effects of methamphetamine, as indicated by a dose-dependent increase in responding for a low 0.03 mg/kg dose of methamphetamine, that by itself failed to maintain responding above saline substitution levels, and a decrease in responding for a higher 0.06 mg/kg training dose of methamphetamine. In contrast, neither thioperamide nor clobenpropit treatment increased responding during saline substitution. In other rats trained to discriminate intraperitoneal (i.p.) injection of 1.0 mg/kg methamphetamine from i.p. injection of saline, both thioperamide and clobenpropit (0.3-3.0 mg/kg, s.c.) dose dependently increased methamphetamine-appropriate responding when administered with a low 0.3 mg/kg i.p. dose of methamphetamine, which by itself produced predominantly saline-appropriate responding. However, thioperamide and clobenpropit produced only saline-appropriate responding when administered with saline vehicle. Finally, thioperamide and clobenpropit potentiated methamphetamine-induced elevations in extracellular dopamine levels in the shell of the nucleus accumbens, but did

  7. Rosae Multiflorae Fructus Hot Water Extract Inhibits a Murine Allergic Asthma Via the Suppression of Th2 Cytokine Production and Histamine Release from Mast Cells.

    PubMed

    Song, Chang Ho; Bui, Thi Tho; Piao, Chun Hua; Shin, Hee Soon; Shon, Dong-Hwa; Han, Eui-Hyeog; Kim, Hyoung Tae; Chai, Ok Hee

    2016-09-01

    Mast cell-mediated anaphylactic reactions are involved in many allergic diseases, including asthma and allergic rhinitis. In Korea, where it has been used as a traditional medicine, Rosae Multiflorae fructus (RMF) is known to have potent antioxidative, analgesic, and anti-inflammatory activities and to have no obvious acute toxicity. However, its specific effect on asthma is still unknown. In this study, we evaluated whether or not RMF hot water extracts (RMFW) could inhibit ovalbumin (OVA)-induced allergic asthma and evaluated compound 48/80-induced mast cell activation to elucidate the mechanisms of asthma inhibition by RMFW. Oral administration of RMFW decreased the number of eosinophils and lymphocytes in the lungs of mice challenged by OVA and downregulated histological changes such as eosinophil infiltration, mucus accumulation, goblet cell hyperplasia, and collagen fiber deposits. In addition, RMFW significantly reduced T helper 2 cytokines, TNF-α, IL-4, and IL-6 levels in the BAL fluid of mice challenged by OVA. Moreover, RMFW suppressed compound 48/80-induced rat peritoneal mast cell degranulation and inhibited histamine release from mast cells induced by compound 48/80 in a dose-dependent manner. These results suggest that RMFW may act as an antiallergic agent by inhibitingTh2 cytokine production from Th2 cells and histamine release from mast cells, and could be used as a therapy for patients with Th2-mediated or mast cell-mediated allergic diseases. PMID:27574849

  8. Histamine H3 receptor activation counteracts adenosine A2A receptor-mediated enhancement of depolarization-evoked [3H]-GABA release from rat globus pallidus synaptosomes.

    PubMed

    Morales-Figueroa, Guadalupe-Elide; Márquez-Gómez, Ricardo; González-Pantoja, Raúl; Escamilla-Sánchez, Juan; Arias-Montaño, José-Antonio

    2014-08-20

    High levels of histamine H3 receptors (H3Rs) are found in the globus pallidus (GP), a neuronal nucleus in the basal ganglia involved in the control of motor behavior. By using rat GP isolated nerve terminals (synaptosomes), we studied whether H3R activation modified the previously reported enhancing action of adenosine A2A receptor (A2AR) stimulation on depolarization-evoked [(3)H]-GABA release. At 3 and 10 nM, the A2AR agonist CGS-21680 enhanced [(3)H]-GABA release induced by high K(+) (20 mM) and the effect of 3 nM CGS-21680 was prevented by the A2AR antagonist ZM-241385 (100 nM). The presence of presynaptic H3Rs was confirmed by the specific binding of N-α-[methyl-(3)H]-histamine to membranes from GP synaptosomes (maximum binding, Bmax, 1327 ± 79 fmol/mg protein; dissociation constant, Kd, 0.74 nM), which was inhibited by the H3R ligands immepip, clobenpropit, and A-331440 (inhibition constants, Ki, 0.28, 8.53, and 316 nM, respectively). Perfusion of synaptosomes with the H3R agonist immepip (100 nM) had no effect on K(+)-evoked [(3)H]-GABA release, but inhibited the stimulatory action of A2AR activation. In turn, the effect of immepip was blocked by the H3R antagonist clobenpropit, which had no significant effect of its own on K(+)-induced [(3)H]-GABA release. These data indicate that H3R activation selectively counteracts the facilitatory action of A2AR stimulation on GABA release from striato-pallidal projections.

  9. Histamine H3 Receptor Activation Counteracts Adenosine A2A Receptor-Mediated Enhancement of Depolarization-Evoked [3H]-GABA Release from Rat Globus Pallidus Synaptosomes

    PubMed Central

    2014-01-01

    High levels of histamine H3 receptors (H3Rs) are found in the globus pallidus (GP), a neuronal nucleus in the basal ganglia involved in the control of motor behavior. By using rat GP isolated nerve terminals (synaptosomes), we studied whether H3R activation modified the previously reported enhancing action of adenosine A2A receptor (A2AR) stimulation on depolarization-evoked [3H]-GABA release. At 3 and 10 nM, the A2AR agonist CGS-21680 enhanced [3H]-GABA release induced by high K+ (20 mM) and the effect of 3 nM CGS-21680 was prevented by the A2AR antagonist ZM-241385 (100 nM). The presence of presynaptic H3Rs was confirmed by the specific binding of N-α-[methyl-3H]-histamine to membranes from GP synaptosomes (maximum binding, Bmax, 1327 ± 79 fmol/mg protein; dissociation constant, Kd, 0.74 nM), which was inhibited by the H3R ligands immepip, clobenpropit, and A-331440 (inhibition constants, Ki, 0.28, 8.53, and 316 nM, respectively). Perfusion of synaptosomes with the H3R agonist immepip (100 nM) had no effect on K+-evoked [3H]-GABA release, but inhibited the stimulatory action of A2AR activation. In turn, the effect of immepip was blocked by the H3R antagonist clobenpropit, which had no significant effect of its own on K+-induced [3H]-GABA release. These data indicate that H3R activation selectively counteracts the facilitatory action of A2AR stimulation on GABA release from striato-pallidal projections. PMID:24884070

  10. Histamine H(3) receptor-mediated inhibition of depolarization-induced, dopamine D(1) receptor-dependent release of [(3)H]-gamma-aminobutryic acid from rat striatal slices.

    PubMed

    Arias-Montaño, J A; Floran, B; Garcia, M; Aceves, J; Young, J M

    2001-05-01

    1. A study was made of the regulation of [(3)H]-gamma-aminobutyric acid ([(3)H]-GABA) release from slices of rat striatum by endogenous dopamine and exogenous histamine and a histamine H(3)-agonist. Depolarization-induced release of [(3)H]-GABA was Ca(2+)-dependent and was increased in the presence of the dopamine D(2) receptor family antagonist, sulpiride (10 microM). The sulpiride-potentiated release of [(3)H]-GABA was strongly inhibited by the dopamine D(1) receptor family antagonist, SCH 23390 (1 microM). Neither antagonist altered basal release. 2. The 15 mM K(+)-induced release of [(3)H]-GABA in the presence of sulpiride was inhibited by 100 microM histamine (mean inhibition 78+/-3%) and by the histamine H(3) receptor-selective agonist, immepip, 1 microM (mean inhibition 81+/-5%). The IC(50) values for histamine and immepip were 1.3+/-0.2 microM and 16+/-2 nM, respectively. The inhibitory effects of histamine and immepip were reversed by the H(3) receptor antagonist, thioperamide, 1 microM. 3. The inhibition of 15 mM K(+)-induced [(3)H]-GABA release by immepip was reversed by the H(3) receptor antagonist, clobenpropit, K(d) 0.11+/-0.04 nM. Clobenpropit alone had no effect on basal or stimulated release of [(3)H]-GABA. 4. Elevated K(+) caused little release of [(3)H]-GABA from striatal slices from reserpinized rats, unless the D(1) partial agonist, R(+)-SKF 38393, 1 microM, was also present. The stimulated release in the presence of SKF 38393 was reduced by 1 microM immepip to the level obtained in the absence of SKF 38393. 5. These observations demonstrate that histamine H(3) receptor activation strongly inhibits the dopamine D(1) receptor-dependent release of [(3)H]-GABA from rat striatum; primarily through an interaction at the terminals of GABA neurones.

  11. Histamine Promotes the Release of Interleukin-6 via the H1R/p38 and NF-κB Pathways in Nasal Fibroblasts

    PubMed Central

    Park, Il-Ho; Um, Ji-Young; Cho, Jung-Sun; Lee, Seung Hoon; Lee, Sang Hag

    2014-01-01

    Purpose Based on the close relationship between histamine and interleukin 6 (IL-6), we hypothesized that histamine may regulate the production of cytokines, such as IL-6, during allergic inflammation. Here, we examined the role of histamine in IL-6 production and histamine receptor activity in nasal fibroblasts, along with the mechanisms underlying these effects. Methods Experiments were performed using nasal fibroblasts from 8 normal patients. RT-PCR was used to identify the major histamine receptors expressed in nasal fibroblasts. Fibroblasts were then treated with histamine with or without histamine-receptor antagonists, and monitored for IL-6 production using an ELISA. Four potential downstream signaling molecules, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and NF-κB, were evaluated by Western blot, and a luciferase reporter assay. Results Elevated expression was seen for all histamine receptors, with IL-6 protein levels increasing significantly following histamine stimulation. Among the histamine-receptor specific antagonists, only the H1R antagonist significantly decreased IL-6 production in histamine-stimulated nasal fibroblasts. Histamine increased the expression level of phosphorylated p38 (pp38), pERK, and pJNK, as well as NF-κB induction. The H1R antagonist actively suppressed pp38 and NF-κB expression in histamine-induced nasal fibroblasts, but not pERK and pJNK. The p38 inhibitor strongly attenuated IL-6 production in histamine-stimulated nasal fibroblasts. Conclusions The data presented here suggest that antihistamines may be involved in the regulation of cytokines, such as IL-6, due to the role of histamine as an inflammatory mediator in nasal fibroblasts. PMID:25374757

  12. The histamine H3 receptor and eating behavior.

    PubMed

    Passani, Maria Beatrice; Blandina, Patrizio; Torrealba, Fernando

    2011-01-01

    Interest in the histaminergic system as a potential target for the treatment of feeding disorders is driven by the unsatisfactory history of the pharmacotherapy of obesity. Eating behavior is regulated by a complex interplay of central neurotransmitter systems, peripheral endocrine stimuli, the circadian rhythm, and environmental cues, all factors that change the behavioral state and alter homeostatic aspects of appetite and energy expenditure. Key factors driving eating behavior are appetite and satiety that are regulated through different mechanisms. Brain histamine has long been considered a satiety signal in the nervous system. Recent observations, however, indicate that histamine does not meet the criteria for being a satiety signal, because augmented histamine release accompanies the appetitive phase of feeding behavior rather than food consumption and satiety. The appetitive phase requires a high and yet optimal arousal state, and the histaminergic system is crucial for sustaining a high degree of arousal during motivated behavior. Histamine H(1) receptors in the brain are crucial for the regulation of the diurnal rhythm of food intake and the regulation of obesity; however, from a therapeutic standpoint, no brain-penetrating H(1) receptor agonists have been identified that would have antiobesity effects. Despite conflicting preclinical data, insights are emerging into the potential role of histamine H(3) receptors as a target of antiobesity therapeutics. The aim of this review is to outline the relevance of the histaminergic system in controlling feeding behavior and evaluate the potential therapeutic use of histaminergic ligands for the treatment of eating disorders.

  13. Histamine H3 receptor activation prevents dopamine D1 receptor-mediated inhibition of dopamine release in the rat striatum: a microdialysis study.

    PubMed

    Alfaro-Rodriguez, Alfonso; Alonso-Spilsbury, María; Arch-Tirado, Emilio; Gonzalez-Pina, Rigoberto; Arias-Montaño, José-Antonio; Bueno-Nava, Antonio

    2013-09-27

    Histamine H3 receptors (H3Rs) co-localize with dopamine (DA) D1 receptors (D1Rs) on striatal medium spiny neurons and functionally antagonize D1R-mediated responses. The intra-striatal administration of D1R agonists reduces DA release whereas D1R antagonists have the opposite effect. In this work, a microdialysis method was used to study the effect of co-activating D1 and H3 receptors on the release of DA from the rat dorsal striatum. Infusion of the D1R agonist SKF-38393 (0.5 and 1 μM) significantly reduced DA release (26-58%), and this effect was prevented by co-administration of the H3R agonist immepip (10 μM). In turn, the effect of immepip was blocked by the H3R antagonist thioperamide (10 μM). Our results indicate that co-stimulation of post-synaptic D1 and H3 receptors may indirectly regulate basal DA release in the rat striatum and provide in vivo evidence for a functional interaction between D1 and H3 receptors in the basal ganglia.

  14. Histamine in neurotransmission and brain diseases.

    PubMed

    Nuutinen, Saara; Panula, Pertti

    2010-01-01

    Apart from its central role in the mediation of allergic reactions, gastric acid secretion and inflammation in the periphery, histamine serves an important function as a neurotransitter in the central nervous system. The histaminergic neurons originate from the tuberomamillary nucleus of the posterior hypothalamus and send projections to most parts of the brain. The central histamine system is involved in many brain functions such as arousal, control of pituitary hormone secretion, suppression ofeating and cognitive functions. The effects of neuronal histamine are mediated via G-protein-coupled H1-H4 receptors. The prominent role of histamine as a wake-promoting substance has drawn interest to treat sleep-wake disorders, especially narcolepsy, via modulation of H3 receptor function. Post mortem studies have revealed alterations in histaminergic system in neurological and psychiatric diseases. Brain histamine levels are decreased in Alzheimer's disease patients whereas abnormally high histamine concentrations are found in the brains of Parkinson's disease and schizophrenic patients. Low histamine levels are associated with convulsions and seizures. The release of histamine is altered in response to different types of brain injury: e.g. increased release of histamine in an ischemic brain trauma might have a role in the recovery from neuronal damage. Neuronal histamine is also involved in the pain perception. Drugs that increase brain and spinal histamine concentrations have antinociceptive properties. Histaminergic drugs, most importantly histamine H3 receptors ligands, have shown efficacy in many animal models of the above-mentioned disorders. Ongoing clinical trials will reveal the efficacy and safety of these drugs in the treatment of human patients.

  15. Histamine in the regulation of wakefulness.

    PubMed

    Thakkar, Mahesh M

    2011-02-01

    The histaminergic system is exclusively localized within the posterior hypothalamus with projection to almost all the major regions of the central nervous system. Strong and consistent evidence exist to suggest that histamine, acting via H₁ and/or H₃ receptor has a pivotal role in the regulation of sleep-wakefulness. Administration of histamine or H₁ receptor agonists induces wakefulness, whereas administration of H₁ receptor antagonists promotes sleep. The H₃ receptor functions as an auto-receptor and regulates the synthesis and release of histamine. Activation of H₃ receptor reduces histamine release and promotes sleep. Conversely, blockade of H₃ receptor promotes wakefulness. Histamine release in the hypothalamus and other target regions is highest during wakefulness. The histaminergic neurons display maximal activity during the state of high vigilance, and cease their activity during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. The cerebrospinal levels of histamine are reduced in diseased states where hypersomnolence is a major symptom. The histamine deficient L-histidine decarboxylase knockout (HDC KO) mice display sleep fragmentation and increased REM sleep during the light period along with profound wakefulness deficit at dark onset, and in novel environment. Similar results have been obtained when histamine neurons are lesioned. These studies strongly implicate the histaminergic neurons of the TMN to play a critical role in the maintenance of high vigilance state during wakefulness.

  16. HISTAMINE IN THE REGULATION OF WAKEFULNESS

    PubMed Central

    Thakkar, Mahesh M.

    2010-01-01

    The histaminergic system is exclusively localized within the posterior hypothalamus with projection to almost all the major regions of the central nervous system. Strong and consistent evidence exist to suggest that histamine, acting via H1 and/or H3 receptor has a pivotal role in the regulation of sleep-wakefulness. Administration of histamine or H1 receptor agonists induced wakefulness, whereas administration of H1 receptor antagonists promoted sleep. The H3 receptor functions as an auto-receptor and regulates the synthesis and release of histamine. Activation of H3 receptor decreased histamine release and promoted sleep. Conversely, blockade of H3 receptor promoted wakefulness. Histamine release in the hypothalamus and other target regions was highest during wakefulness. The histaminergic neurons displayed maximal activity during the state of vigilance, and cease their activity during NREM and REM sleep. The cerebrospinal levels of histamine were reduced in diseased states where hypersomnolence was a major symptom. The histamine deficient HDC KO mice displayed sleep fragmentation and increased REM sleep during the light period along with profound wakefulness deficit at dark onset, and in novel environment. Similar results were obtained when histamine neurons were lesioned. These studies strongly implicate the histaminergic neurons of the TMN to play a critical role in the maintenance of high vigilance state during wakefulness. PMID:20851648

  17. Gender-Related Effects of Sex Steroids on Histamine Release and FcεRI Expression in Rat Peritoneal Mast Cells

    PubMed Central

    Muñoz-Cruz, Samira; Mendoza-Rodríguez, Yolanda; Nava-Castro, Karen E.; Yepez-Mulia, Lilián; Morales-Montor, Jorge

    2015-01-01

    Mast cells (MCs) are versatile effector and regulatory cells in various physiologic, immunologic, and pathologic processes. In addition to the well-characterized IgE/FcεRI-mediated degranulation, a variety of biological substances can induce MCs activation and release of their granule content. Sex steroids, mainly estradiol and progesterone, have been demonstrated to elicit MCs activation. Most published studies have been conducted on MCs lines or freshly isolated peritoneal and bone marrow-derived MC without addressing gender impact on MC response. Our goal was to investigate if the effect of estradiol, progesterone, testosterone, and dihydrotestosterone (DHT) on MCs may differ depending on whether female or male rats are used as MCs donors. Our results demonstrated that effect of sex steroids on MCs histamine release is dose- and gender-dependent and can be direct, synergistic, or inhibitory depending on whether hormones are used alone or to pretreat MCs followed by substance P-stimulation or upon IgE-mediated stimulation. In contrast, sex steroids did not have effect on the MC expression of the IgE high affinity receptor, FcεRI, no matter female or male rats were used. In conclusion, MCs degranulation is modulated by sex hormones in a gender-selective fashion, with MC from females being more susceptible than MC from males to the effects of sex steroids. PMID:25973435

  18. The in vivo effects of interleukin-3 on histamine levels in non-Hodgkin's lymphoma patients.

    PubMed

    Hovgaard, D J; Stahl Skov, P; Nissen, N I

    1997-06-01

    Recombinant human Interleukin-3 (RhIL-3) is a haemopoietic growth factor with effect both on early and differentiated cells, such as eosinophils and basophils, and it also acts as a histamine-releasing agent. The purpose of the present study was to examine whether in vivo rhIL-3 administration after chemotherapy affected basophil histamine levels and whether a concordance between rhIL-3 induced histamine release and side effects during the treatment could be demonstrated. Thirty patients with non-Hodgkin's lymphoma entered the study. All patients received 6 courses of chemotherapy, rhIL-3 was administered subcutaneously once daily after the second and the fourth course of chemotherapy from cycle day 2-15 at the dose levels 0.5, 1.0, 5.0, 7.5 and 10 micrograms/kg with 6 patients at each dose level. In cycle 6 recombinant human Granulocyte-Macrophage Colony-Stimulating Factor (rhGM-CSF) (3.0 micrograms/kg) was administered sequential/concurrent day 9-15 to rhIL-3 (day 2-15) at all dose levels except 7.5 micrograms/kg, where rhIL-3 was given day 2-8 and rhGM-CSF sequential day 9-15. Cycles 1, 3 and 5 served as control cycles with no cytokine therapy. During rhIL-3 treatment, and after CHOP chemotherapy, the basophil counts increased moderately especially during the recovery period day 15-22, and mainly at the two highest dose levels 7.5 and 10 micrograms/kg, but never exceeded the normal upper limit. Histamine levels in basophils were the same in patients before chemotherapy and healthy volunteers, and except from a trend to increased histamine level at 10 micrograms/kg on day 15, no difference was noted between rhIL-3 cycles and control cycles. Within 3-4 hr after rhIL-3 administration, a drop in histamine level in basophils was noted, which could be due to histamine-releasing properties of rhIL-3 as previously demonstrated by in vitro studies. No serious side effects were noted during the cytokine treatment, and despite that most patients had mild flushing of the

  19. H4 Histamine Receptors Mediate Cell Cycle Arrest in Growth Factor-Induced Murine and Human Hematopoietic Progenitor Cells

    PubMed Central

    Petit-Bertron, Anne-France; Machavoine, François; Defresne, Marie Paule; Gillard, Michel; Chatelain, Pierre; Mistry, Prakash

    2009-01-01

    The most recently characterized H4 histamine receptor (H4R) is expressed preferentially in the bone marrow, raising the question of its role during hematopoiesis. Here we show that both murine and human progenitor cell populations express this receptor subtype on transcriptional and protein levels and respond to its agonists by reduced growth factor-induced cell cycle progression that leads to decreased myeloid, erythroid and lymphoid colony formation. H4R activation prevents the induction of cell cycle genes through a cAMP/PKA-dependent pathway that is not associated with apoptosis. It is mediated specifically through H4R signaling since gene silencing or treatment with selective antagonists restores normal cell cycle progression. The arrest of growth factor-induced G1/S transition protects murine and human progenitor cells from the toxicity of the cell cycle-dependent anticancer drug Ara-C in vitro and reduces aplasia in a murine model of chemotherapy. This first evidence for functional H4R expression in hematopoietic progenitors opens new therapeutic perspectives for alleviating hematotoxic side effects of antineoplastic drugs. PMID:19662098

  20. Histamine H3 receptors modulate reactive hyperemia in rat gut.

    PubMed

    Pawlik, W W; Obuchowicz, R; Pawlik, M W; Sendur, R; Biernat, J; Brzozowski, T; Konturek, S J

    2004-09-01

    Reactive hyperemia (RH) is an abrupt blood flow increase following release from mechanical occlusion of an artery, with restoration of intra-arterial pressure. The mechanism of this postocclusion increase in blood flow in the gut is multifactorial. Relaxation of intestinal resistance vessels, observed during RH, may involve myogenic, metabolic, hormonal and neurogenic factors. Evidence exists that histamine is an important endogenous mediator of various functions of the gut, including blood flow. The vascular effects of histamine in the intestinal circulation are due its agonistic action on histamine H1, H2 and H3 receptors. In the present study the hypothesis was tested that peripheral histamine H3 receptors are involved in the mediation of RH in the intestinal circulation. In anesthetized rats, anterior mesenteric artery blood flow (MBF) was determined with ultrasonic Doppler flowmeter, and arterial pressure (AP) was determined with a transducer. The increase in the volume of blood accumulating during RH (RH-volume), the peak increase of arterial blood flow (RH-peak response) and the duration of the hyperemia (RH-duration) were used to quantify RH after occluding the anterior mesenteric artery for 30, 60 and 120 s. Hyperemia parameters were determined before and after administration of the selective histamine H3 receptor antagonist clobenpropit. Pretreatment with clobenpropit was without any effect on control MBF and AP but significantly reduced most of RH responses. These findings support the hypothesis that histamine H3 receptors do not play any role in the control of intestinal vasculature at basal conditions but these receptors participate in the intestinal hyperemic reaction in response to complete temporal intestinal ischemia.

  1. Rabbit IgG directed to a synthetic C-terminal peptide of the major grass pollen allergen Lol p I inhibits human basophil histamine release induced by natural Lol p I.

    PubMed

    van Ree, R; Aalberse, R C

    1995-03-01

    The potential role of allergen-specific IgG antibodies as 'blocking' antibodies in allergen-induced human basophil histamine release was investigated. This was studied in a model with the major grass pollen allergen Lol p I and polyclonal rabbit antisera directed against this allergen and against a synthetic peptide of its C terminus. When allergen and antibodies were allowed to preincubate, Lol p I induced histamine release was inhibited up to 85% by the antiserum against Lol p I. By omitting preincubation, and thereby more closely mimicking an in vivo situation, up to 55% inhibition was realized. This indicates that allergen-specific IgG can act as 'blocking' antibody without preincubation. Immunization of rabbits with a synthetic C-terminal peptide of Lol p I resulted in antibodies reactive with natural Lol p I. Despite their 100-fold lower avidity for Lol p I (as compared with antinatural Lol p I), these antibodies had the capacity to inhibit Lol p I induced histamine release for > 90% (up to 50% without preincubation). This indicates that it is possible to block histamine release induced by a major allergen with low-avidity IgG antibodies directed against a minor proportion of the allergen (25 amino acids). IgE antibodies from the donors studied were unreactive with this synthetic peptide, indicating that for blocking activity identical epitope specificity of IgE and IgG is not essential. This opens interesting perspectives for application of synthetic peptides in immunotherapy, distinct from their effects on T cell reactivity.

  2. Dynamics of histamine H(3) receptor antagonists on brain histamine metabolism: do all histamine H(3) receptor antagonists act at a single site?

    PubMed

    Barnes, W; Boyd, D; Hough, L

    2001-11-16

    Thioperamide, the prototypical histamine H(3) receptor antagonist, acts at the brain histamine H(3) autoreceptor to promote the release and metabolism of neuronal histamine, resulting in higher brain levels of the metabolite tele-methylhistamine. However, unlike thioperamide, several new histamine H(3) receptor antagonists enter the central nervous system (CNS), block brain histamine H(3) receptors and increase histamine release without increasing brain tele-methylhistamine levels. Experiments were performed presently in an attempt to understand these results. Consistent with previous findings, thioperamide significantly increased the content and synthesis rate of tele-methylhistamine in mouse and rat brain. In contrast, the histamine H(3) receptor antagonists GT-2227 (4-(6-cyclohexylhex-cis-3-enyl)imidazole) and clobenpropit did not affect tele-methylhistamine synthesis rate in mouse whole brain. The histamine H(3) receptor ligand GT-2016 (5-cyclohexyl-1-(4-imidazol-4-ylpiperidyl)pentan-1-one) had no effect on tele-methylhistamine levels in any rat brain region and decreased tele-methylhistamine synthesis rates in the mouse whole brain. To examine the possibility that these histamine H(3) receptor antagonists might prevent the methylation of newly released histamine, they were co-administered with thioperamide to determine their effects on the thioperamide-induced stimulation of tele-methylhistamine synthesis. GT-2016 significantly reduced the thioperamide-induced activation of tele-methylhistamine synthesis in mouse whole brain and in several regions of rat brain. Although further clarification is needed, these results suggest that some histamine H(3) receptor antagonists may promote the release of neuronal histamine, but also act to reduce histamine methylation in vivo by an unknown mechanism.

  3. Histamine regulates the inflammatory response of the tunicate Styela plicata.

    PubMed

    García-García, Erick; Gómez-González, Nuria E; Meseguer, José; García-Ayala, Alfonsa; Mulero, Victoriano

    2014-10-01

    Histamine is stored inside hemocytes of the tunicate Styela plicata (Chordata, Tunicata, Ascidiacea), but no evidence on its role in the regulation of the immune response of this species has been reported. We examined whether histamine participated in the regulation of inflammation and host defense in S. plicata. The presence of histamine inside S. plicata hemocytes was confirmed by flow cytometry, and histamine release was detected by ELISA, after in vitro hemocyte stimulation with different PAMPs. In vitro hemocyte treatment with histamine, or specific histamine-receptor agonists, reduced their phagocytic ability. Injection of histamine into the tunic recruited hemocytes to the site of injection. Systemic injection of histamine, or the histamine-releasing agent compound 48/80, decreased the phagocytic ability of hemocytes. Histamine promoted the constriction of tunic hemolymph vessels in vivo, having a direct effect on vasoconstriction in tunic explants. These results provide for the first time clear evidence for the involvement of histamine in the regulation of inflammation and host defense in tunicates.

  4. Fusion of Na-ASP-2 with human immunoglobulin Fcγ abrogates histamine release from basophils sensitized with anti-Na-ASP-2 IgE.

    PubMed

    Zhan, Bin; Santiago, H; Keegan, B; Gillespie, P; Xue, J; Bethony, J; de Oliveira, L M; Jiang, D; Diemert, D; Xiao, S-H; Jones, K; Feng, X; Hotez, P J; Bottazzi, M E

    2012-01-01

    Na-ASP-2 is a major protein secreted by infective third-stage larvae (L3) of the human hookworm Necator americanus upon host entry. It was chosen as a lead vaccine candidate for its ability to elicit protective immune responses. However, clinical development of this antigen as a recombinant vaccine was halted because it caused allergic reactions among some of human volunteers previously infected with N. americanus. To prevent IgE-mediated allergic reactions induced by Na-ASP-2 but keep its immunogenicity as a vaccine antigen, we designed and tested a genetically engineered fusion protein, Fcγ/Na-ASP-2, composed of full-length Na-ASP-2 and truncated human IgG Fcγ1 that targets the negative signalling receptor FcγRIIb expressed on pro-allergic cells. The chimeric recombinant Fcγ/Na-ASP-2 protein was expressed in Pichia pastoris and shared the similar antigenicity as native Na-ASP-2. Compared to Na-ASP-2, the chimeric fusion protein efficiently reduced the release of histamine in human basophils sensitized with anti-Na-ASP-2 IgE obtained from individuals living in a hookworm-endemic area. In dogs infected with canine hookworm, Fcγ/Na-ASP-2 resulted in significantly reduced immediate-type skin reactivity when injected intradermally compared with Na-ASP-2. Hamsters vaccinated with Fcγ/Na-ASP-2 formulated with Alhydrogel(®) produced specific IgG that recognized Na-ASP-2 and elicited similar protection level against N. americanus L3 challenge as native Na-ASP-2.

  5. Histamine reduces GPIbα-mediated adhesion of platelets to TNF-α-activated vascular endothelium.

    PubMed

    Brown, T P; Forouzan, O; Shevkoplyas, S S; Khismatullin, D B

    2013-02-01

    Histamine and tumor necrosis factor-α (TNF-α) are critical mediators of acute and chronic inflammation that are generated by mast cells and macrophages in atherosclerotic lesions or systemically during allergic attacks. Both of them induce activation of vascular endothelium and thus may play a role in thrombosis. Here we studied the interplay between histamine and TNF-α in glycoprotein (GP) Ibα-mediated platelet adhesion to cultured human vascular endothelial cells under static and shear flow conditions. The stimulation of endothelial cells with histamine or TNF-α increased the number of adherent or slow rolling GP Ibα-coated microbeads or washed human platelets. However, the application of histamine to endothelium pre-activated by TNF-α inhibited GP Ibα-mediated platelet adhesion. These effects were found to be associated with changes in the concentration of ultra large von Willebrand factor (ULVWF) strings anchored to endothelium. The results of this study indicate that histamine released during mast cell degranulation may cause or inhibit thrombosis, depending on whether it acts on resting endothelial cells or on cells pre-activated by other inflammatory stimuli.

  6. Role of Histamine and Its Receptors in Cerebral Ischemia

    PubMed Central

    2012-01-01

    Histamine is recognized as a neurotransmitter or neuromodulator in the brain, and it plays a major role in the pathogenic progression after cerebral ischemia. Extracellular histamine increases gradually after ischemia, and this may come from histaminergic neurons or mast cells. Histamine alleviates neuronal damage and infarct volume, and it promotes recovery of neurological function after ischemia; the H1, H2, and H3 receptors are all involved. Further studies suggest that histamine alleviates excitotoxicity, suppresses the release of glutamate and dopamine, and inhibits inflammation and glial scar formation. Histamine may also affect cerebral blood flow by targeting to vascular smooth muscle cells, and promote neurogenesis. Moreover, endogenous histamine is an essential mediator in the cerebral ischemic tolerance. Due to its multiple actions, affecting neurons, glia, vascular cells, and inflammatory cells, histamine is likely to be an important target in cerebral ischemia. But due to its low penetration of the blood-brain barrier and its wide actions in the periphery, histamine-related agents, like H3 antagonists and carnosine, show potential for cerebral ischemia therapy. However, important questions about the molecular aspects and pathophysiology of histamine and related agents in cerebral ischemia remain to be answered to form a solid scientific basis for therapeutic application. PMID:22860191

  7. Helicobacter pylori neutrophil-activating protein induces release of histamine and interleukin-6 through G protein-mediated MAPKs and PI3K/Akt pathways in HMC-1 cells.

    PubMed

    Tsai, Chung-Che; Kuo, Ting-Yu; Hong, Zhi-Wei; Yeh, Ying-Chieh; Shih, Kuo-Shun; Du, Shin-Yi; Fu, Hua-Wen

    2015-01-01

    Helicobacter pylori neutrophil-activating protein (HP-NAP) activates several innate leukocytes including neutrophils, monocytes, and mast cells. It has been reported that HP-NAP induces degranulation and interleukin-6 (IL-6) secretion of rat peritoneal mast cells. However, the molecular mechanism is not very clear. Here, we show that HP-NAP activates human mast cell line-1 (HMC-1) cells to secrete histamine and IL-6. The secretion depends on pertussis toxin (PTX)-sensitive heterotrimeric G proteins but not on Toll-like receptor 2. Moreover, HP-NAP induces PTX-sensitive G protein-mediated activation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38-mitogen-activated protein kinase (p38 MAPK), and Akt in HMC-1 cells. Inhibition of ERK1/2, p38 MAPK, or phosphatidylinositol 3-kinase (PI3K) suppresses HP-NAP-induced release of histamine and IL-6 from HMC-1 cells. Thus, the activation of HMC-1 cells by HP-NAP is through Gi-linked G protein-coupled receptor-mediated MAPKs and PI3K/Akt pathways.

  8. Histamine and motivation

    PubMed Central

    Torrealba, Fernando; Riveros, Maria E.; Contreras, Marco; Valdes, Jose L.

    2012-01-01

    Brain histamine may affect a variety of different behavioral and physiological functions; however, its role in promoting wakefulness has overshadowed its other important functions. Here, we review evidence indicating that brain histamine plays a central role in motivation and emphasize its differential involvement in the appetitive and consummatory phases of motivated behaviors. We discuss the inputs that control histaminergic neurons of the tuberomamillary nucleus (TMN) of the hypothalamus, which determine the distinct role of these neurons in appetitive behavior, sleep/wake cycles, and food anticipatory responses. Moreover, we review evidence supporting the dysfunction of histaminergic neurons and the cortical input of histamine in regulating specific forms of decreased motivation (apathy). In addition, we discuss the relationship between the histamine system and drug addiction in the context of motivation. PMID:22783171

  9. Histamine H3 receptors and sleep-wake regulation.

    PubMed

    Lin, Jian-Sheng; Sergeeva, Olga A; Haas, Helmut L

    2011-01-01

    The histaminergic system fulfills a major role in the maintenance of waking. Histaminergic neurons are located exclusively in the posterior hypothalamus from where they project to most areas of the central nervous system. The histamine H(3) receptors are autoreceptors damping histamine synthesis, the firing frequency of histamine neurons, and the release of histamine from axonal varicosities. It is noteworthy that this action also extends to heteroreceptors on the axons of most other neurotransmitter systems, allowing a powerful control over multiple homeostatic functions. The particular properties and locations of histamine H(3) receptors provide quite favorable attributes to make this a most promising target for pharmacological interventions of sleep and waking disorders associated with narcolepsy, Parkinson's disease, and other neuropsychiatric indications.

  10. Mental illness, criminal risk factors and parole release decisions.

    PubMed

    Matejkowski, Jason; Draine, Jeffrey; Solomon, Phyllis; Salzer, Mark S

    2011-01-01

    Research has not examined whether higher rates of parole denial among inmates with mental illness (MI) are the result of the increased presence of criminal risk factors among this population. Employing a representative sample of inmates with (n  =  219) and without (n  =  184) MI receiving parole release decisions in 2007, this study tested whether the central eight risk factors for recidivism considered in parole release decisions intervened in the relationship between MI and parole release. MI was associated with possession of a substance use disorder, antisocial personality disorder and violent charges while incarcerated; however, these factors were not related to release decisions. MI was found to have neither a direct nor an indirect effect on release decisions. While results indicate that release decisions appear, to some extent, to be evidence-based, they also suggest considerable discretion is being implemented by parole board members in release decisions above and beyond consideration of criminal risk factors.

  11. [Histamine intolerance - are the criteria of an adverse reaction met?].

    PubMed

    Reese, Imke

    2016-06-01

    Searching the internet for an explaination of recurring symptoms, many people come across the so-called histamine intolerance disorder. Also many practitioners like to diagnose this disorder without making sure that reproducibility, a prerequisite for an adverse reaction, is present. Consequently, presumably affected persons are often advised to follow a low-histamine diet. Depending on the source of information, these diets often avoid a huge variety of foods containing more or less histamine, which has a considerable impact on patient quality of life. While most persons benefit from such a diet in the beginning - this might be due to the change in dietary habits or the expectation of symptom improvement by dieting - in the long run the expected loss of symptoms will not happen. Underlying a diminished capacity for histamine degradation, the lack of partial or complete symptom improvement might be due to the fact that endogenous histamine release is responsible for reactions. The role of ingested histamine is discussed controversially. However, it is more than obvious that the histamine content of a certain food alone is not enough to predict its tolerance.If histamine intolerance is suspected, an individual diagnostic and therapeutic procedure is mandatory in order to minimize avoidance and to preserve a high quality of life. Ideally this is done in a close cooperation between allergologists and nutritionists/dieticians. PMID:27177895

  12. Is the analysis of histamine and/or interleukin-4 release after isocyanate challenge useful in the identification of patients with IgE-mediated isocyanate asthma?

    PubMed

    Blindow, Silke; Preisser, Alexandra M; Baur, Xaver; Budnik, Lygia T

    2015-07-01

    Isocyanates are a well-known and frequent cause of occupational asthma. The implementation of specific inhalation challenges (SICs) is the gold standard in asthma diagnosis supporting occupational case history, lung function testing, specific skin prick tests and the detection of specific IgE. However, the diagnosis is not always definitive. An interesting new approach, analyses of individual genetic susceptibilities, requires discrimination between a positive SIC reaction arising from IgE-mediated immune responses and one from other pathophysiological mechanisms. Hence, additional refinement tools would be helpful in defining sub-classes of occupational asthma and diagnosis. We used total IgE levels, specific IgE and SIC results for sub-classification of 27 symptomatic isocyanate workers studied. Some mutations in glutathione S-transferases (GSTs) are suspected either to enhance or to decrease the individual risk in the development of isocyanate asthma. Our patient groups were assessed for the point mutations GSTP1*I105V and GSTP1*A114V as well as deletions (null mutations) of GSTM1 and GSTT1. There seems to be a higher risk in developing IgE-mediated reactions when GSTM1 is deleted, while GSTT1 deletions were found more frequently in the SIC positive group. Blood samples taken before SIC, 30-60 min and 24h after SIC, were analyzed for histamine and IL-4, classical markers for the IgE-mediated antigen-specific activation of basophils or mast cells. We suggest that the utility of histamine measurements might provide an additional useful marker reflecting isocyanate-induced cellular reactions (although the sampling times require optimization). The promising measurement of IL-4 is not feasible at present due to the lack of a reliable, validated assay.

  13. Corticotropin-releasing factor administered centrally, but not peripherally, stimulates hippocampal acetylcholine release.

    PubMed

    Day, J C; Koehl, M; Le Moal, M; Maccari, S

    1998-08-01

    In addition to corticotropin-releasing factor's well-known role in mediating hormonal and behavioral responses to stress, this peptide also reportedly affects arousal and cognition, processes that classically have been associated with forebrain cholinergic systems. Corticotropin-releasing factor stimulation of cholinergic neurons might thus provide a mechanism for this peptide's cognitive effects. To examine this possibility, the present experiments characterize the effect of corticotropin-releasing factor on cholinergic neurotransmission, using in vivo microdialysis to measure hippocampal acetylcholine release. Corticotropin-releasing factor (0.5-5.0 microg/rat intracerebroventricularly) was found to increase dialysate concentrations of acetylcholine in a dose-dependent manner in comparison with a control injection, the ovine peptide having a greater effect than the same dose of the human/rat peptide. This effect was found to be centrally mediated, independent of the peripheral effects of an exogenous corticotropin-releasing factor injection; subcutaneous injections of the peptide increased plasma concentrations of corticosterone, the adrenal hormone ultimately secreted in the rat's stress response, to the same level as did the central injections, without affecting hippocampal acetylcholine release. These results demonstrate that corticotropin-releasing factor, acting centrally, regulates hippocampal cholinergic activity, and suggest that corticotropin-releasing factor/acetylcholine interactions may underlie some of the previously identified roles of these neurotransmitters in arousal, cognition, and stress.

  14. Corticotropin-releasing factor administered centrally, but not peripherally, stimulates hippocampal acetylcholine release.

    PubMed

    Day, J C; Koehl, M; Le Moal, M; Maccari, S

    1998-08-01

    In addition to corticotropin-releasing factor's well-known role in mediating hormonal and behavioral responses to stress, this peptide also reportedly affects arousal and cognition, processes that classically have been associated with forebrain cholinergic systems. Corticotropin-releasing factor stimulation of cholinergic neurons might thus provide a mechanism for this peptide's cognitive effects. To examine this possibility, the present experiments characterize the effect of corticotropin-releasing factor on cholinergic neurotransmission, using in vivo microdialysis to measure hippocampal acetylcholine release. Corticotropin-releasing factor (0.5-5.0 microg/rat intracerebroventricularly) was found to increase dialysate concentrations of acetylcholine in a dose-dependent manner in comparison with a control injection, the ovine peptide having a greater effect than the same dose of the human/rat peptide. This effect was found to be centrally mediated, independent of the peripheral effects of an exogenous corticotropin-releasing factor injection; subcutaneous injections of the peptide increased plasma concentrations of corticosterone, the adrenal hormone ultimately secreted in the rat's stress response, to the same level as did the central injections, without affecting hippocampal acetylcholine release. These results demonstrate that corticotropin-releasing factor, acting centrally, regulates hippocampal cholinergic activity, and suggest that corticotropin-releasing factor/acetylcholine interactions may underlie some of the previously identified roles of these neurotransmitters in arousal, cognition, and stress. PMID:9681452

  15. Inhibition of histidine decarboxylase ablates the autocrine tumorigenic effects of histamine in human cholangiocarcinoma

    PubMed Central

    Francis, Heather; DeMorrow, Sharon; Venter, Julie; Onori, Paolo; White, Mellanie; Gaudio, Eugenio; Francis, Taylor; Greene, John F; Tran, Steve; Meininger, Cynthia J; Alpini, Gianfranco

    2011-01-01

    Background In several tumours the endogenous activity of histidine decarboxylase (HDC), the enzyme stimulating histamine synthesis, sustains the autocrine trophic effect of histamine on cancer progression. Cholangiocarcinoma is a biliary cancer with limited treatment options. Histamine interacts with four G-protein coupled receptors, H1–H4 histamine receptors (HRs). Objective To determine the effects of histamine stimulation and inhibition of histamine synthesis (by modulation of HDC) on cholangiocarcinoma growth. Methods In vitro studies were performed using multiple human cholangiocarcinoma lines. The expression levels of the histamine synthetic machinery and HRs were evaluated along with the effects of histamine stimulation and inhibition on cholangiocarcinoma proliferation. A xenograft tumour model was used to measure tumour volume after treatment with histamine or inhibition of histamine synthesis by manipulation of HDC. Vascular endothelial growth factor (VEGF) expression was measured in cholangiocarcinoma cells concomitant with the evaluation of the expression of CD31 in endothelial cells in the tumour microenvironment. Results Cholangiocarcinoma cells display (1) enhanced HDC and decreased monoamine oxidase B expression resulting in increased histamine secretion; and (2) increased expression of H1–H4 HRs. Inhibition of HDC and antagonising H1HR decreased histamine secretion in Mz-ChA-1 cells. Long-term treatment with histamine increased proliferation and VEGF expression in cholangiocarcinoma that was blocked by HDC inhibitor and the H1HR antagonist. In nude mice, histamine increased tumour growth (up to 25%) and VEGF expression whereas inhibition of histamine synthesis (by reduction of HDC) ablated the autocrine stimulation of histamine on tumour growth (~80%) and VEGF expression. No changes in angiogenesis (evaluated by changes in CD31 immunoreactivity) were detected in the in vivo treatment groups. Conclusion The novel concept that an autocrine loop

  16. A novel double-isotope technique for the enzymatic assay of plasma histamine: application to estimation of mast cell activation assessed by antigen challenge in asthmatics

    SciTech Connect

    Brown, M.J.; Ind, P.W.; Causon, R.; Lee, T.H.

    1982-01-01

    The concentration of plasma histamine may provide an index of mast cell activation (degranulation) and can be measured by a sensitive radioenzymatic assay based on its specific conversion to (/sup 3/H)-methylhistamine in the presence of histamine-N-methyltransferase and (/sup 3/H)-S-adenosyl-L-methionine. In this assay, the separation of excess (/sup 3/H)-S-adenosyl-L-methionine from (/sup 3/H)-methylhistamine requires several steps, for which a correction factors is necessary to maintain precision. In the present modification, duplicate 50-microliters aliquots of each plasma sample were incubated with histamine-N-methyltransferase and (/sup 3/H)-S-adenosyl-L-methionine. A further aliquot, with an added standard of 200 ng/ml histamine, was incubated with histamine-N-methyl-transferase and (/sup 14/C)-S-adenosyl-L-methionine. This standard was converted to (/sup 14/C)-methylhistamine, and its recovery at the end of the assay corrected both for varying efficiency of methylation among plasma samples and for losses during the subsequent extraction and separation stages. The sensitivity of the assay was 25 pg/ml. The intra-assay and interassay coefficients of variation were 7.2% and 11.6%, respectively. In five asthmatics, antigen challenge caused a 28% fall in FEV1, and this was associated with a twofold to threefold rise in plasma histamine concentration. This assay may thus prove a useful method for assessing the role of mast cell release of mediators in vivo.

  17. New kid on the block: does histamine get along with inflammation in amyotrophic lateral sclerosis?

    PubMed

    Volonté, Cinzia; Parisi, Chiara; Apolloni, Savina

    2015-01-01

    Results from amyotrophic lateral sclerosis (ALS) patients and pre-clinical studies strongly suggest that systemic and CNS-intrinsic immune activation plays a central role in ALS pathogenesis. Microglial cells are emerging in this context as master regulators with a bi-functional role in the progression of the pathological response. They foster a pro-inflammatory setting through the production of cytotoxic cytokines and chemokines (M1 phenotype), after an aborted effort to sustain an anti-inflammatory environment for motor neurons through the release of beneficial cytokines and growth factors (M2 phenotype). In this review, we gather information meant to propose that histamine and ATP, which are released from mast cells, microglia and damaged neurons at sites of injury where they function as transmitters, have to be considered as new players in the ALS neuroinflammatory arena. After all, abnormal histamine and ATP signalling in the brain are already documented in neurodegenerative/neuroinflammatory conditions such as multiple sclerosis, Alzheimer and Parkinson's disease and, at present, histamine- as well as ATP-related compounds are in clinical trial for these same pathologies. Concerning ALS, while emerging data are now available about purinergic mechanisms, the involvement of histamine is basically unexplored. The circumstantial evidence that we present here thus constitutes a solid background for formulating novel hypotheses, stimulating a scientific debate and, most of all, inspiring future research. We deem that a new potential role of histamine in the setting of ALS neuroinflammation might find a fertile ground where to thrive. ALS is still a disease without a cure: why not to play with a new kid on the block?

  18. Histamine receptors and cancer pharmacology

    PubMed Central

    Medina, Vanina A; Rivera, Elena S

    2010-01-01

    Considerable evidence has been collected indicating that histamine can modulate proliferation of different normal and malignant cells. High histamine biosynthesis and content together with histamine receptors have been reported in different human neoplasias including melanoma, colon and breast cancer, as well as in experimental tumours in which histamine has been postulated to behave as an important paracrine and autocrine regulator of proliferation. The discovery of the human histamine H4 receptor in different tissues has contributed to our understanding of histamine role in numerous physiological and pathological conditions revealing novel functions for histamine and opening new perspectives in histamine pharmacology research. In the present review we aimed to briefly summarize current knowledge on histamine and histamine receptor involvement in cancer before focusing on some recent evidence supporting the novel role of histamine H4 receptor in cancer progression representing a promising molecular target and avenue for cancer drug development. LINKED ARTICLES BJP has previously published a Histamine themed issue (2009). To view this issue visit http://dx.doi.org/10.1111/bph.2009.157.issue-1 PMID:20636392

  19. Histamine poisoning and control measures in fish and fishery products

    PubMed Central

    Visciano, Pierina; Schirone, Maria; Tofalo, Rosanna; Suzzi, Giovanna

    2014-01-01

    Histamine poisoning is one of the most common form of intoxication caused by the ingestion of fish and fishery products. Cooking, canning, or freezing cannot reduce the levels of histamine because this compound is heat stable. All humans are susceptible to histamine and its effects can be described as intolerance or intoxication depending on the severity of the symptoms. The amount of histamine in food, the individual sensitivity, and the detoxification activity in human organism represent the main factors affecting the toxicological response in consumers. Histamine is the only biogenic amine with regulatory limits set by European Legislation, up to a maximum of 200 mg/kg in fresh fish and 400 mg/kg in fishery products treated by enzyme maturation in brine. PMID:25295035

  20. Histamine Induces Vascular Hyperpermeability by Increasing Blood Flow and Endothelial Barrier Disruption In Vivo.

    PubMed

    Ashina, Kohei; Tsubosaka, Yoshiki; Nakamura, Tatsuro; Omori, Keisuke; Kobayashi, Koji; Hori, Masatoshi; Ozaki, Hiroshi; Murata, Takahisa

    2015-01-01

    Histamine is a mediator of allergic inflammation released mainly from mast cells. Although histamine strongly increases vascular permeability, its precise mechanism under in vivo situation remains unknown. We here attempted to reveal how histamine induces vascular hyperpermeability focusing on the key regulators of vascular permeability, blood flow and endothelial barrier. Degranulation of mast cells by antigen-stimulation or histamine treatment induced vascular hyperpermeability and tissue swelling in mouse ears. These were abolished by histamine H1 receptor antagonism. Intravital imaging showed that histamine dilated vasculature, increased blood flow, while it induced hyperpermeability in venula. Whole-mount staining showed that histamine disrupted endothelial barrier formation of venula indicated by changes in vascular endothelial cadherin (VE-cadherin) localization at endothelial cell junction. Inhibition of nitric oxide synthesis (NOS) by L-NAME or vasoconstriction by phenylephrine strongly inhibited the histamine-induced blood flow increase and hyperpermeability without changing the VE-cadherin localization. In vitro, measurements of trans-endothelial electrical resistance of human dermal microvascular endothelial cells (HDMECs) showed that histamine disrupted endothelial barrier. Inhibition of protein kinase C (PKC) or Rho-associated protein kinase (ROCK), NOS attenuated the histamine-induced barrier disruption. These observations suggested that histamine increases vascular permeability mainly by nitric oxide (NO)-dependent vascular dilation and subsequent blood flow increase and maybe partially by PKC/ROCK/NO-dependent endothelial barrier disruption.

  1. In vivo histamine voltammetry in the mouse premammillary nucleus.

    PubMed

    Samaranayake, Srimal; Abdalla, Aya; Robke, Rhiannon; Wood, Kevin M; Zeqja, Anisa; Hashemi, Parastoo

    2015-06-01

    Histamine plays a major role in the mediation of allergic reactions such as peripheral inflammation. This classical monoamine is also a neurotransmitter involved in the central nervous system but its role in this context is poorly understood. Studying histamine neurotransmission is important due to its implications in many neurological disorders. The sensitivity, selectivity and high temporal resolution of fast scan cyclic voltammetry (FSCV) offer many advantages for studying electroactive neurotransmitters. Histamine has previously been studied with FSCV; however, the lack of a robust Faradaic electrochemical signal makes it difficult to selectively identify histamine in complex media, as found in vivo. In this work, we optimize an electrochemical waveform that provides a stimulation-locked and unique electrochemical signal towards histamine. We describe in vitro waveform optimization and a novel in vivo physiological model for stimulating histamine release in the mouse premammillary nucleus via stimulation of the medial forebrain bundle. We demonstrate that a robust signal can be used to effectively identify histamine and characterize its in vivo kinetics.

  2. Histamine: a new immunomodulatory player in the neuron-glia crosstalk

    PubMed Central

    Rocha, Sandra M.; Pires, Joel; Esteves, Marta; Graça, Baltazar; Bernardino, Liliana

    2014-01-01

    Histamine is an amine acting as a major peripheral inflammatory mediator. In the brain, histamine was initially viewed as a neurotransmitter, but new evidences support its involvement in the modulation of innate immune responses. Recently, we showed that histamine modulates microglial migration and cytokine release. Its pleiotropic actions, ranging from neurotransmission to inflammation, highlight histamine as a key player in a vast array of brain physiologic activities and also in the pathogenesis of several neurodegenerative diseases. Herein, we emphasize the role of histamine as a modulator of brain immune reactions, either by acting on invading peripheral immune cells and/or on resident microglial cells. We also unveil the putative involvement of histamine in the microglial-neuronal communication. We first show that histamine modulates the release of inflammatory mediators, namely nitric oxide, by microglia cells. Consequently, the microglia secretome released upon histamine stimulation fosters dopaminergic neuronal death. These data may reveal important new pharmacological applications on the use histamine and antihistamines, particularly in the context of Parkinson’s disease. PMID:24817841

  3. Modulation of bradykinin-induced gastric-cardiovascular reflexes by histamine.

    PubMed

    Stebbins, C L; Stahl, G L; Theodossy, S J; Longhurst, J C

    1992-01-01

    Both histamine and bradykinin induce gastric-cardiovascular reflexes and are released during several pathophysiological conditions. This study examined the possibility that histamine modulates the magnitude of the reflex response to stimulation by bradykinin. Thus in chloralose anesthetized cats, the cardiovascular response to stimulation of the gastric serosa with 1 microgram/ml bradykinin was monitored before and after topical application of 100 micrograms/ml histamine (n = 6) or 1 mg/ml diphenhydramine (H1-receptor antagonist) and histamine (n = 5). After application of histamine, bradykinin-induced increases in mean arterial pressure and left ventricular pressure were attenuated by 23 and 27%, respectively. Conversely, when the H1-receptors on the serosal surface of the stomach were blocked (n = 5) before application of histamine, the pressor response to bradykinin was augmented by 26%. To determine the afferents that might contribute to the attenuating effect of histamine, we recorded single unit activity in 14 A delta and 21 C visceral afferent fibers in response to bradykinin stimulation before and after histamine stimulation. We observed that the impulse activity of 10 of the A delta and 14 of the C fibers to bradykinin stimulation was reduced after treatment with histamine. These results suggest that histamine induces an inhibitory effect on the nerve endings of visceral A delta and C fibers to the action of bradykinin through an H1-receptor mechanism. This inhibitory effect attenuates the magnitude of the consequent cardiovascular reflex response.

  4. Histamine-induced inhibition of leukotriene biosynthesis in human neutrophils: involvement of the H2 receptor and cAMP

    PubMed Central

    Flamand, Nicolas; Plante, Hendrick; Picard, Serge; Laviolette, Michel; Borgeat, Pierre

    2004-01-01

    Histamine is generally regarded as a pro-inflammatory mediator in diseases such as allergy and asthma. A growing number of studies, however, suggest that this autacoid is also involved in the downregulation of human polymorphonuclear leukocyte (PMN) functions and inflammatory responses through activation of the Gs-coupled histamine H2 receptor. We report here that histamine inhibits thapsigargin- and ligand (PAF and fMLP)-induced leukotriene (LT) biosynthesis in human PMN in a dose-dependent manner. The suppressive effect of histamine on LT biosynthesis was abrogated by the histamine H2 receptor antagonists cimetidine, ranitidine, and tiotidine. In contrast, the histamine H1, H3, and H4 receptor antagonists used in this study were ineffective in counteracting the inhibitory effect of histamine on the biosynthesis of LT in activated human PMN. The inhibition of LT biosynthesis by histamine was characterized by decreased arachidonic acid release and 5-lipoxygenase translocation to the nuclear membrane. Incubation of PMN with the cAMP-dependent protein kinase (PKA) inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide prevented the inhibitory effect of histamine on LT biosynthesis, suggesting an important role for PKA in this effect of histamine on LT biosynthesis in PMN. These data provide the first evidences that, similarly to adenosine and prostaglandin E2, histamine is a potent suppressor of LT biosynthesis, and support the concept that histamine may play a dual role in the regulation of inflammation. PMID:14744809

  5. Histamine Blood Concentration in Ischemic Heart Disease Patients

    PubMed Central

    Zdravkovic, Vladimir; Pantovic, Suzana; Rosic, Gvozden; Tomic-Lucic, Aleksandra; Zdravkovic, Nemanja; Colic, Maja; Obradovic, Zdravko; Rosic, Mirko

    2011-01-01

    The aim of this study was to investigate histamine blood concentration in subjects suffering from different types of ischemic heart diseases during the period of eight days. Our results showed that the histamine blood level was associated with different types of ischemic heart diseases. The blood histamine level in all investigated patients was significantly higher when compared to control subjects (44.87 ± 1.09 ng mL−1), indicating the increase of histamine release in patients suffering from coronary diseases. In patients suffering from ACS-UA and ACS-STEMI, the second day peak of histamine level occurs (90.85 ± 6.34 ng mL−1 and 121.7 ± 6.34 ng mL−1, resp.) probably as the reperfusion event. Furthermore, our data suggest that histamine can be additional parameter of myocardial ischemia along with cardiac specific enzymes and may prove to be an excellent single prognostic marker for multitude of ischemic heart diseases. PMID:21687546

  6. Role of substance P on histamine H(3) antagonist-induced scratching behavior in mice.

    PubMed

    Hossen, Maria Alejandra; Inoue, Toshio; Shinmei, Yoshifumi; Fujii, Yoko; Watanabe, Takeshi; Kamei, Chiaki

    2006-04-01

    The purpose of the present study was to investigate the involvement of chemical mediators, other than histamine, in the scratching behavior induced by H(3) antagonists. Scratching behavior was induced by the histamine H(3) antagonists iodophenpropit and clobenpropit (10 nmol/site) when they were injected intradermally into the rostral part of the back of mast-cell-deficient (WBB6F1 W/W(v)) and wild-type (WBB6F1 +/+) mice. Subsequently, the effect of spantide, a tachykinin NK(1) antagonist, was measured for 60 min. The effects of the H(3) antagonists on in vitro histamine release from rat peritoneal mast cells were also investigated. When spantide was injected intradermally at a dose of 0.5 nmol/site, it significantly inhibited the response. Furthermore, iodophenpropit and clobenpropit (10(-6)-10(-8) M) did not induce histamine release in isolated rat peritoneal mast cells. Our results indicate that substance P is involved in the skin responses elicited by the histamine H(3) antagonists. Moreover, the fact that these histamine H(3) antagonists did not induce significant increases in the histamine release from rat peritoneal mast cells suggests that the histamine H(3) receptor may not be present in the peripheral cells considered in this study.

  7. Histamine: an undercover agent in multiple rare diseases?

    PubMed Central

    Pino-Ángeles, Almudena; Reyes-Palomares, Armando; Melgarejo, Esther; Sánchez-Jiménez, Francisca

    2012-01-01

    Histamine is a biogenic amine performing pleiotropic effects in humans, involving tasks within the immune and neuroendocrine systems, neurotransmission, gastric secretion, cell life and death, and development. It is the product of the histidine decarboxylase activity, and its effects are mainly mediated through four different G-protein coupled receptors. Thus, histamine-related effects are the results of highly interconnected and tissue-specific signalling networks. Consequently, alterations in histamine-related factors could be an important part in the cause of multiple rare/orphan diseases. Bearing this hypothesis in mind, more than 25 rare diseases related to histamine physiopathology have been identified using a computationally assisted text mining approach. These newly integrated data will provide insight to elucidate the molecular causes of these rare diseases. The data can also help in devising new intervention strategies for personalized medicine for multiple rare diseases. PMID:22435405

  8. Factors affecting water quality in the releases from hydropower reservoirs

    SciTech Connect

    Ruane, R.J.; Hauser, G.E. )

    1990-01-01

    Typical water quality concerns with releases from hydropower reservoirs include low dissolved oxygen, inappropriate temperature for downstream uses, supersaturation of total dissolved gases, and water quality constituents associated with low dissolved oxygen. Except for supersaturation of total dissolved gases, which is usually caused by by-passing turbines and spilling water, all of these concerns are related to the limnology of the upstream reservoir. Various limnological factors affect water quality, particularly dissolved oxygen (DO) in turbine releases. This paper describes three groups of reservoirs, thermal stratification characteristics for each group, DO effects for each group, the main factors that affect DO in TVA turbine releases, and other water quality constituents that are related to low DO.

  9. An in vitro study of histamine on the pulmonary artery of the Wistar-Kyoto and spontaneously hypertensive rats.

    PubMed

    Lau, Wing Hung; Kwan, Yiu Wa; Au, Alice Lai Shan; Cheung, Wui Hang

    2003-05-30

    (clobenpropit-sensitive) was observed with imetit (a histamine H(3)/H(4) receptor agonist) (> or =3 microM). Under resting tension, imetit (> or =0.3 microM) caused a clobenpropit (10 nM)- and prazosin (1 microM)-sensitive, concentration-dependent contraction, with a greater contraction in the WKY rats. Our results suggest that inhibition of histamine catabolism using SKF 91488 (histamine N-methyl-transferase inhibitor) resulted in a reduction of histamine-mediated relaxation that was due to the activation of the clobenpropit-sensitive, histamine H(3)/H(4) receptor and the release of catecholamine. In addition, activation of histamine H(1) and H(2) receptors resulted in relaxation whereas histamine H(3)/H(4) receptor activation by imetit yielded a prazosin-sensitive contraction of the pulmonary artery.

  10. Host factors involved in retroviral budding and release.

    PubMed

    Martin-Serrano, Juan; Neil, Stuart J D

    2011-06-16

    The plasma membrane is the final barrier that enveloped viruses must cross during their egress from the infected cell. Here, we review recent insights into the cell biology of retroviral assembly and release; these insights have driven a new understanding of the host proteins, such as the ESCRT machinery, that are used by retroviruses to promote their final separation from the host cell. We also review antiviral host factors such as tetherin, which can directly inhibit the release of retroviral particles. These studies have illuminated the role of the lipid bilayer as the unexpected target for virus restriction by the innate immune response.

  11. Release characteristics of encapsulated formulations incorporating plant growth factors.

    PubMed

    Wybraniec, Slawomir; Schwartz, Liliana; Wiesman, Zeev; Markus, Arie; Wolf, David

    2002-05-01

    The release characteristics of encapsulated formulations containing a combination of plant growth factors (PGF)--plant hormones (IBA, paclobutrazol), nutrients (fertilizers, microelements), and fungicide (prochloraz)--were studied. The formulations were prepared by encapsulating the active ingredients in a polyethylene matrix and, in some cases, subsequently coating the product with polyurethane. Dissolution experiments were carried out with both coated and non-coated formulations to determine the sustained release patterns of the active ingredients. The PGF controlled-release systems obtained have been shown to promote development of root systems, vegetative growth, and reproductive development in cuttings, potted plants, or garden plants of various plant species. These beneficial effects are attributable to the lasting and balanced PGF availability provided by these systems. PMID:12009194

  12. Release characteristics of encapsulated formulations incorporating plant growth factors.

    PubMed

    Wybraniec, Slawomir; Schwartz, Liliana; Wiesman, Zeev; Markus, Arie; Wolf, David

    2002-05-01

    The release characteristics of encapsulated formulations containing a combination of plant growth factors (PGF)--plant hormones (IBA, paclobutrazol), nutrients (fertilizers, microelements), and fungicide (prochloraz)--were studied. The formulations were prepared by encapsulating the active ingredients in a polyethylene matrix and, in some cases, subsequently coating the product with polyurethane. Dissolution experiments were carried out with both coated and non-coated formulations to determine the sustained release patterns of the active ingredients. The PGF controlled-release systems obtained have been shown to promote development of root systems, vegetative growth, and reproductive development in cuttings, potted plants, or garden plants of various plant species. These beneficial effects are attributable to the lasting and balanced PGF availability provided by these systems.

  13. Regulation of ERK2 phosphorylation by histamine in splenocytes.

    PubMed

    Dandekar, Radhika D; Khan, Manzoor M

    2011-06-01

    Histamine is implicated in allergic disease and asthma and ERK1/2 is involved in allergic inflammation including Th2 differentiation and proliferation. This study was designed to study the effects of histamine on ERK1/2 phosphorylation in splenocytes. C57/BL6 splenocytes were treated with different concentrations of histamine (10(-4) to 10(-11) M). Histamine (10(-4) M) increased ERK2 phosphorylation. There was, however, no significant effect seen at other concentrations (10(-11) to 10(-6) M). Surprisingly, H1 receptor agonist β-histine (10(-5) M), H2 agonist amthamine (10(-5) M), H3 agonist methimepip (10(-6) M), and H4 agonist 4-methyl histamine (10(-6) M), all increased ERK2 phosphorylation. H1R antagonist pyrilamine (10(-6) M), H2R antagonist ranitidine (10(-5) M), H3/H4R antagonist thioperamide (10(-6) M), and H3R antagonist clobenpropit (10(-5) M) inhibited histamine-mediated ERK2 phosphorylation suggesting that all four histamine receptor subtypes played some role in this phosphorylation. Because tumor necrosis factor-α (TNF-α) causes phosphorylation of ERK1/2, we investigated whether histamine acted via secretion of TNF-α to affect ERK1/2 phosphorylation. As a consequence, TNF-α knockout mice were used and we found that there was inhibition of ERK1 and ERK2 phosphorylation by H2, H3, and H4 agonists. This was in contrast to the wild-type splenocytes where histamine augmented the phosphorylation of ERK2 via H2, H3, and H4 receptors. In TNF-α knockout mice histamine did not affect the phosphorylation of ERK2 via H1 receptors. The results suggested that histamine indirectly caused the ERK2 phosphorylation via its effects on the secretion of TNF-α and these effects were mediated via H1, H2, H3, and H4 receptors.

  14. Glucagon effects on 3H-histamine uptake by the isolated guinea-pig heart during anaphylaxis.

    PubMed

    Rosic, Mirko; Parodi, Oberdan; Jakovljevic, Vladimir; Colic, Maja; Zivkovic, Vladimir; Jokovic, Vuk; Pantovic, Suzana

    2014-01-01

    We estimated the influence of acute glucagon applications on (3)H-histamine uptake by the isolated guinea-pig heart, during a single (3)H-histamine passage through the coronary circulation, before and during anaphylaxis, and the influence of glucagon on level of histamine, NO, O2 (-), and H2O2 in the venous effluent during anaphylaxis. Before anaphylaxis, glucagon pretreatment does not change (3)H-histamine Umax and the level of endogenous histamine. At the same time, in the presence of glucagon, (3)H-histamine Unet is increased and backflux is decreased when compared to the corresponding values in the absence of glucagon. During anaphylaxis, in the presence of glucagon, the values of (3)H-histamine Umax and Unet are significantly higher and backflux is significantly lower in the presence of glucagon when compared to the corresponding values in the absence of glucagon. The level of endogenous histamine during anaphylaxis in the presence of glucagon (6.9-7.38 × 10(-8) μM) is significantly lower than the histamine level in the absence of glucagon (10.35-10.45 × 10(-8) μM). Glucagon pretreatment leads to a significant increase in NO release (5.69 nmol/mL) in comparison with the period before glucagon administration (2.49 nmol/mL). Then, in the presence of glucagon, O2 (-) level fails to increase during anaphylaxis. Also, our results show no significant differences in H2O2 levels before, during, and after anaphylaxis in the presence of glucagon, but these values are significantly lower than the corresponding values in the absence of glucagon. In conclusion, our results show that glucagon increases NO release and prevents the increased release of free radicals during anaphylaxis, and decreases histamine level in the venous effluent during cardiac anaphylaxis, which may be a consequence of decreased histamine release and/or intensified histamine capturing by the heart during anaphylaxis.

  15. Uniformity of Peptide Release Is Maintained by Methylation of Release Factors.

    PubMed

    Pierson, William E; Hoffer, Eric D; Keedy, Hannah E; Simms, Carrie L; Dunham, Christine M; Zaher, Hani S

    2016-09-27

    Termination of protein synthesis on the ribosome is catalyzed by release factors (RFs), which share a conserved glycine-glycine-glutamine (GGQ) motif. The glutamine residue is methylated in vivo, but a mechanistic understanding of its contribution to hydrolysis is lacking. Here, we show that the modification, apart from increasing the overall rate of termination on all dipeptides, substantially increases the rate of peptide release on a subset of amino acids. In the presence of unmethylated RFs, we measure rates of hydrolysis that are exceptionally slow on proline and glycine residues and approximately two orders of magnitude faster in the presence of the methylated factors. Structures of 70S ribosomes bound to methylated RF1 and RF2 reveal that the glutamine side-chain methylation packs against 23S rRNA nucleotide 2451, stabilizing the GGQ motif and placing the side-chain amide of the glutamine toward tRNA. These data provide a framework for understanding how release factor modifications impact termination. PMID:27681416

  16. Uniformity of Peptide Release Is Maintained by Methylation of Release Factors.

    PubMed

    Pierson, William E; Hoffer, Eric D; Keedy, Hannah E; Simms, Carrie L; Dunham, Christine M; Zaher, Hani S

    2016-09-27

    Termination of protein synthesis on the ribosome is catalyzed by release factors (RFs), which share a conserved glycine-glycine-glutamine (GGQ) motif. The glutamine residue is methylated in vivo, but a mechanistic understanding of its contribution to hydrolysis is lacking. Here, we show that the modification, apart from increasing the overall rate of termination on all dipeptides, substantially increases the rate of peptide release on a subset of amino acids. In the presence of unmethylated RFs, we measure rates of hydrolysis that are exceptionally slow on proline and glycine residues and approximately two orders of magnitude faster in the presence of the methylated factors. Structures of 70S ribosomes bound to methylated RF1 and RF2 reveal that the glutamine side-chain methylation packs against 23S rRNA nucleotide 2451, stabilizing the GGQ motif and placing the side-chain amide of the glutamine toward tRNA. These data provide a framework for understanding how release factor modifications impact termination.

  17. Brain histamine and feeding behavior.

    PubMed

    Morimoto, T; Yamamoto, Y; Yamatodani, A

    2001-10-15

    Food intake is regulated by many endogenous substances, such as peptides and neurotransmitters in the central nervous system. Based on the clinical observation that some antidepressants and antipsychotics with antihistaminic activity stimulate food intake and increase body weight, histamine has been thought to be an anorectic agent. Several lines of evidence suggest that histamine decreases food intake via H(1)-receptors (H1R) at least in the ventromedial hypothalamus or the paraventricular nucleus. Recently, mutant mice lacking H1R were generated and the interaction between the histaminergic system and leptin-induced suppression of food intake was evidenced by using these mice. In regulating food intake, histamine is indicated to functionally associate with neuropeptide Y, peptide YY, and bombesin. However, the question remained as to why the circadian variation in the level of histamine is inversely correlated to the pattern of feeding.

  18. Modulation of ConA-induced inflammatory ascites by histamine - short communication.

    PubMed

    Baintner, Károly

    2015-03-01

    The early phase of the ConA-induced inflammatory ascites was studied, with special reference to histamine. Concanavalin A (ConA), a cell-surface binding lectin was injected i.p. (25 mg/kg bw) to mice. After 1 h the animals were killed, the ascitic fluid collected and measured. Other agents were injected s.c., 10 min before the ConA-challenge. Exogenous histamine markedly inhibited the ConA-induced ascites. Release of endogenous vasoactive agents from the mast cells by Compound 48/80 had a similar, but slight effect. Cromolyn, a mast cell stabilizing agent, and chloropyramine, a histamine H1 receptor antagonist was ineffective. Although histamine increases endothelial permeability, it did not enhance the formation of ascitic fluid, on the contrary, it inhibited the ConA-induced ascites, presumably due to its known hypotonic effect. It is concluded that ConA-induced ascites is not mediated by mast cell histamine.

  19. Histamine in the locus coeruleus promotes descending noradrenergic inhibition of neuropathic hypersensitivity.

    PubMed

    Wei, Hong; Jin, Cong-Yu; Viisanen, Hanna; You, Hao-Jun; Pertovaara, Antti

    2014-12-01

    Among brain structures receiving efferent projections from the histaminergic tuberomammillary nucleus is the pontine locus coeruleus (LC) involved in descending noradrenergic control of pain. Here we studied whether histamine in the LC is involved in descending regulation of neuropathic hypersensitivity. Peripheral neuropathy was induced by unilateral spinal nerve ligation in the rat with a chronic intracerebral and intrathecal catheter for drug administrations. Mechanical hypersensitivity in the injured limb was assessed by monofilaments. Heat nociception was assessed by determining radiant heat-induced paw flick. Histamine in the LC produced a dose-related (1-10μg) mechanical antihypersensitivity effect (maximum effect at 15min and duration of effect 30min), without influence on heat nociception. Pretreatment of LC with zolantidine (histamine H2 receptor antagonist), but not with pyrilamine (histamine H1 receptor antagonist), and spinal administration of atipamezole (an α2-adrenoceptor antagonist), prazosine (an α1-adrenoceptor antagonist) or bicuculline (a GABAA receptor antagonist) attenuated the antihypersensitivity effect of histamine. The histamine-induced antihypersensitivity effect was also reduced by pretreatment of LC with fadolmidine, an α2-adrenoceptor agonist inducing autoinhibition of noradrenergic cell bodies. Zolantidine or pyrilamine alone in the LC failed to influence pain behavior, while A-960656 (histamine H3 receptor antagonist) suppressed hypersensitivity. A plausible explanation for these findings is that histamine, due to excitatory action mediated by the histamine H2 receptor on noradrenergic cell bodies, promotes descending spinal α1/2-adrenoceptor-mediated inhibition of neuropathic hypersensitivity. Blocking the autoinhibitory histamine H3 receptor on histaminergic nerve terminals in the LC facilitates release of histamine and thereby, increases descending noradrenergic pain inhibition.

  20. Histamine-HisCl1 receptor axis regulates wake-promoting signals in Drosophila melanogaster.

    PubMed

    Oh, Yangkyun; Jang, Donghoon; Sonn, Jun Young; Choe, Joonho

    2013-01-01

    Histamine and its two receptors, histamine-gated chloride channel subunit 1 (HisCl1) and ora transientless (Ort), are known to control photoreception and temperature sensing in Drosophila. However, histamine signaling in the context of neural circuitry for sleep-wake behaviors has not yet been examined in detail. Here, we obtained mutant flies with compromised or enhanced histamine signaling and tested their baseline sleep. Hypomorphic mutations in histidine decarboxylase (HDC), an enzyme catalyzing the conversion from histidine to histamine, caused an increase in sleep duration. Interestingly, hisCl1 mutants but not ort mutants showed long-sleep phenotypes similar to those in hdc mutants. Increased sleep duration in hisCl1 mutants was rescued by overexpressing hisCl1 in circadian pacemaker neurons expressing a neuropeptide pigment dispersing factor (PDF). Consistently, RNA interference (RNAi)-mediated depletion of hisCl1 in PDF neurons was sufficient to mimic hisCl1 mutant phenotypes, suggesting that PDF neurons are crucial for sleep regulation by the histamine-HisCl1 signaling. Finally, either hisCl1 mutation or genetic ablation of PDF neurons dampened wake-promoting effects of elevated histamine signaling via direct histamine administration. Taken together, these data clearly demonstrate that the histamine-HisCl1 receptor axis can activate and maintain the wake state in Drosophila and that wake-activating signals may travel via the PDF neurons.

  1. Histamine-HisCl1 Receptor Axis Regulates Wake-Promoting Signals in Drosophila melanogaster

    PubMed Central

    Oh, Yangkyun; Jang, Donghoon; Sonn, Jun Young; Choe, Joonho

    2013-01-01

    Histamine and its two receptors, histamine-gated chloride channel subunit 1 (HisCl1) and ora transientless (Ort), are known to control photoreception and temperature sensing in Drosophila. However, histamine signaling in the context of neural circuitry for sleep-wake behaviors has not yet been examined in detail. Here, we obtained mutant flies with compromised or enhanced histamine signaling and tested their baseline sleep. Hypomorphic mutations in histidine decarboxylase (HDC), an enzyme catalyzing the conversion from histidine to histamine, caused an increase in sleep duration. Interestingly, hisCl1 mutants but not ort mutants showed long-sleep phenotypes similar to those in hdc mutants. Increased sleep duration in hisCl1 mutants was rescued by overexpressing hisCl1 in circadian pacemaker neurons expressing a neuropeptide pigment dispersing factor (PDF). Consistently, RNA interference (RNAi)-mediated depletion of hisCl1 in PDF neurons was sufficient to mimic hisCl1 mutant phenotypes, suggesting that PDF neurons are crucial for sleep regulation by the histamine-HisCl1 signaling. Finally, either hisCl1 mutation or genetic ablation of PDF neurons dampened wake-promoting effects of elevated histamine signaling via direct histamine administration. Taken together, these data clearly demonstrate that the histamine-HisCl1 receptor axis can activate and maintain the wake state in Drosophila and that wake-activating signals may travel via the PDF neurons. PMID:23844178

  2. Role of Corticotropin-releasing Factor in Gastrointestinal Permeability

    PubMed Central

    Rodiño-Janeiro, Bruno K; Alonso-Cotoner, Carmen; Pigrau, Marc; Lobo, Beatriz; Vicario, María; Santos, Javier

    2015-01-01

    The interface between the intestinal lumen and the mucosa is the location where the majority of ingested immunogenic particles face the scrutiny of the vast gastrointestinal immune system. Upon regular physiological conditions, the intestinal micro-flora and the epithelial barrier are well prepared to process daily a huge amount of food-derived antigens and non-immunogenic particles. Similarly, they are ready to prevent environmental toxins and microbial antigens to penetrate further and interact with the mucosal-associated immune system. These functions promote the development of proper immune responses and oral tolerance and prevent disease and inflammation. Brain-gut axis structures participate in the processing and execution of response signals to external and internal stimuli. The brain-gut axis integrates local and distant regulatory networks and super-systems that serve key housekeeping physiological functions including the balanced functioning of the intestinal barrier. Disturbance of the brain-gut axis may induce intestinal barrier dysfunction, increasing the risk of uncontrolled immunological reactions, which may indeed trigger transient mucosal inflammation and gut disease. There is a large body of evidence indicating that stress, through the brain-gut axis, may cause intestinal barrier dysfunction, mainly via the systemic and peripheral release of corticotropin-releasing factor. In this review, we describe the role of stress and corticotropin-releasing factor in the regulation of gastrointestinal permeability, and discuss the link to both health and pathological conditions. PMID:25537677

  3. Controlled growth factor release from synthetic extracellular matrices

    NASA Astrophysics Data System (ADS)

    Lee, Kuen Yong; Peters, Martin C.; Anderson, Kenneth W.; Mooney, David J.

    2000-12-01

    Polymeric matrices can be used to grow new tissues and organs, and the delivery of growth factors from these matrices is one method to regenerate tissues. A problem with engineering tissues that exist in a mechanically dynamic environment, such as bone, muscle and blood vessels, is that most drug delivery systems have been designed to operate under static conditions. We thought that polymeric matrices, which release growth factors in response to mechanical signals, might provide a new approach to guide tissue formation in mechanically stressed environments. Critical design features for this type of system include the ability to undergo repeated deformation, and a reversible binding of the protein growth factors to polymeric matrices to allow for responses to repeated stimuli. Here we report a model delivery system that can respond to mechanical signalling and upregulate the release of a growth factor to promote blood vessel formation. This approach may find a number of applications, including regeneration and engineering of new tissues and more general drug-delivery applications.

  4. Interactions of release factor RF3 with the translation machinery.

    PubMed

    O'Connor, Michael

    2015-08-01

    The bacterial release factor RF3 is a GTPase that has been implicated in multiple, incompletely understood steps of protein synthesis. This study explores the genetic interaction of RF3 with other components of the translation machinery. RF3 contributes to translation termination by recycling the class I release factors RF1 and RF2 off post-termination ribosomes. RF3 has also been implicated in dissociation of peptidyl-tRNAs from elongating ribosomes and in a post-peptidyltransferase quality control (post-PT QC) mechanism that selectively terminates ribosomes carrying erroneous peptides. A majority of the in vivo studies on RF3 have been carried out in K-12 strains of Escherichia coli which carry a partially defective RF2 protein with an Ala to Thr substitution at position 246. Here, the contribution of the K-12 specific RF2 variant to RF3 activities has been investigated. Strain reconstruction experiments in both E. coli and Salmonella enterica demonstrate that defects in termination and post-PT QC that are associated with RF3 loss, as well as phenotypes uncovered by phenotypic profiling, are all substantially ameliorated when the incompletely active K-12-specific RF2 protein is replaced by a fully active Ala246 RF2. These results indicate that RF3 loss is well tolerated in bacteria with fully active class I release factors, but that many of the previously reported phenotypes for RF3 deletion strains have been compromised by the presence of a partially defective RF2. PMID:25636454

  5. GH responses to growth hormone releasing factor in depression.

    PubMed

    Thomas, R; Beer, R; Harris, B; John, R; Scanlon, M

    1989-01-01

    The growth hormone (GH), thyrotrophin (TSH) and prolactin response to growth hormone releasing factor (GRF) was investigated in 18 patients suffering from major depression with melancholia and in 18 age- and sex-matched normal controls. There was no significant difference in the GH response to GRF stimulation between the patients and controls and in neither subject group was there a demonstrable TSH or prolactin response to GRF. These findings indicate that the pathophysiology underlying the blunted GH response to pharmacological challenge, demonstrated in other studies, must lie at a suprapituitary level.

  6. Clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, inhibits electrically induced convulsions in mice.

    PubMed

    Yokoyama, H; Onodera, K; Maeyama, K; Sakurai, E; Iinuma, K; Leurs, R; Timmerman, H; Watanabe, T

    1994-07-21

    The effect of clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, on electrically induced convulsions was studied in mice. Clobenpropit significantly and dose dependently decreased the duration of each convulsive phase. Its anticonvulsant effects were prevented by pretreatment with (R)-alpha-methylhistamine and imetit (VUF-8325), histamine H3 receptor agonists. These findings suggest that the effect of clobenpropit on electrically induced convulsions is due to an increase in endogenous histamine release in the brain, which is consistent with biochemical results that clobenpropit increased brain histidine decarboxylase activity dose dependently. The anticonvulsive effect of clobenpropit was antagonized by mepyramine, a histamine H1 receptor antagonist, but not by zolantidine, a histamine H2 receptor antagonist, indicating that histamine released by the anticonvulsant effect of clobenpropit interacts with histamine H1 receptors of postsynaptic neurons. The present findings of the effect of clobenpropit on electrically induced convulsions are fully consistent with those of thioperamide as described previously (Yokoyama et al., 1993, Eur. J. Pharmacol. 234, 129), supporting the hypothesis that the central histaminergic neuron system is involved in the inhibition of seizures.

  7. Histamine function in brain disorders.

    PubMed

    Fernández-Novoa, L; Cacabelos, R

    2001-10-15

    The neurotransmitter histamine (HA) has been implicated in the regulation of numerous and important activities of the central nervous system as arousal, cognition, circadian rhythms and neuroendocrine regulation. The data presented here indicate the participation of the histaminergic system in central nervous system disorders, such as Alzheimer's disease and schizophrenia. We also present experimental data on histamine in an animal model of neurodegeneration and the cytotoxic effects of histamine on cultured rat endothelial cells. More studies are needed to investigate the role of the histaminergic system in central nervous system disorders. Peripheral cellular studies in health and disease, molecular studies on receptors and in vivo pharmacological studies may help us to better understand the function of the histaminergic system in health and disease.

  8. Signaling mechanism underlying the histamine-modulated action of hypoglossal motoneurons.

    PubMed

    Liu, Zi-Long; Wu, Xu; Luo, Yan-Jia; Wang, Lu; Qu, Wei-Min; Li, Shan-Qun; Huang, Zhi-Li

    2016-04-01

    Histamine, an important modulator of the arousal states of the central nervous system, has been reported to contribute an excitatory drive at the hypoglossal motor nucleus to the genioglossus (GG) muscle, which is involved in the pathogenesis of obstructive sleep apnea. However, the effect of histamine on hypoglossal motoneurons (HMNs) and the underlying signaling mechanisms have remained elusive. Here, whole-cell patch-clamp recordings were conducted using neonatal rat brain sections, which showed that histamine excited HMNs with an inward current under voltage-clamp and a depolarization membrane potential under current-clamp via histamine H1 receptors (H1Rs). The phospholipase C inhibitor U-73122 blocked H1Rs-mediated excitatory effects, but protein kinase A inhibitor and protein kinase C inhibitor did not, indicating that the signal transduction cascades underlying the excitatory action of histamine on HMNs were H1R/Gq/11 /phospholipase C/inositol-1,4,5-trisphosphate (IP3). The effects of histamine were also dependent on extracellular Na(+) and intracellular Ca(2+), which took place via activation of Na(+)-Ca(2+) exchangers. These results identify the signaling molecules associated with the regulatory effect of histamine on HMNs. The findings of this study may provide new insights into therapeutic approaches in obstructive sleep apnea. We proposed the post-synaptic mechanisms underlying the modulation effect of histamine on hypoglossal motoneuron. Histamine activates the H1Rs via PLC and IP3, increases Ca(2+) releases from intracellular stores, promotes Na(+) influx and Ca(2+) efflux via the NCXs, and then produces an inward current and depolarizes the neurons. Histamine modulates the excitability of HMNs with other neuromodulators, such as noradrenaline, serotonin and orexin. We think that these findings should provide an important new direction for drug development for the treatment of obstructive sleep apnea.

  9. Regulation of gonadotropins by corticotropin-releasing factor and urocortin.

    PubMed

    Kageyama, Kazunori

    2013-01-01

    While stress activates the hypothalamic-pituitary-adrenal (HPA) axis, it suppresses the hypothalamic-pituitary-gonadal (HPG) axis. Corticotropin-releasing factor (CRF) is a major regulatory peptide in the HPA axis during stress. Urocortin 1 (Ucn1), a member of the CRF family of peptides, has a variety of physiological functions and both CRF and Ucn1 contribute to the stress response via G protein-coupled seven transmembrane receptors. Ucn2 and Ucn3, which belong to a separate paralogous lineage from CRF, are highly selective for the CRF type 2 receptor (CRF(2) receptor). The HPA and HPG axes interact with each other, and gonadal function and reproduction are suppressed in response to various stressors. In this review, we focus on the regulation of gonadotropins by CRF and Ucn2 in pituitary gonadotrophs and of gonadotropin-releasing hormone (GnRH) via CRF receptors in the hypothalamus. In corticotrophs, stress-induced increases in CRF stimulate Ucn2 production, which leads to the inhibition of gonadotropin secretion via the CRF(2) receptor in the pituitary. GnRH in the hypothalamus is regulated by a variety of stress conditions. CRF is also involved in the suppression of the HPG axis, especially the GnRH pulse generator, via CRF receptors in the hypothalamus. Thus, complicated regulation of GnRH in the hypothalamus and gonadotropins in the pituitary via CRF receptors contributes to stress responses and adaptation of gonadal functions.

  10. Sugarcane transgenics expressing MYB transcription factors show improved glucose release

    DOE PAGES

    Poovaiah, Charleson R.; Bewg, William P.; Lan, Wu; Ralph, John; Coleman, Heather D.

    2016-07-15

    In this study, sugarcane, a tropical C4 perennial crop, is capable of producing 30-100 tons or more of biomass per hectare annually. The lignocellulosic residue remaining after sugar extraction is currently underutilized and can provide a significant source of biomass for the production of second-generation bioethanol. As a result, MYB31 and MYB42 were cloned from maize and expressed in sugarcane with and without the UTR sequences. The cloned sequences were 98 and 99 % identical to the published nucleotide sequences. The inclusion of the UTR sequences did not affect any of the parameters tested. There was little difference in plantmore » height and the number of internodes of the MYB-overexpressing sugarcane plants when compared with controls. MYB transgene expression determined by qPCR exhibited continued expression in young and maturing internodes. MYB31 downregulated more genes within the lignin biosynthetic pathway than MYB42. MYB31 and MYB42 expression resulted in decreased lignin content in some lines. All MYB42 plants further analyzed showed significant increases in glucose release by enzymatic hydrolysis in 72 h, whereas only two MYB31 plants released more glucose than control plants. This correlated directly with a significant decrease in acid-insoluble lignin. Soluble sucrose content of the MYB42 transgenic plants did not vary compared to control plants. In conclusion, this study demonstrates the use of MYB transcription factors to improve the production of bioethanol from sugarcane bagasse remaining after sugar extraction.« less

  11. Growth-hormone-releasing factor immunoreactivity in human endocrine tumors.

    PubMed Central

    Bostwick, D. G.; Quan, R.; Hoffman, A. R.; Webber, R. J.; Chang, J. K.; Bensch, K. G.

    1984-01-01

    Seventy-three human tumors and adjacent nonneoplastic tissues were analyzed immunohistochemically for the presence of growth-hormone-releasing factor (GRF). Four of 9 pancreatic endocrine tumors, 2 of 3 appendiceal carcinoids, and 1 of 5 cecal carcinoids were immunoreactive for GRF. One of the GRF-containing pancreatic tumors was associated with acromegaly. Histologically, the growth patterns of these tumors were variable, and the distribution of immunoreactive cells was patchy and irregular. There were no normal cells that contained GRF. These results indicate that GRF production by human tumors is more common than previously thought, although clinical acromegaly may not be apparent in patients who harbor such neoplasms. Images Figure 1 PMID:6093542

  12. Histamine H1 and H2 receptor antagonists accelerate skin barrier repair and prevent epidermal hyperplasia induced by barrier disruption in a dry environment.

    PubMed

    Ashida, Y; Denda, M; Hirao, T

    2001-02-01

    Keratinocytes have histamine H1 and H2 receptors, but their functions are poorly understood. To clarify the role of histamine receptors in the epidermis, we examined the effects of histamine receptor antagonists and agonists applied epicutaneously on the recovery of skin barrier function disrupted by tape stripping in hairless mice. Histamine H2 receptor antagonists famotidine and cimetidine accelerated the recovery of skin barrier function, but histamine and histamine H2 receptor agonist dimaprit delayed the barrier repair. Application of compound 48/80, a histamine releaser, also delayed the recovery. Imidazole, an analog of histamine, had no effect. The histamine H1 receptor antagonists diphenhydramine and tripelennamine accelerated the recovery. Histamine H3 receptor agonist Nalpha-methylhistamine and antagonist thioperamide had no effect. In addition, topical application of famotidine or diphenhydramine prevented epidermal hyperplasia in mice with skin barrier disrupted by acetone treatment in a dry environment (humidity < 10%) for 4 d. In conclusion, both the histamine H1 and H2 receptors in the epidermis are involved in skin barrier function and the cutaneous condition of epidermal hyperplasia.

  13. Factors controlling phosphorus release from sediments in coastal archipelago areas.

    PubMed

    Puttonen, Irma; Kohonen, Tuula; Mattila, Johanna

    2016-07-15

    In coastal archipelago areas of the northern Baltic Sea, significantly higher phosphate concentrations (6.0±4.5μmol/l, mean±SD) were measured in water samples close to the sediment surface compared with those from 1m above the seafloor (1.6±2.0μmol/l). The results indicated notable phosphate release from sediments under the bottom water oxygen concentrations of up to 250μmol/l, especially in areas that had experienced recent temporal fluctuation between oxic and hypoxic/anoxic conditions. No single factor alone was found to control the elevated PO4-P concentrations in the near-bottom water. In addition to the oxygen in the water, the contents of potentially mobile phosphorus fractions, grain-size, the organic content at the sediment surface, and the water depth were all important factors controlling the internal loading of phosphorus. The complexity of this process needs to be accounted for in assessments of the internal loading of phosphorus and in potential mitigation plans. PMID:27184132

  14. The accuracy of codon recognition by polypeptide release factors

    PubMed Central

    Freistroffer, David V.; Kwiatkowski, Marek; Buckingham, Richard H.; Ehrenberg, Måns

    2000-01-01

    The precision with which individual termination codons in mRNA are recognized by protein release factors (RFs) has been measured and compared with the decoding of sense codons by tRNA. An Escherichia coli system for protein synthesis in vitro with purified components was used to study the accuracy of termination by RF1 and RF2 in the presence or absence of RF3. The efficiency of factor-dependent termination at all sense codons differing from any of the three stop codons by a single mutation was measured and compared with the efficiency of termination at the three stop codons. RF1 and RF2 discriminate against sense codons related to stop codons by between 3 and more than 6 orders of magnitude. This high level of accuracy is obtained without energy-driven error correction (proofreading), in contrast to codon-dependent aminoacyl-tRNA recognition by ribosomes. Two codons, UAU and UGG, stand out as hotspots for RF-dependent premature termination. PMID:10681447

  15. Corticotropin releasing factor (CRF): immunocytochemical localization and radioimmunoassay (RIA). [Rats

    SciTech Connect

    Vigh, S.; Merchenthaler, I.; Torres-Aleman, I.; Sueiras-Diaz, J.; Coy, D.; Carter, W.H.; Petrusz, P.; Schally, A.V.

    1982-11-29

    Two fragments of the amino acid sequence corresponding to ovine corticotropin releasing factor (CRF 37-41 and CRF 22-41), as well as the full sequence of 41 residues (CRF 1-41), synthesized in our laboratories by solid-phase methods, were coupled to bovine serum albumin (BSA) with glutaraldehyde. New Zealand white rabbits were immunized with the emulsified mixtures of peptide-BSA conjugates and Freund's adjuvant as immunogens. The specificity of the generated antibodies was studied by agar-gel diffusion, absorption tests in the immunohistochemical system, and with the aid of displacement curves in RIA. /sup 125/I-Tyr(35)-CRF 36-41 and /sup 125/I-Tyr(0)-CRF 1-41 were used as radioligands in the RIA. The minimum detectable dose was 20 pg. The linearity observed in RIA for immunoreactive CRF in extracts of rat hypothalami, together with the immunocytochemical findings in the rat brain, indicate the presence of substance(s) immunologically indistinguishable from CRF. Immunohistochemistry with the peroxidase-antiperoxidase (PAP) technique detected the following CRF-immunoreactive structures in vibratome sections of hypothalami of colchicine-treated rats: CRF-containing cell bodies were observed mainly in smaller neurons of the paraventricular nucleus. CRF-positive nerve fibers and/or terminals were present in the external zone of the median eminence, with some immunoreactive CRF also present in the internal zone. The CRF-positive terminals were localized in the central regions of the median eminence. Data reinforce the view that this polypeptide plays a physiological role in the control of ACTH release.

  16. Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake

    PubMed Central

    Provensi, Gustavo; Coccurello, Roberto; Umehara, Hayato; Munari, Leonardo; Giacovazzo, Giacomo; Galeotti, Nicoletta; Nosi, Daniele; Gaetani, Silvana; Romano, Adele; Moles, Anna; Blandina, Patrizio; Passani, Maria Beatrice

    2014-01-01

    Key factors driving eating behavior are hunger and satiety, which are controlled by a complex interplay of central neurotransmitter systems and peripheral stimuli. The lipid-derived messenger oleoylethanolamide (OEA) is released by enterocytes in response to fat intake and indirectly signals satiety to hypothalamic nuclei. Brain histamine is released during the appetitive phase to provide a high level of arousal in anticipation of feeding, and mediates satiety. However, despite the possible functional overlap of satiety signals, it is not known whether histamine participates in OEA-induced hypophagia. Using different experimental settings and diets, we report that the anorexiant effect of OEA is significantly attenuated in mice deficient in the histamine-synthesizing enzyme histidine decarboxylase (HDC-KO) or acutely depleted of histamine via interocerebroventricular infusion of the HDC blocker α-fluoromethylhistidine (α-FMH). α-FMH abolished OEA-induced early occurrence of satiety onset while increasing histamine release in the CNS with an H3 receptor antagonist-increased hypophagia. OEA augmented histamine release in the cortex of fasted mice within a time window compatible to its anorexic effects. OEA also increased c-Fos expression in the oxytocin neurons of the paraventricular nuclei of WT but not HDC-KO mice. The density of c-Fos immunoreactive neurons in other brain regions that receive histaminergic innervation and participate in the expression of feeding behavior was comparable in OEA-treated WT and HDC-KO mice. Our results demonstrate that OEA requires the integrity of the brain histamine system to fully exert its hypophagic effect and that the oxytocin neuron-rich nuclei are the likely hypothalamic area where brain histamine influences the central effects of OEA. PMID:25049422

  17. Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake.

    PubMed

    Provensi, Gustavo; Coccurello, Roberto; Umehara, Hayato; Munari, Leonardo; Giacovazzo, Giacomo; Galeotti, Nicoletta; Nosi, Daniele; Gaetani, Silvana; Romano, Adele; Moles, Anna; Blandina, Patrizio; Passani, Maria Beatrice

    2014-08-01

    Key factors driving eating behavior are hunger and satiety, which are controlled by a complex interplay of central neurotransmitter systems and peripheral stimuli. The lipid-derived messenger oleoylethanolamide (OEA) is released by enterocytes in response to fat intake and indirectly signals satiety to hypothalamic nuclei. Brain histamine is released during the appetitive phase to provide a high level of arousal in anticipation of feeding, and mediates satiety. However, despite the possible functional overlap of satiety signals, it is not known whether histamine participates in OEA-induced hypophagia. Using different experimental settings and diets, we report that the anorexiant effect of OEA is significantly attenuated in mice deficient in the histamine-synthesizing enzyme histidine decarboxylase (HDC-KO) or acutely depleted of histamine via interocerebroventricular infusion of the HDC blocker α-fluoromethylhistidine (α-FMH). α-FMH abolished OEA-induced early occurrence of satiety onset while increasing histamine release in the CNS with an H3 receptor antagonist-increased hypophagia. OEA augmented histamine release in the cortex of fasted mice within a time window compatible to its anorexic effects. OEA also increased c-Fos expression in the oxytocin neurons of the paraventricular nuclei of WT but not HDC-KO mice. The density of c-Fos immunoreactive neurons in other brain regions that receive histaminergic innervation and participate in the expression of feeding behavior was comparable in OEA-treated WT and HDC-KO mice. Our results demonstrate that OEA requires the integrity of the brain histamine system to fully exert its hypophagic effect and that the oxytocin neuron-rich nuclei are the likely hypothalamic area where brain histamine influences the central effects of OEA.

  18. Effect of inhaled ozone on lung histamine in conscious guinea pigs

    SciTech Connect

    Shields, R.L.; Gold, W.M.

    1987-04-01

    The effect of short-term ozone (O/sub 3/) exposure on pulmonary mast cell function was examined. Guinea pigs were continuously exposed to 1.0 ppm O/sub 3/ for 2, 4, and 8 hr. O/sub 3/ exposure produced a significant decrease in lung histamine concentration. Two-hour exposure to O/sub 3/ caused a 22.4 +/- 7.0% decrease in lung histamine concentration compared with controls. Ozone exposures of 4 and 8 hr caused lung histamine concentrations to decrease by 43.7 +/- 7.7 and 49.0 +/- 7.5%, respectively, without significant changes in lung water or protein, or evidence of cytotoxicity. These results suggest that O/sub 3/ or its metabolites affect pulmonary mast cell function by stimulating the release of histamine from the lung.

  19. The effect of indomethacin on the kinetics of histamine, 48/80 and antigen wealing.

    PubMed Central

    Humphreys, F; Shuster, S

    1990-01-01

    1. The kinetics of weal formation and disappearance following intradermal injection of histamine, compound 48/80 and antigen were measured in indomethacin and inert geltreated human forearm skin. 2. Rates of formation went in descending order for histamine, 48/80 and antigen; rate constants of disappearance for equal sized weals were the same for histamine and 48/80 but were much less for antigen. The corresponding half-lives were 77, 73 and 160 min for histamine, 48/80 and antigen weal disappearance respectively. 3. Cyclo-oxygenase inhibition by topical indomethacin had no effect either on the immediate weal and flare responses or on the rates of formation and disappearance of the weals. 4. These findings together with previous studies using H1-receptor antagonists indicate that 48/80 acts by histamine release but that antigen releases both histamine and an additional material or materials which are not related to cyclo-oxygenase activity. 5. Exacerbation of chronic idiopathic urticaria by cyclo-oxygenase inhibitors is therefore likely to be part of the urticarial disease process. PMID:2106336

  20. Effects of multivalent histamine supported on gold nanoparticles: activation of histamine receptors by derivatized histamine at subnanomolar concentrations.

    PubMed

    Gasiorek, Friederike; Pouokam, Ervice; Diener, Martin; Schlecht, Sabine; Wickleder, Mathias S

    2015-10-21

    Colloidal gold nanoparticles with a functionalized ligand shell were synthesized and used as new histamine receptor agonists. Mercaptoundecanoic acid moieties were attached to the surface of the nanoparticles and derivatized with native histamine. The multivalent presentation of the immobilized ligands carried by the gold nanoparticles resulted in extremely low activation concentrations for histamine receptors on rat colonic epithelium. As a functional read-out system, chloride secretion resulting from stimulation of neuronal and epithelial histamine H1 and H2 receptors was measured in Ussing chamber experiments. These responses were strictly attributed to the histamine entities as histamine-free particles Au-MUDOLS or the monovalent ligand AcS-MUDA-HA proved to be ineffective. The vitality of the tissues used was not impaired by the nanoparticles.

  1. Release factor one is nonessential in Escherichia coli.

    PubMed

    Johnson, David B F; Wang, Chong; Xu, Jianfeng; Schultz, Matthew D; Schmitz, Robert J; Ecker, Joseph R; Wang, Lei

    2012-08-17

    Recoding a stop codon to an amino acid may afford orthogonal genetic systems for biosynthesizing new protein and organism properties. Although reassignment of stop codons has been found in extant organisms, a model organism is lacking to investigate the reassignment process and to direct code evolution. Complete reassignment of a stop codon is precluded by release factors (RFs), which recognize stop codons to terminate translation. Here we discovered that RF1 could be unconditionally knocked out from various Escherichia coli stains, demonstrating that the reportedly essential RF1 is generally dispensable for the E. coli species. The apparent essentiality of RF1 was found to be caused by the inefficiency of a mutant RF2 in terminating all UAA stop codons; a wild type RF2 was sufficient for RF1 knockout. The RF1-knockout strains were autonomous and unambiguously reassigned UAG to encode natural or unnatural amino acids (Uaas) at multiple sites, affording a previously unavailable model for studying code evolution and a unique host for exploiting Uaas to evolve new biological functions.

  2. Electrospinning Growth Factor Releasing Microspheres into Fibrous Scaffolds

    PubMed Central

    Whitehead, Tonya J.; Sundararaghavan, Harini G.

    2014-01-01

    This procedure describes a method to fabricate a multifaceted substrate to direct nerve cell growth. This system incorporates mechanical, topographical, adhesive and chemical signals. Mechanical properties are controlled by the type of material used to fabricate the electrospun fibers. In this protocol we use 30% methacrylated Hyaluronic Acid (HA), which has a tensile modulus of ~500 Pa, to produce a soft fibrous scaffold. Electrospinning on to a rotating mandrel produces aligned fibers to create a topographical cue. Adhesion is achieved by coating the scaffold with fibronectin. The primary challenge addressed herein is providing a chemical signal throughout the depth of the scaffold for extended periods. This procedure describes fabricating poly(lactic-co-glycolic acid) (PLGA) microspheres that contain Nerve Growth Factor (NGF) and directly impregnating the scaffold with these microspheres during the electrospinning process. Due to the harsh production environment, including high sheer forces and electrical charges, protein viability is measured after production. The system provides protein release for over 60 days and has been shown to promote primary nerve cell growth. PMID:25178038

  3. Conformational thermostabilisation of corticotropin releasing factor receptor 1.

    PubMed

    Kean, James; Bortolato, Andrea; Hollenstein, Kaspar; Marshall, Fiona H; Jazayeri, Ali

    2015-01-01

    Recent technical advances have greatly facilitated G-protein coupled receptors crystallography as evidenced by the number of successful x-ray structures that have been reported recently. These technical advances include novel detergents, specialised crystallography techniques as well as protein engineering solutions such as fusions and conformational thermostabilisation. Using conformational thermostabilisation, it is possible to generate variants of GPCRs that exhibit significantly increased stability in detergent micelles whilst preferentially occupying a single conformation. In this paper we describe for the first time the application of this technique to a member of a class B GPCR, the corticotropin releasing factor receptor 1 (CRF1R). Mutational screening in the presence of the inverse agonist, CP-376395, resulted in the identification of a construct with twelve point mutations that exhibited significantly increased thermal stability in a range of detergents. We further describe the subsequent construct engineering steps that eventually yielded a crystallisation-ready construct which recently led to the solution of the first x-ray structure of a class B receptor. Finally, we have used molecular dynamic simulation to provide structural insight into CRF1R instability as well as the stabilising effects of the mutants, which may be extended to other class B receptors considering the high degree of structural conservation. PMID:26159865

  4. A Glial Variant of the Vesicular Monoamine Transporter Is Required To Store Histamine in the Drosophila Visual System

    PubMed Central

    Simon, Anne F.; Grygoruk, Anna; Yee, Susan K.; Shyer, Amy; Ackerson, Larry C.; Maidment, Nigel T.; Meinertzhagen, Ian A.; Hovemann, Bernhard T.; Krantz, David E.

    2008-01-01

    Unlike other monoamine neurotransmitters, the mechanism by which the brain's histamine content is regulated remains unclear. In mammals, vesicular monoamine transporters (VMATs) are expressed exclusively in neurons and mediate the storage of histamine and other monoamines. We have studied the visual system of Drosophila melanogaster in which histamine is the primary neurotransmitter released from photoreceptor cells. We report here that a novel mRNA splice variant of Drosophila VMAT (DVMAT-B) is expressed not in neurons but rather in a small subset of glia in the lamina of the fly's optic lobe. Histamine contents are reduced by mutation of dVMAT, but can be partially restored by specifically expressing DVMAT-B in glia. Our results suggest a novel role for a monoamine transporter in glia that may be relevant to histamine homeostasis in other systems. PMID:18989452

  5. Factors affecting the release of flavor encapsulated in carbohydrate matrixes.

    PubMed

    Gunning, Y M; Gunning, P A; Kemsley, E K; Parker, R; Ring, S G; Wilson, R H; Blake, A

    1999-12-01

    The effects of water content and temperature variation on the release of flavor components into the headspace over flavors, encapsulated by an extrusion process, in low water content carbohydrate matrixes is studied. The largest amounts of release occurred when the matrix was above its glass transition temperature, whether this was due to increased water content or elevated temperature. Under these conditions up to 70% of the sucrose in the matrix crystallized over a period of 10 days, as quantified using Fourier transform Raman spectroscopy. Smaller amounts of headspace release occurred when the water content of the encapsulated flavor system was decreased from 3. 5 to 3.1% w/w. Small amounts of release occurred from the "as prepared" materials, which were associated with the presence of small amounts of unencapsulated flavor oil with direct access to the headspace. It was concluded that release due to matrix permeability was relatively slow as compared with the above mechanisms.

  6. Histamine Modulates Sweating and Affects Clinical Manifestations of Atopic Dermatitis.

    PubMed

    Takahashi, Aya; Tani, Saki; Murota, Hiroyuki; Katayama, Ichiro

    2016-01-01

    Many factors such as food or environmental allergens, bacteria, fungi, and mental stress aggravate the condition of atopic dermatitis (AD) eczema. Sweating can also exacerbate AD, and patients are aware of that. In the past, it has been reported that contamination of skin surface antigens by sweat induces acute allergic reactions and that sweating functions of AD patients via axonal reflexes are decreased. Histamine demonstrably inhibits acetylcholine-induced sweating in both mice and humans via histamine H1 receptor-mediated signaling. In sweat glands, acetylcholine inactivates glycogen synthase kinase 3β (GSK3β), a kinase involved in endocytosis and secretion, whereas simultaneous stimulation with histamine activates GSK3β and inhibits sweat secretion. Thus, histamine might be involved in the mechanism of abnormal skin dryness in patients with AD via decreasing sweat secretion. On another front, some patients secrete sweat normally. Patients with regular sweating are prone to develop skin disorders such as papules or erythema by residual sweat left on the skin surface. Patients with decreased sweating are prone to develop disorders characterized by xerosis, lichenoid changes, prurigo by elevated skin temperature, skin dryness, and compromised skin conditions. Careful inspection of skin manifestations provides a good indication of a patient's ability to sweat. PMID:27584962

  7. Stress-Derived Corticotropin Releasing Factor Breaches Epithelial Endotoxin Tolerance

    PubMed Central

    Yu, Yong; Geng, Xiao-Rui; Yang, Gui; Liu, Zhi-Gang; Zheng, Peng-Yuan; Yang, Ping-Chang

    2013-01-01

    Background and aims Loss of the endotoxin tolerance of intestinal epithelium contributes to a number of intestinal diseases. The etiology is not clear. Psychological stress is proposed to compromise the intestinal barrier function. The present study aims to elucidate the role of the stress-derived corticotropin releasing factor (CRF) in breaching the established intestinal epithelial endotoxin tolerance. Methods Epithelial cells of HT-29, T84 and MDCK were exposed to lipopolysaccharide to induce the endotoxin tolerance; the cells were then stimulated with CRF. The epithelial barrier function was determined using as indicators of the endotoxin tolerant status. A water-avoid stress mouse model was employed to test the role of CRF in breaching the established endotoxin tolerance in the intestine. Results The established endotoxin tolerance in the epithelial cell monolayers was broken down by a sequent exposure to CRF and LPS manifesting a marked drop of the transepithelial resistance (TER) and an increase in the permeability to a macromolecular tracer, horseradish peroxidase (HRP). The exposure to CRF also increased the expression of Cldn2 in the epithelial cells, which could be mimicked by over expression of TLR4 in epithelial cells. Over expression of Cldn2 resulted in low TER in epithelial monolayers and high permeability to HRP. After treating mice with the 10-day chronic stress, the intestinal epithelial barrier function was markedly compromised, which could be prevented by blocking either CRF, or TLR4, or Cldn2. Conclusions Psychological stress-derived CRF can breach the established endotoxin tolerance in the intestinal mucosa. PMID:23840363

  8. Draft Genome Sequences of Histamine- and Non-Histamine-Producing Photobacterium Strains

    PubMed Central

    Sanchez Leon, Maria; Dunlap, Paul V.; Benner, Ronald A.

    2016-01-01

    Histamine-producing bacteria (HPBs) have recently been identified from the marine environment. The identification and characterization of HPBs is important to developing effective mitigation strategies for scombrotoxin fish poisoning. We report here the draft genomes of seven histamine-producing and two non-histamine-producing marine Photobacterium strains. PMID:27660786

  9. Draft Genome Sequences of Histamine- and Non-Histamine-Producing Photobacterium Strains.

    PubMed

    Bjornsdottir-Butler, Kristin; Sanchez Leon, Maria; Dunlap, Paul V; Benner, Ronald A

    2016-01-01

    Histamine-producing bacteria (HPBs) have recently been identified from the marine environment. The identification and characterization of HPBs is important to developing effective mitigation strategies for scombrotoxin fish poisoning. We report here the draft genomes of seven histamine-producing and two non-histamine-producing marine Photobacterium strains. PMID:27660786

  10. Vasopeptidase-activated latent ligands of the histamine receptor-1.

    PubMed

    Gera, Lajos; Roy, Caroline; Charest-Morin, Xavier; Marceau, François

    2013-11-01

    Whether peptidases present in vascular cells can activate prodrugs active on vascular cells has been tested with 2 potential latent ligands of the histamine H1 receptor (H1R). First, a peptide consisting of the antihistamine cetirizine (CTZ) condensed at the N-terminus of ε-aminocaproyl-bradykinin (εACA-BK) was evaluated for an antihistamine activity that could be revealed by degradation of the peptide part of the molecule. CTZ-εACA-BK had a submicromolar affinity for the BK B2 receptor (B2R; IC50 of 590 nM, [(3)H]BK binding competition), but a non-negligible affinity for the human H1 receptor (H1R; IC50 of 11 μM for [(3)H]pyrilamine binding). In the human isolated umbilical vein, a system where both endogenous B2R and H1R mediate strong contractions, CTZ-εACA-BK exerted mild antagonist effects on histamine-induced contraction that were not modified by omapatrilat or by a B2R antagonist that prevents endocytosis of the BK conjugate. Cells expressing recombinant ACE or B2R incubated with CTZ-εACA-BK did not release a competitor of [(3)H]pyrilamine binding to H1Rs. Thus, there is no evidence that CTZ-εACA-BK can release free cetirizine in biological environments. The second prodrug was a blocked agonist, L-alanyl-histamine, potentially activated by aminopeptidase N (APN). This compound did not compete for [(3)H]pyrilamine binding to H1Rs. The human umbilical vein contractility assay responded to L-alanyl-histamine (EC50 54.7 μM), but the APN inhibitor amastatin massively (17-fold) reduced its apparent potency. Amastatin did not influence the potency of histamine as a contractile agent. One of the 2 tested latent H1R ligands, L-alanyl-histamine, supported the feasibility of pro-drug activation by vascular ectopeptidases.

  11. Histamine and prostaglandin E2 up-regulate the production of Th2-attracting chemokines (CCL17 and CCL22) and down-regulate IFN-γ-induced CXCL10 production by immature human dendritic cells

    PubMed Central

    McIlroy, Anne; Caron, Gersende; Blanchard, Simon; Frémaux, Isabelle; Duluc, Dorothée; Delneste, Yves; Chevailler, Alain; Jeannin, Pascale

    2006-01-01

    Effector memory T helper 2 (Th2) cells that accumulate in target organs (i.e. skin or bronchial mucosa) have a central role in the pathogenesis of allergic disorders. To date, the factors that selectively trigger local production of Th2-attracting chemokines remain poorly understood. In mucosa, at the sites of allergen entry, immature dendritic cells (DC) are in close contact with mast cells. Histamine and prostaglandin E2 (PGE2) are two mediators released by allergen-activated mast cells that favour the polarization of maturing DC into Th2-polarizing cells. We analysed here the effects of histamine and PGE2 on the prototypic, Th2-(CCL17, CCL22) versus Th1-(CXCL10) chemokine production by human DC. We report that histamine and PGE2 dose-dependently up-regulate CCL17 and CCL22 by monocyte-derived immature DC. These effects were potentiated by tumour necrosis factor-α, still observed in the presence of the Th1-cytokine interferon-γ (IFN-γ) and abolished by the immunomodulatory cytokine interleukin-10. In addition, histamine and PGE2 down-regulated IFN-γ-induced CXCL10 production by monocyte-derived DC. These properties of histamine and PGE2 were observed at the transcriptional level and were mediated mainly through H2 receptors for histamine and through EP2 and EP4 receptors for PGE2. Finally, histamine and PGE2 also up-regulated CCL17 and CCL22 and decreased IFN-γ-induced CXCL10 production by purified human myeloid DC. In conclusion, these data show that, in addition to polarizing DC into mature cells that promote naïve T-cell differentiation into Th2 cells, histamine and PGE2 may act on immature DC to trigger local Th2 cell recruitment through a selective control of Th1/Th2-attracting chemokine production, thereby contributing to maintain a microenvironment favourable to persistent immunoglobulin E synthesis. PMID:16556265

  12. Histamine Recycling Is Mediated by CarT, a Carcinine Transporter in Drosophila Photoreceptors

    PubMed Central

    Xu, Ying; An, Futing; Borycz, Jolanta A.; Borycz, Janusz; Meinertzhagen, Ian A.; Wang, Tao

    2015-01-01

    Histamine is an important chemical messenger that regulates multiple physiological processes in both vertebrate and invertebrate animals. Even so, how glial cells and neurons recycle histamine remains to be elucidated. Drosophila photoreceptor neurons use histamine as a neurotransmitter, and the released histamine is recycled through neighboring glia, where it is conjugated to β-alanine to form carcinine. However, how carcinine is then returned to the photoreceptor remains unclear. In an mRNA-seq screen for photoreceptor cell-enriched transporters, we identified CG9317, an SLC22 transporter family protein, and named it CarT (Carcinine Transporter). S2 cells that express CarT are able to take up carcinine in vitro. In the compound eye, CarT is exclusively localized to photoreceptor terminals. Null mutations of cart alter the content of histamine and its metabolites. Moreover, null cart mutants are defective in photoreceptor synaptic transmission and lack phototaxis. These findings reveal that CarT is required for histamine recycling at histaminergic photoreceptors and provide evidence for a CarT-dependent neurotransmitter trafficking pathway between glial cells and photoreceptor terminals. PMID:26713872

  13. Histamine Recycling Is Mediated by CarT, a Carcinine Transporter in Drosophila Photoreceptors.

    PubMed

    Xu, Ying; An, Futing; Borycz, Jolanta A; Borycz, Janusz; Meinertzhagen, Ian A; Wang, Tao

    2015-12-01

    Histamine is an important chemical messenger that regulates multiple physiological processes in both vertebrate and invertebrate animals. Even so, how glial cells and neurons recycle histamine remains to be elucidated. Drosophila photoreceptor neurons use histamine as a neurotransmitter, and the released histamine is recycled through neighboring glia, where it is conjugated to β-alanine to form carcinine. However, how carcinine is then returned to the photoreceptor remains unclear. In an mRNA-seq screen for photoreceptor cell-enriched transporters, we identified CG9317, an SLC22 transporter family protein, and named it CarT (Carcinine Transporter). S2 cells that express CarT are able to take up carcinine in vitro. In the compound eye, CarT is exclusively localized to photoreceptor terminals. Null mutations of cart alter the content of histamine and its metabolites. Moreover, null cart mutants are defective in photoreceptor synaptic transmission and lack phototaxis. These findings reveal that CarT is required for histamine recycling at histaminergic photoreceptors and provide evidence for a CarT-dependent neurotransmitter trafficking pathway between glial cells and photoreceptor terminals.

  14. Stopping (or slowing) the revolving door: factors related to NGRI acquittees' maintenance of a conditional release.

    PubMed

    Monson, C M; Gunnin, D D; Fogel, M H; Kyle, L L

    2001-06-01

    The current study sought to extend the knowledge about factors associated with NGRI acquittees' maintenance of a conditional release after hospital discharge. The medical and forensic records of 125 NGRI acquittees were reviewed to collect a variety of demographic, clinical, criminal, and aftercare factors. A hierarchical survival analysis approach to determining success was compared to data analysis strategies typically employed in the area. Survival analysis, which accounts for both conditional release success status and time on conditional release, revealed that minority status, substance abuse diagnosis, and a prior criminal history were the factors that significantly predicted conditional release revocation. Treatment and policy implications of these results are discussed.

  15. The Presence of Histamine and a Histamine Receptor in the Bivalve Mollusc, Crassostrea virginica

    PubMed Central

    Harrison, Jarreau; LaFleur, Kisha; Mantone, Daniel; Boisette, Beatrix; Harris, Ave; Catapane, Edward J.; Carroll, Margaret A.

    2015-01-01

    Histamine, a biogenic amine, is a neurotransmitter in neurons and sensory receptors in invertebrates. Histamine has rarely been reported in bivalves. We used HPLC with pre-column derivatization using 2,3-naphthalenedicarboxaldehyde (NDA) as a fluorescent labeling agent to measure histamine in ganglia, and peripheral tissues of the oyster Crassostrea virginica. We also used Western Blot technique to look for the presence of a histamine receptor in the mantle rim. HPLC results found histamine present in ng amounts in both the cerebral and visceral ganglia, as well as the mantle rim and other peripheral tissues of C. virginica. The study confirms and quantifies histamine as an endogenous biogenic amine in C. virginica in the nervous system and innervated organs. Western Blot technique also identified a histamine H2-like receptor present in sensory tissue of the oyster's mantle rim. PMID:26120600

  16. Factors Associated with Releasing for Adoption among Adolescent Mothers.

    ERIC Educational Resources Information Center

    Donnelly, Brenda W.; Voydanoff, Patricia

    1991-01-01

    Examined relative importance of demographic characteristics, perceived alternatives to early childbearing, attitudes toward adoption and expectations regarding pregnancy, and relationships and experiences in adolescent mothers' (n=177) decisions to keep or release their child for adoption. Results indicated demographic characteristics and…

  17. Histamine and Seizures : Implications for the Treatment of Epilepsy.

    PubMed

    Yokoyama, H; Iinuma, K

    1996-05-01

    Experimental studies have indicated that the central histaminergic neuron system plays an important role in the inhibition of seizures through stimulation of histamine H1 receptors, especially in the developmental period. This has therapeutic implications for currently available drugs that act at histamine receptors. H1 receptor antagonists, including classical antihistamines and anti-allergy drugs, occasionally induce convulsions in healthy children and patients with epilepsy. In particular, promethazine, carbinoxamine, mepyramine (pyrilamine) and ketotifen should be used with caution in these patients. These drugs are widely used as components of over-the-counter medications. The use of the d-chlorphenamine (d-chlorpheniramine) activation study with EEG monitoring is useful for assessing the seizure susceptibility of patients who have had convulsions secondary to administration of H1 receptor antagonists.H2 receptor antagonists have also occasionally been reported to induce convulsions in critically ill and polymedicated patients, and patients with chronic renal or hepatic failure. However, experimental findings have not been consistent with these clinical reports, such that the role of these receptors and their ligands in inducing seizures cannot be confirmed.Recently, H3 receptor antagonists, which enhance endogenous histamine release in the brain, have been demonstrated to have a potent anticonvulsant action. Therefore, these compounds may represent a new avenue for the development of antiepileptic drugs. Considering that H3 receptor antagonists also induce arousal patterns on the EEG, it is possible that they will not be associated with the sedative effects of many conventional antiepileptic drugs.

  18. Growth-Factor Nanocapsules That Enable Tunable Controlled Release for Bone Regeneration.

    PubMed

    Tian, Haijun; Du, Juanjuan; Wen, Jing; Liu, Yang; Montgomery, Scott R; Scott, Trevor P; Aghdasi, Bayan; Xiong, Chengjie; Suzuki, Akinobu; Hayashi, Tetsuo; Ruangchainikom, Monchai; Phan, Kevin; Weintraub, Gil; Raed, Alobaidaan; Murray, Samuel S; Daubs, Michael D; Yang, Xianjin; Yuan, Xu-Bo; Wang, Jeffrey C; Lu, Yunfeng

    2016-08-23

    Growth factors are of great potential in regenerative medicine. However, their clinical applications are largely limited by the short in vivo half-lives and the narrow therapeutic window. Thus, a robust controlled release system remains an unmet medical need for growth-factor-based therapies. In this research, a nanoscale controlled release system (degradable protein nanocapsule) is established via in situ polymerization on growth factor. The release rate can be finely tuned by engineering the surface polymer composition. Improved therapeutic outcomes can be achieved with growth factor nanocapsules, as illustrated in spinal cord fusion mediated by bone morphogenetic protein-2 nanocapsules. PMID:27227573

  19. Histamine intolerance-like symptoms in healthy volunteers after oral provocation with liquid histamine.

    PubMed

    Wöhrl, Stefan; Hemmer, Wolfgang; Focke, Margarete; Rappersberger, Klemens; Jarisch, Reinhart

    2004-01-01

    Histamine in food at non-toxic doses has been proposed to be a major cause of food intolerance causing symptoms like diarrhea, hypotension, headache, pruritus and flush ("histamine intolerance"). Histamine-rich foods such as cheese, sausages, sauerkraut, tuna, tomatoes, and alcoholic beverages may contain histamine up to 500 mg/kg. We conducted a randomized, double-blind, placebo-controlled cross-over study in 10 healthy females (age range 22-36 years, mean 29.1 +/- 5.4) who were hospitalized and challenged on two consecutive days with placebo (peppermint tea) or 75 mg of pure histamine (equaling 124 mg histamine dihydrochloride, dissolved in peppermint tea). Objective parameters (heart rate, blood pressure, skin temperature, peak flow) as well as a total clinical symptom score using a standardized protocol were recorded at baseline, 10, 20, 40, 80 minutes, and 24 hours. The subjects received a histamine-free diet also low in allergen 24 hours before hospitalization and over the whole observation period. Blood samples were drawn at baseline, 10, 20, 40, and 80 minutes, and histamine and the histamine-degrading enzyme diamine oxidase (DAO) were determined. After histamine challenge, 5 of 10 subjects showed no reaction. One individual experienced tachycardia, mild hypotension after 20 minutes, sneezing, itching of the nose, and rhinorrhea after 60 minutes. Four subjects experienced delayed symptoms like diarrhea (4x), flatulence (3x), headache (3x), pruritus (2x) and ocular symptoms (1x) starting 3 to 24 hours after provocation. No subject reacted to placebo. No changes were observed in histamine and DAO levels within the first 80 minutes in non-reactors as well as reactors. There was no difference in challenge with histamine versus challenge with placebo. We conclude that 75 mg of pure liquid oral histamine--a dose found in normal meals--can provoke immediate as well as delayed symptoms in 50% of healthy females without a history of food intolerance. PMID:15603203

  20. Research Advances in Tissue Engineering Materials for Sustained Release of Growth Factors

    PubMed Central

    Zhao, Hai-yang; Wu, Jiang; Zhu, Jing-jing; Xiao, Ze-cong; He, Chao-chao; Shi, Hong-xue; Li, Xiao-kun; Yang, Shu-lin; Xiao, Jian

    2015-01-01

    Growth factors are a class of cytokines that stimulate cell growth and are widely used in clinical practice, such as wound healing, revascularization, bone repair, and nervous system disease. However, free growth factors have a short half-life and are instable in vivo. Therefore, the search of excellent carriers to enhance sustained release of growth factors in vivo has become an area of intense research interest. The development of controlled-release systems that protect the recombinant growth factors from enzymatic degradation and provide sustained delivery at the injury site during healing should enhance the growth factor's application in tissue regeneration. Thus, this study reviews current research on commonly used carriers for sustained release of growth factors and their sustained release effects for preservation of their bioactivity and their accomplishment in tissue engineering approaches. PMID:26347885

  1. Research Advances in Tissue Engineering Materials for Sustained Release of Growth Factors.

    PubMed

    Zhao, Hai-yang; Wu, Jiang; Zhu, Jing-jing; Xiao, Ze-cong; He, Chao-chao; Shi, Hong-xue; Li, Xiao-kun; Yang, Shu-lin; Xiao, Jian

    2015-01-01

    Growth factors are a class of cytokines that stimulate cell growth and are widely used in clinical practice, such as wound healing, revascularization, bone repair, and nervous system disease. However, free growth factors have a short half-life and are instable in vivo. Therefore, the search of excellent carriers to enhance sustained release of growth factors in vivo has become an area of intense research interest. The development of controlled-release systems that protect the recombinant growth factors from enzymatic degradation and provide sustained delivery at the injury site during healing should enhance the growth factor's application in tissue regeneration. Thus, this study reviews current research on commonly used carriers for sustained release of growth factors and their sustained release effects for preservation of their bioactivity and their accomplishment in tissue engineering approaches.

  2. 76 FR 68183 - Highlights of the Exposure Factors Handbook: 2011 Update Release of Final Report

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-03

    ... AGENCY Highlights of the Exposure Factors Handbook: 2011 Update Release of Final Report AGENCY... the report Highlights of the Exposure Factors Handbook: 2011 Update. The Highlights of the Exposure Factors Handbook: 2011 Update provides a summary of the recommended exposure factors extracted from...

  3. Studies on the role of central histamine in the acquisition of a radiation-induced conditioned taste aversion

    SciTech Connect

    Rabin, B.M.; Hunt, W.A.; Lee, J.

    1982-06-01

    The experiments described in this report were designed to test two hypotheses about how exposure to low-level radiation can affect the behavior of an organism: first, tht radiation effects on behavior are mediated by a radiation-induced release of histamine; and second, that this radiation-induced histamine release can exert relatively direct effects on the central nervous system. The results of the first experiment showed that microinjection of histamine directly into the fourth ventricle of rats produced a taste aversion to a novel sucrose solution. Pretreating rats with intraventricular H/sub 1/ or H/sub 2/ blockers was not effective in preventing the acquisition of the radiation-induced aversion, although the H/sub 1/ blocker did prevent the acquisition of a histamine-induced taste aversion. It also was not possible to establish a cross-tolerance between centrally administered histamine and radiation. The results are interpreted as not supporting the hypothesis that a radiation-induced release of central histamine mediates the acquisition of a conditioned taste aversion following exposure to low-level radiation.

  4. Histamine influences body temperature by acting at H1 and H3 receptors on distinct populations of preoptic neurons

    PubMed Central

    Lundius, Ebba Gregorsson; Sanchez-Alavez, Manuel; Ghochani, Yasmin; Klaus, Joseph; Tabarean, Iustin V.

    2010-01-01

    The preoptic area/anterior hypothalamus (PO/AH), a region that contains neurons that control thermoregulation, is the main locus at which histamine affects body temperature. Here we report that histamine reduced the spontaneous firing rate of GABAergic preoptic neurons by activating H3 subtype histamine receptors. This effect involved a decrease in the level of phosphorylation of the extracellular signal-regulated kinase (ERK) and was not dependent on synaptic activity. Furthermore, a population of nonGABAergic neurons was depolarized and their firing rate was enhanced by histamine acting at H1 subtype receptors. In our experiments, activation of the H1R receptors was linked to the PLC pathway and Ca2+ release from intracellular stores. This depolarization persisted in TTX or when fast synaptic potentials were blocked indicating that it represents a postsynaptic effect. Single-cell reverse transcription –PCR analysis revealed expression of H3 receptors in a population of GABAergic neurons while H1 receptors were expressed in nonGABAergic cells. Histamine applied in the median preoptic nucleus induced a robust, long lasting hyperthermia effect that was mimicked by either H1 or H3 histamine receptor subtype specific agonists. Our data indicate that histamine modulates the core body temperature by acting at two distinct populations of preoptic neurons which express H1 and H3 receptor subtypes, respectively. PMID:20335473

  5. Gas chromatographic analysis of histamine in mahi-mahi (Coryphaena hippurus).

    PubMed

    Antoine, Francis R; Wei, Cheng-I; Otwell, W Steve; Sims, Charlie A; Littell, Ramon C; Hogle, Amanda D; Marshall, Maurice R

    2002-08-14

    Several authors have studied histamine using gas chromatography (GC) as a tool for quantitation, but the methods used were not always suitable depending on the kind of food. Problems frequently cited include incomplete histamine elution from the columns and peak tailing. Histamine is of interest because it is the factor common to all cases of scombroid poisoning, it has physiological and biological activity, and it is a chemical indicator of fish quality. In this study a modified GC method was used to quantify histamine in mahi-mahi (Coryphaena hippurus). Mean recovery was 67% for the GC method, compared with 90% for the AOAC fluorometric method. There was a 0.96 correlation of the GC histamine values with those of the AOAC fluorometric method. A temperature program, splitless/split injection, and analyte cleanup were essential for GC properties. Histamine retention time was 8.2 min. The method allowed peak height to be used for quantitation and simultaneous analysis of cadaverine and putrescine. PMID:12166956

  6. FACTORS RELATING TO THE RELEASE OF STACHYBOTRYS CHARTARUM SPORES FROM CONTAMINATED SOURCES

    EPA Science Inventory

    The paper describes preliminary results of a research project to determine the factors that control the release of S. chartarum spores from a contaminated source and test ways to reduce spore release and thus exposure. As anticipated, S. chartarum spore emissions from gypsum boar...

  7. Short-term desensitization of the histamine H1 receptor in human HeLa cells: involvement of protein kinase C dependent and independent pathways.

    PubMed Central

    Smit, M. J.; Bloemers, S. M.; Leurs, R.; Tertoolen, L. G.; Bast, A.; de Laat, S. W.; Timmerman, H.

    1992-01-01

    1. In this study we have investigated the effects of short-term exposure of cells to histamine on the subsequent H1 receptor responsiveness in HeLa cells, using Ca2+ fluorescence microscopy and video digital imaging. 2. In HeLa cells, histamine (100 microM) induces an immediate H1 receptor-mediated biphasic elevation of the intracellular Ca2+ concentration ([Ca2+]i) (basal [Ca2+]i: 81 +/- 30 nM, histamine-induced Ca2+ response: first phase: 1135 +/- 79 nM; second phase: 601 +/- 52 nM, n = 11). 3. The histamine H1 receptors on HeLa cells are readily susceptible to desensitization since repetitive exposure of the same group of cells to histamine (100 microM) markedly affected the release and influx component of the induced Ca2+ response (second application of histamine: first phase: 590 +/- 92 nM, second phase: 279 +/- 47 nM; third application of histamine: first phase: 454 +/- 127 nM, second phase: 240 +/- 45 nM, n = 6). Video digital imaging revealed an increase in the lag time between stimulation and monitoring of the Ca2+ response and a reduced increase in [Ca2+]i after desensitization with histamine. 4. Neither the release component of the ATP response (50 microM) nor the caffeine (3 mM)-induced Ca2+ release were found to be affected by desensitization with 100 microM histamine. However, the second phase of the ATP response was significantly reduced after desensitization with histamine (control cells: 516 +/- 33 nM; desensitized cells: 331 +/- 96 nM, n = 4, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 2 PMID:1422591

  8. Effects of cocaine and corticotropin-releasing factor on pulsatile ACTH and cortisol release in ovariectomized rhesus monkeys.

    PubMed

    Sarnyai, Z; Mello, N K; Mendelson, J H; Nguyen, P H; Erös-Sarnyai, M

    1995-09-01

    Cocaine stimulates ACTH secretion by a corticotropin-releasing factor (CRF)-dependent mechanism in male rats, rhesus monkeys, and humans. To determine the generality of this effect, we examined the effects of acute cocaine administration on the pulsatile release of ACTH and cortisol in three ovariectomized (OVX) rhesus monkeys and compared its effects to stimulation with CRF. Venous blood samples were collected at 2-min intervals for 60 min before and after iv administration of cocaine (0.4 and 0.8 mg/kg) and CRF (1.0 and 10 micrograms/kg). Cluster analysis procedures were used to evaluate the pulsatile characteristics of ACTH and cortisol release. After placebo administration, an ACTH pulse frequency of 3 peaks/h was detected. After cocaine administration, plasma cocaine levels peaked at 92 +/- 3.0 and 201 +/- 60 ng/mL within 2 min. However, in contrast to normal intact males, cocaine did not stimulate the pulsatile release of ACTH in OVX females. Cocaine (0.4 mg/kg) decreased ACTH incremental peak height and valley levels compared with pre-cocaine values, and a higher dose of cocaine produced no changes in ACTH release. Bolus injection of a low dose of CRF (1.0 micrograms/kg, iv) significantly increased ACTH incremental peak height (P < 0.05), and a higher dose of CRF (10 micrograms/kg) increased ACTH peak amplitude, percentage increase in peak amplitude, area under the peaks, and incremental peak heights as well as ACTH valley level and nadir (10 micrograms/kg, iv) (P < 0.05). ACTH pulse frequency did not change after CRF or cocaine administration. Pulsatile release of cortisol was 2.7 peaks/h under placebo conditions and did not change after cocaine or CRF administration. Cortisol pulse amplitude was increased after low and high doses of CRF. High doses of CRF (10 micrograms/kg) also increased the mean level of cortisol valleys. In summary, we found that CRF but not cocaine stimulated pulsatile ACTH and cortisol release in OVX rhesus monkeys. The profound ACTH

  9. Controllable mineral coatings on scaffolds as carriers for growth factor release for bone tissue engineering

    NASA Astrophysics Data System (ADS)

    Saurez-Gonzalez, Darilis

    The work presented in this document, focused on the development and characterization of mineral coatings on scaffold materials to serve as templates for growth factor binding and release. Mineral coatings were formed using a biomimetic approach that consisted in the incubation of scaffolds in modified simulated body fluids (mSBF). To modulate the properties of the mineral coating, which we hypothesized would dictate growth factor release, we used carbonate (HCO3) concentration in mSBF of 4.2 mM, 25mM, and 100mM. Analysis of the mineral coatings formed using scanning electron microscopy indicated growth of a continuous layer of mineral with different morphologies. X-ray diffraction analysis showed peaks associated with hydroxyapatite. FTIR data confirmed the substitution of HCO3 in the mineral. As the extent of HCO3 substitution increased, the coating exhibited more rapid dissolution kinetics in an environment deficient in calcium and phosphate. The mineral coatings provided an effective mechanism for bioactive growth factor binding and release. Peptide versions of vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2) were bound with efficiencies up to 90% to mineral-coated PCL scaffolds. Recombinant human vascular endothelial growth factor (rhVEGF) also bound to mineral coated scaffolds with lower efficiency (20%) and released with faster release kinetics compared to peptides growth factor. Released rhVEGF induced human umbilical vein endothelial cell (HUVEC) proliferation in vitro and enhanced blood vessel formation in vivo in an intramuscular sheep model. In addition to the use the mineral coatings for single growth factor release, we expanded the concept and bound both an angiogenic (rhVEGF) and osteogenic (mBMP2) growth factor by a simple double dipping process. Sustained release of both growth factors was demonstrated for over 60 days. Released rhVEGF enhanced blood vessel formation in vivo in sheep and its biological activity was

  10. Corneal organ cultures in tyrosinemia release chemotactic factors.

    PubMed

    Lohr, K M; Hyndiuk, R A; Hatchell, D L; Kurth, C E

    1985-05-01

    Corneal inflammation with subsequent scarring and blindness occurs in the inherited human metabolic disease tyrosinemia type II, yet putative inflammatory mediators in this disorder and in the avascular cornea in general are poorly defined. In a Tyr-fed rat model of tyrosinemia type II, intracellular crystals, presumably Tyr, are hypothesized to be responsible for the increased lysosomal activity observed in corneal epithelial lesions. Because polymorphonuclear leukocytes (PMNs) are seen only at the site of these lesions, we used this model to study humoral mediators released from Tyr-fed rat corneal organ cultures. Only Tyr-fed rats developed stromal edema and linear granular opacities in gray edematous corneal epithelium, compatible with a noninfectious keratitis. Electron micrographs confirmed epithelial edema and showed focal epithelial necrosis with PMN invasion of the stroma. Only Tyr-fed rat corneal culture supernatants contained chemotactic activity that was heat labile and moderately trypsin sensitive. Four peaks with varying amounts of chemotactic activity were found on Sephadex G-75 chromatography. Although the identity of these peaks of activity has not yet been established, we suggest that they may be responsible for the PMN infiltration observed in this model of corneal inflammation.

  11. Cardiovascular histamine receptors in the domestic chicken.

    PubMed

    Chand, N; Eyre, P

    1975-08-01

    The effects of mepyramine (H1-antagonist) and burimamide (H2-antagonist) were studied on histamine, 2-methylhistamine (a selective H1-agonist), 4-methylhistamine (a selective H2-agonist) and acetylcholine-induced changes in systemic arterial and central venous pressure and respiration in anaesthetized chickens. The result of this study suggested a predominance of H1 and some H2 histamine receptors in the cardiovascular system of domestic fowl where both are mediating systemic hypotension. There also appears to be predominance of H1 receptors mediating venous hypertension and respiratory apnoea to large doses of histamine and 2-methylhistamine. In addition, a possible involvement of H2-receptors in the cardiovascular system of chicken is suggested by the finding that burimamide always blocked mepyramine potentiated secondary pressor response to histamine and its analogues.

  12. Mast Cell-Derived Histamine Mediates Cystitis Pain

    PubMed Central

    Rudick, Charles N.; Bryce, Paul J.; Guichelaar, Laura A.; Berry, Ruth E.; Klumpp, David J.

    2008-01-01

    Background Mast cells trigger inflammation that is associated with local pain, but the mechanisms mediating pain are unclear. Interstitial cystitis (IC) is a bladder disease that causes debilitating pelvic pain of unknown origin and without consistent inflammation, but IC symptoms correlate with elevated bladder lamina propria mast cell counts. We hypothesized that mast cells mediate pelvic pain directly and examined pain behavior using a murine model that recapitulates key aspects of IC. Methods and Findings Infection of mice with pseudorabies virus (PRV) induces a neurogenic cystitis associated with lamina propria mast cell accumulation dependent upon tumor necrosis factor alpha (TNF), TNF-mediated bladder barrier dysfunction, and pelvic pain behavior, but the molecular basis for pelvic pain is unknown. In this study, both PRV-induced pelvic pain and bladder pathophysiology were abrogated in mast cell-deficient mice but were restored by reconstitution with wild type bone marrow. Pelvic pain developed normally in TNF- and TNF receptor-deficient mice, while bladder pathophysiology was abrogated. Conversely, genetic or pharmacologic disruption of histamine receptor H1R or H2R attenuated pelvic pain without altering pathophysiology. Conclusions These data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and TNF, respectively. Therefore, pain is independent of pathology and inflammation, and histamine receptors represent direct therapeutic targets for pain in IC and other chronic pain conditions. PMID:18461160

  13. Desipramine Inhibits Histamine H1 Receptor-Induced Ca2+ Signaling in Rat Hypothalamic Cells

    PubMed Central

    Lee, Kwang Min; Cho, Sukhee; Seo, Jinsoo; Hur, Eun-Mi; Park, Chul-Seung; Baik, Ja-Hyun; Choi, Se-Young

    2012-01-01

    The hypothalamus in the brain is the main center for appetite control and integrates signals from adipose tissue and the gastrointestinal tract. Antidepressants are known to modulate the activities of hypothalamic neurons and affect food intake, but the cellular and molecular mechanisms by which antidepressants modulate hypothalamic function remain unclear. Here we have investigated how hypothalamic neurons respond to treatment with antidepressants, including desipramine and sibutramine. In primary cultured rat hypothalamic cells, desipramine markedly suppressed the elevation of intracellular Ca2+ evoked by histamine H1 receptor activation. Desipramine also inhibited the histamine-induced Ca2+ increase and the expression of corticotrophin-releasing hormone in hypothalamic GT1-1 cells. The effect of desipramine was not affected by pretreatment with prazosin or propranolol, excluding catecholamine reuptake activity of desipramine as an underlying mechanism. Sibutramine which is also an antidepressant but decreases food intake, had little effect on the histamine-induced Ca2+ increase or AMP-activated protein kinase activity. Our results reveal that desipramine and sibutramine have different effects on histamine H1 receptor signaling in hypothalamic cells and suggest that distinct regulation of hypothalamic histamine signaling might underlie the differential regulation of food intake between antidepressants. PMID:22563449

  14. Temporally controlled release of multiple growth factors from a self-assembling peptide hydrogel.

    PubMed

    Bruggeman, Kiara F; Rodriguez, Alexandra L; Parish, Clare L; Williams, Richard J; Nisbet, David R

    2016-09-23

    Protein growth factors have demonstrated great potential for tissue repair, but their inherent instability and large size prevents meaningful presentation to biologically protected nervous tissue. Here, we create a nanofibrous network from a self-assembling peptide (SAP) hydrogel to carry and stabilize the growth factors. We significantly reduced growth factor degradation to increase their lifespan by over 40 times. To control the temporal release profile we covalently attached polysaccharide chitosan molecules to the growth factor to increase its interactions with the hydrogel nanofibers and achieved a 4 h delay, demonstrating the potential of this method to provide temporally controlled growth factor delivery. We also describe release rate based analysis to examine the growth factor delivery in more detail than standard cumulative release profiles allow and show that the chitosan attachment method provided a more consistent release profile with a 60% reduction in fluctuations. To prove the potential of this system as a complex growth factor delivery platform we demonstrate for the first time temporally distinct release of multiple growth factors from a single tissue specific SAP hydrogel: a significant goal in regenerative medicine. PMID:27517970

  15. Temporally controlled release of multiple growth factors from a self-assembling peptide hydrogel

    NASA Astrophysics Data System (ADS)

    Bruggeman, Kiara F.; Rodriguez, Alexandra L.; Parish, Clare L.; Williams, Richard J.; Nisbet, David R.

    2016-09-01

    Protein growth factors have demonstrated great potential for tissue repair, but their inherent instability and large size prevents meaningful presentation to biologically protected nervous tissue. Here, we create a nanofibrous network from a self-assembling peptide (SAP) hydrogel to carry and stabilize the growth factors. We significantly reduced growth factor degradation to increase their lifespan by over 40 times. To control the temporal release profile we covalently attached polysaccharide chitosan molecules to the growth factor to increase its interactions with the hydrogel nanofibers and achieved a 4 h delay, demonstrating the potential of this method to provide temporally controlled growth factor delivery. We also describe release rate based analysis to examine the growth factor delivery in more detail than standard cumulative release profiles allow and show that the chitosan attachment method provided a more consistent release profile with a 60% reduction in fluctuations. To prove the potential of this system as a complex growth factor delivery platform we demonstrate for the first time temporally distinct release of multiple growth factors from a single tissue specific SAP hydrogel: a significant goal in regenerative medicine.

  16. Effect of Cellulose Acetate Beads on the Release of Transforming Growth Factor-β.

    PubMed

    Nishise, Shoichi; Abe, Yasuhiko; Nomura, Eiki; Sato, Takeshi; Sasaki, Yu; Iwano, Daisuke; Yagi, Makoto; Sakuta, Kazuhiro; Shibuya, Rika; Mizumoto, Naoko; Kanno, Nana; Ueno, Yoshiyuki

    2015-08-01

    Transforming growth factor-β (TGF-β) is released by activated platelets and induces the differentiation of T-helper 17 from naïve T cells. Contact between blood and cellulose acetate (CA) beads induces cytokine release, although their inflammatory effects on TGF-β release are unclear. We aimed to clarify the effect of CA beads on the release of TGF-β in vitro. We incubated peripheral blood with and without CA beads and measured platelets and TGF-β. Compared with blood samples incubated without beads, the platelet count and amount of TGF-β significantly decreased in blood samples incubated with CA beads. In conclusion, CA beads inhibited the release of TGF-β from adsorbed platelets. The biological effects of this reduction of TGF-β release during platelet adsorption to CA beads need further clarification.

  17. Nitric Oxide and Histamine Signal Attempts to Swallow: A Component of Learning that Food Is Inedible in "Aplysia"

    ERIC Educational Resources Information Center

    Katzoff, Ayelet; Miller, Nimrod; Susswein, Abraham J.

    2010-01-01

    Memory that food is inedible in "Aplysia" arises from training requiring three contingent events. Nitric oxide (NO) and histamine are released by a neuron responding to one of these events, attempts to swallow food. Since NO release during training is necessary for subsequent memory and NO substitutes for attempts to swallow, it was suggested that…

  18. Prenatal stress enhances stress- and corticotropin-releasing factor-induced stimulation of hippocampal acetylcholine release in adult rats.

    PubMed

    Day, J C; Koehl, M; Deroche, V; Le Moal, M; Maccari, S

    1998-03-01

    There is growing evidence that stressors occurring during pregnancy can impair biological and behavioral responses to stress in the adult offspring. For instance, prenatal stress enhances emotional reactivity, anxiety, and depressive-like behaviors associated with a prolonged stress-induced corticosterone secretion and a reduction in hippocampal corticosteroid receptors. Among the neurotransmitters involved in these hormonal and behavioral responses, acetylcholine may play a critical role. However, it is unknown whether prenatal stressful events also may influence the development of cholinergic systems. In the present study, hippocampal acetylcholine was measured, by in vivo microdialysis, in both male and female adult prenatally stressed rats, under basal conditions, after a mild stress (saline injection) or after intracerebroventricular administration of corticotropin-releasing factor (CRF; 0.1 nM). No difference in basal release of acetylcholine was observed between control and prenatally stressed rats of both genders. Mild stress was found to increase hippocampal acetylcholine release to a greater extent in prenatally stressed rats than in controls. In males, the CRF-induced increase in hippocampal acetylcholine release was larger in prenatally stressed rats, as compared with controls, during the first hour after the injection and in females during the third hour after the injection. These data indicate that prenatal stress has long-term effects on the development of forebrain cholinergic systems. The augmented increase in hippocampal acetylcholine release after the mild stress and CRF injection in prenatally stressed rats may be involved in some of the hormonal and behavioral abnormalities found in prenatally stressed rats. PMID:9465013

  19. Circadian variation of brain histamine in goldfish.

    PubMed

    Burns, Tiffany A; Huston, Joseph P; Spieler, Richard E

    2003-01-15

    Teleosts may make an excellent model to study brain histamine function. Fishes are phylogenetically closer to the basic vertebrate blueprint than higher vertebrates. They appear to have a simpler histaminergic system in terms of central nervous system distribution and, contrary to higher vertebrates, brain histamine appears to be strictly neuronal. In this preliminary study, we examined circadian variation of brain histamine in goldfish, Carassius auratus, as this neurotransmitter correlates with circadian behavior of some mammals. Two groups of juvenile goldfish were held in 24 60L aquaria, six fish per aquarium, on reversed photoperiods; L:D 12:12 with light onset either at 0700 or 1900h. Fish were sampled every 4h. At a sampling time, all the fish in a tank were taken; each sampling, for both groups, was done in replicate. Brain histamine was determined by immunoassay. There was a significant circadian variation in histamine on both photoperiod regimes with the highest levels during the photophase. These results support the hypothesis of an early phylogenic role for histamine in vertebrate circadian physiology.

  20. Histamine H3 receptors--general characterization and their function in the cardiovascular system.

    PubMed

    Malinowska, B; Godlewski, G; Schlicker, E

    1998-06-01

    The histamine H3 receptor was initially identified as a presynaptic autoreceptor controlling histamine release and synthesis in the brain. It belongs to the superfamily of G protein-coupled receptors. The existence of the H3 receptor which has not yet been cloned was definitely established by the design of highly potent and selective agonists (R-(-)-alpha-methylhistamine, imetit) and antagonists (thioperamide, clobenpropit). These receptors also occur as heteroreceptors both in the central nervous system and on peripheral neurons of the gastrointestinal and bronchial tract, where they regulate the release of a variety of neurotransmitters. In the cardiovascular system, histamine H3 receptors are mainly located presynaptically on the postganglionic sympathetic nerve fibers innervating the blood vessels and the heart. Their activation leads to the inhibition of noradrenaline release and consequently to the reduction of the neurogenic vasopressor and cardiostimulatory responses. The presence of such receptors has been shown both in vitro (human, pig, guinea-pig, rabbit, rat isolated tissues) and in vivo (rat, guinea-pig). The vascular and cardiac presynaptic H3 receptors may be activated by endogenous histamine. The vascular H3 receptors appear to be operative in hypertension and interact with presynaptic alpha 2-adrenoceptors. Postsynaptic vasodilatatory H3 receptors have been detected in several vascular beds as well. H3 receptor ligands affect basal cardiovascular parameters in conscious and anesthetized guinea-pigs but not rats. Presynaptic H3 receptors may play a role in the pathophysiology of headache and cardiac ischemia.

  1. Scaffolds for Controlled Release of Cartilage Growth Factors.

    PubMed

    Morille, Marie; Venier-Julienne, Marie-Claire; Montero-Menei, Claudia N

    2015-01-01

    In recent years, cell-based therapies using adult stem cells have attracted considerable interest in regenerative medicine. A tissue-engineered construct for cartilage repair should provide a support for the cell and allow sustained in situ delivery of bioactive factors capable of inducing cell differentiation into chondrocytes. Pharmacologically active microcarriers (PAMs), made of biodegradable and biocompatible poly (D,L-lactide-co-glycolide acid) (PLGA), are a unique system which combines these properties in an adaptable and simple microdevice. This device relies on nanoprecipitation of proteins encapsulated in polymeric microspheres with a solid in oil in water emulsion-solvent evaporation process, and their subsequent coating with extracellular matrix protein molecules. Here, we describe their preparation process, and some of their characterization methods for an application in cartilage tissue engineering. PMID:26445838

  2. Influence of the hippocampus on amino acid utilizing and cholinergic neurons within the nucleus accumbens is promoted by histamine via H1 receptors

    PubMed Central

    Kraus, M M; Prast, H; Philippu, A

    2013-01-01

    Background and Purpose The influence of the neurotransmitter histamine on spontaneous and stimulation-evoked release of glutamate, aspartate, GABA and ACh in the nucleus accumbens (NAc) was investigated in vivo. Experimental Approach Using the push–pull superfusion technique, histaminergic compounds were applied to the NAc and neurotransmitter release was assessed. In some experiments, the fornix/fimbria of the hippocampus was electrically stimulated by a microelectrode and evoked potentials were monitored in the NAc. Key Results Superfusion of the NAc with the H1 receptor antagonist triprolidine (50 μM) decreased spontaneous outflow of glutamate, aspartate and ACh, while release of GABA remained unaffected. Superfusion with histamine elevated release of ACh, without influencing that of the amino acids. Electrical stimulation of the fornix/fimbria enhanced the output of amino acids and ACh within the NAc. The evoked outflow of glutamate and ACh was diminished on superfusion with triprolidine, while release of aspartate and GABA was not affected. Superfusion of the NAc with histamine intensified the stimulation-evoked release of glutamate and Ach. Histamine also elevated the stimulation-induced release of aspartate, without influencing that of GABA. Presuperfusion with triprolidine abolished the reinforced effect of histamine on stimulation-evoked transmitter release within the NAc. Conclusion and Implications Neuronal histamine activates H1 receptors and increases spontaneous release of glutamate, aspartate and ACh within the NAc. Stimulation of the hippocampal fornix/fimbria tract also enhances release of glutamate and ACh within the NAc and this effect is intensified by H1 receptor stimulation within the NAc. The latter effects, which are mediated by hippocampal afferences, might play an important role in mnemonic performance and in emotional processes such as anxiety and stress disorders. Linked Articles This article is part of a themed issue on Histamine

  3. Polymethylmethacrylate-induced release of bone-resorbing factors

    SciTech Connect

    Herman, J.H.; Sowder, W.G.; Anderson, D.; Appel, A.M.; Hopson, C.N. )

    1989-12-01

    A pseudomembranous structure that has the histological characteristics of a foreign-body-like reaction invariably develops at the bone-cement interface in the proximity of resorption of bone around aseptically loosened cemented prostheses. This study was an attempt to implicate polymethylmethacrylate in this resorptive process. Unfractionated peripheral-blood mononuclear cells (consisting of lymphocytes and monocytes) and surface-adherent cells (monocyte-enriched) were prepared from control subjects who did and did not have clinical evidence of osteoarthrosis and from patients who had osteoarthrosis and were having a revision for failure of a cemented hip or knee implant. Cells were cultured for varying periods in the presence and absence of nonpolymerized methacrylate (one to two-micrometer spherules), pulverized polymerized material, or culture chambers that were pre-coated with polymerized cement. Conditioned media that were derived from both methacrylate-stimulated cell populations were shown to contain specific bone-resorbing mediators (interleukin-1, tumor necrosis factor, or prostaglandin E2) and to directly affect bone resorption in 45Ca-labeled murine limb-bone assays.

  4. Characterization of release of basic fibroblast growth factor from bovine retinal endothelial cells in monolayer cultures.

    PubMed Central

    Brooks, R A; Burrin, J M; Kohner, E M

    1991-01-01

    Release of basic fibroblast growth factor (bFGF) was investigated in bovine retinal endothelial cells (BREC) maintained in monolayer culture. Confluent cells released bFGF into serum-free culture medium or medium containing 5% serum at rates of up to 105.2 and 61.3 pM/day respectively. bFGF release coincided with a decrease in monolayer cell number and increases in lactate dehydrogenase (LDH) concentration and cells and cell-debris particles in the medium, which suggested that cell damage and lysis were responsible for growth-factor release. Maximum bFGF release at 24 h (230 +/- 10 pM) occurred when the cells were treated with lipopolysaccharide (10 micrograms/ml), which also produced the greatest changes in parameters of cell damage. Sub-confluent cells showed little overt damage at 24 h, but released bFGF (78 +/- 20 pM) along with LDH, indicating that some cell lysis had occurred. Insulin-like growth factor 1 (IGF-1) was also released into serum-free culture medium at a rate of 0.34 nM/day, but not into medium containing serum or when the cells were treated with lipopolysaccharide. This implies that the mechanism of IGF-1 release is different from that of bFGF and is not related to cell damage. Culture medium conditioned by BREC stimulated the proliferation of these cells, as measured by an increase in their incorporation of [methyl-3H]thymidine from 7550 +/- 479 to 10467 +/- 924 d.p.m. These results demonstrate that bFGF is released from damaged BREC and that medium conditioned by these cells can stimulate retinal-endothelial-cell proliferation. This strengthens the case for an involvement of this growth factor in retinal neovascularization. Images Fig. 1. PMID:2039465

  5. Protective effect of histamine microinjected into the cerebellar fastigial nucleus on stress-induced gastric mucosal damage in rats

    PubMed Central

    Qiao, Xiao; Tang, Xiaolong; Zhang, Jianfu; Chen, Ke; Zhang, Yanming; Wang, Changcheng; Fei, Sujuan; Zhu, Jinzhou; Zhu, Shengping; Liu, Zhangbo; Li, Tingting; Lv, Shengxiang; Liang, Yong

    2015-01-01

    Aims: We investigated the effffects and the possible mechanism of microinjection of histamine into cerebellar fastigial nucleus (FN) on stress-induced gastric mucosal damage (SGMD) in rats. The effect of microinjection of histamine into FN on SGMD was observed. Methods: The model of SGMD was established by restraint and water (21 ± 1°C)-immersion (RWI) for 3 h in rats. The gastric mucosal damage index indicated the severity of SGMD. Western blotting was performed to assess gastric mucosal cell apoptosis and proliferation. Results: We observed that histamine microinjection into the FN markedly attenuated SGMD in a dose-dependent manner, and was prevented by pre-treatment with the ranitidine (a selective histamine H2 receptor antagonist) into the FN. The effect of histamine was abolished by pre-treatment with 3-MPA (a glutamic acid decarboxylase antagonist) into the FN. There was a decrease in the discharge frequency of greater splanchnic nerve, and an increase in gastric mucosal blood flow after histamine injection into the FN. Additionally, anti-apoptotic and anti-oxidative factors of gastric mucosa might be involved in this process. Conclusion: The exogenous histamine in FN participates in the regulation of SGMD, and our results may help to provide new ideas on the treatment of gastroenterological diseases. PMID:26550464

  6. Psycho-Social Factors as Predictors of Success in a Work-Release Program.

    ERIC Educational Resources Information Center

    Brahen, Leonard S.; And Others

    1979-01-01

    Investigates the significance of social and environmental factors as predictors of the rehabilitative potential of an inmate. Work history must be used as a whole. The more recent a good history, the more successful an inmate's jail record. Work factors may aid in selecting narcotics-addicted inmates for work-release programs. (Author/BEF)

  7. Histamine and Immune Biomarkers in CNS Disorders

    PubMed Central

    Cacabelos, Ramón; Torrellas, Clara; Fernández-Novoa, Lucía; López-Muñoz, Francisco

    2016-01-01

    Neuroimmune dysregulation is a common phenomenon in different forms of central nervous system (CNS) disorders. Cross-links between central and peripheral immune mechanisms appear to be disrupted as reflected by a series of immune markers (CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56) which show variability in brain disorders such as anxiety, depression, psychosis, stroke, Alzheimer's disease, Parkinson's disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation, and posttraumatic brain injury. Histamine (HA) is a pleiotropic monoamine involved in several neurophysiological functions, neuroimmune regulation, and CNS pathogenesis. Changes in brain HA show an age- and sex-related pattern, and alterations in brain HA levels are present in different CNS regions of patients with Alzheimer's disease (AD). Brain HA in neuronal and nonneuronal compartments plays a dual role (neurotrophic versus neurotoxic) in a tissue-specific manner. Pathogenic mechanisms associated with neuroimmune dysregulation in AD involve HA, interleukin-1β, and TNF-α, whose aberrant expression contributes to neuroinflammation as an aggravating factor for neurodegeneration and premature neuronal death. PMID:27190492

  8. Time-dependent release of growth factors from implant surfaces treated with plasma rich in growth factors.

    PubMed

    Sánchez-Ilárduya, María Belén; Trouche, Elodie; Tejero, Ricardo; Orive, Gorka; Reviakine, Ilya; Anitua, Eduardo

    2013-05-01

    Plasma rich in growth factors (PRGFs) technology is an autologous platelet-rich plasma approach that provides a pool of growth factors and cytokines that have been shown to increase tissue regeneration and accelerate dental implant osseointegration. In this framework, the spatiotemporal release of growth factors and the establishment of a provisional fibrin matrix are likely to be key aspects governing the stimulation of the early phases of tissue regeneration around implants. We investigated the kinetics of growth factor release at implant surfaces functionalized either with PRGFs or platelet-poor plasma and correlated the results obtained with the morphology of the resulting interfaces. Our main finding is that activation and clot formation favors longer residence times of the growth factors at the interfaces studied, probably due to their retention in the adsorbed fibrin matrix. The concentration of the platelet-derived growth factors above the interfaces becomes negligible after 2-4 days and is significantly higher in the case of activated interfaces than in the case of nonactivated ones, whereas that of the plasmatic hepatocyte growth factor is independent of platelet concentration and activation, and remains significant for up to 9 days. Platelet-rich plasma preparations should be activated to permit growth factor release and thereby facilitate implant surface osseointegration.

  9. Controllable mineral coatings on PCL scaffolds as carriers for growth factor release

    PubMed Central

    Suárez-González, Darilis; Barnhart, Kara; Migneco, Francesco; Flanagan, Colleen; Hollister, Scott J.; Murphy, William L.

    2011-01-01

    In this study, we have developed mineral coatings on polycaprolactone scaffolds to serve as templates for growth factor binding and release. Mineral coatings were formed using a biomimetic approach that consisted in the incubation of scaffolds in modified simulated body fluids (mSBF). To modulate the properties of the mineral coating, which we hypothesized would dictate growth factor release, we used carbonate (HCO3) concentration in mSBF of 4.2 mM, 25mM, and 100mM. Analysis of the mineral coatings formed using scanning electron microscopy indicated growth of a continuous layer of mineral with different morphologies. X-ray diffraction analysis showed peaks associated with hydroxyapatite, the major inorganic constituent of human bone tissue in coatings formed in all HCO3 concentrations. Mineral coatings with increased HCO3 substitution showed more rapid dissolution kinetics in an environment deficient in calcium and phosphate but showed re-precipitation in an environment with the aforementioned ions. The mineral coating provided an effective mechanism for growth factor binding and release. Peptide versions of vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2) were bound with efficiencies up to 90% to mineral mineral-coated PCL scaffolds. We also demonstrated sustained release of all growth factors with release kinetics that were strongly dependent in the solubility of the mineral coating. PMID:22014948

  10. Histamine-1 receptor blockade does not prevent nitroglycerin induced migraine. Support for the NO-hypothesis of migraine.

    PubMed

    Lassen, L H; Thomsen, L L; Kruuse, C; Iversen, H K; Olesen, J

    1996-01-01

    It has previously been shown that in migraine sufferers infusion of glyceryl trinitrate (GTN) and histamine causes an immediate headache during the infusion and a genuine migraine attack one to several hours after the infusion. This identical time profile indicates a common mechanism of action. To evaluate whether GTN causes headache via liberation of histamine, we studied the effect of GTN 0.5 micrograms.kg-1.min-1 for 20 min in seven migraine sufferers, once after pretreatment with the histamine-1 (H1)-receptor blocker mepyramine (0.5 mg.kg-1) and once without pretreatment. This mepyramine dose is known to completely abolish histamine-induced headache. After pretreatment with mepyramine five patients experienced migraine, and without pretreatment six patients did so. The median peak headache score was 7 on a 0-10 scale with and without mepyramine pretreatment. The arterial responses, evaluated with transcranial Doppler, were also unaffected by the mepyramine pretreatment. Our results demonstrate that neither headache nor arterial dilatation due to GTN infusion is caused by histamine release. In all likelihood the common mediator of migraine induction by GTN and histamine is nitric oxide.

  11. Biological activity of recombinant human growth factors released from biocompatible bone implants.

    PubMed

    Ziegler, Joerg; Anger, Dominique; Krummenauer, Frank; Breitig, Dieter; Fickert, Stefan; Guenther, Klaus-Peter

    2008-07-01

    The present investigation was performed to study the bioactivity of osteoinductive and osteoproliferative growth factors after release from biocompatible bone implants. Three types of porous carriers were used in this study: hydroxyapatite, alpha tricalcium phosphate, and a neutralized glass ceramic. Implants were loaded with recombinant human bone morphogenetic protein 2 (rh-BMP-2) and recombinant human basic fibroblast growth factor (rh-bFGF) in a concentration of 2 microg/150 microL PBS each. The released growth factors were then applicated into SAOS-2-cell cultures. After 3, 5, and 7 days cell differentiation was measured by the activity of alkaline phosphatase (ALP), cell proliferation by using a MTT assay as well as a cell counter. Rh-BMP-2 released during the first hour from the scaffolds led to a significant increase of the activity of ALP in the incubated SAOS-2-cell culture after 3, 5, and 7 days. However, the incubation with rh-BMP-2 released after 24 h was not found to increase the expression of ALP. The incubation of cell cultures with rh-bFGF released during the first hour led to a significant increase of cell number and of extinction in the MTT assay, whereas this increase was not observed after incubation with rh-bFGF released after 24 h. The in vitro measured biological activity of released growth factors from the surface of synthetic implants is time-depending. If prolonged osteoinductive and osteoproliferative potency of growth factors is desired, a modified application technique should be chosen to stabilize those proteins.

  12. Histamine from Brain Resident MAST Cells Promotes Wakefulness and Modulates Behavioral States

    PubMed Central

    Chikahisa, Sachiko; Kodama, Tohru; Soya, Atsushi; Sagawa, Yohei; Ishimaru, Yuji; Séi, Hiroyoshi; Nishino, Seiji

    2013-01-01

    Mast cell activation and degranulation can result in the release of various chemical mediators, such as histamine and cytokines, which significantly affect sleep. Mast cells also exist in the central nervous system (CNS). Since up to 50% of histamine contents in the brain are from brain mast cells, mediators from brain mast cells may significantly influence sleep and other behaviors. In this study, we examined potential involvement of brain mast cells in sleep/wake regulations, focusing especially on the histaminergic system, using mast cell deficient (W/Wv) mice. No significant difference was found in the basal amount of sleep/wake between W/Wv mice and their wild-type littermates (WT), although W/Wv mice showed increased EEG delta power and attenuated rebound response after sleep deprivation. Intracerebroventricular injection of compound 48/80, a histamine releaser from mast cells, significantly increased histamine levels in the ventricular region and enhanced wakefulness in WT mice, while it had no effect in W/Wv mice. Injection of H1 antagonists (triprolidine and mepyramine) significantly increased the amounts of slow-wave sleep in WT mice, but not in W/Wv mice. Most strikingly, the food-seeking behavior observed in WT mice during food deprivation was completely abolished in W/Wv mice. W/Wv mice also exhibited higher anxiety and depression levels compared to WT mice. Our findings suggest that histamine released from brain mast cells is wake-promoting, and emphasizes the physiological and pharmacological importance of brain mast cells in the regulation of sleep and fundamental neurobehavior. PMID:24205232

  13. Histamine from brain resident MAST cells promotes wakefulness and modulates behavioral states.

    PubMed

    Chikahisa, Sachiko; Kodama, Tohru; Soya, Atsushi; Sagawa, Yohei; Ishimaru, Yuji; Séi, Hiroyoshi; Nishino, Seiji

    2013-01-01

    Mast cell activation and degranulation can result in the release of various chemical mediators, such as histamine and cytokines, which significantly affect sleep. Mast cells also exist in the central nervous system (CNS). Since up to 50% of histamine contents in the brain are from brain mast cells, mediators from brain mast cells may significantly influence sleep and other behaviors. In this study, we examined potential involvement of brain mast cells in sleep/wake regulations, focusing especially on the histaminergic system, using mast cell deficient (W/W(v)) mice. No significant difference was found in the basal amount of sleep/wake between W/W(v) mice and their wild-type littermates (WT), although W/W(v) mice showed increased EEG delta power and attenuated rebound response after sleep deprivation. Intracerebroventricular injection of compound 48/80, a histamine releaser from mast cells, significantly increased histamine levels in the ventricular region and enhanced wakefulness in WT mice, while it had no effect in W/W(v) mice. Injection of H1 antagonists (triprolidine and mepyramine) significantly increased the amounts of slow-wave sleep in WT mice, but not in W/W(v) mice. Most strikingly, the food-seeking behavior observed in WT mice during food deprivation was completely abolished in W/W(v) mice. W/W(v) mice also exhibited higher anxiety and depression levels compared to WT mice. Our findings suggest that histamine released from brain mast cells is wake-promoting, and emphasizes the physiological and pharmacological importance of brain mast cells in the regulation of sleep and fundamental neurobehavior.

  14. Hypothalamic hamartoma: a source of luteinizing-hormone-releasing factor in precocious puberty.

    PubMed

    Judge, D M; Kulin, H E; Page, R; Santen, R; Trapukdi, S

    1977-01-01

    The presence of a hypothalamic hamartoma and precocious puberty in a 19-month-old boy provided an opportunity to study their relation. Excised tissue had the ultrastructural characteristics of an independent neuroendocrine unit -- i.e., neurons containing neurosecretory granules and blood vessels with fenestrated endothelium and double basement membranes. Immunofluorescence studies using specific antibody to luteinizing-hormone-releasing factor showed antigenicity to the factor in the hamartoma. The testicular-hypothalamic-pituitary axis was tested. Clomiphene unresponsiveness suggested a lack of maturation of central-nervous-system events characteristic of normal puberty. The negative feedback system between gonad and brain was intact but partially resistant to steroid suppression. These studies suggest that hypothalamic hamartomas may cause precocious puberty by autonomous production and release of luteinizing-hormone-releasing factor into vessels that communicate with the pituitary portal blood system.

  15. Modulation of audiogenic seizures by histamine and adenosine receptors in the inferior colliculus.

    PubMed

    Feng, H J; Faingold, C L

    2000-05-01

    Susceptibility to behaviorally similar audiogenic seizures (AGS) occurs genetically and is inducible during ethanol withdrawal (ETX). Comparisons between AGS mechanisms of genetically epilepsy-prone rats (GEPR-9s) and ethanol-withdrawn rats (ETX-Rs) are yielding information about general pathophysiological mechanisms of epileptogenesis. The inferior colliculus (IC) is the AGS initiation site. Excitatory amino acid (EAA) abnormalities in the IC are implicated in AGS, and histamine and adenosine receptor activation each reduce EAA release and inhibit several seizure types. Previous studies indicate that focal infusion of an adenosine receptor agonist into the IC blocked AGS in GEPR-9s, but the effects of adenosine receptor activation in the IC on AGS in ETX-Rs are unknown. The effects of histamine receptor activation on either form of AGS are also unexamined. The present study evaluated effects of histamine or a nonselective adenosine A(1) agonist, 2-chloroadenosine, on AGS by focal microinjection into the IC. Ethanol dependence and AGS susceptibility were induced in normal rats by intragastric ethanol. Histamine (40 or 60 nmol/side) significantly reduced AGS in GEPR-9s, but histamine in doses up to 120 nmol/side did not affect AGS in ETX-Rs. 2-Chloroadenosine (5 or 10 nmol/side) did not affect AGS in ETX-Rs, despite the effectiveness of lower doses of this agent in GEPR-9s reported previously. Thus, histamine and adenosine receptors in the IC modulate AGS of GEPR-9s, but do not modulate ETX-induced AGS. The reasons for this difference may involve the chronicity of AGS susceptibility in GEPR-9s, which may lead to more extensive neuromodulation as compensatory mechanisms to limit the seizures compared to the acute AGS of ETX-Rs.

  16. Inhibition of guinea-pig lymphocyte activation by histamine and histamine analogues.

    PubMed Central

    Beets, J. L.; Dale, M. M.

    1979-01-01

    1 The incorporation of [3H]-thymidine into guinea-pig lymphocytes stimulated by a plant lectin (concanavalin A), soluble antigen (tuberculin (P.P.D.)) and syngeneic hepatoma cells, was partially inhibited (50%) by histamine in vitro. 2 The effect of histamine on both mitogen and antigen dose-response curves suggests a non-competitive, probably physiological antagonism. 3 The inhibitory dose range of histamine lay between 10 nM and 30 microM with an ID50 of approximately 400 nM. 4 The potency order for histamine analogues for the inhibition of lymphocyte activation was histamine greater than or equal to 4-methylhistamine greater than 2-methylhistamine greater than 3-methylhistamine. This is in accord with the mediation of the response through an H2-receptor. 5 H2-receptor antagonists reversed the inhibitory effect of histamine in a dose-related manner, but both metiamide and burimamide, in high concentrations, augmented lymphocyte activation in their own right. This precluded the determination of affinity constants and made it impossible to state with certainty that the inhibition of lymphocyte activation by histamine was mediated by an H2-receptor. PMID:526705

  17. Control of Histamine-Producing Bacteria and Histamine Formation in Fish Muscle by Trisodium Phosphate.

    PubMed

    Bjornsdottir-Butler, Kristin; Green, David P; Bolton, Greg E; McClellan-Green, Patricia D

    2015-06-01

    Scombrotoxin fish poisoning remains the primary cause of seafood poisoning outbreaks despite preventive guidelines. The purpose of this study was to investigate the use of pH for the control of growth and histamine formation by histamine-producing bacteria in fish muscle. We examined pH effects on growth and histamine formation in tuna fish infusion broth and in inoculated tuna and mahi-mahi fish muscle. Histamine production was significantly less for all bacterial strains at pH 8.5 compared to pH 5.5 in tuna fish infusion broth with no significant difference in growth. Elevated pH due to phosphate treatment of fish muscle tissues significantly reduced histamine formation with no effect on the growth of histamine-producing bacteria. This study revealed that phosphate treatment of mahi-mahi and tuna fish muscle resulted in significantly lower histamine production over 4 d of storage at 10 °C. Phosphate treatment of fish muscle may serve as a secondary barrier in addition to FDA recommended time and temperature controls for reducing public health concerns of scombrotoxin fish poisoning.

  18. Insulin antagonizes the phagocytosis stimulating action of histamine in Tetrahymena.

    PubMed

    Csaba, G; Darvas, Z

    1992-02-01

    Histamine increased specifically the phagocytic activity of the unicellular Tetrahymena, whereas insulin had no influence on it. Insulin antagonized the phagocytosis stimulating action of histamine after simultaneous exposure and after preexposure two days earlier as well, although in the latter case to a lesser degree. Double exposure to a combination of histamine+insulin didn't influence the phagocytic activity at all, demonstrating the histamine antagonizing effect of insulin in this model.

  19. The expression of non-mast histamine in tumor associated microvessels in human colorectal cancers.

    PubMed

    Cui, Jing; Xu, Gang; Liu, Jinzhong; Pang, Zhigang; Florholmen, Jon; Cui, Guanglin

    2013-04-01

    Angiogenesis is essential for the growth, expansion and metastasis of human colorectal cancers (CRCs). Histamine produced by mast cells is a potent proangiogenic factor. However, the significance of non-mast cell expressing histamine in the tumor microenvironment remains unknown. In this study, we evaluated the histamine positive microvessels with the specific marker for biosynthesis of histamine L-histidine decarboxylase (HDC) in the CRC tumor microenvironment. The relationship between HDC positive microvessel density (HDC-MVD) and clinical pathological parameters was assessed. The results revealed that HDC-MVD in the tumor microenvironment of CRCs was significantly increased as compared with the controls. CRC patients with lymph node invasion had a particularly higher density of HDC-MVD than those without. The density of HDC-MVD accounted for ~79 % of CD34 positive MVD in CRCs and double IHC analysis demonstrated that these HDC positive microvessels were mostly CD34 positive microvessels and with a high proliferative activity. Our results suggest that histamine expressed in microvessels could be an additional cellular source and involved in the cancer invasion through promoting angiogenesis in human CRCs.

  20. New insights into the role of histamine in subventricular zone-olfactory bulb neurogenesis

    PubMed Central

    Eiriz, Maria F.; Valero, Jorge; Malva, João O.; Bernardino, Liliana

    2014-01-01

    The subventricular zone (SVZ) contains neural stem cells (NSCs) that generate new neurons throughout life. Many brain diseases stimulate NSCs proliferation, neuronal differentiation and homing of these newborns cells into damaged regions. However, complete cell replacement has never been fully achieved. Hence, the identification of proneurogenic factors crucial for stem cell-based therapies will have an impact in brain repair. Histamine, a neurotransmitter and immune mediator, has been recently described to modulate proliferation and commitment of NSCs. Histamine levels are increased in the brain parenchyma and at the cerebrospinal fluid (CSF) upon inflammation and brain injury, thus being able to modulate neurogenesis. Herein, we add new data showing that in vivo administration of histamine in the lateral ventricles has a potent proneurogenic effect, increasing the production of new neuroblasts in the SVZ that ultimately reach the olfactory bulb (OB). This report emphasizes the multidimensional effects of histamine in the modulation of NSCs dynamics and sheds light into the promising therapeutic role of histamine for brain regenerative medicine. PMID:24982610

  1. Influences of key factors on manganese release from soil of a reservoir shore.

    PubMed

    Chen, Lei; Zheng, Xilai; Wang, Tiejun; Zhang, Junjie

    2015-08-01

    In the summertime, the manganese pollution in moderately deep lakes and reservoirs caused by thermal stratification processes has been a serious problem. To mitigate the issue, understanding the key factors that control manganese releases from reservoir soils is a critical step. To this end, batch experiments and the response surface methodology (RSM) analysis were conducted in this study to investigate the release of Mn(diss) and Mn(III) (0.45 μm filterable) from soil samples collected along a reservoir shore under different combined effects of pH, dissolved oxygen (DO), temperature, and dissolved organic carbon (DOC). According to the three-dimensional (3-D) response surfaces plotted from the mathematical model, the highest concentrations of Mn(diss) and Mn(III) released from the studied soils were achieved when the release process was carried out at 30.0 °C using a citric acid solution (10.8 mg/L) of pH 6.0 with the DO concentration of 0.0 mg/L. It was found that pH was the most significant factor affecting the release of Mn(diss) and Mn(III) among the four factors. The combined effect of pH and DOC was also very significant to stimulate Mn(III) releases. In addition, both Mn(diss) and Mn(III) followed the same release principle under the coupled effects of the four factors. A close agreement between experimental and predicted values from the developed models was found.

  2. Sustained postexercise vasodilatation and histamine receptor activation following small muscle-mass exercise in humans.

    PubMed

    Barrett-O'Keefe, Zachary; Kaplon, Rachelle E; Halliwill, John R

    2013-01-01

    A sustained postexercise vasodilatation, which is histamine receptor mediated, has been observed following single bouts of whole-body exercise, but the mechanisms that regulate activation of histamine receptors following exercise are undefined. Exploration of vasodilatation after small muscle-mass dynamic or resistance exercise could provide novel insight into the pathways responsible for histamine receptor activation. We hypothesized that there would be a vasodilatation of the previously exercised limb following small muscle-mass dynamic and resistance exercise, which would be mediated by histamine receptors. We studied men and women before and after single-leg dynamic (n = 9) or resistance knee-extension exercise (n = 12) on control and blockade days (combined oral H(1) and H(2) receptor antagonism with fexofenadine and ranitidine). We measured arterial blood pressure (automated brachial oscillometry) and femoral artery blood flow (Doppler ultrasound). Dynamic exercise elevated leg vascular conductance in the active leg by 27.2 ± 8.4% at 60 min postexercise (P < 0.05 versus pre-exercise), but did not alter conductance in the rested leg (change, 4.6 ± 3.5%; P = 0.8 versus pre-exercise). The rise in conductance was abolished on the blockade day (change, 3.7 ± 5.1%; P = 0.8 versus pre-exercise, P = 0.2 versus control). Resistance exercise did not produce a sustained vasodilatation (change, -4.3 ± 4.7% at 60 min postexercise; P = 0.7 versus pre-exercise). These data indicate that histamine receptors are activated following dynamic, but not resistance, exercise. Furthermore, these data suggest that local factors associated with aerobic exercise, and not systemic factors or factors associated with high muscle force, are responsible for activation of histamine receptors in the previously exercised muscle.

  3. Somatostatin and macrophage function: modulation of hydrogen peroxide, nitric oxide and tumor necrosis factor release.

    PubMed

    Chao, T C; Cheng, H P; Walter, R J

    1995-07-21

    Recent studies have shown that somatostatin modulates lymphocyte function, but the effects of somatostatin on macrophage function are not clearly defined. In the present study, peritoneal macrophages (Mluminal diameter) obtained from male rats were treated in vitro with somatostatin or octreotide and their effects on the release of hydrogen peroxide (H2O2), nitrite, and tumor necrosis factor (TNF) determined. Macrophages treated with somatostatin (10(-9) M to 10(-7) M) or octreotide (10(-8) M and 10(-7) M) released significantly greater amounts of PMA-stimulated H2O2 than did the untreated controls. In addition, 10(-9) M of somatostatin significantly enhanced PMA-stimulated H2O2 release by LPS-treated Mluminal diameter. Octreotide had no effect on H2O2 release by LPS-treated Mluminal diameter. At concentrations of 10(-14) M, 10(-13) M, or greater than 10(-8) M, somatostatin or octreotide suppressed nitrite release by Mluminal diameter. Somatostatin or octreotide did not affect nitrite release by LPS-treated Mluminal diameter. On the other hand, Mluminal diameter treated with 10(-11) M of somatostatin or octreotide released greater amounts of TNF than did the untreated controls. In contrast, TNF release by Mluminal diameter treated with 10(-9) M to 10(-5) M of somatostatin or 10(-7) M to 10(-5) M of octreotide was less than that of the controls. Anti-TNF antibody (1:1000) caused a reduction in the release of H2O2 and nitrite. These findings demonstrate that somatostatin and octreotide modulate the release of H2O2, nitric oxide, and TNF by Mluminal diameter depending on the concentration of hormones used.

  4. Draft Genome Sequences of Histamine-Producing Morganella psychrotolerans Strains

    PubMed Central

    Leon, Maria Sanchez; Benner, Ronald A.

    2016-01-01

    Histamine-producing bacteria are responsible for scombrotoxin (histamine) fish poisoning, a leading cause of fish poisoning in the United States. We report here the first draft genomes of three histamine-producing Morganella psychrotolerans strains, isolated from tuna and mahi-mahi. PMID:27635011

  5. Draft Genome Sequences of Histamine-Producing Morganella psychrotolerans Strains.

    PubMed

    Bjornsdottir-Butler, Kristin; Leon, Maria Sanchez; Benner, Ronald A

    2016-01-01

    Histamine-producing bacteria are responsible for scombrotoxin (histamine) fish poisoning, a leading cause of fish poisoning in the United States. We report here the first draft genomes of three histamine-producing Morganella psychrotolerans strains, isolated from tuna and mahi-mahi. PMID:27635011

  6. Modulation of colony stimulating factor release and apoptosis in human colon cancer cells by anticancer drugs

    PubMed Central

    Calatayud, S; Warner, T D; Mitchell, J A

    2002-01-01

    Modulation of the immune response against tumour cells is emerging as a valuable approach for cancer treatment. Some experimental studies have shown that secretion of colony stimulating factors by cancer cells reduces their tumorigenicity and increases their immunogenicity probably by promoting the cytolitic and antigen presenting activities of leukocytes. We have observed that human colon cancer cells (HT-29) are able to secrete granulocyte-macrophage-colony stimulating factor, granulocyte-colony stimulating factor and macrophage-colony stimulating factor when stimulated with cytokines (IL-1β and TNF-α). In this study we assessed, for the first time, the effects of several anticancer drugs on colony stimulating factor release or apoptosis in HT-29 cells. Cytokine-induced release of granulocyte-macrophage-colony stimulating factor, granulocyte-colony stimulating factor and macrophage-colony stimulating factor was significantly increased by cisplatin and 6-mercaptopurine. Taxol only increased macrophage-colony stimulating factor release while reduced that of granulocyte-colony stimulating factor. No changes in colony stimulating factor secretion were observed after treatment with methotrexate. Only cisplatin and taxol induced apoptosis in these cells. Secretion of colony stimulating factors by colon cancer cells may contribute to the immune host response against them. Anticancer drugs such as cisplatin and 6-mercaptopurine increase colony stimulating factor secretion by cytokine stimulated cancer cells probably through mechanisms different to those leading to cell apoptosis, an effect that may contribute to their anti-neoplasic action. British Journal of Cancer (2002) 86, 1316–1321. DOI: 10.1038/sj/bjc/6600240 www.bjcancer.com © 2002 Cancer Research UK PMID:11953891

  7. Platelet activating factor induces dopamine release in PC-12 cell line

    SciTech Connect

    Bussolino, F.; Tessari, F.; Turrini, F.; Braquet, P.; Camussi, G.; Prosdocimi, M.; Bosia, A. Institut Henri Beaufour, Le Plessis Robinson )

    1988-10-01

    The ability of platelet activating factor (PAF) to stimulate dopamine release and modify calcium homeostasis in PC-12 cell line was studied. PAF-induced dopamine release is related to its molecular form, with only the R-form steric configuration ((R)PAF), but not its S-form or its 2-lyso derivative, effective at being active. In addition, PAF acts at very low concentrations in a dose-dependent manner (0.1-30 nM). Preincubation with PAF receptor antagonists (CV-3988 and BN52021) as well as the specific desensitization of PC-12 cells to (R)PAF abolish the (R)PAF-induced dopamine release. Several lines of evidence suggest that dopamine release is dependent on a (R)PAF-induced calcium influx and efflux modulation. Dopamine release by PC-12 cells challenged with (R)PAF is associated with a rapid {sup 45}Ca influx and efflux and a rise in cytoplasmic calcium concentrations ((Ca{sup 2+}){sub i}) evaluated by using the calcium indicators fura-2 and quin2. At 30 nM (R)PAF, the absence of extracellular calcium inhibits the dopamine release but not the rise of (Ca{sup 2+}){sub i} from the internal stores, suggesting the importance of calcium influx in (R)PAF-induced dopamine release. PAF, which has been reported to be synthesized by stimulated neuronal cells may thus have a physiological modulatory role on cells with neurosecretory properties.

  8. Vascular endothelial growth factor and dexamethasone release from nonfouling sensor coatings affect the foreign body response

    PubMed Central

    Norton, L.W.; Koschwanez, H.E.; Wisniewski, N.A.; Klitzman, B.; Reichert, W.M.

    2014-01-01

    Vascular endothelial growth factor (VEGF) and dexamethasone (DX) release from hydrogel coatings were examined as a means to modify tissue inflammation and induce angiogenesis. Antibiofouling hydrogels for implantable glucose sensor coatings were prepared from 2-hydro-xyethyl methacrylate, N-vinyl pyrrolidinone, and polyethylene glycol. Microdialysis sampling was used to test the effect of the hydrogel coating on glucose recovery. VEGF-releasing hydrogel-coated fibers increased vascularity and inflammation in the surrounding tissue after 2 weeks of implantation compared to hydrogel-coated fibers. DX-releasing hydrogel-coated fibers reduced inflammation compared to hydrogel-coated fibers and had reduced capsule vascularity compared to VEGF-releasing hydrogel-coated fibers. Hydrogels that released both VEGF and DX simultaneously also showed reduced inflammation at 2 weeks implantation; however, no enhanced vessel formation was observed indicating that the DX diminished the VEGF effect. At 6 weeks, there were no detectable differences between drug-releasing hydrogel-coated fibers and control fibers. From this study, hydrogel drug release affected initial events of the foreign body response with DX inhibiting VEGF, but once the drug depot was exhausted these effects disappeared. PMID:17236219

  9. Involvement of ionotropic purinergic receptors in the histamine-induced enhancement of the cough reflex sensitivity in guinea pigs.

    PubMed

    Kamei, Junzo; Takahashi, Yoshiki

    2006-10-10

    We examined the effect of inhaled histamine on citric acid-induced coughs and clarified the role of ionotropic purinergic receptors in the resulting changes. Although the inhalation of 0.1 M citric acid by itself produced only a few coughs in guinea pigs, exposure to histamine, at concentrations of 0.3 to 1 mM, for 2 min concentration dependently increased the number of citric acid-induced coughs. This histamine-induced increase in the number of citric acid-induced coughs was dose dependently and significantly reduced when animals were pretreated with fexofenadine, a histamine H1 receptor antagonist. The histamine-induced increase in the number of citric acid-induced coughs was completely reduced when animals were co-pretreated with 2',3'-O-(2,4,6-trinitrophenyl) adenosine 5-triphosphate (TNP-ATP, 50 microM), a P2X receptor antagonist, and reactive blue 2, a P2Y receptor antagonist, for 2 min. Furthermore, the ATP-induced increase in the number of citric acid-induced coughs was dose dependently and significantly decreased when animals were pretreated with fexofenadine, at doses of 0.3, 1 and 3 mg/kg, p.o. These results suggest that histamine enhances the excitability of rapidly adapting receptors to tussive stimuli via modulation of ATP release in the airways. Furthermore, ATP might act not only on P2X receptors to directly activate rapidly adapting receptors, but also on P2Y receptors to increase histamine release, indirectly increasing the cough reflex sensitivity.

  10. Study of the biological effectiveness of a nanosilver-epidermal growth factor sustained-release carrier.

    PubMed

    Zhou, Jian-DA; Wang, Shao-Hua; Liu, Rui; Zhou, Chun-Jiao; Cao, Ke; Liu, Jin-Yan; Chen, Yao; Chen, Feng-Hua

    2013-04-01

    The aim of the present study was to elucidate the biological effectiveness and character of a nanosilver-epidermal growth factor (EGF) sustained-release carrier. This was synthesized using the self-assembly method and then characterized by transmission electron microscopy and UV spectrophotometry. The biological activity of the sustained release carrier was determined through cytological, bacteriological and wound-healing experiments. The results showed that the nanosilver-EGF sustained-release carrier was well dispersed with uniform particle size and that it had good antibacterial properties similar to those of nanosilver. The nanosilver-EGF sustained-release carrier is superior to EGFs in effectively promoting cell division and proliferation. The results of the wound-healing experiments provide evidence of its curative effects.

  11. Platelet-activating factor induces eosinophil peroxidase release from purified human eosinophils.

    PubMed Central

    Kroegel, C; Yukawa, T; Dent, G; Chanez, P; Chung, K F; Barnes, P J

    1988-01-01

    The degranulation response of purified human eosinophils to platelet-activating factor (PAF) has been studied. PAF induced release of eosinophil peroxidase (EPO) and beta-glucuronidase from highly purified human eosinophils with an EC50 of 0.9 nM. The order of release was comparable with that induced by phorbol myristate acetate (PMA). The new specific PAF antagonist 3-[4-(2-chlorophenyl)-9-methyl-H-thieno[3,2-f] [1,2,4]triazolo-[4,3a][1,4]-diazepin-2-yl](4-morpholinyl)- 1-propane-one (WEB 2086) inhibited the PAF-induced enzyme release by human eosinophils in a dose-dependent manner. The viability of eosinophils were unaffected both by PAF and WEB 2086. The results suggest that PAF may amplify allergic and inflammatory reactions by release of preformed proteins from eosinophil granules. PMID:3410498

  12. Affinity of pyridylalkylamines for nicotinic, muscarinic and histaminic recognition sites in brain tissue preparations.

    PubMed

    Repond, C; Pratt, J A; Stolerman, I P; Mayer, J M; Jenner, P; Marsden, C D; Testa, B

    1986-08-01

    The affinity of 15 regioisomeric and homologous pyridylalkylamines was examined in brain preparations for nicotinic, muscarinic, and H1-histaminic binding sites as labeled by [3H]-nicotine, [3H]-dexetimide and [3H]-mepyramine, respectively. Overall, the compounds show a clear selectivity for the nicotinic versus muscarinic binding sites, and a weak affinity for the H1-histaminic sites. Variations in affinity appear to be partly influenced by steric factors (such as position of attachment, length and rigidity of side-chain) and marginally by lipophilicity. PMID:3778556

  13. RAS is required for epidermal growth factor-stimulated arachidonic acid release in rat-1 fibroblasts.

    PubMed

    Warner, L C; Hack, N; Egan, S E; Goldberg, H J; Weinberg, R A; Skorecki, K L

    1993-12-01

    Previous studies have provided suggestive evidence for an interaction between ras activation and signalling pathways involved in agonist-stimulated arachidonic acid release in a variety of cell systems. In order to clarify this interaction, we have measured epidermal growth factor (EGF)-stimulated arachidonic acid release in rat-1 fibroblasts transfected with the N-17 dominant negative mutation of ras. Cells transfected with the N-17 ras mutant, display a markedly attenuated arachidonic acid-release response to EGF, compared to sham-transfected and non-transfected cells. In contrast, the response to phorbol myristate acetate (PMA) was not attenuated in the N-17-mutant expressing cells. No differences were detected between sham-transfected and N-17 mutant expressing cells in levels of immunodetectable EGF receptor, cytosolic phospholipase A2 or mitogen-activated protein (MAP) kinase. Attenuation of EGF-stimulated arachidonic acid release in the N-17 mutant expressing cells, was accompanied by a marked diminution in EGF-stimulated tyrosine phosphorylation of MAP kinase. We conclude that the signalling pathway involved in epidermal growth factor-stimulated arachidonic acid release is similar to the signalling pathway for mitogenic responses to epidermal growth factor and requires ras activation, likely followed by a downstream cascade of kinases eventuating in MAP kinase activation.

  14. Luteinizing hormone releasing factor in rat hypophysial portal blood collected during electrical stimulation of the hypothalamus

    PubMed Central

    Harris, G. W.; Ruf, K. B.

    1970-01-01

    1. Ovulation was induced in Nembutal-blocked pro-oestrous rats by electrical stimulation of the hypothalamus. 2. The same type of electrical stimulation was applied during the collection of hypophysial portal blood. 3. Pooled hypophysial portal plasma from donors in pro-oestrus, oestrus and met-oestrus was assayed for ovarian ascorbic acid depleting (OAAD) activity. 4. Electrical stimulation of the hypothalamus increased the OAAD activity, believed to be due to luteinizing hormone releasing factor (LRF), in pro-oestrus and met-oestrus, but not in oestrus. 5. It is concluded that the hypothalamic nerve fibres responsible for releasing LRF into the hypophysial portal vessels are depleted of their store of this releasing factor, or are refractory to electrical stimulation, during oestrus. PMID:5499765

  15. Release kinetics of platelet-derived and plasma-derived growth factors from autologous plasma rich in growth factors.

    PubMed

    Anitua, Eduardo; Zalduendo, Mari Mar; Alkhraisat, Mohammad Hamdan; Orive, Gorka

    2013-10-01

    Many studies have evaluated the biological effects of platelet rich plasma reporting the final outcomes on cell and tissues. However, few studies have dealt with the kinetics of growth factor delivery by plasma rich in growth factors. Venous blood was obtained from three healthy volunteers and processed with PRGF-Endoret technology to prepare autologous plasma rich in growth factors. The gel-like fibrin scaffolds were then incubated in triplicate, in a cell culture medium to monitor the release of PDGF-AB, VEGF, HGF and IGF-I during 8 days of incubation. A leukocyte-platelet rich plasma was prepared employing the same technology and the concentrations of growth factors and interleukin-1β were determined after 24h of incubation. After each period, the medium was collected, fibrin clot was destroyed and the supernatants were stored at -80°C until analysis. The growth factor delivery is diffusion controlled with a rapid initial release by 30% of the bioactive content after 1h of incubation and a steady state release when almost 70% of the growth factor content has been delivered. Autologous fibrin matrix retained almost 30% of the amount of the growth factors after 8 days of incubation. The addition of leukocytes to the formula of platelet rich plasma did not increase the concentration of the growth factors, while it drastically increased the presence of pro-inflammatory IL-1β. Further studies employing an in vitro inflammatory model would be interesting to study the difference in growth factors and pro-inflammatory cytokines between leukocyte-free and leukocyte-rich platelet rich plasma.

  16. 77 FR 4227 - Implantation or Injectable Dosage Form New Animal Drugs; Gonadotropin Releasing Factor Analog...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-27

    ... regulations in 21 CFR 522.1083 are amended to reflect the approval. In accordance with the freedom of... CFR part 522 continues to read as follows: Authority: 21 U.S.C. 360b. 0 2. In Sec. 522.1083, revise paragraphs (c)(1) and (c)(3) to read as follows: Sec. 522.1083 Gonadotropin releasing factor...

  17. Ethanol and corticotropin releasing factor receptor modulation of central amygdala neurocircuitry: An update and future directions.

    PubMed

    Silberman, Yuval; Winder, Danny G

    2015-05-01

    The central amygdala is a critical brain region for many aspects of alcohol dependence. Much of the work examining the mechanisms by which the central amygdala mediates the development of alcohol dependence has focused on the interaction of acute and chronic ethanol with central amygdala corticotropin releasing factor signaling. This work has led to a great deal of success in furthering the general understanding of central amygdala neurocircuitry and its role in alcohol dependence. Much of this work has primarily focused on the hypothesis that ethanol utilizes endogenous corticotropin releasing factor signaling to upregulate inhibitory GABAergic transmission in the central amygdala. Work that is more recent suggests that corticotropin releasing factor also plays an important role in mediating anxiety-like behaviors via the enhancement of central amygdala glutamatergic transmission, implying that ethanol/corticotropin releasing factor interactions may modulate excitatory neurotransmission in this brain region. In addition, a number of studies utilizing optogenetic strategies or transgenic mouse lines have begun to examine specific central amygdala neurocircuit dynamics and neuronal subpopulations to better understand overall central amygdala neurocircuitry and the role of neuronal subtypes in mediating anxiety-like behaviors. This review will provide a brief update on this literature and describe some potential future directions that may be important for the development of better treatments for alcohol addiction.

  18. 76 FR 27888 - Implantation or Injectable Dosage Form New Animal Drugs; Gonadotropin Releasing Factor-Diphtheria...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-13

    ... drug regulations to reflect approval of a new animal drug application (NADA) filed by Pfizer, Inc. The NADA provides for the veterinary prescription use of gonadotropin releasing factor-diphtheria toxoid...-5755, filed NADA 141-322 that provides for the veterinary prescription use of IMPROVEST...

  19. Brain histamine in Alzheimer's disease.

    PubMed

    Cacabelos, R; Yamatodani, A; Niigawa, H; Hariguchi, S; Tada, K; Nishimura, T; Wada, H; Brandeis, L; Pearson, J

    1989-05-01

    The concentration of histamine (HA) has been determined by high-performance liquid chromatography (HPLC) with fluorometric detection in 21 different regions of brains from patients with senile dementia of the Alzheimer type (SDAT) and subjects (CB) whose causes of death were not related to neuropsychiatric, neurological and/or neurodegenerative diseases. The highest levels of HA in the central nervous system (CNS) of both control (CB) and SDAT samples were found in the posterior hypothalamus (CB = 3.13 +/- 0.63 pmol/mg; SDAT = 7.75 +/- 1.43 pmol/mg, p less than 0.005), where the HA neurons are located, and in the anterior hypothalamus (CB = 1.77 +/- 0.33 pmol/mg; SDAT = 2.82 +/- 0.45 pmol/mg, p less than 0.005). The lowest HA levels were detected in the cerebellum (CB = 0.12 +/- 0.04 pmol/mg; SDAT = 0.24 +/- 0.09 pmol/mg, p less than 0.01) and medulla oblongata. HA levels were significantly higher in SDAT than in CB in the following areas: motor cortex (Brodmann's area 4) (A4), premotor cortex (A6), postcentral gyrus (A1,2), posterior parietal cortex (A5,7), superior temporal gyrus (A41,42), temporal pole (A38), primary and secondary visual cortices (A17,18), anterior and posterior regions of the hypothalamus, putamen, caudate nucleus, nucleus accumbens, thalamus, hippocampus, pons, medulla oblongata and cerebellum. No changes were seen in globus pallidus and corpus callosum. Since the origin of HA in the brain is dependent upon three main compartments (neuronal, mast cell, vascular smooth muscle), with approximately 60-80% of the total HA belonging to the neuronal pool, on the basis of neurochemical data we postulate that the increase in the levels of HA in SDAT might account for or be associated with alterations in neuroendocrine, cognitive, neurovascular and sleep-wakefulness functions. PMID:2755282

  20. Klebsiella pneumoniae produces no histamine: Raoultella planticola and Raoultella ornithinolytica strains are histamine producers.

    PubMed

    Kanki, Masashi; Yoda, Tomoko; Tsukamoto, Teizo; Shibata, Tadayoshi

    2002-07-01

    Histamine fish poisoning is caused by histamine-producing bacteria (HPB). Klebsiella pneumoniae and Klebsiella oxytoca are the best-known HPB in fish. However, 22 strains of HPB from fish first identified as K. pneumoniae or K. oxytoca by commercialized systems were later correctly identified as Raoultella planticola (formerly Klebsiella planticola) by additional tests. Similarly, five strains of Raoultella ornithinolytica (formerly Klebsiella ornithinolytica) were isolated from fish as new HPB. R. planticola and R. ornithinolytica strains were equal in their histamine-producing capabilities and were determined to possess the hdc genes, encoding histidine decarboxylase. On the other hand, a collection of 61 strains of K. pneumoniae and 18 strains of K. oxytoca produced no histamine.

  1. Pharmacological characterisation of cardiovascular histamine receptors in man in vivo.

    PubMed

    Boyce, M J

    1982-09-01

    Data from pharmacological studies carried out in healthy subjects using systemic histamine or impromidine and their antagonists are reviewed. Exogenous histamine by rapid injection appears to stimulate only H1-receptors. Chlorpheniramine alone antagonised the responses to histamine. The effects of cardiovascular H2-receptor stimulation are demonstrated best by a sustained and large dose of histamine given by infusion. If it be considered desirable to antagonise all the cardiovascular responses to endogenous histamine, the available pharmacological data in man suggest this would be achieved best by a combination of an H1-and H2-receptor antagonist.

  2. Novel function of histamine signaling in hyperlipidemia-induced atherosclerosis: Histamine H1 receptors protect and H2 receptors accelerate atherosclerosis.

    PubMed

    Yamada, Sohsuke; Wang, Ke-Yong; Tanimoto, Akihide; Sasaguri, Yasuyuki

    2015-02-01

    Histamine is not only essential for acute inflammatory reactions, but it also participates in a chronic inflammatory disorder. We generated apolipoprotein E (apoE) and histamine receptors (HHRs), including the major H1 and H2 receptors (HH1R, HH2R) double knockout mice (DKO) to clarify the role of HHRs in hyperlipidemia-induced atherosclerosis, in which apoE-KO and DKO mice were fed a high cholesterol diet. We found that pronounced hyperlipidemia-induced atherosclerotic progression occurred in HH1R/apoE-DKO mice, but in HH2R/apoE-DKO mice less atherosclerosis, despite pro-atherogenic serum cholesterol levels compared with apoE-KO mice. Furthermore, the increased expressions of scavenger receptors (SRs), such as SR-A, CD36 and lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), nuclear factor-kappa B (NFκB), monocyte chemoattractant protein (MCP-1), matrix metalloproteinases (MMPs) or liver X receptor (LXR)-related inflammatory signaling factors, were consistent with the pro-atherogenic phenotype of HH2R/apoE-DKO mice. We hypothesize that histamine/HH1R and HH2R signaling has conflicting innate functions, inflammatory/atherogenic and anti-inflammatory/anti-atherogenic actions, and that there are innate links between histamine signaling and hyperlipidemia-induced atherosclerosis, independently of serum cholesterol metabolism. Specific histamine signaling blockers, in particular, HH2R blockers, are a possible novel therapeutic target for hyperlipidemia-induced atherosclerosis. PMID:25581821

  3. Novel function of histamine signaling in hyperlipidemia-induced atherosclerosis: Histamine H1 receptors protect and H2 receptors accelerate atherosclerosis.

    PubMed

    Yamada, Sohsuke; Wang, Ke-Yong; Tanimoto, Akihide; Sasaguri, Yasuyuki

    2015-02-01

    Histamine is not only essential for acute inflammatory reactions, but it also participates in a chronic inflammatory disorder. We generated apolipoprotein E (apoE) and histamine receptors (HHRs), including the major H1 and H2 receptors (HH1R, HH2R) double knockout mice (DKO) to clarify the role of HHRs in hyperlipidemia-induced atherosclerosis, in which apoE-KO and DKO mice were fed a high cholesterol diet. We found that pronounced hyperlipidemia-induced atherosclerotic progression occurred in HH1R/apoE-DKO mice, but in HH2R/apoE-DKO mice less atherosclerosis, despite pro-atherogenic serum cholesterol levels compared with apoE-KO mice. Furthermore, the increased expressions of scavenger receptors (SRs), such as SR-A, CD36 and lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), nuclear factor-kappa B (NFκB), monocyte chemoattractant protein (MCP-1), matrix metalloproteinases (MMPs) or liver X receptor (LXR)-related inflammatory signaling factors, were consistent with the pro-atherogenic phenotype of HH2R/apoE-DKO mice. We hypothesize that histamine/HH1R and HH2R signaling has conflicting innate functions, inflammatory/atherogenic and anti-inflammatory/anti-atherogenic actions, and that there are innate links between histamine signaling and hyperlipidemia-induced atherosclerosis, independently of serum cholesterol metabolism. Specific histamine signaling blockers, in particular, HH2R blockers, are a possible novel therapeutic target for hyperlipidemia-induced atherosclerosis.

  4. Effect of growth hormone-releasing factor on growth hormone release in children with radiation-induced growth hormone deficiency

    SciTech Connect

    Lustig, R.H.; Schriock, E.A.; Kaplan, S.L.; Grumbach, M.M.

    1985-08-01

    Five male children who received cranial irradiation for extrahypothalamic intracranial neoplasms or leukemia and subsequently developed severe growth hormone (GH) deficiency were challenged with synthetic growth hormone-releasing factor (GRF-44), in an attempt to distinguish hypothalamic from pituitary dysfunction as a cause of their GH deficiency, and to assess the readily releasable GH reserve in the pituitary. In response to a pulse of GRF-44 (5 micrograms/kg intravenously), mean peak GH levels rose to values higher than those evoked by the pharmacologic agents L-dopa or arginine (6.4 +/- 1.3 ng/mL v 1.5 +/- 0.4 ng/mL, P less than .05). The peak GH value occurred at a mean of 26.0 minutes after administration of GRF-44. These responses were similar to those obtained in children with severe GH deficiency due to other etiologies (peak GH 6.3 +/- 1.7 ng/mL, mean 28.0 minutes). In addition, there was a trend toward an inverse relationship between peak GH response to GRF-44 and the postirradiation interval. Prolactin and somatomedin-C levels did not change significantly after the administration of a single dose of GRF-44. The results of this study support the hypothesis that cranial irradiation in children can lead to hypothalamic GRF deficiency secondary to radiation injury of hypothalamic GRF-secreting neurons. This study also lends support to the potential therapeutic usefulness of GRF-44 or an analog for GH deficiency secondary to cranial irradiation.

  5. Exercise induced release of von Willebrand factor: evidence for hypoxic reperfusion microvascular injury in rheumatoid arthritis.

    PubMed Central

    Farrell, A J; Williams, R B; Stevens, C R; Lawrie, A S; Cox, N L; Blake, D R

    1992-01-01

    Experimental evidence suggests that rheumatoid synovitis may be perpetuated by the generation of reactive oxygen species during hypoxic reperfusion injury. The latter occurs because increased intra-articular pressure during exercise exceeds synovial capillary perfusion pressure, impairing blood flow. The object of this study was to establish a marker for and the mechanism of synovial hypoxic reperfusion injury. Von Willebrand factor (vWF) is only released from endothelial cells and platelets and is an in vivo and in vitro marker of endothelial injury. In vivo exercise induced changes in plasma vWF were therefore investigated in patients with rheumatoid arthritis (RA) compared with controls and in vitro vWF release by human umbilical vein endothelial cells subjected to hypoxia reperfusion. Pre-exercise plasma vWF levels were 1001 and 817 IU/l, increasing after exercise to 1658 and 845 IU/l in patients with RA and controls respectively. Von Willebrand factor release from human umbilical vein endothelial cells followed a biphasic pattern, occurring during both hypoxia and reperfusion. Hypoxia reperfusion induced vWF release by human umbilical vein endothelial cells in vitro suggests that exercise induced vWF release in patients with RA is best explained by synovial hypoxic reperfusion injury. This study supports evidence that generation of reactive oxygen species plays a principal part in synovial hypoxic reperfusion injury and suggests vWF as a useful marker of this phenomenon. Images PMID:1444624

  6. The Transcription Factor NIN-LIKE PROTEIN7 Controls Border-Like Cell Release.

    PubMed

    Karve, Rucha; Suárez-Román, Frank; Iyer-Pascuzzi, Anjali S

    2016-07-01

    The root cap covers the tip of the root and functions to protect the root from environmental stress. Cells in the last layer of the root cap are known as border cells, or border-like cells (BLCs) in Arabidopsis (Arabidopsis thaliana). These cells separate from the rest of the root cap and are released from its edge as a layer of living cells. BLC release is developmentally regulated, but the mechanism is largely unknown. Here, we show that the transcription factor NIN-LIKE PROTEIN7 (NLP7) is required for the proper release of BLCs in Arabidopsis. Mutations in NLP7 lead to BLCs that are released as single cells instead of an entire layer. NLP7 is highly expressed in BLCs and is activated by exposure to low pH, a condition that causes BLCs to be released as single cells. Mutations in NLP7 lead to decreased levels of cellulose and pectin. Cell wall-loosening enzymes such as CELLULASE5 (CEL5) and a pectin lyase-like gene, as well as the root cap regulators SOMBRERO and BEARSKIN1/2, are activated in nlp7-1 seedlings. Double mutant analysis revealed that the nlp7-1 phenotype depends on the expression level of CEL5 Mutations in NLP7 lead to an increase in susceptibility to a root-infecting fungal pathogen. Together, these data suggest that NLP7 controls the release of BLCs by acting through the cell wall-loosening enzyme CEL5.

  7. Activity-dependent release of transforming growth factor-beta in a neuronal network in vitro.

    PubMed

    Lacmann, A; Hess, D; Gohla, G; Roussa, E; Krieglstein, K

    2007-12-12

    For neurotrophins and also for members of the transforming growth factor beta (TGF-beta) family an activity-dependent regulation of synthesis and release has been proposed. Together with the observation that the secretion of neurotransmitters is initiated by neurotrophic factors, it is reasonable to assume that they might act as retrograde modulators enhancing the efficacy and stabilization of synapses. In the present study, we have tested this hypothesis and studied the release and regulation of TGF-beta in vitro using mouse primary hippocampal neurons at embryonic day E16.5 as model. We show that neuronal activity regulates TGF-beta release and TGF-beta expression in vitro. Treatment of the cultures with KCl, 3-veratroylveracevine (veratridine), glutamate or carbamylcholine chloride (carbachol) increased the levels of secreted TGF-beta, as assessed by the MLEC/plasminogen activator inhibitor (PAI)-luciferase-assay, whereas TGF-beta release stimulated by KCl or veratridine was reduced in the presence of tetrodotoxin or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). In addition, application of glutamate significantly upregulated expression of TGF-beta2 and TGF-beta3 in the culture. Notably, KCl stimulation caused Smad (composite term from SMA (C. elegans) and MAD=mothers against dpp (Drosophila)) translocation into the nucleus and upregulated TGF-beta inducible early gene (Tieg1) expression, demonstrating that activity-dependent released TGF-beta may exert autocrine actions and thereby activate the TGF-beta-dependent signaling pathway. Together, these results suggest an activity-dependent release and gene transcription of TGF-beta from mouse hippocampal neurons in vitro as well as subsequent autocrine functions of the released TGF-beta within the hippocampal network.

  8. Histamine in diabetes: Is it time to reconsider?

    PubMed

    Pini, Alessandro; Obara, Ilona; Battell, Emma; Chazot, Paul L; Rosa, Arianna Carolina

    2016-09-01

    The first studies of histamine and diabetes date back to the 1950s. Since that time the involvement of histamine in diabetes was related to its well known vasoactive properties and permeability leakage effects. In particular, the first evidence for a correlation between histamine and diabetes arose in 1989 when an increase in plasma and leucocyte histamine content was observed. Limited independent evidence followed in the subsequent two decades, focusing on both histamine glyceamic control and macro- and microvascular complications of diabetes. However, recent observations have sparked the question whether it is time to reconsider the functional contribution of histamine in diabetes. We reveal an interesting upsurge in the field which provides scope for new insights into the role of histamine in diabetes. PMID:27343700

  9. Population pharmacokinetic/pharmacodynamic modeling of histamine response measured by histamine iontophoresis laser Doppler.

    PubMed

    Liu, Xiaoxi; Jones, Bridgette L; Roberts, Jessica K; Sherwin, Catherine M

    2016-08-01

    The epicutaneous histamine (EH) test is the current gold standard method for the clinical evaluation of allergic conditions. However, the EH method is limited in providing an objective and qualitative assessment of histamine pharmacodynamic response. The histamine iontophoresis with laser Doppler (HILD) monitoring method, an alternative method, allows a fixed dose of histamine to be delivered and provides an objective, continuous, and dynamic measurement of histamine epicutaneous response in children and adults. However, due to the high sampling frequency (up to 40 Hz), the output files are usually too cumbersome to be directly used for further analysis. In this study, we developed an averaging algorithm that efficiently reduces the HILD data in size. The reduced data was further analyzed and a population linked effect pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the local histamine response. The model consisted of a one-compartment PK model and a direct-response fractional maximum effect (Emax) model. The parameter estimates were obtained as follows: absorption rate constant (ka), 0.094/min; absorption lag time (Tlag), 2.72 min; partitioning clearance from local depot to systemic circulation (CLpar), 0.0006 L/min; baseline effect (E0), 13.1 flux unit; Emax, 13.4; concentration at half maximum effect (EC50) 31.1 mg/L. Covariate analysis indicated that age and race had significant influence on Tlag and EC50, respectively.

  10. Involvement of prostaglandins and histamine in radiation-induced temperature responses in rats

    SciTech Connect

    Kandasamy, S.B.; Hunt, W.A. )

    1990-01-01

    Exposure of rats to 1-15 Gy of gamma radiation induced hyperthermia, whereas exposure to 20-150 Gy produced hypothermia. Since radiation exposure induced the release of prostaglandins (PGs) and histamine, the role of PGs and histamine in radiation-induced temperature changes was examined. Radiation-induced hyper- and hypothermia were antagonized by pretreatment with indomethacin, a cyclooxygenase inhibitor. Intracerebroventricular administration of PGE2 and PGD2 induced hyper- and hypothermia, respectively. Administration of SC-19220, a specific PGE2 antagonist, attenuated PGE2- and radiation-induced hyperthermia, but it did not antagonize PGD2- or radiation-induced hypothermia. Consistent with an apparent role of histamine in hypothermia, administration of disodium cromoglycate (a mast cell stabilizer), mepyramine (H1-receptor antagonist), or cimetidine (H2-receptor antagonist) attenuated PGD2- and radiation-induced hypothermia. These results suggest that radiation-induced hyperthermia is mediated via PGE2 and that radiation-induced hypothermia is mediated by another PG, possibly PGD2, via histamine.

  11. Modulation of hematopoiesis through histamine receptor signaling.

    PubMed

    Schneider, Elke; Bertron, Anne-France; Dy, Michel

    2011-01-01

    Histamine is one of the most versatile biogenic amines targeting a variety of cells through extra- and intracellular binding sites and specific receptors, which trigger different signal transduction pathways. It has been associated with cell growth ever since G. Kahlson demonstrated that its synthesis was increased in rapidly growing tissues of plants and animals. He proposed that the newly formed amine, as opposed to its stored counterpart, might play a major role in growth processes. Later on, a number of investigators provided evidence for the contribution of histamine to the expansion of normal and malignant cells, whether of hematopoietic origin or not. These studies have generated conflicting results, revealing growth-promoting as well as inhibitory effects, most likely because the final outcome of exposure to histamine depends on the signaling pathways triggered by distinct receptors and their differential distribution among the target population. The purpose of the present review is to outline our current understanding of the regulatory functions of histamine during growth and differentiation of hematopoietic progenitors, focusing on those mediated through its H4 receptor.

  12. Bronchial responsiveness to histamine in wheezy infants.

    PubMed Central

    Prendiville, A; Green, S; Silverman, M

    1987-01-01

    Little is known about airway responsiveness in infancy. The bronchial response to incremental doses of nebulised histamine (to a maximum dose of 8 g/l) was measured in 11 wheezy infants with a mean age of 8.7 months. The study was repeated after a 30-40 minute recovery period in seven infants and again on a separate day in 10. The index of response was the provoking concentration of histamine that produced a 30% fall in the maximum expiratory flow at functional residual capacity (PC30), taken from partial forced expiratory flow-volume curves produced in a pressure jacket. Nine of 11 infants had a PC30 of less than 8 g/l. The response was consistent between tests in both the nine responders and the two who failed to respond at 8 g/l. The PC30 was lower in infants with more severe baseline airway obstruction. Spontaneous recovery after challenge was complete in 30 minutes in seven of eight infants studied. The highest doses of histamine caused changes in the configuration of the flow-volume curves and symptomatic cough and wheeze in addition to a change in forced flow rates. This study provides clear evidence of intrathoracic airway responsiveness to histamine in infancy. PMID:3433246

  13. Effect of food intake on urinary excretions of histamine, N tau-methylhistamine, imidazole acetic acid and its conjugate(s) in humans and mice.

    PubMed

    Imamura, I; Watanabe, T; Maeyama, K; Kubota, A; Okada, A; Wada, H

    1984-12-01

    The urinary excretions by young healthy men of histamine and its metabolites, N tau-methylhistamine, imidazole acetic acid, and imidazole acetic acid conjugate(s), increased 1-3 h after food intake. The increase was seen even after the intake of konnyaku (mannan) as a protein-deficient food, suggesting that physical stimulation of the gastric mucosa by food is the main cause of histamine release. This suggestion was confirmed by the following findings in patients and mice. In patients with stomach diseases, gastrectomy resulted in decreases in the excretion of histamine and its metabolites in the urine, and patients subjected to intravenous hyperalimentation excreted less histamine and its metabolites in the urine than normal subjects. In mice, a correlation of histamine excretion with food intake was demonstrated experimentally. Namely, mice fed only during the night (21:00-0:00) showed increased excretions of histamine and its metabolites at 23:00-3:00, whereas those fed in the morning (9:00-12:00) showed increased excretions of those compounds at 11:00-15:00. All these results are consistent with the idea that urinary histamine and its metabolites mainly originate from the stomach.

  14. Effect of endogenous histamine in the ventral hippocampus on fear memory deficits induced by scopolamine as evaluated by step-through avoidance response in rats.

    PubMed

    Yu, Chaoyang; Shen, Yao; Xu, Lisha; Zhu, Yuanyuan; Zhuge, Zhenbin; Huang, Yuwen; Henk, Timmerman; Rob, Leurs; Wei, Erqing; Chen, Zhong

    2006-04-15

    In the present study, the effects of endogenous histamine in the ventral hippocampus on fear memory deficits induced by scopolamine were investigated as evaluated by step-through avoidance response in adult male rats. Bilateral ventral hippocampal injection of scopolamine (i.h., 2, 5 microg/site) significantly produced depressant effects on the active avoidance response in a dose-dependent manner. Histamine H(3)-antagonist clobenpropit (5, 10 microg/site) significantly ameliorated the fear memory deficits induced by scopolamine in a dose-dependent manner. Its procognitive effect was completely antagonized by immepip (10 microg/site), a selective histamine H(3)-agonist. Both histamine H(1)-antagonist pyrilamine and H(2)-antagonist cimetidine, also inhibited the procognitive effects of clobenpropit. Additionally, the procognitive effects of clobenpropit on the fear memory deficits induced by scopolamine were significantly potentiated by intraperitoneal (i.p.) injection of histidine, a precursor of histamine, but markedly reversed by i.h. injection of alpha-fluoromethylhistidine (FMH, 10 microg/site), a selective and potent histidine decarboxylase inhibitor. It is concluded that the increased endogenous histamine release in the ventral hippocampus ameliorates the scopolamine-induced fear memory deficits, and its action is mainly mediated by histamine presynaptic H(3)-receptors and postsynaptic H(1)- and H(2)-receptors.

  15. Mast Cell Proteases 6 and 7 Stimulate Angiogenesis by Inducing Endothelial Cells to Release Angiogenic Factors

    PubMed Central

    de Souza, Devandir Antonio; Borges, Antonio Carlos; Santana, Ana Carolina; Oliver, Constance; Jamur, Maria Célia

    2015-01-01

    Mast cell proteases are thought to be involved with tumor progression and neo-vascularization. However, their exact role is still unclear. The present study was undertaken to further elucidate the function of specific subtypes of recombinant mouse mast cell proteases (rmMCP-6 and 7) in neo-vascularization. SVEC4-10 cells were cultured on Geltrex® with either rmMCP-6 or 7 and tube formation was analyzed by fluorescence microscopy and scanning electron microscopy. Additionally, the capacity of these proteases to induce the release of angiogenic factors and pro and anti-angiogenic proteins was analyzed. Both rmMCP-6 and 7 were able to stimulate tube formation. Scanning electron microscopy showed that incubation with the proteases induced SVEC4-10 cells to invade the gel matrix. However, the expression and activity of metalloproteases were not altered by incubation with the mast cell proteases. Furthermore, rmMCP-6 and rmMCP-7 were able to induce the differential release of angiogenic factors from the SVEC4-10 cells. rmMCP-7 was more efficient in stimulating tube formation and release of angiogenic factors than rmMCP-6. These results suggest that the subtypes of proteases released by mast cells may influence endothelial cells during in vivo neo-vascularization. PMID:26633538

  16. Interaction of stress, corticotropin-releasing factor, arginine vasopressin and behaviour

    PubMed Central

    Beurel, Eléonore; Nemeroff, Charles B.

    2014-01-01

    Stress mediates the activation of a variety of systems ranging from inflammatory to behavioral responses. In this review we focus on two neuropeptide systems, corticotropin-releasing factor (CRF) and arginine vasopressin (AVP), and their roles in regulating stress responses. Both peptides have been demonstrated to be involved in anxiogenic and depressive effects, actions mediated in part through their regulation of the hypothalamic-pituitary-adrenal axis and the release of adrenocorticotropic hormone. Because of the depressive effects of CRF and AVP, drugs modifying the stress-associated detrimental actions of CRF and AVP are under development, particularly drugs antagonizing CRF and AVP receptors for therapy in depression. PMID:24659554

  17. Interleukin 10 release during endotoxaemia in chimpanzees: role of platelet-activating factor and interleukin 6.

    PubMed

    van der Poll, T; Jansen, J; Levi, M; ten Cate, H; Hack, C E; Aarden, L A; ten Cate, J W; van Deventer, S J

    1996-01-01

    Interleukin (IL-)10 has been demonstrated to inhibit endotoxin-induced production of a number of pro-inflammatory cytokines. The present study sought to compare the appearances in the circulation of IL-10, IL-6 and IL-8, and to assess the roles of endogenously produced platelet-activating factor (PAF) and IL-6 in IL-10 release during endotoxaemia in chimpanzees. Intravenous injection of endotoxin (lot EC-5, 4 ng/kg, n = 8) induced a transient rise in serum IL-10 concentrations, peaking after 2 h (213 +/- 70 pg/ml; P < 0.05). No correlations existed between peak IL-10 levels, and peak IL-6 and IL-8 levels. Neither infusion of the specific PAF antagonist TCV-309 (n = 4), nor infusion of a neutralizing anti-IL-6 monoclonal antibody (n = 4) influenced endotoxin-induced IL-10 release. IL-10 release elicited by injection of endotoxin is not mediated by PAF or IL6.

  18. Endotoxin and tumor necrosis factor-alpha-induced interleukin-8 release in humans.

    PubMed

    van Deventer, S J; Hart, M; van der Poll, T; Hack, C E; Aarden, L A

    1993-02-01

    Neutrophil recruitment and activation are thought to play an important role in tissue damage observed in septicemia. Interleukin-8 (IL-8) is a small cytokine with important neutrophil-activating and chemoattractant properties. IL-8 release was studied after injection of human volunteers with low doses of either endotoxin (2 ng/kg of body weight) or tumor necrosis factor-alpha (TNF alpha) (50 micrograms/m2). After TNF-alpha injection, IL-8 appeared at 30 min, whereas increased levels were first observed after 90 min in endotoxin-challenged volunteers. Peak levels were measured at 120 min after both endotoxin (192 +/- 193 ng/L) and TNF alpha (500 +/- 236 ng/L) injection. These data indicate that IL-8 is released in humans after injection of endotoxin and TNF alpha and suggest that endotoxin-induced IL-8 release is mediated by TNF alpha.

  19. Induction of release of tumor necrosis factor from human monocytes by staphylococci and staphylococcal peptidoglycans.

    PubMed Central

    Timmerman, C P; Mattsson, E; Martinez-Martinez, L; De Graaf, L; Van Strijp, J A; Verbrugh, H A; Verhoef, J; Fleer, A

    1993-01-01

    The role of cytokines in gram-positive infections is still relatively poorly defined. The purpose of this study was to establish whether or not intact staphylococci and purified peptidoglycans and peptidoglycan components derived from staphylococci are capable of stimulating the release of tumor necrosis factor (TNF) by human monocytes. We show here that intact staphylococci and purified peptidoglycans, isolated from three Staphylococcus epidermidis and three S. aureus strains, were indeed able to induce secretion of TNF by human monocytes in a concentration-dependent fashion. TNF release was detected by both enzyme immunoassay and the L929 fibroblast bioassay. In the enzyme immunoassay, a minimal concentration of peptidoglycan of 1 micrograms/ml was required to detect TNF release by monocytes, whereas in the bioassay a peptidoglycan concentration of 10 micrograms/ml was needed to detect a similar amount of TNF release. Peptidoglycan components such as the stem peptide, tetra- and pentaglycine, and muramyl dipeptide were unable to induce TNF release from human monocytes. PMID:8406805

  20. Material-mediated proangiogenic factor release pattern modulates quality of regenerated blood vessels.

    PubMed

    Rich, Max H; Lee, Min Kyung; Baek, Kwanghyun; Jeong, Jae Hyun; Kim, Dong Hyun; Millet, Larry J; Bashir, Rashid; Kong, Hyunjoon

    2014-12-28

    Hydrogels designed to sustainably release bioactive molecules are extensively used to enhance tissue repair and regenerative therapies. Along this line, numerous efforts are made to control the molecular release rate and amount. In contrast, few efforts are made to control the molecular release pattern, and, subsequently, modulate the spatial organization of newly forming tissues, including blood vessels. Therefore, using a hydrogel printed to release vascular endothelial growth factor (VEGF) into a pre-defined pattern, this study demonstrates that spatial distribution of VEGF is important in guiding growth direction of new blood vessels, and also in retaining the structural integrity of pre-existing vasculature. Guided by a computational model, we fabricated a patch composed of micro-sized VEGF-releasing poly(ethylene glycol) diacrylate (PEGDA) hydrogel cylinders using an ink-jet printer. Interestingly, hydrogel printed with computationally optimized spacing created anisotropically aligned vasculature exclusively when the printed gel pattern was placed parallel to pre-existing blood vessels. In contrast, vascular sprouting from placing the printed gel pattern perpendicular to pre-existing vessels resulted in deformation and structural disintegration of the original vasculature. We envision that this study will be useful to better understand angiogenesis-modulated neovascularization and further improve the treatment quality for various wounds and tissue defects. PMID:25450405

  1. Nerve growth factor released from a novel PLGA nerve conduit can improve axon growth

    NASA Astrophysics Data System (ADS)

    Lin, Keng-Min; Shea, Jill; Gale, Bruce K.; Sant, Himanshu; Larrabee, Patti; Agarwal, Jay

    2016-04-01

    Nerve injury can occur due to penetrating wounds, compression, traumatic stretch, and cold exposure. Despite prompt repair, outcomes are dismal. In an attempt to help resolve this challenge, in this work, a poly-lactic-co-glycolic acid (PLGA) nerve conduit with associated biodegradable drug reservoir was designed, fabricated, and tested. Unlike current nerve conduits, this device is capable of fitting various clinical scenarios by delivering different drugs without reengineering the whole system. To demonstrate the potential of this device for nerve repair, a series of experiments were performed using nerve growth factor (NGF). First, an NGF dosage curve was developed to determine the minimum NGF concentration for optimal axonal outgrowth on chick dorsal root ganglia (DRG) cells. Next, PLGA devices loaded with NGF were evaluated for sustained drug release and axon growth enhancement with the released drug. A 20 d in vitro release test was conducted and the nerve conduit showed the ability to meet and maintain the minimum NGF requirement determined previously. Bioactivity assays of the released NGF showed that drug released from the device between the 15th and 20th day could still promote axon growth (76.6-95.7 μm) in chick DRG cells, which is in the range of maximum growth. These novel drug delivery conduits show the ability to deliver NGF at a dosage that efficiently promotes ex vivo axon growth and have the potential for in vivo application to help bridge peripheral nerve gaps.

  2. Material-mediated proangiogenic factor release pattern modulates quality of regenerated blood vessels.

    PubMed

    Rich, Max H; Lee, Min Kyung; Baek, Kwanghyun; Jeong, Jae Hyun; Kim, Dong Hyun; Millet, Larry J; Bashir, Rashid; Kong, Hyunjoon

    2014-12-28

    Hydrogels designed to sustainably release bioactive molecules are extensively used to enhance tissue repair and regenerative therapies. Along this line, numerous efforts are made to control the molecular release rate and amount. In contrast, few efforts are made to control the molecular release pattern, and, subsequently, modulate the spatial organization of newly forming tissues, including blood vessels. Therefore, using a hydrogel printed to release vascular endothelial growth factor (VEGF) into a pre-defined pattern, this study demonstrates that spatial distribution of VEGF is important in guiding growth direction of new blood vessels, and also in retaining the structural integrity of pre-existing vasculature. Guided by a computational model, we fabricated a patch composed of micro-sized VEGF-releasing poly(ethylene glycol) diacrylate (PEGDA) hydrogel cylinders using an ink-jet printer. Interestingly, hydrogel printed with computationally optimized spacing created anisotropically aligned vasculature exclusively when the printed gel pattern was placed parallel to pre-existing blood vessels. In contrast, vascular sprouting from placing the printed gel pattern perpendicular to pre-existing vessels resulted in deformation and structural disintegration of the original vasculature. We envision that this study will be useful to better understand angiogenesis-modulated neovascularization and further improve the treatment quality for various wounds and tissue defects.

  3. Determination of trans- and cis-urocanic acid in relation to histamine, putrescine, and cadaverine contents in tuna (Auxis Thazard) at different storage temperatures.

    PubMed

    Zare, Davood; Muhammad, Kharidah; Bejo, Mohd Hair; Ghazali, H M

    2015-02-01

    Scombroid fish poisoning is usually associated with consumption of fish containing high levels of histamine. However, reports indicate that some cases have responded to antihistamine therapy while ingested histamine levels in these cases were low. Potentiation of histamine toxicity by some biogenic amines, and release of endogenous histamine by other compounds such as cis-urocanic acid (UCA) are some hypotheses that have been put forth to explain this anomaly. Very little is known about the effects of storage conditions on the production of both UCA isomers and biogenic amines in tuna. Thus, the production of trans- and cis-UCA, histamine, putrescine, and cadaverine in tuna during 15 d of storage at 0, 3, and 10 °C and 2 d storage at ambient temperature were monitored. The initial trans- and cis-UCA contents in fresh tuna were 2.90 and 1.47 mg/kg, respectively, whereas the levels of putrescine and cadaverine were less than 2 mg/kg, and histamine was not detected. The highest levels of trans- and cis-UCA were obtained during 15 d storage at 3 °C (23.74 and 21.79 mg/kg, respectively) while the highest concentrations of histamine (2796 mg/kg), putrescine (220.32 mg/kg) and cadaverine (1045.20 mg/kg) were obtained during storage at room temperature, 10 and 10 °C, respectively. Histamine content increased considerably during storage at 10 °C whereas trans- and cis-UCA contents changed slightly. The initial trans-UCA content decreased during storage at ambient temperature. Thus, unlike histamine, concentrations of trans- and cis-UCA did not result in elevated levels during storage of tuna.

  4. Synthesis of multilayered alginate microcapsules for the sustained release of fibroblast growth factor-1

    PubMed Central

    Khanna, Omaditya; Moya, Monica L; Opara, Emmanuel C; Brey, Eric M

    2010-01-01

    Alginate microcapsules coated with a permselective poly-L-ornithine (PLO) membrane have been investigated for the encapsulation and transplantation of islets as a treatment for type 1 diabetes. The therapeutic potential of this approach could be improved through local stimulation of microvascular networks in order to meet mass transport demands of the encapsulated cells. Fibroblast growth factor-1 (FGF-1) is a potent angiogenic factor with optimal effect occurring when it is delivered in a sustained manner. In this paper, a technique is described for the generation of multilayered alginate microcapsules with an outer alginate layer that can be used for the delivery of FGF-1. The influence of alginate concentration and composition (high mannuronic acid (M) or guluronic acid (G) content) on outer layer size and stability, protein encapsulation efficiency, and release kinetics was investigated. The technique results in a stable outer layer of alginate with a mean thickness between 113–164 µm, increasing with alginate concentration and G-content. The outer layer was able to encapsulate and release FGF-1 for up to thirty days, with 1.25% of high G alginate displaying the most sustained release. The released FGF-1 retained its biologic activity in the presence of heparin, and the addition of the outer layer did not alter the permselectivity of the PLO coat. This technique could be used to generate encapsulation systems that deliver proteins to stimulate local neovascularization around encapsulated islets. PMID:20725969

  5. Influence of Formulation Factors and Compression Force on Release Profile of Sustained Release Metoprolol Tablets using Compritol® 888ATO as Lipid Excipient

    PubMed Central

    Patere, Shilpa N.; Kapadia, Chhanda J.; Nagarsenker, Mangal S.

    2015-01-01

    Tablets containing metoprolol succinate and Compritol® 888ATO in the ratio of 1:2 yielded the desired sustained release profile in phosphate buffer pH 6.8 when evaluated using USP type II paddle apparatus and was selected as the optimized formulation. Robustness of optimized formulation was assessed by studying the effect of factors like varying source of metoprolol succinate and Compritol® 888ATO, compression force and hydroalcoholic dissolution medium on the release profile. No significant difference (P>0.05) in release profile was observed when metoprolol succinate from three different sources and Compritol® 888ATO from two different batches were used. Release profile of sustained release tablets of metoprolol succinate in media containing various concentrations of ethanol was comparable with media devoid of ethanol as evaluated by f2 test. This indicated that release profile of sustained release tablets of metoprolol succinate was reliable with no significant change due to variation in source of active pharmaceutical ingredient, particularly due to particle size distribution. Sustained release tablets of metoprolol succinate yielded release pattern within specifications irrespective of presence or absence of ethanol in the medium indicating that release properties of Compritol® 888ATO matrix are not affected by ethanol. Tablets compressed at compression force of <100 kg/cm2 exhibited low hardness with total porosity of 15.39% and significantly increased (P<0.05) metoprolol succinate release as compared to tablets compressed at 2000 kg/cm2 with 6.90% of total porosity revealing influence of compression force. Compritol® 888ATO holds great potential in providing reliable and controlled release profile of highly water soluble metoprolol succinate. PMID:26798179

  6. Influence of Formulation Factors and Compression Force on Release Profile of Sustained Release Metoprolol Tablets using Compritol(®) 888ATO as Lipid Excipient.

    PubMed

    Patere, Shilpa N; Kapadia, Chhanda J; Nagarsenker, Mangal S

    2015-01-01

    Tablets containing metoprolol succinate and Compritol(®) 888ATO in the ratio of 1:2 yielded the desired sustained release profile in phosphate buffer pH 6.8 when evaluated using USP type II paddle apparatus and was selected as the optimized formulation. Robustness of optimized formulation was assessed by studying the effect of factors like varying source of metoprolol succinate and Compritol(®) 888ATO, compression force and hydroalcoholic dissolution medium on the release profile. No significant difference (P>0.05) in release profile was observed when metoprolol succinate from three different sources and Compritol(®) 888ATO from two different batches were used. Release profile of sustained release tablets of metoprolol succinate in media containing various concentrations of ethanol was comparable with media devoid of ethanol as evaluated by f2 test. This indicated that release profile of sustained release tablets of metoprolol succinate was reliable with no significant change due to variation in source of active pharmaceutical ingredient, particularly due to particle size distribution. Sustained release tablets of metoprolol succinate yielded release pattern within specifications irrespective of presence or absence of ethanol in the medium indicating that release properties of Compritol(®) 888ATO matrix are not affected by ethanol. Tablets compressed at compression force of <100 kg/cm(2) exhibited low hardness with total porosity of 15.39% and significantly increased (P<0.05) metoprolol succinate release as compared to tablets compressed at 2000 kg/cm(2) with 6.90% of total porosity revealing influence of compression force. Compritol(®) 888ATO holds great potential in providing reliable and controlled release profile of highly water soluble metoprolol succinate. PMID:26798179

  7. Mast cell histamine promotes the immunoregulatory activity of myeloid-derived suppressor cells.

    PubMed

    Martin, Rebecca K; Saleem, Sheinei J; Folgosa, Lauren; Zellner, Hannah B; Damle, Sheela R; Nguyen, Giang-Kim T; Ryan, John J; Bear, Harry D; Irani, Anne-Marie; Conrad, Daniel H

    2014-07-01

    It has been shown recently that MCs are required for differential regulation of the immune response by granulocytic versus monocytic MDSCs. Granulocytic MDSCs promoted parasite clearance, whereas monocytic MDSCs enhanced tumor progression; both activities were abrogated in MC-deficient mice. Herein, we demonstrate that the lack of MCs also influences MDSC trafficking. Preferential trafficking to the liver was not seen in MC-deficient mice. In addition, evidence that the MC mediator histamine was important in MDSC trafficking and activation is also shown. MDSCs express HR1-3. Blockade of these receptors by HR1 or HR2 antagonists reversed the histamine enhancement of MDSC survival and proliferation observed in cell culture. In addition, histamine differentially influenced Arg1 and iNOS gene expression in MDSCs and greatly enhanced IL-4 and IL-13 message, especially in granulocytic MDSCs. Evidence that histamine influenced activity seen in vitro translated to in vivo when HR1 and HR2 antagonists blocked the effect of MDSCs on parasite expulsion and tumor metastasis. All of these data support the MDSC-mediated promotion of Th2 immunity, leading to the suggestion that allergic-prone individuals would have elevated MDSC levels. This was directly demonstrated by looking at the relative MDSC levels in allergic versus control patients. Monocytic MDSCs trended higher, whereas granulocytic MDSCs were increased significantly in allergic patients. Taken together, our studies indicate that MCs and MC-released histamine are critical for MDSC-mediated immune regulation, and this interaction should be taken into consideration for therapeutic interventions that target MDSCs.

  8. An in vitro assay system as a potential replacement for the histamine sensitisation test for acellular pertussis based combination vaccines.

    PubMed

    Yuen, Chun-Ting; Horiuchi, Yoshinobu; Asokanathan, Catpagavalli; Cook, Sarah; Douglas-Bardsley, Alexandra; Ochiai, Masaki; Corbel, Michael; Xing, Dorothy

    2010-05-01

    The histamine sensitisation test (HIST) for pertussis toxin is currently an official batch release test for acellular pertussis containing combination vaccines in Europe and North America. However, HIST, being a lethal endpoint assay, often leads to repeated tests due to large variations in test performance. Although a more precise HIST test based on measurement of temperature reduction after the histamine challenge is used in Asian countries, this test still uses animals. An in vitro test system based on a combination of enzyme coupled-HPLC and carbohydrate-binding assays with results analysed by a mathematical formula showed a good agreement with the in vivo HIST results based on measurement of temperature reduction after histamine challenge. The new in vitro test system was shown to be a potential alternative to the current in vivo HIST.

  9. Macrophage activation by factors released from acetaminophen-injured hepatocytes: Potential role of HMGB1

    SciTech Connect

    Dragomir, Ana-Cristina; Laskin, Jeffrey D.; Laskin, Debra L.

    2011-06-15

    Toxic doses of acetaminophen (AA) cause hepatocellular necrosis. Evidence suggests that activated macrophages contribute to the pathogenic process; however, the factors that activate these cells are unknown. In these studies, we assessed the role of mediators released from AA-injured hepatocytes in macrophage activation. Treatment of macrophages with conditioned medium (CM) collected 24 hr after treatment of mouse hepatocytes with 5 mM AA (CM-AA) resulted in increased production of reactive oxygen species (ROS). Macrophage expression of heme oxygenase-1 (HO-1) and catalase mRNA was also upregulated by CM-AA, as well as cyclooxygenase (COX)-2 and 12/15-lipoxygenase (LOX). CM-AA also upregulated expression of the proinflammatory chemokines, MIP-1{alpha} and MIP-2. The effects of CM-AA on expression of COX-2, MIP-1{alpha} and MIP-2 were inhibited by blockade of p44/42 MAP kinase, suggesting a biochemical mechanism mediating macrophage activation. Hepatocytes injured by AA were found to release HMGB1, a potent macrophage activator. This was inhibited by pretreatment of hepatocytes with ethyl pyruvate (EP), which blocks HMGB1 release. EP also blocked CM-AA induced ROS production and antioxidant expression, and reduced expression of COX-2, but not MIP-1{alpha} or MIP-2. These findings suggest that HMGB1 released by AA-injured hepatocytes contributes to macrophage activation. This is supported by our observation that expression of the HMGB1 receptor RAGE is upregulated in macrophages in response to CM-AA. These data indicate that AA-injured hepatocytes contribute to the inflammatory environment in the liver through the release of mediators such as HMGB1. Blocking HMGB1/RAGE may be a useful approach to limiting classical macrophage activation and AA-induced hepatotoxicity. - Research Highlights: > These studies analyze macrophage activation by mediators released from acetaminophen-damaged hepatocytes. > Factors released from acetaminophen-injured hepatocytes induce

  10. The metabolism of histamine in the Drosophila optic lobe involves an ommatidial pathway: β-alanine recycles through the retina.

    PubMed

    Borycz, Janusz; Borycz, Jolanta A; Edwards, Tara N; Boulianne, Gabrielle L; Meinertzhagen, Ian A

    2012-04-15

    Flies recycle the photoreceptor neurotransmitter histamine by conjugating it to β-alanine to form β-alanyl-histamine (carcinine). The conjugation is regulated by Ebony, while Tan hydrolyses carcinine, releasing histamine and β-alanine. In Drosophila, β-alanine synthesis occurs either from uracil or from the decarboxylation of aspartate but detailed roles for the enzymes responsible remain unclear. Immunohistochemically detected β-alanine is present throughout the fly's entire brain, and is enhanced in the retina especially in the pseudocone, pigment and photoreceptor cells of the ommatidia. HPLC determinations reveal 10.7 ng of β-alanine in the wild-type head, roughly five times more than histamine. When wild-type flies drink uracil their head β-alanine increases more than after drinking l-aspartic acid, indicating the effectiveness of the uracil pathway. Mutants of black, which lack aspartate decarboxylase, cannot synthesize β-alanine from l-aspartate but can still synthesize it efficiently from uracil. Our findings demonstrate a novel function for pigment cells, which not only screen ommatidia from stray light but also store and transport β-alanine and carcinine. This role is consistent with a β-alanine-dependent histamine recycling pathway occurring not only in the photoreceptor terminals in the lamina neuropile, where carcinine occurs in marginal glia, but vertically via a long pathway that involves the retina. The lamina's marginal glia are also a hub involved in the storage and/or disposal of carcinine and β-alanine.

  11. Potency of various peptides as histamine liberators in the rat hind limb.

    PubMed

    Rioux, F; Kérouac, R; St-Pierre, S

    1985-07-01

    The potency of several peptides and drugs as histamine liberators was assessed using the rat isolated hind limb preparation. Neurotensin (NT) and compound 48/80 (C48/80) were effective in concentrations as low as 10(-9) M and 10(-8) M, respectively. Threshold concentrations of vasoactive intestinal peptide (VIP) and substance P (SP) varied between 5 X 10(-7) to 5 X 10(-6) M while somatostatin (SS) was barely active at 6 X 10(-6) M. No histamine release could be detected following the use of high concentrations of thyrotropin releasing hormone (TRH) (6 X 10(-6) M), dynorphin (DYN) (6 X 10(-6) M) bradykinin (BK), des-Arg9-BK or bombesin (BB) (at 10(-5) M). Poly-L-Lysine and the calcium ionophore A23187 were about 100 times less active than NT. Concanavalin A (Con A) was inactive at 10(-6) M. These results indicate that NT is more potent (on a molar basis) as histamine liberator in the rat hind limb preparation (which contains a large population of cutaneous and subcutaneous mast cells) than any of the other compounds tested. Histamine release by NT was inhibited by preexposure of the rat hind limb mast cells to a high concentration of SP (1.5 X 10(-6) M). This result adds further support to the hypothesis suggesting that NT and SP might share a common mechanism of action and/or act through common receptors at least in rat mast cells.

  12. The Transcription Factor NIN-LIKE PROTEIN7 Controls Border-Like Cell Release1[OPEN

    PubMed Central

    Karve, Rucha

    2016-01-01

    The root cap covers the tip of the root and functions to protect the root from environmental stress. Cells in the last layer of the root cap are known as border cells, or border-like cells (BLCs) in Arabidopsis (Arabidopsis thaliana). These cells separate from the rest of the root cap and are released from its edge as a layer of living cells. BLC release is developmentally regulated, but the mechanism is largely unknown. Here, we show that the transcription factor NIN-LIKE PROTEIN7 (NLP7) is required for the proper release of BLCs in Arabidopsis. Mutations in NLP7 lead to BLCs that are released as single cells instead of an entire layer. NLP7 is highly expressed in BLCs and is activated by exposure to low pH, a condition that causes BLCs to be released as single cells. Mutations in NLP7 lead to decreased levels of cellulose and pectin. Cell wall-loosening enzymes such as CELLULASE5 (CEL5) and a pectin lyase-like gene, as well as the root cap regulators SOMBRERO and BEARSKIN1/2, are activated in nlp7-1 seedlings. Double mutant analysis revealed that the nlp7-1 phenotype depends on the expression level of CEL5. Mutations in NLP7 lead to an increase in susceptibility to a root-infecting fungal pathogen. Together, these data suggest that NLP7 controls the release of BLCs by acting through the cell wall-loosening enzyme CEL5. PMID:27221617

  13. Fluid flow releases fibroblast growth factor-2 from human aortic smooth muscle cells

    NASA Technical Reports Server (NTRS)

    Rhoads, D. N.; Eskin, S. G.; McIntire, L. V.

    2000-01-01

    This study tested the hypothesis that fluid shear stress regulates the release of fibroblast growth factor (FGF)-2 from human aortic smooth muscle cells. FGF-2 is a potent mitogen that is involved in the response to vascular injury and is expressed in a wide variety of cell types. FGF-2 is found in the cytoplasm of cells and outside cells, where it associates with extracellular proteoglycans. To test the hypothesis that shear stress regulates FGF-2 release, cells were exposed to flow, and FGF-2 amounts were measured from the conditioned medium, pericellular fraction (extracted by heparin treatment), and cell lysate. Results from the present study show that after 15 minutes of shear stress at 25 dyne/cm(2) in a parallel-plate flow system, a small but significant fraction (17%) of the total FGF-2 was released from human aortic smooth muscle cells. FGF-2 levels in the circulating medium increased 10-fold over medium from static controls (P<0.01). A 50% increase in FGF-2 content versus control (P<0.01) was found in the pericellular fraction (extracted by heparin treatment). Furthermore, a significant decrease in FGF-2 was detected in the cell lysate, indicating that FGF-2 was released from inside the cell. Cell permeability studies with fluorescent dextran were performed to examine whether transient membrane disruption caused FGF-2 release. Flow cytometry detected a 50% increase in mean fluorescence of cells exposed to 25 dyne/cm(2) versus control cells. This indicates that the observed FGF-2 release from human aortic smooth muscle cells is likely due to transient membrane disruption on initiation of flow.

  14. Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors.

    PubMed

    Miyatake, Shouta; Shimizu-Motohashi, Yuko; Takeda, Shin'ichi; Aoki, Yoshitsugu

    2016-01-01

    Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD. PMID:27621596

  15. Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors

    PubMed Central

    Miyatake, Shouta; Shimizu-Motohashi, Yuko; Takeda, Shin’ichi; Aoki, Yoshitsugu

    2016-01-01

    Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD.

  16. Outrage Factors in Government Press Releases of Food Risk and Their Influence on News Media Coverage.

    PubMed

    Ju, Youngkee; Lim, Jeongsub; Shim, Minsun; You, Myoungsoon

    2015-08-01

    An appropriate level of risk perception should be a critical issue in modern "risk society." There have been many studies on the influences on risk perception. This study investigates whether risk communication scholar Dr. Peter Sandman's outrage factors intensify journalistic attention to health risks from food consumption. A content analysis of a health institution's press releases was conducted to examine 15 outrage factors of food risks conveyed in the governmental risk communication. In addition, the news stories covering the food risks informed by the press releases were calculated to evaluate the relation between outrage factors of a risk and the number of news stories covering the risk. Results showed that controllability was the most salient outrage factor, followed by trust, voluntariness, familiarity, and human origin; the greater the outrage score of a risk, the more news stories of the risk. For individual outrage factors, a risk with an implication of catastrophic potential was associated with an increase of news stories. Food providers' distrustful behaviors also influenced journalistic attention to the food risks. The implication of the findings to health message designers is discussed.

  17. Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors.

    PubMed

    Miyatake, Shouta; Shimizu-Motohashi, Yuko; Takeda, Shin'ichi; Aoki, Yoshitsugu

    2016-01-01

    Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD.

  18. Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors

    PubMed Central

    Miyatake, Shouta; Shimizu-Motohashi, Yuko; Takeda, Shin’ichi; Aoki, Yoshitsugu

    2016-01-01

    Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD. PMID:27621596

  19. Outrage Factors in Government Press Releases of Food Risk and Their Influence on News Media Coverage.

    PubMed

    Ju, Youngkee; Lim, Jeongsub; Shim, Minsun; You, Myoungsoon

    2015-08-01

    An appropriate level of risk perception should be a critical issue in modern "risk society." There have been many studies on the influences on risk perception. This study investigates whether risk communication scholar Dr. Peter Sandman's outrage factors intensify journalistic attention to health risks from food consumption. A content analysis of a health institution's press releases was conducted to examine 15 outrage factors of food risks conveyed in the governmental risk communication. In addition, the news stories covering the food risks informed by the press releases were calculated to evaluate the relation between outrage factors of a risk and the number of news stories covering the risk. Results showed that controllability was the most salient outrage factor, followed by trust, voluntariness, familiarity, and human origin; the greater the outrage score of a risk, the more news stories of the risk. For individual outrage factors, a risk with an implication of catastrophic potential was associated with an increase of news stories. Food providers' distrustful behaviors also influenced journalistic attention to the food risks. The implication of the findings to health message designers is discussed. PMID:26065830

  20. Low brain histamine content affects ethanol-induced motor impairment.

    PubMed

    Lintunen, Minnamaija; Raatesalmi, Kristiina; Sallmen, Tina; Anichtchik, Oleg; Karlstedt, Kaj; Kaslin, Jan; Kiianmaa, Kalervo; Korpi, Esa R; Panula, Pertti

    2002-02-01

    The effect of ethanol on motor performance in humans is well established but how neural mechanisms are affected by ethanol action remains largely unknown. To investigate whether the brain histaminergic system is important in it, we used a genetic model consisting of rat lines selectively outbred for differential ethanol sensitivity. Ethanol-sensitive rats had lower levels of brain histamine and lower densities of histamine-immunoreactive fibers than ethanol-insensitive rats, although both rat lines showed no changes in histamine synthesizing neurons. Lowering the high brain histamine content of the ethanol-insensitive rats with alpha-fluoromethylhistidine before ethanol administration increased their ethanol sensitivity in a behavioral motor function test. Higher H3 receptor ligand binding and histamine-induced G-protein activation was detected in several brain regions of ethanol-naive ethanol-sensitive rats. Brain histamine levels and possibly signaling via H3 receptors may thus correlate with genetic differences in ethanol-induced motor impairment.

  1. Plasma histamine after methacholine, allergen, and aspirin challenges.

    PubMed

    Kinsella, M; Salari, H; Chan, H; Tse, K S; Chan-Yeung, M

    1987-01-01

    Plasma histamine levels were measured by radio-enzymatic technique in seven patients following 10 challenges: five methacholine challenge tests, four antigen inhalation challenge tests, and one oral aspirin challenge test. Baseline plasma histamine was the same in all patients except in the aspirin-challenged patient, who had a higher baseline histamine level. There was no statistical change in the level of histamine throughout the test in either the methacholine-challenged or the antigen-challenged patients, whereas there was a marked increase in histamine levels in the aspirin challenged patient. A possible explanation is that methacholine and antigen are inhaled and therefore have primarily local effects on the lung, whereas oral aspirin has a systemic effect with consequently systemic changes in histamine which are detectable as changes in plasma level.

  2. Histamine pharmacology and new CNS drug targets.

    PubMed

    Tiligada, Ekaterini; Kyriakidis, Konstantinos; Chazot, Paul L; Passani, M Beatrice

    2011-12-01

    During the last decade, the identification of a number of novel drug targets led to the development of promising new compounds which are currently under evaluation for their therapeutic prospective in CNS related disorders. Besides the established pleiotropic regulatory functions in the periphery, the interest in the potential homeostatic role of histamine in the brain was revived following the identification of H(3) and H(4) receptors some years ago. Complementing classical CNS pharmacology, the development of selective histamine receptor agonists, antagonists, and inverse agonists provides the lead for the potential exploitation of the histaminergic system in the treatment of brain pathologies. Although no CNS disease entity has been associated directly to brain histamine dysfunction until now, the H(3) receptor is recognized as a drug target for neuropathic pain, sleep-wake disorders, including narcolepsy, and cognitive impairment associated with attention deficit hyperactivity disorder, schizophrenia, Alzheimer's, or Parkinson's disease, while the first H(3) receptor ligands have already entered phase I-III clinical trials. Interestingly, the localization of the immunomodulatory H(4) receptor in the nervous system exposes attractive perspectives for the therapeutic exploitation of this new drug target in neuroimmunopharmacology. This review focuses on a concise presentation of the current "translational research" approach that exploits the latest advances in histamine pharmacology for the development of beneficial drug targets for the treatment of neuronal disorders, such as neuropathic pain, cognitive, and sleep-wake pathologies. Furthermore, the role of the brain histaminergic system(s) in neuroprotection and neuroimmunology/inflammation remains a challenging research area that is currently under consideration.

  3. Histamine facilitates consolidation of fear extinction.

    PubMed

    Bonini, Juliana Sartori; Da Silva, Weber Cláudio; Da Silveira, Clarice Kras Borges; Köhler, Cristiano André; Izquierdo, Iván; Cammarota, Martín

    2011-10-01

    Non-reinforced retrieval induces memory extinction, a phenomenon characterized by a decrease in the intensity of the learned response. This attribute has been used to develop extinction-based therapies to treat anxiety and post-traumatic stress disorders. Histamine modulates memory and anxiety but its role on fear extinction has not yet been evaluated. Therefore, using male Wistar rats, we determined the effect of the intra-hippocampal administration of different histaminergic agents on the extinction of step-down inhibitory avoidance (IA), a form of aversive learning. We found that intra-CA1 infusion of histamine immediately after non-reinforced retrieval facilitated consolidation of IA extinction in a dose-dependent manner. This facilitation was mimicked by the histamine N-methyltransferase inhibitor SKF91488 and the H2 receptor agonist dimaprit, reversed by the H2 receptor antagonist ranitidine, and unaffected by the H1 antagonist pyrilamine, the H3 antagonist thioperamide and the antagonist at the NMDA receptor (NMDAR) polyamine-binding site ifenprodil. Neither the H1 agonist 2-2-pyridylethylamine nor the NMDAR polyamine-binding site agonist spermidine affected the consolidation of extinction while the H3 receptor agonist imetit hampered it. Extinction induced the phosphorylation of ERK1 in dorsal CA1 while intra-CA1 infusion of the MEK inhibitor U0126 blocked extinction of the avoidance response. The extinction-induced phosphorylation of ERK1 was enhanced by histamine and dimaprit and blocked by ranitidine administered to dorsal CA1 after non-reinforced retrieval. Taken together, our data indicate that the hippocampal histaminergic system modulates the consolidation of fear extinction through a mechanism involving the H2-dependent activation of ERK signalling.

  4. Corticotropin releasing factor and catecholamines enhance glutamatergic neurotransmission in the lateral subdivision of the central amygdala.

    PubMed

    Silberman, Yuval; Winder, Danny G

    2013-07-01

    Glutamatergic neurotransmission in the central nucleus of the amygdala (CeA) plays an important role in many behaviors including anxiety, memory consolidation and cardiovascular responses. While these behaviors can be modulated by corticotropin releasing factor (CRF) and catecholamine signaling, the mechanism(s) by which these signals modify CeA glutamatergic neurotransmission remains unclear. Utilizing whole-cell patch-clamp electrophysiology recordings from neurons in the lateral subdivision of the CeA (CeAL), we show that CRF, dopamine (DA) and the β-adrenergic receptor agonist isoproterenol (ISO) all enhance the frequency of spontaneous excitatory postsynaptic currents (sEPSC) without altering sEPSC kinetics, suggesting they increase presynaptic glutamate release. The effect of CRF on sEPSCs was mediated by a combination of CRFR1 and CRFR2 receptors. While previous work from our lab suggests that CRFRs mediate the effect of catecholamines on excitatory transmission in other subregions of the extended amygdala, blockade of CRFRs in the CeAL failed to significantly alter effects of DA and ISO on glutamatergic transmission. These findings suggest that catecholamine and CRF enhancement of glutamatergic transmission onto CeAL neurons occurs via distinct mechanisms. While CRF increased spontaneous glutamate release in the CeAL, CRF caused no significant changes to optogenetically evoked glutamate release in this region. The dissociable effects of CRF on different types of glutamatergic neurotransmission suggest that CRF may specifically regulate spontaneous excitatory transmission.

  5. Anorexia induced by interleukin 1: involvement of corticotropin-releasing factor.

    PubMed

    Uehara, A; Sekiya, C; Takasugi, Y; Namiki, M; Arimura, A

    1989-09-01

    It has recently been demonstrated by three independent research groups including ours that interleukin 1 (IL-1), a polypeptide hormone produced by activated monocytes or macrophages, or both, stimulates the release of hypothalamic corticotropin-releasing factor (CRF). Since CRF acts centrally in the brain to reduce food intake, we hypothesized that IL-1 might induce anorexia through this central action of CRF. The present study was carried out to examine the hypothesis, using male Wistar rats. Based on three lines of evidence, we report here that IL-1, both endogenously released and exogenously administered, induces the suppression of food intake in rats and that endogenous CRF in the brain is involved in the IL-1-induced anorexia. First, lipopolysaccharide (LPS), a potent stimulant of the release and production of endogenous IL-1, caused anorexia in a dose-related manner, and this effect was significantly blocked by pretreatment with glucocorticoid hormones, which have been shown to inhibit the production of endogenous IL-1 by LPS. Second, intraperitoneal injection of IL-1 resulted in a dose-related suppression of food intake. Third, anorexia induced by IL-1 was diminished by the immunoneutralization of endogenous CRF in the brain. These results provide further evidence of the existence of bidirectional communication between the immune and neuroendocrine systems. Furthermore, this connection between IL-1 and CRF may represent a mechanism by which anorexia results from the activation of the immune system by such immunological challenges as acute infectious diseases.

  6. Neuroprotection elicited by nerve growth factor and brain-derived neurotrophic factor released from astrocytes in response to methylmercury.

    PubMed

    Takemoto, Takuya; Ishihara, Yasuhiro; Ishida, Atsuhiko; Yamazaki, Takeshi

    2015-07-01

    The protective roles of astrocytes in neurotoxicity induced by environmental chemicals, such as methylmercury (MeHg), are largely unknown. We found that conditioned medium of MeHg-treated astrocytes (MCM) attenuated neuronal cell death induced by MeHg, suggesting that astrocytes-released factors can protect neuronal cells. The increased expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) was observed in MeHg-treated astrocytes. NGF and BDNF were detected in culture media as homodimers, which are able to bind specific tyrosine kinase receptors, tropomyosin related kinase (Trk) A and TrkB, respectively. The TrkA antagonist and TrkB antagonist abolished the protective effects of MCM in neuronal cell death induced by MeHg. Taken together, astrocytes synthesize and release NGF and BDNF in response to MeHg to protect neurons from MeHg toxicity. This study is considered to show a novel defense mechanism against MeHg-induced neurotoxicity.

  7. Pulmonary serotonin and histamine in experimental asbestosis

    SciTech Connect

    Keith, I.M.; Day, R.; Lemaire, S.

    1986-03-01

    Adult male Wistar rats were treated once with tracheal instillation of 5 mg Crysotile B asbestos fibers in 0.5 ml saline under ketamine/xylaxine anesthesia. Control rats (n = 37) received 0.5 ml saline. Test and control rats were killed at 7 and 14 d., and 1, 3 and 6 mo. post instillation. Serotonin (5-HT) was quantitated in lung tissue homogenate from all rats using HPLC and electrochemical detection. Among rats killed at 1, 3 and 6 mo., lung tissue histamine-o-phthaldialdehyde complex was quantitated using reverse phase HPLC coupled to a fluorometric detector. Furthermore, 5-HT was quantitated in the cytoplasm of grouped (NEB) and individual (NEC) neuroendocrine cells and in mast cells using formaldehyde-vapor-induced fluorescence and microspectrofluorometry, and mast cell numbers were determined. Test rats had higher pulmonary 5-HT and histamine levels than controls at 1, 3 and 6 mo. Test rats also had higher cellular 5-HT compared to controls in NEB's at 1 mo., but not in NECs, and tended to have higher 5-HT-levels in mast cells at 6 mo. Mast cell numbers were higher among tests at 1 and 3 mo. The authors results suggest that NEBs may contribute to the early asbestos induced rise in 5-HT, and that the major source of 5-HT and histamine is from the increased numbers of mast cells.

  8. Histamine poisoning (scombroid fish poisoning): an allergy-like intoxication.

    PubMed

    Taylor, S L; Stratton, J E; Nordlee, J A

    1989-01-01

    Histamine poisoning results from the consumption of foods, typically certain types of fish and cheeses, that contain unusually high levels of histamine. Spoiled fish of the families, Scombridae and Scomberesocidae (e.g. tuna, mackerel, bonito), are commonly implicated in incidents of histamine poisoning, which leads to the common usage of the term, "scombroid fish poisoning", to describe this illness. However, certain non-scombroid fish, most notably mahi-mahi, bluefish, and sardines, when spoiled are also commonly implicated in histamine poisoning. Also, on rare occasions, cheeses especially Swiss cheese, can be implicated in histamine poisoning. The symptoms of histamine poisoning generally resemble the symptoms encountered with IgE-mediated food allergies. The symptoms include nausea, vomiting, diarrhea, an oral burning sensation or peppery taste, hives, itching, red rash, and hypotension. The onset of the symptoms usually occurs within a few minutes after ingestion of the implicated food, and the duration of symptoms ranges from a few hours to 24 h. Antihistamines can be used effectively to treat this intoxication. Histamine is formed in foods by certain bacteria that are able to decarboxylate the amino acid, histidine. However, foods containing unusually high levels of histamine may not appear to be outwardly spoiled. Foods with histamine concentrations exceeding 50 mg per 100 g of food are generally considered to be hazardous. Histamine formation in fish can be prevented by proper handling and refrigerated storage while the control of histamine formation in cheese seems dependent on insuring that histamine-producing bacteria are not present in significant numbers in the raw milk.

  9. Cyclic strain alters the expression and release of angiogenic factors by human tendon cells.

    PubMed

    Mousavizadeh, Rouhollah; Khosravi, Shahram; Behzad, Hayedeh; McCormack, Robert G; Duronio, Vincent; Scott, Alex

    2014-01-01

    Angiogenesis is associated with the tissue changes underlying chronic overuse tendinopathy. We hypothesized that repetitive, cyclic loading of human tendon cells would lead to increased expression and activity of angiogenic factors. We subjected isolated human tendon cells to overuse tensile loading using an in vitro model (1 Hz, 10% equibiaxial strain). We found that mechanically stimulated human tendon cells released factors that promoted in vitro proliferation and tube formation by human umbilical vein endothelial cells (HUVEC). In response to cyclic strain, there was a transient increase in the expression of several angiogenic genes including ANGPTL4, FGF-2, COX-2, SPHK1, TGF-alpha, VEGF-A and VEGF-C, with no change in anti-angiogenic genes (BAI1, SERPINF1, THBS1 and 2, TIMP1-3). Cyclic strain also resulted in the extracellular release of ANGPTL4 protein by tendon cells. Our study is the first report demonstrating the induction of ANGPTL4 mRNA and release of ANGPTL4 protein in response to cyclic strain. Tenocytes may contribute to the upregulation of angiogenesis during the development of overuse tendinopathy. PMID:24824595

  10. Calcium-Alginate Hydrogel-Encapsulated Fibroblasts Provide Sustained Release of Vascular Endothelial Growth Factor

    PubMed Central

    Hunt, Nicola C.; Shelton, Richard M.; Henderson, Deborah J.

    2013-01-01

    Vascularization of engineered or damaged tissues is essential to maintain cell viability and proper tissue function. Revascularization of the left ventricle (LV) of the heart after myocardial infarction is particularly important, since hypoxia can give rise to chronic heart failure due to inappropriate remodeling of the LV after death of cardiomyocytes (CMs). Fibroblasts can express vascular endothelial growth factor (VEGF), which plays a major role in angiogenesis and also acts as a chemoattractant and survival factor for CMs and cardiac progenitors. In this in vitro model study, mouse NIH 3T3 fibroblasts encapsulated in 2% w/v Ca-alginate were shown to remain viable for 150 days. Semiquantitative reverse transcription–polymerase chain reaction and immunohistochemistry demonstrated that over 21 days of encapsulation, fibroblasts continued to express VEGF, while enzyme-linked immunosorbent assay showed that there was sustained release of VEGF from the Ca-alginate during this period. The scaffold degraded gradually over the 21 days, without reduction in volume. Cells released from the Ca-alginate at 7 and 21 days as a result of scaffold degradation were shown to retain viability, to adhere to fibronectin in a normal manner, and continue to express VEGF, demonstrating their potential to further contribute to maintenance of cardiac function after scaffold degradation. This model in vitro study therefore demonstrates that fibroblasts encapsulated in Ca-alginate provide sustained release of VEGF. PMID:23082964

  11. Synthesis of new thiazolo[4,5-d]pyrimidines as Corticotropin releasing factor modulators.

    PubMed

    Kuppast, Bhimanna; Spyridaki, Katerina; Lynch, Christophina; Hu, Yueshan; Liapakis, George; Davies, Gareth E; Fahmy, Hesham

    2014-01-01

    Corticotropin-releasing factor (CRF) is a neurohormone that plays a crucial role in integrating the body's overall response to stress. It appears necessary and sufficient for the organism to mount functional, physiological and endocrine responses to stressors. CRF is released in response to various triggers such as chronic stress. The role of CRF and its involvement in these neurological disorders suggest that new drugs that can target the CRF function or bind to its receptors may represent a new development of neuropsychiatric medicines to treat various stress-related disorders including depression, anxiety and addictive disorders. Based on pharmacophore of the CRF1 receptor antagonists, a new series of thiazolo[4,5-d] pyrimidines were synthesized as Corticotropin-releasing factor (CRF) receptor modulators and the prepared compounds carry groups shown to produce optimum binding affinity to CRF receptors. Twenty two compounds were evaluated for their CRF1 receptor binding affinity in HEK 293 cell lines and two compounds 5o and 5s showed approximately 25% binding affinity to CRF1 receptors. Selected compounds (5c and 5f) were also evaluated for their effect on expression of genes associated with depression and anxiety disorders such as CRF1, CREB1, MAO-A, SERT, NPY, DatSLC6a3, and DBH and significant upregulation of CRF1 mRNA has been observed with compound 5c. PMID:25059547

  12. Injectable gelatin derivative hydrogels with sustained vascular endothelial growth factor release for induced angiogenesis

    PubMed Central

    Li, Zhe; Qu, Tiejun; Ding, Chen; Ma, Chi; Sun, Hongchen; Li, Shirong; Liu, Xiaohua

    2014-01-01

    Injectable biomaterials are attractive for soft tissue regeneration because they are handled in a minimally invasive manner and can easily adapt to complex defects. However, inadequate vascularization of the injectable constructs has long been a barrier, leading to necrosis or volume reduction after implantation. In this work, we developed a three-step process to synthesize injectable gelatin-derived hydrogels that are capable of controlling growth factor delivery to induce angiogenesis. In our approach, tyramine was first introduced into gelatin chains to provide enzymatical crosslinking points for gel formation after injection. Next, heparin, a polysaccharide with binding domains to many growth factors, was covalently linked to the tyramine-modified gelatin. Finally, vascular endothelial growth factor (VEGF) was incorporated into the gelatin derivative by binding with the heparin in the gelatin derivative, and an injectable gel with controlled VEGF release was formed by an enzymatic catalytic reaction with hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). The gelation time, mechanical properties and degradation of the gel was readily tailored by the gelatin concentration and the ratio of H2O2/HRP. Binding VEGF to heparin stabilizes this growth factor, protects it from denaturation and proteolytic degradation, and subsequently prolongs the sustained release. An in vitro release study and bioactivity assay indicated that the VEGF was released in a sustained manner with high bioactivity for over 3 weeks. Furthermore, a chicken chorioallantoic membrane (CAM) assay and animal experiments were performed to evaluate in vivo bioactivity of the VEGF released from the hydrogels. After 5 days of incubation on CAM, the number of blood vessels surrounding the heparin-modified hydrogels was 2.4-fold increase than that of the control group. Deeper and denser cell infiltration and angiogenesis in the heparin-modified gelatin/VEGF gels were observed than in the controls

  13. Injectable gelatin derivative hydrogels with sustained vascular endothelial growth factor release for induced angiogenesis.

    PubMed

    Li, Zhe; Qu, Tiejun; Ding, Chen; Ma, Chi; Sun, Hongchen; Li, Shirong; Liu, Xiaohua

    2015-02-01

    Injectable biomaterials are attractive for soft tissue regeneration because they are handled in a minimally invasive manner and can easily adapt to complex defects. However, inadequate vascularization of the injectable constructs has long been a barrier, leading to necrosis or volume reduction after implantation. In this work, we developed a three-step process to synthesize injectable gelatin-derived hydrogels that are capable of controlling growth factor delivery to induce angiogenesis. In our approach, tyramine was first introduced into gelatin chains to provide enzymatic crosslinking points for gel formation after injection. Next, heparin, a polysaccharide with binding domains to many growth factors, was covalently linked to the tyramine-modified gelatin. Finally, vascular endothelial growth factor (VEGF) was incorporated into the gelatin derivative by binding with the heparin in the gelatin derivative, and an injectable gel with controlled VEGF release was formed by an enzymatic catalytic reaction with hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). The gelation time, mechanical properties and degradation of the gel was readily tailored by the gelatin concentration and the ratio of H2O2/HRP. Binding VEGF to heparin stabilizes this growth factor, protects it from denaturation and proteolytic degradation and subsequently prolongs the sustained release. An in vitro release study and bioactivity assay indicated that the VEGF was released in a sustained manner with high bioactivity for over 3 weeks. Furthermore, a chicken chorioallantoic membrane (CAM) assay and animal experiments were performed to evaluate in vivo bioactivity of the VEGF released from the hydrogels. After 5 days of incubation on CAM, the number of blood vessels surrounding the heparin-modified hydrogels was increased by 2.4-fold compared with that of the control group. Deeper and denser cell infiltration and angiogenesis in the heparin-modified gelatin/VEGF gels were observed compared to

  14. Injectable gelatin derivative hydrogels with sustained vascular endothelial growth factor release for induced angiogenesis.

    PubMed

    Li, Zhe; Qu, Tiejun; Ding, Chen; Ma, Chi; Sun, Hongchen; Li, Shirong; Liu, Xiaohua

    2015-02-01

    Injectable biomaterials are attractive for soft tissue regeneration because they are handled in a minimally invasive manner and can easily adapt to complex defects. However, inadequate vascularization of the injectable constructs has long been a barrier, leading to necrosis or volume reduction after implantation. In this work, we developed a three-step process to synthesize injectable gelatin-derived hydrogels that are capable of controlling growth factor delivery to induce angiogenesis. In our approach, tyramine was first introduced into gelatin chains to provide enzymatic crosslinking points for gel formation after injection. Next, heparin, a polysaccharide with binding domains to many growth factors, was covalently linked to the tyramine-modified gelatin. Finally, vascular endothelial growth factor (VEGF) was incorporated into the gelatin derivative by binding with the heparin in the gelatin derivative, and an injectable gel with controlled VEGF release was formed by an enzymatic catalytic reaction with hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). The gelation time, mechanical properties and degradation of the gel was readily tailored by the gelatin concentration and the ratio of H2O2/HRP. Binding VEGF to heparin stabilizes this growth factor, protects it from denaturation and proteolytic degradation and subsequently prolongs the sustained release. An in vitro release study and bioactivity assay indicated that the VEGF was released in a sustained manner with high bioactivity for over 3 weeks. Furthermore, a chicken chorioallantoic membrane (CAM) assay and animal experiments were performed to evaluate in vivo bioactivity of the VEGF released from the hydrogels. After 5 days of incubation on CAM, the number of blood vessels surrounding the heparin-modified hydrogels was increased by 2.4-fold compared with that of the control group. Deeper and denser cell infiltration and angiogenesis in the heparin-modified gelatin/VEGF gels were observed compared to

  15. Insufficient intake of L-histidine reduces brain histamine and causes anxiety-like behaviors in male mice.

    PubMed

    Yoshikawa, Takeo; Nakamura, Tadaho; Shibakusa, Tetsuro; Sugita, Mayu; Naganuma, Fumito; Iida, Tomomitsu; Miura, Yamato; Mohsen, Attayeb; Harada, Ryuichi; Yanai, Kazuhiko

    2014-10-01

    L-histidine is one of the essential amino acids for humans, and it plays a critical role as a component of proteins. L-histidine is also important as a precursor of histamine. Brain histamine is synthesized from L-histidine in the presence of histidine decarboxylase, which is expressed in histamine neurons. In the present study, we aimed to elucidate the importance of dietary L-histidine as a precursor of brain histamine and the histaminergic nervous system. C57BL/6J male mice at 8 wk of age were assigned to 2 different diets for at least 2 wk: the control (Con) diet (5.08 g L-histidine/kg diet) or the low L-histidine diet (LHD) (1.28 g L-histidine/kg diet). We measured the histamine concentration in the brain areas of Con diet-fed mice (Con group) and LHD-fed mice (LHD group). The histamine concentration was significantly lower in the LHD group [Con group vs. LHD group: histamine in cortex (means ± SEs): 13.9 ± 1.25 vs. 9.36 ± 0.549 ng/g tissue; P = 0.002]. Our in vivo microdialysis assays revealed that histamine release stimulated by high K(+) from the hypothalamus in the LHD group was 60% of that in the Con group (P = 0.012). However, the concentrations of other monoamines and their metabolites were not changed by the LHD. The open-field tests showed that the LHD group spent a shorter amount of time in the central zone (87.6 ± 14.1 vs. 50.0 ± 6.03 s/10 min; P = 0.019), and the light/dark box tests demonstrated that the LHD group spent a shorter amount of time in the light box (198 ± 8.19 vs. 162 ± 14.1 s/10 min; P = 0.048), suggesting that the LHD induced anxiety-like behaviors. However, locomotor activity, memory functions, and social interaction did not differ between the 2 groups. The results of the present study demonstrated that insufficient intake of histidine reduced the brain histamine content, leading to anxiety-like behaviors in the mice.

  16. Cardiovascular response to histamine during normoxaemia and hypoxaemia in piglets.

    PubMed

    Taylor, B J

    1989-02-01

    The cardiovascular effects of exogenously administered histamine were investigated in conscious newborn piglets aged 10-11 days during normoxia (21% (v/v) O2) and during isocapneic alveolar hypoxia (10% O2, 3% CO2, 87% N2) to determine its influence on preexisting vascular tone. In the first set of experiments (n = 6), four histamine doses (1,10,50,100 micrograms/kg) were tested in sequence during normoxia. Histamine was injected intravenously and cardiovascular variables were recorded. Heart rate increased at all doses studied. Pulmonary and systemic arterial pressures, cardiac output and stroke volume were unchanged at the low histamine doses (1 and 10 micrograms), but all decreased at the high doses (50 and 100 micrograms). Pulmonary and systemic vascular resistances were unchanged at each dose. In the second set of experiments (n = 7), two histamine doses (1 and 5 micrograms/kg) were administered during alveolar hypoxia. Hypoxia caused increases in heart rate and pulmonary arterial pressure and resistance. After injection of each dose of histamine, pulmonary pressure and resistance decreased but remained higher than baseline. No other measured cardiovascular variables were altered. Thus, during normoxia histamine did not alter vascular tone, but high doses did adversely affect myocardial function. During alveolar hypoxia histamine caused weak pulmonary vasodilation at doses that did not alter systemic vascular tone. Histamine is not a potent modifier of the circulation in the newborn piglet during conditions of normoxaemia or hypoxaemia.

  17. Histamine, norepinephrine and serotonin content of nasal polyps.

    PubMed

    Bumsted, R M; El-Ackad, T; Smith, J M; Brody, M J

    1979-05-01

    Histamine, norepinephrine and serotonin were assayed and localized by fluorescence histochemistry in normal mucosa and nasal polyps because of their possible role in the development of inflammation and edema. Histamine was present in greater concentration in nasal polyps than in normal mucosa. Norepinephrine was present primarily in the base of nasal polyps and in greater concentration than in normal mucosa. Patients with aspirin sensitivity and asthma had much lower histamine concentrations in their nasal polyps than all other patients with nasal polyps. A proposal for a possible mechanism of formation of nasal polyps based on vascular and inflammatory mechanisms and incorporative roles for histamine and norepinephrine is presented.

  18. Corticotropin releasing factor receptor type 1: molecular cloning and investigation of alternative splicing in the hamster skin.

    PubMed

    Pisarchik, Alexander; Slominski, Andrzej

    2002-06-01

    The coding region of the hamster corticotropin releasing factor receptor type 1 was sequenced. Hamster gene appeared to be similar to mouse, rat, and human sequences with 95%, 94%, and 91% homology, respectively. Protein substitutions were generally found in the corticotropin releasing factor-binding domain. Thus, this domain can be more prone to mutations leading to changes in amino acid sequence. Hamster pituitary, eye, spleen, heart, skin, and four melanoma lines differentially expressed nine corticotropin releasing factor-R1 isoforms. These included the corticotropin releasing factor-R1alpha and corticotropin releasing factor-R1d homologs of human isoforms as well as e, f, h, j, k, m, and n isoforms. Corticotropin releasing factor-R1e mRNA had deletion of exons 3 and 4, CRF-R1j of exon 5, CRF-R1f of exon 11, CRF-R1k of exon 10, CRF-R1m of exons 11 and 12, and CRF-R1n of exons 10, 11, and 12. Corticotropin releasing factor-R1h had an insertion of a cryptic exon between exons 4 and 5. Reading frames of isoforms e, f, j, k, m, and h contained frameshifts, expected to produce truncated proteins. Corticotropin releasing factor-R1n isoform preserved the reading frame, but the transmembrane domains 6, 7, and one-third of the fifth were deleted. The AbC1 hamster melanoma cell line changed the pattern of alternative splicing after irradiation with ultraviolet light or induction of melanogenesis; this suggests that corticotropin releasing factor receptor alternative splicing may be regulated by common stressors, through modifications of activity and/or availability of splicing factors.

  19. Controlled release of nerve growth factor from heparin-conjugated fibrin gel within the nerve growth factor-delivering implant

    PubMed Central

    Lee, Jin-Yong; Kim, Soung-Min; Kim, Myung-Jin

    2014-01-01

    Objectives Although nerve growth factor (NGF) could promote the functional regeneration of an injured peripheral nerve, it is very difficult for NGF to sustain the therapeutic dose in the defect due to its short half-life. In this study, we loaded the NGF-bound heparin-conjugated fibrin (HCF) gel in the NGF-delivering implants and analyzed the time-dependent release of NGF and its bioactivity to evaluate the clinical effectiveness. Materials and Methods NGF solution was made of 1.0 mg of NGF and 1.0 mL of phosphate buffered saline (PBS). Experimental group A consisted of three implants, in which 0.25 µL of NGF solution, 0.75 µL of HCF, 1.0 µL of fibrinogen and 2.0 µL of thrombin was injected via apex hole with micropipette and gelated, were put into the centrifuge tube. Three implants of experimental group B were prepared with the mixture of 0.5 µL of NGF solution, 0.5 µL HCF, 1.0 µL of fibrinogen and 2.0 µL of thrombin. These six centrifuge tubes were filled with 1.0 mL of PBS and stirred in the water-filled beaker at 50 rpm. At 1, 3, 5, 7, 10, and 14 days, 1.0 mL of solution in each tubes was collected and preserved at -20℃ with adding same amount of fresh PBS. Enzyme-linked immunosorbent assay (ELISA) was done to determine in vitro release profile of NGF and its bioactivity was evaluated with neural differentiation of pheochromocytoma (PC12) cells. Results The average concentration of released NGF in the group A and B increased for the first 5 days and then gradually decreased. Almost all of NGF was released during 10 days. Released NGF from two groups could promote neural differentiation and neurite outgrowth of PC12 cells and these bioactivity was maintained over 14 days. Conclusion Controlled release system using NGF-HCF gel via NGF-delivering implant could be an another vehicle of delivering NGF to promote the nerve regeneration of dental implant related nerve damage. PMID:24627836

  20. Electrically induced brain-derived neurotrophic factor release from Schwann cells.

    PubMed

    Luo, Beier; Huang, Jinghui; Lu, Lei; Hu, Xueyu; Luo, Zhuojing; Li, Ming

    2014-07-01

    Regulating the production of brain-derived neurotrophic factor (BDNF) in Schwann cells (SCs) is critical for their application in traumatic nerve injury, neurodegenerative disorders, and demyelination disease in both central and peripheral nervous systems. The present study investigated the possibility of using electrical stimulation (ES) to activate SCs to release BDNF. We found that short-term ES was capable of promoting BDNF production from SCs, and the maximal BDNF release was achieved by ES at 6 V (3 Hz, 30 min). We further examined the involvement of intracellular calcium ions ([Ca2+]i) in the ES-induced BDNF production in SCs by pharmacological studies. We found that the ES-induced BDNF release required calcium influx through T-type voltage-gated calcium channel (VGCC) and calcium mobilization from internal calcium stores, including inositol triphosphate-sensitive stores and caffeine/ryanodine-sensitive stores. In addition, calcium-calmodulin dependent protein kinase IV (CaMK IV), mitogen-activated protein kinase (MAPK), and cAMP response element-binding protein (CREB) were found to play important roles in the ES-induced BDNF release from SCs. In conclusion, ES is capable of activating SCs to secrete BDNF, which requires the involvement of calcium influx through T-type VGCC and calcium mobilization from internal calcium stores. In addition, activation of CaMK IV, MAPK, and CREB were also involved in the ES-induced BDNF release. The findings indicate that ES can improve the neurotrophic ability in SCs and raise the possibility of developing electrically stimulated SCs as a source of cell therapy for nerve injury in both peripheral and central nervous systems. PMID:24753179

  1. A novel collagen/platelet-rich plasma (COL/PRP) scaffold: preparation and growth factor release analysis.

    PubMed

    Zhang, Xiujie; Wang, Jingwei; Ren, Mingguang; Li, Lifeng; Wang, Qingwen; Hou, Xiaohua

    2016-06-01

    Platelet-rich plasma (PRP) has been widely used in clinical practice for more than 20 years because it causes the release of many growth factors. However, the burst release pattern and short release period of PRP have become obstacles to its application. An optimal controllable release system is an urgent need for researchers. This study investigated whether collagen/PRP (COL/PRP) scaffolds can serve as a vehicle for the controllable release of growth factors. We fabricated a novel scaffold that integrates PRP activated by thrombin or collagen into type I collagen. The mechanical properties, cytotoxicity, and transforming growth factor β1 (TGF-β1), platelet derived growth factor (PDGF), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) content were evaluated. Our results demonstrate that the COL/PRP scaffolds were not cytotoxic to L-929 fibroblasts. The PDGF and FGF content in the thrombin group was at a higher level and lasted for a long period of time. Collagen and thrombin played the same role in the release of TGF-β1 and VEGF. These data suggest that the novel COL/PRP scaffolds provide a carrier for the controllable release of growth factors and may be used in tissue- regenerative therapies.

  2. A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.

    PubMed

    Papoiu, Alexandru D P; Coghill, Robert C; Kraft, Robert A; Wang, Hui; Yosipovitch, Gil

    2012-02-15

    Previous PET and fMRI brain imaging studies targeting neural networks processing itch sensation have used histamine as the sole itch inducer. In contrast with histamine, cowhage-induced itch is mediated via proteinase activated receptors PAR2 and is transmitted through a separate spinothalamic pathway, therefore imaging the brain activation evoked by cowhage could provide further insight into central processing of itch. We report for the first time a functional MRI Arterial Spin Labeling (ASL) study of neuronal processing of itch induced by cowhage, analyzed in contrast with histamine-induced itch. We also explored the brain responses induced by histamine and cowhage combined in a tight sequence. The results of our analyses obtained in a group of 15 healthy volunteers suggested that cowhage and histamine co-activated a core group of brain structures, while also revealing notable differences. Core areas activated by both stimuli were found in the thalamus, primary and secondary somatosensory cortices, posterior parietal cortex, superior and middle temporal cortices, PCC, ACC, precuneus and cuneus. Cowhage induced a notably distinct and more extensive involvement of the insular cortex, claustrum, basal ganglia, putamen, thalamic nuclei and pulvinar. The differences observed between these two itch modalities were investigated to determine the impact of quantitative versus qualitative factors, and correlations between itch intensity and the patterns in brain activation were explored. Our analysis revealed that the most significant differences between cowhage and histamine itch were not affected by stimulus intensity, although a subset of regions displayed activations which were intensity-dependent. The combined application of cowhage and histamine highlighted the role of insula and claustrum in the processing of both itch modalities in the same time. The present results suggest the existence of overlapping but also distinct neuronal networks processing these two

  3. Pathological changes in platelet histamine oxidases in atopic eczema

    PubMed Central

    Ionescu, Gruia

    1993-01-01

    Increased plasma histamine levels were associated with significantly lowered diamine and type B monoamine oxidase activities in platelet-rich plasma of atopic eczema (AE) patients. The diamine oxidase has almost normal cofactor levels (pyridoxal phosphate and Cu2+) but the cofactor levels for type B monoamine oxidase (flavin adenine dinucleotide and Fe2+) are lowered. The biogenic amines putrescine, cadaverine, spermidine, spermine, tyramine and serotonin in the sera, as well as dopamine and epinephrine in EDTA-plasma were found to be normal. It is unlikely, therefore, that these amines are responsible for the decreased activities of monoamine and diamine oxidase in these patients. The most likely causative factors for the inhibition of the diamine oxidase are nicotine, alcohol, food additives and other environmental chemicals, or perhaps a genetic defect of the diamine oxidase. PMID:18475554

  4. Development of a homogeneous binding assay for histamine receptors.

    PubMed

    Crane, Kathy; Shih, Daw-Tsun

    2004-12-01

    Histamine is critically involved in a wide range of physiological and pathological processes through its actions at different receptors. Thus, histamine receptors have been actively pursued as therapeutic targets in the pharmaceutical industry for the treatment of a variety of diseases. There are currently four histamine receptors that have been cloned, all of which are G protein-coupled receptors. Studies from both academia and pharmaceutical companies have identified compounds that modulate the function of specific histamine receptors. These efforts led to the successful introduction of histamine H(1) and H(2) receptor antagonists for the treatment of allergy and excess gastric acid secretion, respectively. Histamine H(3) receptor ligands are currently under investigation for the treatment of obesity and neurological disorders. The recently identified histamine H(4) receptor is preferentially expressed in the immune tissues, suggesting a potential role in normal immune functions and possibly in the pathogenesis of inflammatory diseases. Even with the long history of histamine research and the important applications of histamine receptor ligands, assays to measure the affinity of compounds binding to histamine receptors are still routinely analyzed using a filtration assay, a very low-throughput assay involving washing and filtration steps. This article describes a simple, robust, and homogeneous binding assay based on the scintillation proximity assay (SPA) technology that provides results equivalent to those obtained using the more complex filtration assay. The SPA format is easily adapted to high-throughput screening because it is amenable to automation. In summary, this technique allows high-throughput screening of compounds against multiple histamine receptors and, thus, facilitates drug discovery efforts.

  5. Delivery of Alginate Scaffold Releasing Two Trophic Factors for Spinal Cord Injury Repair

    PubMed Central

    Grulova, I.; Slovinska, L.; Blaško, J.; Devaux, S.; Wisztorski, M.; Salzet, M.; Fournier, I.; Kryukov, O.; Cohen, S.; Cizkova, D.

    2015-01-01

    Spinal cord injury (SCI) has been implicated in neural cell loss and consequently functional motor and sensory impairment. In this study, we propose an alginate -based neurobridge enriched with/without trophic growth factors (GFs) that can be utilized as a therapeutic approach for spinal cord repair. The bioavailability of key GFs, such as Epidermal Growth factor (EGF) and basic Fibroblast Growth Factor (bFGF) released from injected alginate biomaterial to the central lesion site significantly enhanced the sparing of spinal cord tissue and increased the number of surviving neurons (choline acetyltransferase positive motoneurons) and sensory fibres. In addition, we document enhanced outgrowth of corticospinal tract axons and presence of blood vessels at the central lesion. Tissue proteomics was performed at 3, 7 and 10 days after SCI in rats indicated the presence of anti-inflammatory factors in segments above the central lesion site, whereas in segments below, neurite outgrowth factors, inflammatory cytokines and chondroitin sulfate proteoglycan of the lectican protein family were overexpressed. Collectively, based on our data, we confirm that functional recovery was significantly improved in SCI groups receiving alginate scaffold with affinity-bound growth factors (ALG +GFs), compared to SCI animals without biomaterial treatment. PMID:26348665

  6. Performance of optimized noncanonical amino acid mutagenesis systems in the absence of release factor 1.

    PubMed

    Zheng, Yunan; Lajoie, Marc J; Italia, James S; Chin, Melissa A; Church, George M; Chatterjee, Abhishek

    2016-05-24

    Site-specific incorporation of noncanonical amino acids (ncAAs) into proteins expressed in E. coli using UAG-suppression competes with termination mediated by release factor 1 (RF1). Recently, unconditional deletion of RF1 was achieved in a genomically recoded E. coli (C321), devoid of all endogenous UAG stop codons. Here we evaluate the efficiency of ncAA incorporation in this strain using optimized suppression vectors. Even though the absence of RF1 does not benefit the suppression efficiency of a single UAG codon, multi-site incorporation of a series of chemically distinct ncAAs was significantly improved. PMID:27027374

  7. Performance of optimized noncanonical amino acid mutagenesis systems in the absence of release factor 1.

    PubMed

    Zheng, Yunan; Lajoie, Marc J; Italia, James S; Chin, Melissa A; Church, George M; Chatterjee, Abhishek

    2016-05-24

    Site-specific incorporation of noncanonical amino acids (ncAAs) into proteins expressed in E. coli using UAG-suppression competes with termination mediated by release factor 1 (RF1). Recently, unconditional deletion of RF1 was achieved in a genomically recoded E. coli (C321), devoid of all endogenous UAG stop codons. Here we evaluate the efficiency of ncAA incorporation in this strain using optimized suppression vectors. Even though the absence of RF1 does not benefit the suppression efficiency of a single UAG codon, multi-site incorporation of a series of chemically distinct ncAAs was significantly improved.

  8. Neuroendocrine control of the gut during stress: corticotropin-releasing factor signaling pathways in the spotlight.

    PubMed

    Stengel, Andreas; Taché, Yvette

    2009-01-01

    Stress affects the gastrointestinal tract as part of the visceral response. Various stressors induce similar profiles of gut motor function alterations, including inhibition of gastric emptying, stimulation of colonic propulsive motility, and hypersensitivity to colorectal distension. In recent years, substantial progress has been made in our understanding of the underlying mechanisms of stress's impact on gut function. Activation of corticotropin-releasing factor (CRF) signaling pathways mediates both the inhibition of upper gastrointestinal (GI) and the stimulation of lower GI motor function through interaction with different CRF receptor subtypes. Here, we review how various stressors affect the gut, with special emphasis on the central and peripheral CRF signaling systems. PMID:18928406

  9. Development of realistic environmental release factors based on measured data: approach and lessons from the EU metal industry.

    PubMed

    Verdonck, Frederik A M; Van Assche, Frank; Hicks, Keegan; Mertens, Jelle; Voigt, Astrid; Verougstraete, Violaine

    2014-10-01

    The assessment of environmental exposure and risks associated with the production or use of a substance on an industrial site includes the estimation of the releases to the environment. In the absence of measured release data on the specific substance, a risk assessor would rely on default release factors to the environmental compartments as developed in international, national, or regional context. Because a wide variety of substances, processes, and uses has to be covered, default release factors are as a rule conservative, usually leading to significant overprediction of releases and hence to overpredicted environmental exposure concentrations and risks. In practice, unrealistic and worst-case predictions do not support a more efficient management of releases and risk. The objective of this article is to propose a more realistic approach to characterize the environmental releases from manufacture, processing, and downstream uses of the metals and their compounds. Although developed in the European Union (EU), this approach can also be used in other regions and in other chemical management systems addressing metals. A database consisting of more than 1300 recent (1993-2010), site-specific measured release factors to air and water of 18 different metals from various EU Member States was compiled and used to calculate average and reasonable worst-case release factors for multiple metal manufacture and industrial use processes. The parameters influencing releases to water were found to depend predominantly on life cycle step (manufacture and/or use), the sector and/or the solid-water partition coefficient (K(d)). The release factors can be used as advanced tier instrument in environmental safety assessments, increasing the realism of the estimates while still keeping a sufficient level of conservatism. PMID:24944185

  10. Development of realistic environmental release factors based on measured data: approach and lessons from the EU metal industry.

    PubMed

    Verdonck, Frederik A M; Van Assche, Frank; Hicks, Keegan; Mertens, Jelle; Voigt, Astrid; Verougstraete, Violaine

    2014-10-01

    The assessment of environmental exposure and risks associated with the production or use of a substance on an industrial site includes the estimation of the releases to the environment. In the absence of measured release data on the specific substance, a risk assessor would rely on default release factors to the environmental compartments as developed in international, national, or regional context. Because a wide variety of substances, processes, and uses has to be covered, default release factors are as a rule conservative, usually leading to significant overprediction of releases and hence to overpredicted environmental exposure concentrations and risks. In practice, unrealistic and worst-case predictions do not support a more efficient management of releases and risk. The objective of this article is to propose a more realistic approach to characterize the environmental releases from manufacture, processing, and downstream uses of the metals and their compounds. Although developed in the European Union (EU), this approach can also be used in other regions and in other chemical management systems addressing metals. A database consisting of more than 1300 recent (1993-2010), site-specific measured release factors to air and water of 18 different metals from various EU Member States was compiled and used to calculate average and reasonable worst-case release factors for multiple metal manufacture and industrial use processes. The parameters influencing releases to water were found to depend predominantly on life cycle step (manufacture and/or use), the sector and/or the solid-water partition coefficient (K(d)). The release factors can be used as advanced tier instrument in environmental safety assessments, increasing the realism of the estimates while still keeping a sufficient level of conservatism.

  11. Histamine induces the production of matrix metalloproteinase-9 in human astrocytic cultures via H1-receptor subtype.

    PubMed

    Patel, Aarti; Vasanthan, Vishnu; Fu, Wen; Fahlman, Richard P; MacTavish, David; Jhamandas, Jack H

    2016-05-01

    Accumulation of β-amyloid (Aβ) protein within the brain is a neuropathological hallmark of Alzheimer's disease (AD). One strategy to facilitate Aβ clearance from the brain is to promote Aβ catabolism. Matrix metalloproteinase-9 (MMP-9), a member of the family of Zn(+2)-containing endoproteases, known to be expressed and secreted by astrocytes, is capable of degrading Aβ. Histamine, a major aminergic brain neurotransmitter, stimulates the production of MMP-9 in keratinocytes through the histamine H1 receptor (H1R). In the present study, we show that histamine evokes a concentration- and calcium-dependent release of MMP-9 from human astrocytic U373 cells and primary cultures of human and rat astrocytes through the H1R subtype. Activation of H1R on astrocytes elevated intracellular levels of Ca(2+) that was accompanied by time-dependent increases in MAP kinase p44/p42 and PKC. In-cell western blots revealed dose-dependent increases in both enzymes, confirming involvement of these signal transduction pathways. We next investigated the extent of recombinant human MMP-9 (rhMMP-9) proteolytic activity on soluble oligomeric Aβ (soAβ). Mass spectrometry demonstrated time-dependent cleavage of soAβ (20 μM), but not another amyloidogenic protein amylin, upon incubation with rhMMP-9 (100 nM) at 1, 4 and 17 h. Furthermore, Western blots showed a shift in soAβ equilibrium toward lower order, less toxic monomeric species. In conclusion, both MAPK p44/p42 and PKC pathways appear to be involved in histamine-upregulated MMP-9 release via H1Rs in astrocytes. Furthermore, MMP-9 appears to cleave soAβ into less toxic monomeric species. Given the key role of histamine in MMP-9 release, this neurotransmitter may serve as a potential therapeutic target for AD.

  12. Hybrid scaffolds of gelatin-siloxane releasing stromal derived factor-1 effective for cell recruitment.

    PubMed

    Dashnyam, Khandmaa; Perez, Roman; Lee, Eun-Jung; Yun, Ye-Rang; Jang, Jun-Hyeog; Wall, Ivan B; Kim, Hae-Won

    2014-06-01

    Scaffolds with the capacity to deliver signaling molecules are attractive for bone regeneration. Here, we developed bioactive siloxane-gelatin hybrid scaffolds via a sol gel process containing stromal derived factor-1 (SDF-1) to recruit osteoprogenitor/stem cells. The process was undertaken under room temperature aqueous conditions, which enabled therapeutic molecules to be effectively incorporated. After the sol-gel reaction and lyophilization process, well-crosslinked hybrid scaffolds were obtained with porosities of 80-90%. Dynamic mechanical analysis of the hybrid scaffolds showed significant improvement in storage modulus values (from 10 to 110 kPa) with increasing siloxane content. The protein release capacity of the scaffolds was investigated using a model protein cytochrome C (cyto C). The cyto C safely loaded onto the scaffolds exhibited, except the initial burst of 30% within a day, highly sustainable release, with approximately 70-80% of the loading amount for up to 4 weeks. Target molecule SDF-1 was loaded and released from the scaffolds, and the effects on the homing of mesenchymal stem cell were studied. Results demonstrated significant enhancement in the migration of cells to the SDF-1 loaded scaffolds. Taken together, the developed hybrid scaffolds are considered to be useful in loading and delivering signaling molecules such as SDF-1 to recruit osteoprogenitor /mesenchymal stem cells in the bone regeneration process.

  13. Orexin–Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine

    PubMed Central

    Navarro, Gemma; Quiroz, César; Moreno-Delgado, David; Sierakowiak, Adam; McDowell, Kimberly; Moreno, Estefanía; Rea, William; Cai, Ning-Sheng; Aguinaga, David; Howell, Lesley A.; Hausch, Felix; Cortés, Antonio; Mallol, Josefa; Casadó, Vicent; Lluís, Carme; Canela, Enric I.

    2015-01-01

    Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R–OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R–OX1R heteromer. Cocaine binding to the σ1R–CRF1R–OX1R complex promotes a long-term disruption of the orexin-A–CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking. PMID:25926444

  14. Leukotriene B4 and tumor necrosis factor release from leukocytes: effect of peritoneal dialysate.

    PubMed

    Jörres, A; Jörres, D; Gahl, G M; Kessel, M; Müller, C; Köttgen, E; Serke, S; Schulz, E; Mahiout, A

    1991-01-01

    The effect of peritoneal dialysate on the capacity of peripheral blood polymorphonuclear (PMNL) and mononuclear leukocytes (MNC) to release leukotriene B4 (LTB4) and tumor necrosis factor alpha (TNF alpha) was investigated in vitro. Following density gradient separation, aliquots of 5 x 10(6) PMNL or MNC were incubated in peritoneal dialysis fluid containing 1.5% glucose or Hanks' buffer (= control) for 1-2 h at 37 degrees C. TNF alpha and LTB4 production was stimulated with Escherichia coli lipopolysaccharide (LPS) and calcium ionophore A23187, respectively. MNC incubated in buffer and LPS produced (mean +/- SD) 1,006 +/- 522 pg TNF alpha/5 x 10(6) cells; no significant amounts of TNF alpha were detectable in the presence of dialysate. An inhibition of TNF alpha release was also observed in MNC exposed to bicarbonate-buffered dialysates (pH 7.40) and 4.25% and 1.5% glucose solution with physiologic osmolality. Incubation of PMNL in Hanks' buffer followed by A23187 stimulation led to production of 29.1 +/- 19.2 ng LTB4/5 x 10(6) cells, whereas glucose-incubated cells were refractory to ionophore stimulation (less than 0.1 ng LTB4/5 x 10(6) cells). The failure of dialysate-exposed leukocytes to release inflammatory mediators in response to adequate stimuli may contribute to the impairment of cellular host defense in the setting of continuous ambulatory peritoneal dialysis.

  15. Histamine resets the circadian clock in the suprachiasmatic nucleus through the H1R-CaV 1.3-RyR pathway in the mouse.

    PubMed

    Kim, Yoon Sik; Kim, Young-Beom; Kim, Woong Bin; Yoon, Bo-Eun; Shen, Feng-Yan; Lee, Seung Won; Soong, Tuck-Wah; Han, Hee-Chul; Colwell, Christopher S; Lee, C Justin; Kim, Yang In

    2015-10-01

    Histamine, a neurotransmitter/neuromodulator implicated in the control of arousal state, exerts a potent phase-shifting effect on the circadian clock in the rodent suprachiasmatic nucleus (SCN). In this study, the mechanisms by which histamine resets the circadian clock in the mouse SCN were investigated. As a first step, Ca(2+) -imaging techniques were used to demonstrate that histamine increases intracellular Ca(2+) concentration ([Ca(2+) ]i ) in acutely dissociated SCN neurons and that this increase is blocked by the H1 histamine receptor (H1R) antagonist pyrilamine, the removal of extracellular Ca(2+) and the L-type Ca(2+) channel blocker nimodipine. The histamine-induced Ca(2+) transient is reduced, but not blocked, by application of the ryanodine receptor (RyR) blocker dantrolene. Immunohistochemical techniques indicated that CaV 1.3 L-type Ca(2+) channels are expressed mainly in the somata of SCN cells along with the H1R, whereas CaV 1.2 channels are located primarily in the processes. Finally, extracellular single-unit recordings demonstrated that the histamine-elicited phase delay of the circadian neural activity rhythm recorded from SCN slices is blocked by pyrilamine, nimodipine and the knockout of CaV 1.3 channel. Again, application of dantrolene reduced but did not block the histamine-induced phase delays. Collectively, these results indicate that, to reset the circadian clock, histamine increases [Ca(2+) ]i in SCN neurons by activating CaV 1.3 channels through H1R, and secondarily by causing Ca(2+) -induced Ca(2+) release from RyR-mediated internal stores.

  16. Wnt3a regulates tumor necrosis factor-α-stimulated interleukin-6 release in osteoblasts.

    PubMed

    Natsume, Hideo; Tokuda, Haruhiko; Adachi, Seiji; Matsushima-Nishiwaki, Rie; Kato, Kenji; Minamitani, Chiho; Otsuka, Takanobu; Kozawa, Osamu

    2011-01-01

    It is recognized that Wnt pathways regulate bone metabolism. We have previously shown that tumor necrosis factor-α (TNF-α) stimulates synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, via p44/p42 mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3-kinase)/Akt in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of Wnt3a on TNF-α-stimulated IL-6 synthesis in these cells. Wnt3a, which alone did not affect the IL-6 levels, significantly suppressed the TNF-α-stimulated IL-6 release. Lithium Chloride (LiCl), which is an inhibitor of GSK3β, markedly reduced the TNF-α-stimulated IL-6 release, similar to the results with Wnt3a. The suppression by Wnt3a or LiCl was also observed in the intracellular protein levels of IL-6 elicited by TNF-α. Wnt3a failed to affect the TNF-α-induced phosphorylation of p44/p42 MAP kinase, Akt, IκB or NFκB. Either Wnt3a or LiCl failed to reduce, rather increased the IL-6 mRNA expression stimulated by TNF-α. Lactacystin, a proteasome inhibitor, and bafilomycin A1, a lysosomal protease inhibitor, significantly restored the suppressive effect of Wnt3a on TNF-α-stimulated IL-6 release. Taken together, our results strongly suggest that Wnt3a regulates IL-6 release stimulated by TNF-α at post-transcriptional level in osteoblasts.

  17. Luminal CCK-releasing factors in the isolated vascularly perfused rat duodenojejunum.

    PubMed

    Cuber, J C; Bernard, G; Fushiki, T; Bernard, C; Yamanishi, R; Sugimoto, E; Chayvialle, J A

    1990-08-01

    The factors operating at the apical side of the endocrine cell releasing cholecystokinin (CCK) were investigated using the isolated vascularly perfused rat duodenojejunum. In the protease-free intestinal segment, a 30-min infusion of glucose (280 mM), oleic acid (100 mM), or triglycerides containing short- or long-chain fatty acids did not alter significantly the basal level of portal CCK-like immunoreactivity (CCK-LI), while octanoic acid (100 mM) produced a transient rise of plasma CCK-LI to approximately 250% of basal. Infusion of proteins (5% solutions of ovalbumin or casein) or of a mixture of all amino acids brought about a modest CCK secretion. In contrast, isocaloric amounts of an ovalbumin hydrolysate produced a sharp rise of portal CCK-LI to 530% of basal followed by a well-sustained plateau secretion (420% of basal) until the end of the infusion. An acid casein hydrolysate induced a slightly less pronounced CCK-LI release and was followed in decreasing order by meat, casein, and soybean peptones. Simultaneous infusion of trypsin with ovalbumin or casein hydrolysate reduced by approximately 60% the CCK release induced by peptone alone. This effect was reversed by coinfusion of soybean trypsin inhibitor (SBTI) with the trypsin-peptone mixture. Arterial infusion of tetrodotoxin (10(-6) M) or atropine (10(-5) M) had no significant effect on the trypsin-induced inhibition of peptone-mediated CCK-LI release. Administration of SBTI or camostate alone or in combination with trypsin did not alter basal CCK. Monitor peptide produced a dose-dependent transient rise of portal CCK-LI over the range from 2 to 12 micrograms.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Polyoxomatelate functionalized tris(2,2-bipyridyl)dichlororuthenium(II) as the probe for electrochemiluminescence sensing of histamine.

    PubMed

    An, Dong; Chen, Zhuqiu; Zheng, Jiachun; Chen, Siyuan; Wang, Li; Su, Wenjin

    2016-03-01

    A novel electrochemiluminescence (ECL) sensing system was developed to determine histamine in aquatic food with tris(2,2-bipyridyl)dichlororuthenium(II) (Ru(bpy)3(2+)) and Keggin-type polyoxomatelate (H3PMo12O40). A hybrid material was synthesized by mixing Keggin H3PMo12O40 (PMo12) and Ru(bpy)3(2+) and it was applied in capillary electrophoresis-electrochemiluminescence (CE-ECL) as a histamine probe for the first time. Some factors which affected the performances of separation and detection were investigated. Under the optimized conditions, one single quantitative analysis of histamine was achieved at a separation voltage of 16kV, and the limit of detection (LOD, S/N=3) of histamine was 1.0×10(-3)mg/L. The linear concentration range was between 0.01 and 1mg/L and the relative standard deviation (RSD) of peak height was between 0.27% and 1.29%, while the RSD of migration time was between 0.96% and 1.87%. The results indicated that the proposed probe presented good characteristics in terms of higher sensitivity and better reproducibility for histamine detection than those of the Ru(bpy)3(2+) ECL system.

  19. 78 FR 14533 - Official Release of EMFAC2011 Motor Vehicle Emission Factor Model for Use in the State of California

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-06

    ..., calculates air pollution emissions factors for passenger cars, trucks, motorcycles, motor homes and buses... AGENCY Official Release of EMFAC2011 Motor Vehicle Emission Factor Model for Use in the State of... EMission FACtor) for use in state implementation plan (SIP) development and transportation conformity...

  20. Comparative characterization of release factor RF-3 genes of Escherichia coli, Salmonella typhimurium, and Dichelobacter nodosus.

    PubMed Central

    Kawazu, Y; Ito, K; Matsumura, K; Nakamura, Y

    1995-01-01

    The termination of protein synthesis in bacteria requires two codon-specific release factors, RF-1 and RF-2. A gene for a third factor, RF-3, that stimulates the RF-1 and RF-2 activities has been isolated from the gram-negative bacteria Escherichia coli and Dichelobacter nodosus. In this work, we isolated the RF-3 gene from Salmonella typhimurium and compared the three encoded RF-3 proteins by immunoblotting and intergeneric complementation and suppression. A murine polyclonal antibody against E. coli RF-3 reacted with both S. typhimurium and D. nodosus RF-3 proteins. The heterologous RF-3 genes complemented a null RF-3 mutation of E. coli regardless of having different sequence identities at the protein level. Additionally, multicopy expression of either of these RF-3 genes suppressed temperature-sensitive RF-2 mutations of E. coli and S. typhimurium by restoring adequate peptide chain release. These findings strongly suggest that the RF-3 proteins of these gram-negative bacteria share common structural and functional domains necessary for RF-3 activity and support the notion that RF-3 interacts functionally and/or physically with RF-2 during translation termination. PMID:7559341

  1. Transcription termination factor rho prefers catalytically active elongation complexes for releasing RNA.

    PubMed

    Dutta, Dipak; Chalissery, Jisha; Sen, Ranjan

    2008-07-18

    RNA polymerase pauses at different DNA sequences during transcription elongation, and this pausing is associated with distinct conformational state(s) of the elongation complex (EC). Transcription termination by the termination factor Rho, an RNA-dependent molecular motor, requires pausing of the EC in the termination zone of Rho-dependent terminators. We hypothesized that the conformational state(s) of the EC associated with this pausing would influence the action of Rho. Analyses of the pausing behavior of the EC at the termination points of two well known Rho-dependent terminators revealed that Rho prefers actively transcribing complexes for termination. RNA release kinetics from stalled ECs showed that the rate of RNA release by Rho was reduced if the EC was irreversibly backtracked, if its RNA exit channel was modified by an RNA hairpin, or the bridge helix/trigger loop movement in its active site was perturbed. These defects were overcome significantly by enhancing the rate of ATP hydrolysis either by increasing the concentration of ATP or by using a Rho mutant with higher ATPase activity. We propose that the force generated from ATP hydrolysis of Rho is the key factor in dislodging the EC through its molecular motor action, and this process is facilitated when the EC is in a catalytically competent state, undergoing rapid "Brownian ratchet" motion.

  2. Arabidopsis MAP kinase 4 regulates gene expression through transcription factor release in the nucleus.

    PubMed

    Qiu, Jin-Long; Fiil, Berthe Katrine; Petersen, Klaus; Nielsen, Henrik Bjørn; Botanga, Christopher J; Thorgrimsen, Stephan; Palma, Kristoffer; Suarez-Rodriguez, Maria Cristina; Sandbech-Clausen, Signe; Lichota, Jacek; Brodersen, Peter; Grasser, Klaus D; Mattsson, Ole; Glazebrook, Jane; Mundy, John; Petersen, Morten

    2008-08-20

    Plant and animal perception of microbes through pathogen surveillance proteins leads to MAP kinase signalling and the expression of defence genes. However, little is known about how plant MAP kinases regulate specific gene expression. We report that, in the absence of pathogens, Arabidopsis MAP kinase 4 (MPK4) exists in nuclear complexes with the WRKY33 transcription factor. This complex depends on the MPK4 substrate MKS1. Challenge with Pseudomonas syringae or flagellin leads to the activation of MPK4 and phosphorylation of MKS1. Subsequently, complexes with MKS1 and WRKY33 are released from MPK4, and WRKY33 targets the promoter of PHYTOALEXIN DEFICIENT3 (PAD3) encoding an enzyme required for the synthesis of antimicrobial camalexin. Hence, wrky33 mutants are impaired in the accumulation of PAD3 mRNA and camalexin production upon infection. That WRKY33 is an effector of MPK4 is further supported by the suppression of PAD3 expression in mpk4-wrky33 double mutant backgrounds. Our data establish direct links between MPK4 and innate immunity and provide an example of how a plant MAP kinase can regulate gene expression by releasing transcription factors in the nucleus upon activation.

  3. Crystal Structure of a Translation Termination Complex Formed With Release Factor RF2

    SciTech Connect

    Korostelev, A.; Asahara, H.; Lancaster, L.; Laurberg, M.; Hirschi, A.; Zhu, J.; Trakhanov, S.; Scott, W.G.; Noller, H.F.

    2009-05-20

    We report the crystal structure of a translation termination complex formed by the Thermus thermophilus 70S ribosome bound with release factor RF2, in response to a UAA stop codon, solved at 3 {angstrom} resolution. The backbone of helix -5 and the side chain of serine of the conserved SPF motif of RF2 recognize U1 and A2 of the stop codon, respectively. A3 is unstacked from the first 2 bases, contacting Thr-216 and Val-203 of RF2 and stacking on G530 of 16S rRNA. The structure of the RF2 complex supports our previous proposal that conformational changes in the ribosome in response to recognition of the stop codon stabilize rearrangement of the switch loop of the release factor, resulting in docking of the universally conserved GGQ motif in the PTC of the 50S subunit. As seen for the RF1 complex, the main-chain amide nitrogen of glutamine in the GGQ motif is positioned to contribute directly to catalysis of peptidyl-tRNA hydrolysis, consistent with mutational studies, which show that most side-chain substitutions of the conserved glutamine have little effect. We show that when the H-bonding capability of the main-chain N-H of the conserved glutamine is eliminated by substitution with proline, peptidyl-tRNA esterase activity is abolished, consistent with its proposed role in catalysis.

  4. Recognition of the amber UAG stop codon by release factor RF1

    SciTech Connect

    Korostelev, Andrei; Zhu, Jianyu; Asahara, Haruichi; Noller, Harry F.

    2010-08-23

    We report the crystal structure of a termination complex containing release factor RF1 bound to the 70S ribosome in response to an amber (UAG) codon at 3.6-{angstrom} resolution. The amber codon is recognized in the 30S subunit-decoding centre directly by conserved elements of domain 2 of RF1, including T186 of the PVT motif. Together with earlier structures, the mechanisms of recognition of all three stop codons by release factors RF1 and RF2 can now be described. Our structure confirms that the backbone amide of Q230 of the universally conserved GGQ motif is positioned to contribute directly to the catalysis of the peptidyl-tRNA hydrolysis reaction through stabilization of the leaving group and/or transition state. We also observe synthetic-negative interactions between mutations in the switch loop of RF1 and in helix 69 of 23S rRNA, revealing that these structural features interact functionally in the termination process. These findings are consistent with our proposal that structural rearrangements of RF1 and RF2 are critical to accurate translation termination.

  5. Effect of basic fibroblast growth factor released from chitosan-fucoidan nanoparticles on neurite extension.

    PubMed

    Huang, Yi-Cheng; Yang, Ya-Ting

    2016-05-01

    Exogenous growth factors are an integral part of an effective nerve tissue-engineering strategy. Basic fibroblast growth factor (bFGF) has a marked positive effect on angiogenesis and neuronal cell survival. However, bFGF is limited by its short half-life and easy degradation by enzymes. Therefore, in this study novel biodegradable chitosan-fucoidan nanoparticles (CS-F NPs) were designed to carry bFGFs and maintain their activities. The experimental results indicated that chitosan and fucoidan form stable nanoparticles approximately 200 nm in size via electrostatic interactions. Additionally, the effectiveness of nanoparticles is related to their chitosan:fucoidan weight ratio. The CS-F NPs control the release of bFGFs and protect bFGF from deactivation by heat and enzymes. In vitro cell studies demonstrate that CS-F NPs have no cytotoxicity to PC12 cells, as the concentration of NPs is 125 ng/ml. Moreover, the CS-F NPs significantly decrease the amount of bFGF needed for neurite extension. The cumulative release of bFGF from CS-F NPs at 24 h is 0.168 ng/ml, markedly lower than that in solution (4.2 ng/ml). Importantly, CS-F NPs are potential carriers for delivering bFGFs for nerve tissue engineering. Copyright © 2013 John Wiley & Sons, Ltd.

  6. Determination of the radionuclide release factor for an evaporator process using nondestructive assay

    SciTech Connect

    Johnson, R.E.

    1998-07-06

    The 242-A Evaporator is the primary waste evaporator for the Hanford Site radioactive liquid waste stored in underground double-shell tanks. Low pressure evaporation is used to remove water from the waste, thus reducing the amount of tank space required for storage. The process produces a concentrated slurry, a process condensate, and an offgas. The offgas exhausts through two stages of high-efficiency particulate air (HEPA) filters before being discharged to the atmosphere 40 CFR 61 Subpart H requires assessment of the unfiltered exhaust to determine if continuous compliant sampling is required. Because potential (unfiltered) emissions are not measured, methods have been developed to estimate these emissions. One of the methods accepted by the Environmental Protection Agency is the measurement of the accumulation of radionuclides on the HEPA filters. Nondestructive assay (NDA) was selected for determining the accumulation on the HEPA filters. NDA was performed on the HEPA filters before and after a campaign in 1997. NDA results indicate that 2.1 E+4 becquerels of cesium-137 were accumulated on the primary HEPA 1700 filter during the campaign. The feed material processed in the campaign contained a total of 1.4 E+l6 Bq of cesium-137. The release factor for the evaporator process is 1.5 E-12. Based on this release factor, continuous compliant sampling is not required.

  7. Purification of a high-molecular-weight somatoliberin (growth-hormone-releasing factor) from pig hypothalami.

    PubMed Central

    Sykes, J E; Lowry, P J

    1983-01-01

    Preliminary observations [Sykes & Lowry (1980) J. Endocrinol. 85, 42P-43P] had suggested that the major hypothalamic somatoliberin (growth-hormone-releasing factor) was a larger peptide than the other characterized hypothalamic factors, with an elution position on Sephadex G-50 between those of neurophysin and corticotropin. The present paper reports the isolation and preliminary characterization of pig hypothalamic somatoliberin. Acid extracts of pig stalk median eminence were purified by gel filtration and preparative and analytical high-pressure liquid chromatography to yield a preparation that was specific in the release of somatotropin (growth hormone) in vitro, giving a steep dose--response curve at doses in the range 0.20-3.0 ng. Amino acid analysis revealed a non-cysteine-containing peptide with a high number of glutamate (or glutamine) and aspartate (or asparagine) residues. The peptide had about 56-57 amino acid residues and an apparent molecular weight of 6400, in keeping with its elution position on a column of Sephadex G-50. PMID:6409074

  8. Histamine receptors expressed in circulating progenitor cells have reciprocal actions in ligation-induced arteriosclerosis.

    PubMed

    Yamada, Sohsuke; Wang, Ke-Yong; Tanimoto, Akihide; Guo, Xin; Nabeshima, Atsunori; Watanabe, Takeshi; Sasaguri, Yasuyuki

    2013-09-01

    Histamine is synthesized as a low-molecular-weight amine from L-histidine by histidine decarboxylase (HDC). Recently, we demonstrated that carotid artery-ligated HDC gene-deficient mice (HDC(-/-)) showed less neointimal formation than wild-type (WT) mice, indicating that histamine participates in the process of arteriosclerosis. However, little is known about the roles of histamine-specific receptors (HHRs) in arteriosclerosis. To define the roles of HHRs in arteriosclerosis, we investigated intimal remodeling in ligated carotid arteries of HHR-deficient mice (H1R(-/-) or H2R(-/-)). Quantitative analysis showed that H1R(-/-) mice had significantly less arteriosclerogenesis, whereas H2R(-/-) mice had more, as compared with WT mice. Bone marrow transplantation from H1R(-/-) or H2R(-/-) to WT mice confirmed the above observation. Furthermore, the increased expression of monocyte chemoattractant protein (MCP-1), platelet-derived growth factor (PDGF), adhesion molecules and liver X receptor (LXR)-related inflammatory signaling factors, including Toll-like receptor (TLR3), interleukin-1 receptor (IL-1R) and tumor necrosis factor receptor (TNF-R), was consistent with the arteriosclerotic phenotype of H2R(-/-) mice. Peripheral progenitor cells in H2R(-/-) mice accelerate ligation-induced arteriosclerosis through their regulation of MCP-1, PDGF, adhesion molecules and LXR-related inflammatory signaling factors. In contrast, peripheral progenitor cells act to suppress arteriosclerosis in H1R(-/-) mice, indicating that HHRs reciprocally regulate inflammation in the ligation-induced arteriosclerosis.

  9. Histamine-induced itch and its relationship with pain

    PubMed Central

    Shim, Won-Sik; Oh, Uhtaek

    2008-01-01

    Itch is one of the major complications of skin diseases. Although there are various substances that induce itch or pruritus, it is evident that histamine is the best known endogenous agent that evokes itch. Even though histamine-induced itch has been studied for some time, the underlying mechanism of itch is just beginning to emerge. Although various downstream signaling pathways of histamine receptors have been revealed, more studies are required to determine the cause of histamine-induced itch. It appears that itch and pain involve different neuronal pathways. Pain generally inhibits itch, which indicates an inter-communication between the two. Complex interactions between itch and pain may be expected based on reports on disease states and opioids. In this review, we discuss the molecular mechanism and the pharmacological aspects of histamine-induced itch. Especially, the underlying mechanism of TRPV1 (an anti-pruritus target) has been determined to some extent. PMID:18667087

  10. Vasodilator response to histamine: dependence upon the site of administration.

    PubMed

    Galeno, T M; Knuepfer, M M; Brody, M J

    1979-06-15

    Histamine causes vasodilation in part by interacting with histamine H2 receptors. The present study was undertaken to evaluate the difference in vasodilator sensitivity of H2 receptors on the inside compared to the outside of the vessel. In order to induce tone, norepinephrine was administered to an in vitro preparation of rabbit ear artery treated with mepyramine to block H1 receptors. Histamine was then either selectively perfused through the artery or added to the outside of the vessel via the organ bath. The outside of the artery was found to be twice as sensitive to the vasodilator effect of histamine as the inside. These data provide the first evidence for greater extraluminal sensitivity of vascular smooth muscle and suggest that the response to histamine will depend in part on the route the amine takes to reach receptors, e.g., from blood-borne sources or from extraluminal stores.

  11. Effects of histamine and its antagonists on murine T-cells and bone marrow-derived dendritic cells.

    PubMed

    Hu, Xiufen; Zafar, Mohammad Ishraq; Gao, Feng

    2015-01-01

    We determined the effects of histamine and its antagonists on the surface marker expression of dendritic cells (DCs) and the influence of lipopolysaccharide (LPS), histamine, and histamine receptor antagonists on DCs and T-cells. The bone marrow was extracted from the femurs and tibiae of 6- to 8-week-old female Balb/c mice and cultured in medium containing penicillin, streptomycin, L-glutamine, fetal calf serum, or granulocyte macrophage colony-stimulating factor (GM-CSF) alone or with interleukin (IL)-4. The cells received three different doses of LPS and histamine, plus three different doses of descarboethoxyloratadine (DCL). We assayed the supernatant for various cytokines. The spleen cells of DO11.10 mice were examined by flow cytometry, which included labeling and sorting CD4+ T-cells, as well as coculture of DCs and T-cells with ovalbumin (OVA)323-339 peptide. Histamine or histamine plus DCL did not affect the expression of major histocompatibility complex class II, CD11c, CD11b, CD86, and CD80. However, GM-CSF increased the expression of all markers except CD80. Histamine increased interferon-γ production in GM-CSF + IL-4-cultured cells; it also enhanced IL-10 production, but suppressed IL-12 production in LPS-stimulated DCs with no DCL. Cimetidine inhibited IL-10 production and restored IL-12 secretion in LPS-treated DCs. LPS increased IL-10 and decreased IL-12 levels. GM-CSF + IL-4-generated DCs had a stronger stimulatory effect on DO11.10 T-cell proliferation than GM-CSF-generated DCs. Inducible costimulator ligand expression was higher in GM-CSF + IL-4- than in GM-CSF-generated DC groups after 2 days of coculture, but decreased 4 days later. IL-13 production was higher in bone marrow DCs generated with GM-CSF than in those generated with GM-CSF + IL-4. OVA-pulsed DCs and OVA-plus-DCL DCs showed increased IL-12 levels. OVA plus LPS increased both IL-10 and interferon-α. Although histamine or histamine receptor-1 antagonists did not influence DC LPS

  12. C-027 inhibits IgE-mediated passive sensitization bronchoconstriction and acts as a histamine and serotonin antagonist in human airways.

    PubMed

    Cooper, Philip R; Zhang, Jie; Damera, Gautam; Hoshi, Toshinori; Zopf, David A; Panettieri, Reynold A

    2011-01-01

    Atopic asthma is poorly controlled by current therapies. Newer therapies and novel antihistamines are, therefore, required to treat patients whose atopic asthma is not controlled. For the first time, C-027 is shown to antagonize histamine, IgE-mediated and serotonin-induced contraction in human airways and vessels. Human precision-cut lung slices (PCLS, 250 μm thick), containing an airway or blood vessel, were pretreated with either C-027 (2 hours) or with vehicle alone and were contracted with histamine or serotonin. Known antihistamine was used as a comparator in antihistamine studies. Also, human airways were contracted via IgE passive sensitization in the presence or absence of C-027 or fexofenadine. Affinity of C-027 toward human G-protein coupled receptors was also determined, as well as the drug's biodistribution in murine model. C-027 was shown to have the highest affinity toward human histamine and serotonin receptors. Subsequently, C-027 was shown to antagonize histamine- and serotonin-induced airway and vascular smooth muscle contraction, respectively, and histamine-released bronchocontraction mediated by IgE passive sensitization in human small airways. C-027 also inhibited histamine-mediated single-cell calcium ion release. Low levels of C-027 were found in murine brain tissue. Collectively, these data suggest that C-027 markedly inhibits IgE-induced bronchoconstriction and antagonizes histamine and serotonin-contraction with little biodistribution in the brain. The compound may offer a future therapy for allergen-induced airway hyperresponsiveness in patients with asthma.

  13. Histamine H3 receptors, the complex interaction with dopamine and its implications for addiction

    PubMed Central

    Ellenbroek, B A

    2013-01-01

    Histamine H3 receptors are best known as presynaptic receptors inhibiting the release of histamine, as well as other neurotransmitters including acetylcholine and dopamine. However, in the dorsal and ventral striatum, the vast majority of H3 receptors are actually located postsynaptically on medium sized spiny output neurons. These cells also contain large numbers of dopamine (D1 and D2) receptors and it has been shown that H3 receptors form heterodimers with both D1 and D2 receptors. Thus, the anatomical localization of H3 receptors suggests a complex interaction that could both enhance and inhibit dopaminergic neurotransmission. Dopamine, especially within the striatal complex, plays a crucial role in the development of addiction, both in the initial reinforcing effects of drugs of abuse, as well as in maintenance, relapse and reinstatement of drug taking behaviour. It is, therefore, conceivable that H3 receptors can moderate the development and maintenance of drug addiction. In the present review, we appraise the current literature on the involvement of H3 receptors in drug addiction and try to explain these data within a theoretical framework, as well as provide suggestions for further research. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 PMID:23647606

  14. Transmembrane sodium and potassium gradients modulate histamine secretion induced by ionophore A23187.

    PubMed Central

    Amellal, M.; Bronner, C.; Landry, Y.

    1985-01-01

    Histamine secretion was induced from rat peritoneal mast cells by calcium ionophore A23187 in the presence of various extracellular calcium concentrations. Transmembrane sodium and potassium gradients were altered by cold pretreatment of mast cells or through the inhibition of sodium-potassium ATPase by the use of ouabain or potassium-deprivation. Such pretreatments led to a parallel shift to the left of the extracellular calcium concentration-histamine secretion curve, i.e. to an apparent decrease of extracellular calcium requirement for the ionophore-induced histamine release. These effects were fully reversed by warming mast cells, by washing out ouabain or by adding potassium. Metabolic inhibition of mast cells prevented the ionophore-induced secretion in all the experimental conditions described. Secretion observed in the absence of added calcium was inhibited by short term treatment of cells with 5 X 10(-6) M EGTA or EDTA provided magnesium was absent from the assay medium. Data show that ionophore A23187 was able to induce secretion in the presence of micromolar concentrations of extracellular calcium, when the efficiency of the ionophore was not decreased by extracellular magnesium and when transmembrane sodium and potassium gradients were altered. PMID:2412623

  15. Histamine, ZO-1 and increased blood-retinal barrier permeability in diabetic retinopathy.

    PubMed Central

    Gardner, T W

    1995-01-01

    PURPOSES: First, to develop an improved retinal capillary endothelial cell culture system which exhibits some of the physiologic features of the bloodretinal barrier; second, to use this model to determine how histamine and chemical conditions of diabetes effect expression of the tight junction protein, ZO-1; and third, to discuss application of the Henle-Koch postulates to the problem of diabetic retinopathy. METHODS: Bovine retinal capillary endothelial cells were exposed to varying serum and growth factor concentrations, as well as astrocyte-conditioned medium, in order to establish a model of the blood-retinal barrier. Cells were also exposed to varying concentrations of histamine, and of insulin and glucose. The expression of ZO-1 tight junction protein was determined by immunocytochemistry and immunoblotting. RESULTS: Modified concentrations of growth factors reduced endothelial cell proliferation, without reducing viability. Astrocyte conditioned medium increased ZO-1 protein content. Histamine reduced ZO-1 protein content. Both high glucose (20mM) and low insulin (10(-12)M) reduced ZO-1 protein content compared to control conditions (5mM glucose and 10(-9) M insulin). CONCLUSIONS: Control of culture conditions results in a more physiologic in vitro model of the blood-retinal barrier. Soluble factors from astrocytes promote tight junction formation. Both histamine and chemical conditions of diabetes diminish tight junction formation. These factors may mediate blood-retinal barrier breakdown in diabetic retinopathy. Henle-Koch postulates for diabetic retinopathy are presented. Images FIGURE 1A FIGURE 1B FIGURE 2 A FIGURE 2 B FIGURE 3 A FIGURE 3 B FIGURE 3 C FIGURE 4 FIGURE 5 A FIGURE 5 B FIGURE 6 FIGURE 7 FIGURE 8 PMID:8719694

  16. Controlled Release of Growth Factors on Allograft Bone in vitro

    PubMed Central

    Ryu, WonHyoung; Ren, Peigen; Fasching, Rainer; Goodman, Stuart B.

    2008-01-01

    Allografts are important alternatives to autografts for treating defects after major bone loss. Bone growth factors have both local autocrine and paracrine effects and regulate the growth, proliferation, and differentiation of osteoprogenitor cells. To study the effects of prolonged, continuous, local delivery of growth factors on bone growth, we developed a new microelectromechanical system (MEMS) drug delivery device. Bone marrow cells from mice were seeded on mouse allograft discs and cultured in osteogenic media with osteogenic protein 1 (OP-1) and/or basic fibroblast growth factor (FGF-2) delivered from MEMS devices for 6 weeks. We monitored bone formation by changes of bone volume using micro-CT scanning and release of osteocalcin using ELISA. The data suggest the MEMS devices delivered constant concentrations of OP-1 and FGF-2 to the media. Bone marrow cells grew on the allografts and increased bone volume. Addition of OP-1 increased bone formation whereas FGF-2 decreased bone formation. Local delivery of growth factors over a prolonged period modulated the differentiation of osteoprogenitor cells on allograft bone. PMID:18509711

  17. Glutamatergic regulation of brain histamine neurons: In vivo microdialysis and electrophysiology studies in the rat.

    PubMed

    Fell, Matthew J; Flik, Gunnar; Dijkman, Ulrike; Folgering, Joost H A; Perry, Kenneth W; Johnson, Bryan J; Westerink, Ben H C; Svensson, Kjell A

    2015-12-01

    The interactions between the glutamatergic and the histaminergic systems in the brain are not fully understood. Here we studied histamine release in the medial prefrontal cortex and the posterior hypothalamus-tuberomamillary nucleus (PH-TMN) using in vivo microdialysis and electrophysiological recordings of histaminergc neurons in the PH-TMN in vivo to further address the mechanistic details of these interactions. We demonstrated that histaminergic activity was regulated by group II metabotropic glutamate receptors (mGluR 2 and 3) using systemic dosing with mGluR 2/3 agonist and antagonists and an mGluR 2 positive allosteric modulator. These interactions likely occur via direct modulation of glutamate release in the PH-TMN. The importance of circadian rhythm for histamine release was also shown using microdialysis studies with mGluR 2/3 compounds under light and dark conditions. Based on histamine release studies with NMDA and ketamine, we propose the existence of two sub-populations of NMDA receptors where one subtype is located on histaminergic cell bodies in the PH-TMN and the second on GABA-ergic neurons projecting to the PH-TMN. These subpopulations could be distinguished based on function, notably opposing actions were seen on histamine release in the medial prefrontal cortex of the rat. In summary, this paper provides evidence that the histaminergic system is closely regulated by glutamate neurons in multiple ways. In addition, this interaction depends to a great extent on the activity state of the subject.

  18. Effects of rat growth hormone (rGH)-releasing factor and somatostatin on the release and synthesis of rGH in dispersed pituitary cells

    SciTech Connect

    Fukata, J.; Diamond, D.J.; Martin, J.B.

    1985-08-01

    The effects of rat hypothalamic GH-releasing factor (GRF) and somatostatin (SRIF) on the release and biosynthesis of rat GH were studied by RIA and quantitative immunoprecipitation using monolayer cultures of rat anterior pituitary cells. In kinetic studies, GRF stimulation of GH release appeared at the first sampling time (20-min incubation) and the effect began to diminish after 2-h incubation with GRF. On the other hand, total (cell plus medium) content of GH significantly increased only after 24-h incubation. To examine the GH-synthesizing effect of GRF more directly, newly synthesized GH labeled by (TVS)methionine during incubation with GRF was quantified by immunoprecipitation. The amount of immunoprecipitable GH increased significantly and specifically also only after 24-h incubation. When GH pools were labeled with (TVS)methionine under different schedules, the basal release of newly synthesized GH, which was labeled for 1 h immediately before chase incubation was lower during the first 15 min than stored GH which had been labeled earlier. Basal newly synthesized GH secretion exceeded stored GH secretion after 30 min. In this system, SRIF suppressed both the basal and stimulated release of GH but did not modify GH biosynthesis under either condition. Newly synthesized GH showed significant degradation during 24-h incubation; neither GRF nor SRIF affected the rate of GH degradation during the same incubation period.

  19. Mesocosm experiments to assess factors affecting phosphorus retention and release in an extended Wisconsin wetland

    USGS Publications Warehouse

    Elder, J.F.; Manion, B.J.; Goddard, G.L.

    1997-01-01

    Phosphorus retention by wetland sediments and vegetation was investigated in Jackson Creek wetland, an extension of an existing prairie marsh in southeastern Wisconsin. The extended wetland construction was undertaken in 1992-93 to help reduce the phosphorus loading to a downstream eutrophic lake. Two approaches were used to study potential and actual phosphorus retention in the system. Mesocosm experiments of 20-40 days duration indicated that retention of total and dissolved reactive phosphorus in mesocosm cells containing macrophytes and/or sediments was reduced by factors of 2-20 relative to cells containing only water or a copper algicide to suppress metabolic activity. In contrast to the nutrient trapping function, these results show a potential for net phosphorus release that can be associated with increased biological richness. Measurements of water flow and nutrient loads at the wetland's inflow and outflow points demonstrated 9-39% net uptake of phosphorus on an annual scale but frequent occurrences of net phosphorus release over shorter (one-month) time scales. These episodes of release are most likely during the summer months. Thus, the wetland role in phosphorus cycling is not one of a true source or sink, although the annual budget data alone suggest substantial net retention. Effective management of the wetland for its nutrient trapping potential can be hindered by this oversimplification. The system is instead subject to relatively short-term alternation between net import and export. The periodic phosphorus export, although representing a small fraction of net annual import, could be critical for growth of macrophyte and algal communities downstream.

  20. Mutations in eukaryotic release factors 1 and 3 act as general nonsense suppressors in Drosophila.

    PubMed Central

    Chao, Anna T; Dierick, Herman A; Addy, Tracie M; Bejsovec, Amy

    2003-01-01

    In a screen for suppressors of the Drosophila wingless(PE4) nonsense allele, we isolated mutations in the two components that form eukaryotic release factor. eRF1 and eRF3 comprise the translation termination complex that recognizes stop codons and catalyzes the release of nascent polypeptide chains from ribosomes. Mutations disrupting the Drosophila eRF1 and eRF3 show a strong maternal-effect nonsense suppression due to readthrough of stop codons and are zygotically lethal during larval stages. We tested nonsense mutations in wg and in other embryonically acting genes and found that different stop codons can be suppressed but only a subset of nonsense alleles are subject to suppression. We suspect that the context of the stop codon is significant: nonsense alleles sensitive to suppression by eRF1 and eRF3 encode stop codons that are immediately followed by a cytidine. Such suppressible alleles appear to be intrinsically weak, with a low level of readthrough that is enhanced when translation termination is disrupted. Thus the eRF1 and eRF3 mutations provide a tool for identifying nonsense alleles that are leaky. Our findings have important implications for assigning null mutant phenotypes and for selecting appropriate alleles to use in suppressor screens. PMID:14573473

  1. Brainstem reticulospinal neurons are targets for corticotropin-releasing factor-Induced locomotion in roughskin newts.

    PubMed

    Hubbard, Catherine S; Dolence, E Kurt; Rose, James D

    2010-02-01

    Stress-induced release or central administration of corticotropin-releasing factor (CRF) enhances locomotion in a wide range of vertebrates, including the roughskin newt, Taricha granulosa. Although CRF's stimulatory actions on locomotor behavior are well established, the target neurons through which CRF exerts this effect remain unknown. To identify these target neurons, we utilized a fluorescent conjugate of CRF (CRF-TAMRA 1) to track this peptide's internalization into reticulospinal and other neurons in the medullary reticular formation (MRF), a region critically involved in regulating locomotion. Epifluorescent and confocal microscopy revealed that CRF-TAMRA 1 was internalized by diverse MRF neurons, including reticulospinal neurons retrogradely labeled with Cascade Blue dextran. In addition, we immunohistochemically identified a distinct subset of serotonin-containing neurons, located throughout the medullary raphé, that also internalized the fluorescent CRF-TAMRA 1 conjugate. Chronic single-unit recordings obtained from microwire electrodes in behaving newts revealed that intracerebroventricular (icv) administration of CRF-TAMRA 1 increased medullary neuronal firing and that appearance of this firing was associated with, and strongly predictive of, episodes of CRF-induced locomotion. Furthermore, icv administered CRF-TAMRA 1 produced behavioral and neurophysiological effects identical to equimolar doses of unlabeled CRF. Collectively, these findings provide the first evidence that CRF directly targets reticulospinal and serotonergic neurons in the MRF and indicate that CRF may enhance locomotion via direct effects on the hindbrain, including the reticulospinal system.

  2. Baseline and post-atrial pacing release of atrial natriuretic factor in mitral stenosis.

    PubMed

    Malatino, L S; Stancanelli, B; Greco, G; Polizzi, G; Leonardi, C; Russo, G; Tamburino, C; Greco, G; Giuffrida, G; Tamburino, G

    1990-01-01

    To investigate the release of atrial natriuretic factor (ANF) in mitral stenosis and the influence of the increase on the frequency of atrial contraction or atrial distention on ANF secretion, we studied 10 patients with symptoms of congestive heart failure (New York Heart Association classes II and III) in sinus rhythm, who were undergoing cardiac catheterization as part of an evaluation workup for mitral stenosis. Echocardiographic tracings, repeat determinations of mean pulmonary artery wedge pressure (MPAWP) and mean right atrial pressure, and blood sampling from the pulmonary artery for measurements of ANF were performed at baseline, during atrial pacing (pacing rate of 125 beats/min for 5 minutes), and 5 minutes after the pacing protocol was completed. Baseline ANF levels were closely related to right atrial pressure (r = 0.89; p less than 0.001) and increased markedly after atrial pacing from 205.6 +/- 39.8 (SEM) to 343.9 +/- 57.9 (SEM) pg/ml. A similar pacing-induced increase was shown for MPAWP and left atrial size. Our data indicate that pacing-induced increases in atrial distention and intracavitary pressure further stimulate release of ANF. However, an independent effect of frequency of atrial pacing on plasma ANF in humans could not be identified. PMID:2136967

  3. Expression of corticotropin-releasing factor in inflamed tissue is required for intrinsic peripheral opioid analgesia.

    PubMed Central

    Schafer, M; Mousa, S A; Zhang, Q; Carter, L; Stein, C

    1996-01-01

    Immune cell-derived opioid peptides can activate opioid receptors on peripheral sensory nerves to inhibit inflammatory pain. The intrinsic mechanisms triggering this neuroimmune interaction are unknown. This study investigates the involvement of endogenous corticotropin-releasing factor (CRF) and interleukin-1beta (IL-1). A specific stress paradigm, cold water swim (CWS), produces potent opioid receptor-specific antinociception in inflamed paws of rats. This effect is dose-dependently attenuated by intraplantar but not by intravenous alpha-helical CRF. IL-1 receptor antagonist is ineffective. Similarly, local injection of antiserum against CRF, but not to IL-1, dose-dependently reverses this effect. Intravenous anti-CRF is only inhibitory at 10(4)-fold higher concentrations and intravenous CRF does not produce analgesia. Pretreatment of inflamed paws with an 18-mer 3'-3'-end inverted CRF-antisense oligodeoxynucleotide abolishes CWS-induced antinociception. The same treatment significantly reduces the amount of CRF extracted from inflamed paws and the number of CRF-immunostained cells without affecting gross inflammatory signs. A mismatch oligodeoxynucleotide alters neither the CWS effect nor CRF immunoreactivity. These findings identify locally expressed CRF as the predominant agent to trigger opioid release within inflamed tissue. Endogenous IL-1, circulating CRF or antiinflammatory effects, are not involved. Thus, an intact immune system plays an essential role in pain control, which is important for the understanding of pain in immunosuppressed patients with cancer or AIDS. Images Fig. 4 PMID:8650225

  4. Controlled-release of epidermal growth factor from cationized gelatin hydrogel enhances corneal epithelial wound healing.

    PubMed

    Hori, Kuniko; Sotozono, Chie; Hamuro, Junji; Yamasaki, Kenta; Kimura, Yu; Ozeki, Makoto; Tabata, Yasuhiko; Kinoshita, Shigeru

    2007-04-01

    We designed a new ophthalmic drug-delivery system for epidermal growth factor (EGF) from the biodegradable hydrogel of cationized gelatin. We placed a cationized gelatin hydrogel (CGH) with incorporated (125)I-labelled EGF in the conjunctival sac of mice and measured the residual radioactivity at different times to evaluate the in vivo profile of EGF release. Approximately 60-67% and 10-12% of EGF applied initially remained 1 and 7 days after application, respectively; whereas EGF delivered in topically applied solution or via EGF impregnation of soft contact lenses disappeared within the first day. We also placed CGH films with 5.0 mug of incorporated EGF on round corneal defects in rabbits to evaluate the healing process using image analysis software and to assess epithelial proliferation immunohistochemically by counting the number of Ki67-positive cells. The application of a CGH film with incorporated EGF resulted in a reduction in the epithelial defect in rabbit corneas accompanied by significantly enhanced epithelial proliferation compared with the reduction seen after the topical application of EGF solution or the placement of an EGF-free CGH film. The controlled release of EGF from a CGH placed over a corneal epithelial defect accelerated ocular surface wound healing. PMID:17289206

  5. A basophil-activating factor from human T lymphocytes.

    PubMed Central

    Goetzl, E J; Foster, D W; Payan, D G

    1984-01-01

    Human T lymphocytes stimulated with phytohaemagglutinin (PHA) or streptokinase-streptodornase (SK-SD) generate an activity which elicits non-cytotoxic histamine release from human basophils. Filtration of the T lymphocyte-derived activity on columns of Sephadex G-100 and Fractogel 55F sequentially revealed one predominant basophil-activating factor of mol. wt. 70,000-90,000, that was designated BAF-T. BAF-T was composed of two acidic proteins of approximate pI 4.4 and 5.2-5.5, as assessed by isoelectric focusing. The distinction of BAF-T from IgE was confirmed by the failure of BAF-T to bind to an anti-IgE affinity column and the capacity of BAF-T to release histamine maximally from basophils desensitized to IgE-dependent stimuli. The inability of BAF-T to release histamine from human lung mast cells and dog cutaneous mastocytoma cells suggests target cell specificity. The source and activity of BAF-T are consistent with a specific contribution of this mediator to human cellular immune and hypersensitivity responses involving T lymphocytes and basophils. PMID:6208144

  6. Stress, sex, and addiction: potential roles of corticotropin-releasing factor, oxytocin, and arginine-vasopressin.

    PubMed

    Bisagno, Verónica; Cadet, Jean Lud

    2014-09-01

    Stress sensitivity and sex are predictive factors for the development of neuropsychiatric disorders. Life stresses are not only risk factors for the development of addiction but also are triggers for relapse to drug use. Therefore, it is imperative to elucidate the molecular mechanisms underlying the interactions between stress and drug abuse, as an understanding of this may help in the development of novel and more effective therapeutic approaches to block the clinical manifestations of drug addiction. The development and clinical course of addiction-related disorders do appear to involve neuroadaptations within neurocircuitries that modulate stress responses and are influenced by several neuropeptides. These include corticotropin-releasing factor, the prototypic member of this class, as well as oxytocin and arginine-vasopressin that play important roles in affiliative behaviors. Interestingly, these peptides function to balance emotional behavior, with sexual dimorphism in the oxytocin/arginine-vasopressin systems, a fact that might play an important role in the differential responses of women and men to stressful stimuli and the specific sex-based prevalence of certain addictive disorders. Thus, this review aims to summarize (i) the contribution of sex differences to the function of dopamine systems, and (ii) the behavioral, neurochemical, and anatomical changes in brain stress systems.

  7. Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability.

    PubMed

    Fritz, Elsa; Izaurieta, Pamela; Weiss, Alexandra; Mir, Franco R; Rojas, Patricio; Gonzalez, David; Rojas, Fabiola; Brown, Robert H; Madrid, Rodolfo; van Zundert, Brigitte

    2013-06-01

    Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by dysfunction and degeneration of motoneurons starting in adulthood. Recent studies using cell or animal models document that astrocytes expressing disease-causing mutations of human superoxide dismutase 1 (hSOD1) contribute to the pathogenesis of ALS by releasing a neurotoxic factor(s). Neither the mechanism by which this neurotoxic factor induces motoneuron death nor its cellular site of action has been elucidated. Here we show that acute exposure of primary wild-type spinal cord cultures to conditioned medium derived from astrocytes expressing mutant SOD1 (ACM-hSOD1(G93A)) increases persistent sodium inward currents (PC(Na)), repetitive firing, and intracellular calcium transients, leading to specific motoneuron death days later. In contrast to TTX, which paradoxically increased twofold the amplitude of calcium transients and killed motoneurons, reduction of hyperexcitability by other specific (mexiletine) and nonspecific (spermidine and riluzole) blockers of voltage-sensitive sodium (Na(v)) channels restored basal calcium transients and prevented motoneuron death induced by ACM-hSOD1(G93A). These findings suggest that riluzole, the only FDA-approved drug with known benefits for ALS patients, acts by inhibiting hyperexcitability. Together, our data document that a critical element mediating the non-cell-autonomous toxicity of ACM-hSOD1(G93A) on motoneurons is increased excitability, an observation with direct implications for therapy of ALS. PMID:23486205

  8. A specific radioimmunoassay for corticotropin releasing factor (CRF) using synthetic ovine CRF. [Rats

    SciTech Connect

    Hashimoto, K.; Murakami, K.; Ohno, N.; Kageyama, J.; Aoki, Y.; Takahara, J.; Ota, Z.

    1983-02-28

    This newly developed specific radioimmunoassay for corticotropin releasing factor (CRF) had a sensitivity range of 25 pg/tube to 4 ng/tube. Intra and interassay coefficients of variation were 4.6% and 9.8%, respectively. Rat median eminence extracts showed a parallel dose response curve with synthetic ovine CRF and a significant cross reaction was not evident with other tested neuropeptides. The highest mean levels of CRF were found in the median eminence (6.61 ng/mg proparaventricular nucleus, dorsomedial nucleus, suprachiasmatic nucleus and ventromedial nucleus. The immunoreactive CRF of the rat medial basal hypothalamus coeluted with bioassayable CRF and with iodinated CRF on Sephadex G-75 chromatography. The results indicate that rat hypothalamus contains a CRF similar to ovine CRF.

  9. Applications of human factors engineering to LNG release prevention and control

    SciTech Connect

    Shikiar, R.; Rankin, W.L.; Rideout, T.B.

    1982-06-01

    The results of an investigation of human factors engineering and human reliability applications to LNG release prevention and control are reported. The report includes a discussion of possible human error contributions to previous LNG accidents and incidents, and a discussion of generic HF considerations for peakshaving plants. More specific recommendations for improving HF practices at peakshaving plants are offered based on visits to six facilities. The HF aspects of the recently promulgated DOT regulations are reviewed, and recommendations are made concerning how these regulations can be implemented utilizing standard HF practices. Finally, the integration of HF considerations into overall system safety is illustrated by a presentation of human error probabilities applicable to LNG operations and by an expanded fault tree analysis which explicitly recognizes man-machine interfaces.

  10. Expression of growth hormone (GH)-releasing factor gene in GH-producing pituitary adenoma.

    PubMed

    Wakabayashi, I; Inokuchi, K; Hasegawa, O; Sugihara, H; Minami, S

    1992-02-01

    Pituitary cells synthesize various neuropeptides that influence pituitary hormone secretion. GH-releasing factor (GRF) may also be produced by normal or pituitary tumor cells. We examined GRF gene expression in pituitary tumors. Standard techniques for the analysis of GRF gene expression did not appear to be suitable. Highly sensitive reverse transcription coupled to polymerase chain reaction was used. Specimens of pituitary adenoma were obtained by transsphenoidal adenomectomy from six patients with acromegaly and three patients with no clinical evidence of pituitary hormone overproduction; non-functioning adenoma. Pituitary glands were collected at autopsy from three patients who died from nonendocrine disorders. A specific GRF gene transcript was detected in five out of six GH-producing pituitary adenomas, whereas this was not found in three separate specimens of nonfunctioning pituitary adenoma or anterior and posterior pituitary tissue. The data suggest that GRF is synthesized as an intrinsic product in human GH-producing pituitary adenoma.

  11. Distribution of Urocortins and Corticotropin-Releasing Factor Receptors in the Cardiovascular System

    PubMed Central

    Takahashi, Kazuhiro

    2012-01-01

    Urocortins are human homologues of urotensin I, a fish corticotropin-releasing-factor- (CRF-) like peptide secreted from the urophysis. There are three urocortins: urocortin 1, urocortin 2, and urocortin 3 in mammals. We have shown that urocortin 1 and urocortin 3 are endogenously synthesized in the myocardial cells of human heart and may act on CRF type 2 receptor (CRFR2) expressed in the heart. Expression levels of urocortin 1 in the heart and plasma urocortin 1 levels are elevated in patients with heart failure. Recent studies have shown that urocortins have various biological actions in the cardiovascular system, such as a vasodilator action, a positive inotropic action, a cardioprotective action against ischemia/reperfusion injury, and suppressive actions against the renin angiotensin system and the sympathetic nervous system. Urocortins and CRFR2 may therefore be a potential therapeutic target for cardiovascular diseases, such as congestive heart failure, hypertension, and myocardial infarction. PMID:22675352

  12. Sustained release of tissue factor following thrombosis of lower limb trauma.

    PubMed

    Walenga, Jeanine M; Kaiser, Phoebe C; Prechel, M Margaret; Hoppensteadt, Debra; Jeske, Walter P; Misselwitz, Frank; Bacher, Peter; Lassen, Michael R; Fareed, Jawed

    2014-10-01

    This study was undertaken to provide evidence for the mechanism of venous thromboembolism (VTE) in healthy patients with minor lower limb injury (fracture; Achilles tendon rupture) that was medically managed with plaster cast/brace immobilization. The Plaster Cast clinical trial provided a unique opportunity to identify the natural history of VTE using placebo-controlled patients (n = 183) with validation of the mechanism using the low-molecular-weight heparin (LMWH; reviparin)-treated patients (n = 182). Confirmed VTE in this population was associated with a burst of tissue factor release (and a minor fibrinolytic deficit) leading to thrombin generation that was sustained at least 5 weeks, greater with fractures than with soft-tissue injuries and greater with surgery than with conservative treatment. The root cause likely involves platelet/leukocyte activation (inflammation) rather than endothelial cell injury. Thromboprophylaxis with a low dose of LMWH reduced thrombin generation, with patients undergoing surgery benefitting the most.

  13. Cognitive Disruptions in Stress-Related Psychiatric Disorders: A Role for Corticotropin Releasing Factor (CRF)

    PubMed Central

    Bangasser, Debra A.; Kawasumi, Yushi

    2015-01-01

    Stress is a potential etiology contributor to both post-traumatic stress disorders (PTSD) and major depression. One stress-related neuropeptide that is hypersecreted in these disorders is corticotropin releasing factor (CRF). Dysregulation of CRF has long been linked to the emotion and mood symptoms that characterize PTSD and depression. However, the idea that CRF also mediates the cognitive disruptions observed in patients with these disorders has received less attention. Here we review literature indicating that CRF can alter cognitive functions. Detailed are anatomical studies revealing that CRF is poised to modulate regions required for learning and memory. We also describe preclinical behavioral studies that demonstrate CRF’s ability to alter fear conditioning, impair memory consolidation, and alter a number of executive functions, including attention and cognitive flexibility. The implications of these findings for the etiology and treatment of the cognitive impairments observed in stress-related psychiatric disorders are described. PMID:25888454

  14. Knockdown of corticotropin-releasing factor 1 receptors in the ventral tegmental area enhances conditioned fear.

    PubMed

    Chen, Nicola A; Ganella, Despina E; Bathgate, Ross A D; Chen, Alon; Lawrence, Andrew J; Kim, Jee Hyun

    2016-09-01

    The neuropeptide corticotropin-releasing factor (CRF) coordinates the physiological and behavioural responses to stress. CRF receptors are highly expressed in the ventral tegmental area (VTA), an important region for motivated behaviour. Therefore, we examined the role of CRF receptor type 1 (CRFR1) in the VTA in conditioned fear, using a viral-mediated RNA interference approach. Following stereotaxic injection of a lentivirus that contained either shCRF-R1 or a control sequence, mice received tone-footshock pairings. Intra-VTA shCRF-R1 did not affect tone-elicited freezing during conditioning. Once conditioned fear was acquired, however, shCRF-R1 mice consistently showed stronger freezing to the tone even after extinction and reinstatement. These results implicate a novel role of VTA CRF-R1 in conditioned fear, and suggest how stress may modulate aversive learning and memory. PMID:27397862

  15. Corticotropin-releasing factor has an anxiogenic action in the social interaction test.

    PubMed

    Dunn, A J; File, S E

    1987-06-01

    The effects of intracerebroventricular (icv) injections of corticotropin-releasing factor (CRF, 100 and 300 ng) were investigated in the social interaction test of anxiety in rats. Both doses of CRF significantly decreased active social interaction without a concomitant decrease in locomotor activity. CRF also significantly increased self-grooming, an effect that was independent of the decrease in social interaction. These results indicate an anxiogenic action for CRF. Chlordiazepoxide (CDP, 5 mg/kg ip) pretreatment reversed the anxiogenic effects of icv CRF (100 ng), but CRF did not prevent the sedative effects of CDP. There were no statistically significant changes due to CRF in locomotor activity or rears or head dipping in the holeboard test. Both doses of CRF significantly increased plasma concentrations of corticosterone. The possible mechanisms of the behavioral effects of CRF are discussed.

  16. Release of leukemia inhibitory factor in primate sepsis. Analysis of the role of TNF-alpha.

    PubMed

    Jansen, P M; de Jong, I W; Hart, M; Kim, K J; Aarden, L A; Hinshaw, L B; Taylor, F B; Hack, C E

    1996-06-01

    Leukemia inhibitory factor (LIF), a pleiotropic cytokine with many biologic effects overlapping with those of IL-6, has been implicated in the pathogenesis of sepsis. We here analyzed the kinetics of LIF in 13 baboons challenged with a lethal (n=6) or sublethal (n=7) dose of Escherichia coli. In addition, to assess the role of TNF-alpha in the induction of LIF in vivo, seven baboons were studied that had either received a bolus injection of recombinant human TNF-alpha (100 micrograms/kg, n=3), or to whom 15 mg/kg of an anti-TNF mAB before lethal E. coli challenge was administered (n=4). LIF levels increased 2 h after E coli challenge, and reached maximum values at 4 and 8 h after a sublethal (4.4 +/- 1.6 ng/ml) or lethal (40.9 +/- 3.8 ng/ml) dose, respectively. TNF-alpha injection induced a modest rise in LIF concentrations, peaking after 6 h (228 +/- 46 pg/ml). Circulating LIF correlated with plasma levels of IL-6, both after E. coli challenge (Spearman Rank coefficient of correlation (r) = 0.849, p<0.001), as well as upon TNF-alpha injection (r=0.863, p<0.001). Moreover, the E. coli-induced release of either cytokine was reduced 6- to 10-fold after pretreatment with anti-TNF mAb, except in one nonsurviving animal, which exhibited a progressive increase of LIF and IL-6 levels despite the absence of TNF immunoreactivity. These results show that TNF-alpha is an intermediate factor in concerted release of LIF and IL-6 in vivo, and indicate that the enhanced elaboration of these cytokines may predict disease outcome in severe sepsis.

  17. Differential effect of low doses of intracerebroventricular corticotropin-releasing factor in forced swimming test.

    PubMed

    García-Lecumberri, C; Ambrosio, E

    2000-11-01

    In this work, we studied the effect of low doses of intracerebroventricular corticotropin-releasing factor (CRF) in six sessions of forced swimming test (FST). When CRF (0.01 and 0.1 microg) was administered pre-test, results showed that the 0.1-microg dose significantly increased swimming in SESSION2, SESSION3 and SESSION4, while the 0.01-microg dose proved ineffective. When CRF (0.1 and 0.03 microg) was administered post-test to evaluate retention of swimming response, the dose of 0.1 microg impaired retention, while the dose of 0.03 microg improved it, although these effects only reached significance in SESSION2. In an additional session (SESSION6), testing long-term retention of this swimming response, the 0.1-microg dose significantly impaired retention, whereas the 0.03-microg dose proved ineffective. A high dose of CRF (1 microg) was also included as a control of previous results [García-Lecumberri C, Ambrosio E. Role of corticotropin-releasing factor in forced swimming test. Eur J Pharmacol 1998;343:17-26]. In all the FST sessions, this high dose increased swimming when administered pre-test, while impairing retention when administered post-test. Preliminary data obtained with low doses of CRF suggest that a differential effect on retention of swimming response seems to exist depending on the dose, whereas a high dose of CRF clearly impairs retention. The role of CRF in learning and memory processes in FST is discussed.

  18. [Role of central histamine in amygdaloid kindled seizures].

    PubMed

    Kamei, C; Okuma, C

    2001-05-01

    The role of central histamine in amygdaloid kindled seizures in rats was studied. Histamine content in the amygdala was significantly decreased after development of amygdaloid kindling. Intracerebroventricular (i.c.v.) injection of histamine resulted in inhibition of amygdaloid kindled seizures. The H1-agonists 2-methylhistamine and 2-thiazolylethylamine also inhibited amygdaloid kindled seizures. In addition, intraperitoneal (i.p.) injection of histidine and metoprine inhibited amygdaloid kindled seizures at doses that caused increases in histamine contents of the brain. H1-antagonists (diphenhydramine and chlorpheniramine) attenuated histamine- or histidine-induced inhibition of amygdaloid kindled seizures. Both i.c.v. and i.p. injections of H3-antagonists (thioperamide, AQ0145 and clobenpropit) resulted in a dose-related inhibition of amygdaloid kindled seizures. The effects of thioperamide and AQ0145 were inhibited by an H3-agonist (R)-alpha-methylhistamine and H1-antagonists. On the other hand, H2-antagonists showed no antagonistic effect. GABAmimetic drugs, diazepam, sodium valproate and muscimol potentiated the effect of clobenpropit. Bicuculline caused significant antagonism of the inhibition of amygdaloid kindled seizures induced by clobenpropit. These findings suggested that a histaminergic mechanism plays an important role in suppressing amygdaloid kindled seizures through histamine H1-receptors. In addition, an inhibition of amygdaloid kindled seizures induced by histamine is closely related with the action of GABA.

  19. Interactions of the histamine and hypocretin systems in CNS disorders.

    PubMed

    Shan, Ling; Dauvilliers, Yves; Siegel, Jerome M

    2015-07-01

    Histamine and hypocretin neurons are localized to the hypothalamus, a brain area critical to autonomic function and sleep. Narcolepsy type 1, also known as narcolepsy with cataplexy, is a neurological disorder characterized by excessive daytime sleepiness, impaired night-time sleep, cataplexy, sleep paralysis and short latency to rapid eye movement (REM) sleep after sleep onset. In narcolepsy, 90% of hypocretin neurons are lost; in addition, two groups reported in 2014 that the number of histamine neurons is increased by 64% or more in human patients with narcolepsy, suggesting involvement of histamine in the aetiology of this disorder. Here, we review the role of the histamine and hypocretin systems in sleep-wake modulation. Furthermore, we summarize the neuropathological changes to these two systems in narcolepsy and discuss the possibility that narcolepsy-associated histamine abnormalities could mediate or result from the same processes that cause the hypocretin cell loss. We also review the changes in the hypocretin and histamine systems, and the associated sleep disruptions, in Parkinson disease, Alzheimer disease, Huntington disease and Tourette syndrome. Finally, we discuss novel therapeutic approaches for manipulation of the histamine system. PMID:26100750

  20. Itching for answers: how histamine relaxes lymphatic vessels.

    PubMed

    Scallan, Joshua P; Davis, Michael J

    2014-10-01

    In the current issue of Microcirculation, studies by Kurtz et al. and Nizamutdinova et al. together provide new evidence supporting a role for histamine as an endothelial-derived molecule that inhibits lymphatic muscle contraction. In particular, Nizamutdinova et al. show that the effects of flow-induced shear stress on lymphatic endothelium are mediated by both nitric oxide and histamine, since only blockade of both prevents contraction strength and frequency from being altered by flow. Separately, Kurtz et al. used confocal microscopy to determine a preferential expression of histamine receptors on the lymphatic endothelium and demonstrated that histamine applied to spontaneously contracting collecting lymphatics inhibits contractions. Previous studies disagreed on whether histamine stimulates or inhibits lymphatic contractions, but also used differing concentrations, species, and preparations. Together these new reports shed light on how histamine acts within the lymphatic vasculature, but also raise important questions about the cell type on which histamine exerts its effects and the signaling pathways involved. This editorial briefly discusses the contribution of each study and its relevance to lymphatic biology.

  1. Interactions of the histamine and hypocretin systems in CNS disorders.

    PubMed

    Shan, Ling; Dauvilliers, Yves; Siegel, Jerome M

    2015-07-01

    Histamine and hypocretin neurons are localized to the hypothalamus, a brain area critical to autonomic function and sleep. Narcolepsy type 1, also known as narcolepsy with cataplexy, is a neurological disorder characterized by excessive daytime sleepiness, impaired night-time sleep, cataplexy, sleep paralysis and short latency to rapid eye movement (REM) sleep after sleep onset. In narcolepsy, 90% of hypocretin neurons are lost; in addition, two groups reported in 2014 that the number of histamine neurons is increased by 64% or more in human patients with narcolepsy, suggesting involvement of histamine in the aetiology of this disorder. Here, we review the role of the histamine and hypocretin systems in sleep-wake modulation. Furthermore, we summarize the neuropathological changes to these two systems in narcolepsy and discuss the possibility that narcolepsy-associated histamine abnormalities could mediate or result from the same processes that cause the hypocretin cell loss. We also review the changes in the hypocretin and histamine systems, and the associated sleep disruptions, in Parkinson disease, Alzheimer disease, Huntington disease and Tourette syndrome. Finally, we discuss novel therapeutic approaches for manipulation of the histamine system.

  2. Pyridinium derivatives of histamine are potent activators of cytosolic carbonic anhydrase isoforms I, II and VII.

    PubMed

    Dave, Khyati; Scozzafava, Andrea; Vullo, Daniela; Supuran, Claudiu T; Ilies, Marc A

    2011-04-21

    A series of positively-charged derivatives has been prepared by reaction of histamine with substituted pyrylium salts. These pyridinium histamine derivatives were investigated as activators of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) and more precisely the human isoforms hCA I, II and VII. Activities from the subnanomolar to the micromolar range were detected for these compounds as activators of the three isoforms, confirming the validity of current and previous designs. The substitution pattern at the pyridinium ring was the main factor influencing activity, the three isoforms showing different structural requirements for good activity, related with the number of pyridinium substituting groups and their nature, among various alkyl, phenyl and para-substituted styryl moieties. We were successful in identifying nanomolar potent and selective activators for each isozyme and also activators with a relatively good activity against all isozymes tested--valuable lead compounds for physiology and pathology studies involving these isozymes.

  3. Cardiovascular reflexes evoked by histamine stimulation of the stomach.

    PubMed

    Stebbins, C L; Theodossy, S J; Longhurst, J C

    1991-04-01

    This study examined the potential for histamine to cause cardiovascular reflexes when applied to the serosal or mucosal surface of the stomach. Thus, in chloralose-anesthetized cats, histamine was applied to the serosal surface of the stomach in concentrations ranging from 0.5 to 1,000 micrograms/ml. This resulted in graded increases in mean arterial pressure (MAP), maximal left ventricular pressure over time (dP/dt), and heart rate ranging from 9 +/- 4 to 30 +/- 3 mmHg, 450 +/- 103 to 1,710 +/- 610 mmHg/s, and 2 +/- 1 to 13 +/- 4 beats/min, respectively. Histamine stimulation of the gastric serosa evoked a greater pressor response than that observed when the same concentration of histamine (100 micrograms/ml) was applied to the gastric mucosa (43 +/- 7 vs. 13 +/- 3 mmHg, respectively). In six cats, celiac ganglionectomy abolished the previously observed cardiovascular response to histamine stimulation of the serosal surface of the stomach. When the gastric serosa was treated with the H1-receptor antagonist diphenhydramine (1 mg/ml) (n = 5), the cardiovascular response to histamine was abolished. In five other cats, administration of the H2-antagonist ranitidine (1 mg/ml) had no effect on the histamine-induced responses. When indomethacin (2-5 mg/ml), was applied to the serosal surface of the stomach (n = 6), histamine-induced increases in MAP and dP/dt were attenuated. However, application of PGE2 (1 microgram/ml) restored these two responses. These results suggest that histamine stimulates H1-receptors in the gastric wall to cause reflex cardiovascular responses that are dependent, in part, on the local production of prostaglandins.

  4. A role for histamine in cardiovascular regulation in late stage embryos of the red-footed tortoise, Chelonoidis carbonaria Spix, 1824.

    PubMed

    Crossley, Dane A; Sartori, Marina R; Abe, Augusto S; Taylor, Edwin W

    2013-08-01

    A chorioallantoic membrane artery in embryos of the red-footed tortoise, Chelonoidis carbonaria was occlusively cannulated for measurement of blood pressure and injection of drugs. Two age groups of embryos in the final 10 % of incubation were categorized by the ratio of embryonic body to yolk mass. All embryos first received cholinergic and β-adrenergic blockade. This revealed that β-adrenergic control was established in both groups whereas cholinergic control was only established in the older group immediately prior to hatching. The study then progressed as two series. Series one was conducted in a subset of embryos treated with histamine before or after injection of ranitidine, the antagonist of H2 receptors. Injection of histamine caused an initial phasic hypertension which recovered, followed by a longer lasting hypertensive response accompanied by a tachycardia. Injection of the H2 receptor antagonist ranitidine itself caused a hypotensive tachycardia with subsequent recovery of heart rate. Ranitidine also abolished the cardiac effects of histamine injection while leaving the initial hypertensive response intact. In series, two embryos were injected with histamine after injection of diphenhydramine, the antagonist to H1 receptors. This abolished the whole of the pressor response to histamine injection but left the tachycardic response intact. These data indicate that histamine acts as a non-adrenergic, non-cholinergic factor, regulating the cardiovascular system of developing reptilian embryos and that its overall effects are mediated via both H1 and H2 receptor types.

  5. [Antioxidant defense system state in blood plasma and heart muscle of rats under the influence of histamine and sodium hypochlorite].

    PubMed

    Bishko, O I; Harasym, N P; Sanahurs'kyĭ, D I

    2014-01-01

    There is a wide spectrum of antihistamine drugs in the pharmaceutical market, however all these chemical preparations cause side effects. Therefore, new alternative ways for histamine detoxication are to be found. For this aim in our experiment sodium hypochlorite was used because its solution possesses strong oxidizing properties. The influence of histamine and sodium hypochlorite on the antioxidant defence system state of blood plasma and cardiac muscle in rats has been researched. It was shown, that the investigated factors result in the disruption of the antioxidant system. It was found that histamine injection in concentration of 1 and 8 μg/kg in plasma leads to the increase of superoxide dismutase activity during all the experiment. When studying enzymes, that catalyze hydroperoxides and H2O2 decomposition it was shown that under the influence of histamine in a dose 1 μg/kg, the glutathione peroxidase activity increased on the 1st day of the experiment. However, on the 7th day of the experiment the increase of both glutathione peroxidase and catalase activity was fixed. The deviation in superoxide dismutase function in rats plasma under the action of sodium hypochlorite has been established. The activity of enzymes that decompose H2O2 and hydroperoxides were inhibited. Under the influence of histamine in the heart tissues we have stated the disturbance of superoxide dismutase work and increase ofcatalase activity and decrease of glutathione peroxidase activity. The influence of sodium hypochlorite on the myocardium of intact animals as well as joint influence of sodium hypochlorite and histamine result in the increase of superoxide dismutase and catalase activity and lead to the considerable decline of activity of glutathione peroxidase.

  6. Novel Roles for Kv7 Channels in Shaping Histamine-Induced Contractions and Bradykinin-Dependent Relaxations in Pig Coronary Arteries.

    PubMed

    Chen, Xingjuan; Li, Wennan; Hiett, S Christopher; Obukhov, Alexander G

    2016-01-01

    . We propose that in CAs, a decreased expression or a loss of function of Kv7 channels may lead to sustained histamine-induced contractions and reduced endothelium-dependent relaxation, both risk factors for coronary spasm.

  7. Functional Impact of Corticotropin-Releasing Factor Exposure on Tau Phosphorylation and Axon Transport

    PubMed Central

    Le, Michelle H.; Weissmiller, April M.; Monte, Louise; Lin, Po Han; Hexom, Tia C.; Natera, Orlangie; Wu, Chengbiao; Rissman, Robert A.

    2016-01-01

    Stress exposure or increased levels of corticotropin-releasing factor (CRF) induce hippocampal tau phosphorylation (tau-P) in rodent models, a process that is dependent on the type-1 CRF receptor (CRFR1). Although these preclinical studies on stress-induced tau-P provide mechanistic insight for epidemiological work that identifies stress as a risk factor for Alzheimer’s disease (AD), the actual impact of stress-induced tau-P on neuronal function remains unclear. To determine the functional consequences of stress-induced tau-P, we developed a novel mouse neuronal cell culture system to explore the impact of acute (0.5hr) and chronic (2hr) CRF treatment on tau-P and integral cell processes such as axon transport. Consistent with in vivo reports, we found that chronic CRF treatment increased tau-P levels and caused globular accumulations of phosphorylated tau in dendritic and axonal processes. Furthermore, while both acute and chronic CRF treatment led to significant reduction in CREB activation and axon transport of brain-derived neurotrophic factor (BDNF), this was not the case with mitochondrial transport. Acute CRF treatment caused increased mitochondrial velocity and distance traveled in neurons, while chronic CRF treatment modestly decreased mitochondrial velocity and greatly increased distance traveled. These results suggest that transport of cellular energetics may take priority over growth factors during stress. Tau-P was required for these changes, as co-treatment of CRF with a GSK kinase inhibitor prevented CRF-induced tau-P and all axon transport changes. Collectively, our results provide mechanistic insight into the consequences of stress peptide-induced tau-P and provide an explanation for how chronic stress via CRF may lead to neuronal vulnerability in AD. PMID:26790099

  8. Early outgrowth cells release soluble endocrine antifibrotic factors that reduce progressive organ fibrosis.

    PubMed

    Yuen, Darren A; Connelly, Kim A; Zhang, Yanling; Advani, Suzanne L; Thai, Kerri; Kabir, Golam; Kepecs, David; Spring, Christopher; Smith, Christopher; Batruch, Ihor; Kosanam, Hari; Advani, Andrew; Diamandis, Eleftherios; Marsden, Philip A; Gilbert, Richard E

    2013-11-01

    Adult bone marrow-derived cells can improve organ function in chronic disease models, ostensibly by the release of paracrine factors. It has, however, been difficult to reconcile this prevailing paradigm with the lack of cell retention within injured organs and their rapid migration to the reticuloendothelial system. Here, we provide evidence that the salutary antifibrotic effects of bone marrow-derived early outgrowth cells (EOCs) are more consistent with an endocrine mode of action, demonstrating not only the presence of antifibrotic factors in the plasma of EOC-treated rats but also that EOC conditioned medium (EOC-CM) potently attenuates both TGF-β- and angiotensin II-induced fibroblast collagen production in vitro. To examine the therapeutic relevance of these findings in vivo, 5/6 subtotally nephrectomized rats, a model of chronic kidney and heart failure characterized by progressive fibrosis of both organs, were randomized to receive i.v. injections of EOC-CM, unconditioned medium, or 10(6) EOCs. Rats that received unconditioned medium developed severe kidney injury with cardiac diastolic dysfunction. In comparison, EOC-CM-treated rats demonstrated substantially improved renal and cardiac function and structure, mimicking the changes found in EOC-treated animals. Mass spectrometric analysis of EOC-CM identified proteins that regulate cellular functions implicated in fibrosis. These results indicate that EOCs secrete soluble factor(s) with highly potent antifibrotic activity, that when injected intravenously replicate the salutary effects of the cells themselves. Together, these findings suggest that an endocrine mode of action may underlie the effectiveness of cell therapy in certain settings and portend the possibility for systemic delivery of cell-free therapy.

  9. Histamine regulation of hyperplastic and neoplastic cell growth in cholangiocytes

    PubMed Central

    Onori, Paolo; Gaudio, Eugenio; Franchitto, Antonio; Alpini, Gianfranco; Francis, Heather

    2010-01-01

    Histamine has long been known to be involved in inflammatory events. The discovery of antihistamines dates back to the first half of the 20th century when a Swiss-Italian pharmacologist, Daniel Bovet began his work. In 1957 he was awarded a Nobel Prize for his production of antihistamines for allergy relief. Since that time, histamine has been found to play a role in other events besides allergic reaction. Possibly unbelievable to Bovet and his peers, histamine has now been marked as playing a role in liver pathologies including hepatobiliary diseases. PMID:21607141

  10. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    PubMed Central

    Khanfar, Mohammad A.; Affini, Anna; Lutsenko, Kiril; Nikolic, Katarina; Butini, Stefania; Stark, Holger

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures. PMID:27303254

  11. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists.

    PubMed

    Khanfar, Mohammad A; Affini, Anna; Lutsenko, Kiril; Nikolic, Katarina; Butini, Stefania; Stark, Holger

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures. PMID:27303254

  12. Factors associated with the conditional release of persons acquitted by reason of insanity: a decision tree approach.

    PubMed

    Callahan, L A; Silver, E

    1998-04-01

    Most NGRI (not guilty by reason of insanity) acquitties are hospitalized for some period of time following acquittal, which raises the question of when an individual can be safely released into the community. The conditional release (CR) of persons acquitted by reason of insanity, therefore, provokes the question of public safety. This study examines the CR systems in four states--Connecticut, Maryland, New York, and Ohio. A study sample of 529 persons acquitted as NGRI from 1985 to 1987 was followed up for at least five years to determine who is conditionally released. Following a description of the CR systems, findings suggestive of the role of dangerousness and diagnosis as predictors of CR are presented. Personal characteristics are also significant factors in predicting who will be released. The length of hospitalization for this population and other descriptive factors such as history of hospitalization, arrests, substance abuse, family violence, and living arrangements are also addressed.

  13. Insulin/IGF signaling in Drosophila and other insects: factors that regulate production, release and post-release action of the insulin-like peptides.

    PubMed

    Nässel, Dick R; Vanden Broeck, Jozef

    2016-01-01

    Insulin, insulin-like growth factors (IGFs) and insulin-like peptides (ILPs) are important regulators of metabolism, growth, reproduction and lifespan, and mechanisms of insulin/IGF signaling (IIS) have been well conserved over evolution. In insects, between one and 38 ILPs have been identified in each species. Relatively few insect species have been investigated in depth with respect to ILP functions, and therefore we focus mainly on the well-studied fruitfly Drosophila melanogaster. In Drosophila eight ILPs (DILP1-8), but only two receptors (dInR and Lgr3) are known. DILP2, 3 and 5 are produced by a set of neurosecretory cells (IPCs) in the brain and their biosynthesis and release are controlled by a number of mechanisms differing between larvae and adults. Adult IPCs display cell-autonomous sensing of circulating glucose, coupled to evolutionarily conserved mechanisms for DILP release. The glucose-mediated DILP secretion is modulated by neurotransmitters and neuropeptides, as well as by factors released from the intestine and adipocytes. Larval IPCs, however, are indirectly regulated by glucose-sensing endocrine cells producing adipokinetic hormone, or by circulating factors from the intestine and fat body. Furthermore, IIS is situated within a complex physiological regulatory network that also encompasses the lipophilic hormones, 20-hydroxyecdysone and juvenile hormone. After release from IPCs, the ILP action can be modulated by circulating proteins that act either as protective carriers (binding proteins), or competitive inhibitors. Some of these proteins appear to have additional functions that are independent of ILPs. Taken together, the signaling with multiple ILPs is under complex control, ensuring tightly regulated IIS in the organism.

  14. Factors influencing immediate post-release survival of spectacled eiders following surgical implantation of transmitters with percutaneous antennae

    USGS Publications Warehouse

    Sexson, Matthew G.; Mulcahy, Daniel M.; Spriggs, Maria; Myers, Gwen E.

    2014-01-01

    Surgically implanted transmitters are a common method for tracking animal movements. Immediately following surgical implantation, animals pass through a critical recovery phase when behaviors may deviate from normal and the likelihood of individual survival may be reduced. Therefore, data collected during this period may be censored to minimize bias introduced by surgery-related behaviors or mortality. However, immediate post-release mortalities negate a sampling effort and reduce the amount of data potentially collected after the censoring period. Wildlife biologists should employ methods to support an animal’s survival through this period, but factors contributing to immediate post-release survival have not been formally assessed. We evaluated factors that potentially influenced the immediate post-release survival of 56 spectacled eiders (Somateria fischeri) marked with coelomically implanted satellite transmitters with percutaneous antennae in northern Alaska in 2010 and 2011. We modeled survival through the first 14 days following release and assessed the relative importance and effect of 15 covariates hypothesized to influence survival during this immediate post-release period. Estimated daily survival rate increased over the duration of the immediate post-release period; the probability of mortality was greatest within the first 5 days following release. Our top-ranking model included the effect of 2 blood analytes, pH and hematocrit, measured prior to surgical implantation of a transmitter. We found a positive response to pH; eiders exhibiting acidemia (low pH) prior to surgery were less likely to survive the immediate post-release period. We found a curvilinear response to hematocrit; eiders exhibiting extremely low or high pre-surgery hematocrit were also less likely to survive the immediate post-release period. In the interest of maximizing the survival of marked birds following release, hematological data obtained prior to surgical implantation of

  15. Corticotropin-releasing Factor in the Dorsal Raphe Nucleus: Linking Stress Coping and Addiction

    PubMed Central

    Valentino, Rita J.; Lucki, Irwin; Van Bockstaele, Elisabeth

    2009-01-01

    Addiction and stress are linked at multiple levels. Drug abuse is often initiated as a maladaptive mechanism for coping with stress. It is maintained in part by negative reinforcement to prevent the aversive consequences of stress associated with abstinence. Finally, stress is a major factor leading to relapse in subjects in which drug seeking behavior has extinguished. These associations imply overlapping or converging neural circuits and substrates that underlie the processes of addiction and the expression of the stress response. Here we discuss the major brain serotonin (5-HT) system, the dorsal raphe nucleus (DRN)-5-HT system as a point of convergence that links these processes and how the stress-related neuropeptide, corticotropin-releasing factor (CRF) directs this by a bimodal regulation of DRN neuronal activity. The review begins by describing a structural basis for CRF regulation of the DRN-5-HT system. This is followed by a review of the effects of CRF and stress on DRN function based on electrophysiological and microdialysis studies. The concept that multiple CRF receptor subtypes in the DRN facilitate distinct coping behaviors is reviewed with recent evidence for a unique cellular mechanism by which stress history can determine the type of coping behavior. Finally, work on CRF regulation of the DRN-5-HT system is integrated with literature on the role of 5-HT-dopamine interactions in addiction. PMID:19800322

  16. Rapid release of growth factors regenerates force output in volumetric muscle loss injuries.

    PubMed

    Grasman, Jonathan M; Do, Duc M; Page, Raymond L; Pins, George D

    2015-12-01

    A significant challenge in the design and development of biomaterial scaffolds is to incorporate mechanical and biochemical cues to direct organized tissue growth. In this study, we investigated the effect of hepatocyte growth factor (HGF) loaded, crosslinked fibrin (EDCn-HGF) microthread scaffolds on skeletal muscle regeneration in a mouse model of volumetric muscle loss (VML). The rapid, sustained release of HGF significantly enhanced the force production of muscle tissue 60 days after injury, recovering more than 200% of the force output relative to measurements recorded immediately after injury. HGF delivery increased the number of differentiating myoblasts 14 days after injury, and supported an enhanced angiogenic response. The architectural morphology of microthread scaffolds supported the ingrowth of nascent myofibers into the wound site, in contrast to fibrin gel implants which did not support functional regeneration. Together, these data suggest that EDCn-HGF microthreads recapitulate several of the regenerative cues lost in VML injuries, promote remodeling of functional muscle tissue, and enhance the functional regeneration of skeletal muscle. Further, by strategically incorporating specific biochemical factors and precisely tuning the structural and mechanical properties of fibrin microthreads, we have developed a powerful platform technology that may enhance regeneration in other axially aligned tissues.

  17. Relationship between tumor necrosis factorrelease and granulocyte and monocyte adsorption to cellulose acetate beads.

    PubMed

    Nishise, Shoichi; Abe, Yasuhiko; Nomura, Eiki; Sato, Takeshi; Sasaki, Yu; Iwano, Daisuke; Yoshizawa, Kazuya; Yagi, Makoto; Nishise, Yuko; Ueno, Yoshiyuki

    2014-06-01

    Tumor necrosis factor-α, (TNF)-α, a proinflammatory cytokine, is produced by activated granulocytes and monocytes (GMs) and implicated as a major factor in inflammatory bowel disease (IBD) pathogenesis. Reduction of TNF-α should improve IBD pathology. GM adsorptive apheresis (GMA) is an effective therapy for inflammatory disorders including IBD. GM adsorption to cellulose acetate (CA) beads induces anti-inflammatory cytokine release, although these effects on TNF-α release are not clarified. We hypothesized that GMA may inhibit TNF-α release. The aim of the present study was to clarify the effects of GM adsorption to CA beads on TNF-α release in vitro. Peripheral blood was incubated with and without CA beads and TNF-α was measured. For comparison, TNF-α was measured in another lipopolysaccharide (LPS)-containing peripheral blood sample incubated similarly. The amount of TNF-α in blood samples incubated with CA beads was significantly higher than in those incubated without beads, although it was significantly lower than TNF-α incubated with LPS-containing sample without beads. The amount of TNF-α after incubation with CA beads positively correlated with GM adsorption ratio. GM adsorption to CA beads induced a small amount of TNF-α release. This is the first report on TNF-α release induced via GM adsorption stimuli. The biological effects of TNF-α release during GM adsorption need to be clarified.

  18. p Ka calculation of poliprotic acid: histamine

    NASA Astrophysics Data System (ADS)

    De Abreu, Heitor A.; De Almeida, Wagner B.; Duarte, Hélio A.

    2004-01-01

    Various theoretical studies have been reported addressing the performance of solvation models available to estimate p Ka values. However, no attention has been paid so far to the role played by the electronic, thermal and solvation energy individual contributions to the Gibbs free energy of the deprotonation process. In this work, we decompose the total Gibbs free energy into three distinct terms and then evaluate the dependence of each contribution on the level of theory employed for its determination using different levels of theory. The three possible p Kas of histamine have been estimated and compared with available experimental data. We found that the electronic energy term is sensitive to the level of theory and basis set, and, therefore, could be also a source of error in the theoretical calculation of p Kas.

  19. Growth, inactivation and histamine formation of Morganella psychrotolerans and Morganella morganii - development and evaluation of predictive models.

    PubMed

    Emborg, Jette; Dalgaard, Paw

    2008-12-10

    Mathematical models for growth, heat inactivation and histamine formation by Morganella psychrotolerans and Morganella morganii were studied to evaluate the importance of these bacteria in seafood. Curves for growth and histamine formation by M. psychrotolerans in broth and seafood were generated at constant and changing storage temperatures (n=12). Observed and predicted times to formation of 100, 500 and 2000 ppm histamine were used for evaluation of an existing M. psychrotolerans histamine formation model [Emborg, J., Dalgaard, P., 2008-this issue-this issue. Modelling and predicting the growth and histamine formation by Morganella psychrotolerans. International Journal of Food Microbiology. doi:10.1016/j.ijfoodmicro.2008.08.016] Growth rates for M. psychrotolerans and M. morganii were determined at different constant temperatures from 0 degrees C to 42.5 degrees C whereas heat inactivation was studied between 37.5 degrees C and 60 degrees C. A M. morganii growth and histamine formation model was developed by combining these new data (growth rate model) and data from the existing literature (maximum population density and yield factor for histamine formation). The developed M. morganii model was evaluated by comparison of predicted growth and histamine formation with data from the existing literature. Observed and predicted growth rates for M. psychrotolerans, at constant temperatures, were similar with bias- and accuracy factor values of 1.15 and 1.45, respectively (n=11). On average times to formation of critical concentrations of histamine by M. psychrotolerans were acceptably predicted but the model was not highly accurate. Nevertheless, predictions seemed useful to support decisions concerning safe shelf-life in relation to formulation, storage and distribution of chilled seafood. Parameters for the effect of temperature on growth and inactivation of M. psychrotolerans and M. morganii differed markedly with Tmin of -8.3 to -5.9 degrees C vs. 0.3 to 2

  20. Delta opioid receptors colocalize with corticotropin releasing factor in hippocampal interneurons

    PubMed Central

    Williams, Tanya J.; Milner, Teresa A.

    2011-01-01

    The hippocampal formation (HF) is an important site at which stress circuits and endogenous opioid systems intersect, likely playing a critical role in the interaction between stress and drug addiction. Prior study findings suggest that the stress-related neuropeptide corticotropin releasing factor (CRF) and the delta opioid receptor (DOR) may localize to similar neuronal populations within HF lamina. Here, hippocampal sections of male and cycling female adult Sprague-Dawley rats were processed for immunolabeling using antisera directed against the DOR and CRF peptide, as well as interneuron subtype markers somatostatin or parvalbumin, and analyzed by fluorescence and electron microscopy. Both DOR- and CRF-labeling was observed in interneurons in the CA1, CA3, and dentate hilus. Males and normal cycling females displayed a similar number of CRF immunoreactive neurons co-labeled with DOR and a similar average number of CRF-labeled neurons in the dentate hilus and stratum oriens of CA1 and CA3. In addition, 70% of DOR/CRF dual-labeled neurons in the hilar region co-labeled with somatostatin, suggesting a role for these interneurons in regulating perforant path input to dentate granule cells. Ultrastructural analysis of CRF-labeled axon terminals within the hilar region revealed that proestrus females have a similar number of CRF-labeled axon terminals that contain DORs compared to males but an increased number of CRF-labeled axon terminals without DORs. Taken together, these findings suggest that while DORs are anatomically positioned to modulate CRF immunoreactive interneuron activity and CRF peptide release, their ability to exert such regulatory activity may be compromised in females when estrogen levels are high. PMID:21277946

  1. Donepezil, an acetylcholine esterase inhibitor, and ABT-239, a histamine H3 receptor antagonist/inverse agonist, require the integrity of brain histamine system to exert biochemical and procognitive effects in the mouse.

    PubMed

    Provensi, Gustavo; Costa, Alessia; Passani, M Beatrice; Blandina, Patrizio

    2016-10-01

    Histaminergic H3 receptors (H3R) antagonists enhance cognition in preclinical models and modulate neurotransmission, in particular acetylcholine (ACh) release in the cortex and hippocampus, two brain areas involved in memory processing. The cognitive deficits seen in aging and Alzheimer's disease have been associated with brain cholinergic deficits. Donepezil is one of the acetylcholinesterase (AChE) inhibitor approved for use across the full spectrum of these cognitive disorders. We addressed the question if H3R antagonists and donepezil require an intact histamine neuronal system to exert their procognitive effects. The effect of the H3R antagonist ABT-239 and donepezil were evaluated in the object recognition test (ORT), and on the level of glycogen synthase kinase 3 beta (GSK-3β) phosphorylation in normal and histamine-depleted mice. Systemic administration of ABT-239 or donepezil ameliorated the cognitive performance in the ORT. However, these compounds were ineffective in either genetically (histidine decarboxylase knock-out, HDC-KO) or pharmacologically, by means of intracerebroventricular (i.c.v.) injections of the HDC irreversible inhibitor a-fluoromethylhistidine (a-FMHis), histamine-deficient mice. Western blot analysis revealed that ABT-239 or donepezil systemic treatments increased GSK-3β phosphorylation in cortical and hippocampal homogenates of normal, but not of histamine-depleted mice. Furthermore, administration of the PI3K inhibitor LY294002 that blocks GSK-3β phosphorylation, prevented the procognitive effects of both drugs in normal mice. Our results indicate that both donepezil and ABT-239 require the integrity of the brain histaminergic system to exert their procognitive effects and strongly suggest that impairments of PI3K/AKT/GSK-3β intracellular pathway activation is responsible for the inefficacy of both drugs in histamine-deficient animals. PMID:27291828

  2. Histamine acting on H1 receptor promotes inhibition of proliferation via PLC, RAC, and JNK-dependent pathways.

    PubMed

    Notcovich, Cintia; Diez, Federico; Tubio, Maria Rosario; Baldi, Alberto; Kazanietz, Marcelo G; Davio, Carlos; Shayo, Carina

    2010-02-01

    It is well established that histamine modulates cell proliferation through the activation of the histamine H1 receptor (H1R), a G protein-coupled receptor (GPCR) that is known to couple to phospholipase C (PLC) activation via Gq. In the present study, we aimed to determine whether H1R activation modulates Rho GTPases, well-known effectors of Gq/G(11)-coupled receptors, and whether such modulation influences cell proliferation. Experiments were carried out in CHO cells stably expressing H1R (CHO-H1R). By using pull-down assays, we found that both histamine and a selective H1R agonist activated Rac and RhoA in a time- and dose-dependent manner without significant changes in the activation of Cdc42. Histamine response was abolished by the H1R antagonist mepyramine, RGS2 and the PLC inhibitor U73122, suggesting that Rac and RhoA activation is mediated by H1R via Gq coupling to PLC stimulation. Histamine caused a marked activation of serum response factor activity via the H1R, as determined with a serum-responsive element (SRE) luciferase reporter, and this response was inhibited by RhoA inactivation with C3 toxin. Histamine also caused a significant activation of JNK which was inhibited by expression of the Rac-GAP beta2-chimaerin. On the other hand, H1R-induced ERK1/2 activation was inhibited by U73122 but not affected by C3 or beta2-chimaerin, suggesting that ERK1/2 activation was dependent on PLC and independent of RhoA or Rac. [(3)H]-Thymidine incorporation assays showed that both histamine and the H1R agonist inhibited cell proliferation in a dose-dependent manner and that the effect was independent of RhoA but partially dependent on JNK and Rac. Our results reveal that functional coupling of the H1R to Gq-PLC leads to the activation of RhoA and Rac small GTPases and suggest distinct roles for Rho GTPases in the control of cell proliferation by histamine.

  3. Histamine acting on H1 receptor promotes inhibition of proliferation via PLC, RAC, and JNK-dependent pathways

    SciTech Connect

    Notcovich, Cintia; Diez, Federico; Tubio, Maria Rosario; Baldi, Alberto; Kazanietz, Marcelo G.; Davio, Carlos; Shayo, Carina

    2010-02-01

    It is well established that histamine modulates cell proliferation through the activation of the histamine H1 receptor (H1R), a G protein-coupled receptor (GPCR) that is known to couple to phospholipase C (PLC) activation via Gq. In the present study, we aimed to determine whether H1R activation modulates Rho GTPases, well-known effectors of Gq/G{sub 11}-coupled receptors, and whether such modulation influences cell proliferation. Experiments were carried out in CHO cells stably expressing H1R (CHO-H1R). By using pull-down assays, we found that both histamine and a selective H1R agonist activated Rac and RhoA in a time- and dose-dependent manner without significant changes in the activation of Cdc42. Histamine response was abolished by the H1R antagonist mepyramine, RGS2 and the PLC inhibitor U73122, suggesting that Rac and RhoA activation is mediated by H1R via Gq coupling to PLC stimulation. Histamine caused a marked activation of serum response factor activity via the H1R, as determined with a serum-responsive element (SRE) luciferase reporter, and this response was inhibited by RhoA inactivation with C3 toxin. Histamine also caused a significant activation of JNK which was inhibited by expression of the Rac-GAP {beta}2-chimaerin. On the other hand, H1R-induced ERK1/2 activation was inhibited by U73122 but not affected by C3 or {beta}2-chimaerin, suggesting that ERK1/2 activation was dependent on PLC and independent of RhoA or Rac. [{sup 3}H]-Thymidine incorporation assays showed that both histamine and the H1R agonist inhibited cell proliferation in a dose-dependent manner and that the effect was independent of RhoA but partially dependent on JNK and Rac. Our results reveal that functional coupling of the H1R to Gq-PLC leads to the activation of RhoA and Rac small GTPases and suggest distinct roles for Rho GTPases in the control of cell proliferation by histamine.

  4. In-vivo blockage of neutrophil migration by LPS is mimicked by a factor released from LPS-stimulated macrophages.

    PubMed Central

    Cunha, F. Q.; Souza, G. E.; Souza, C. A.; Cerqueira, B. C.; Ferreira, S. H.

    1989-01-01

    The present study was performed to determine the effect of an intravenous injection of the macrophage-derived neutrophil chemotactic factor (MNCF) (Cunha & Ferreira 1986) on neutrophil migration to rat peritoneal cavities, which were challenged with chemotactic stimuli. Macrophage monolayers stimulated by LPS release a factor (MW greater than 10,000 D) which, when injected intravenously, blocked neutrophil migration in carrageenin-induced peritonitis. This inhibition was dependent on dose and lasted more than 2 h. It was not due to neutropaenia, hypotension or LPS contamination. Neutrophil migration induced by LPS, MNCF, the Gram-negative bacterium Pseudomonas aeruginosa was also blocked by intravenous administration of the factor. Intravenous injection of recombinant interleukin 1 beta or tumour necrosis factor-alpha, present in the samples of the factor, failed to reproduce the described inhibitory effect on neutrophil migration. The release of this factor by LPS-stimulated macrophage monolayers was inhibited by dexamethasone but not by indomethacin. It is suggested that the failure of neutrophils to migrate during septicaemia may be the result of a continuous release of chemotactic factors in the circulation, particularly of the macrophage-derived neutrophil chemotactic factor(s). PMID:2647118

  5. The role of histamine H1 and H4 receptors in atopic dermatitis: from basic research to clinical study.

    PubMed

    Ohsawa, Yusuke; Hirasawa, Noriyasu

    2014-12-01

    Histamine plays important roles in inflammation and nervous irritability in allergic disorders, including atopic dermatitis (AD). It has been shown to regulate the expression of pruritic factors, such as nerve growth factor and semaphorin 3A, in skin keratinocytes via histamine H1 receptor (H1R). Furthermore, H1R antagonist reduced the level of IL-31, a cytokine involving the skin barrier and pruritus, in chronic dermatitis lesions in NC/Nga mice and patients with AD. Histamine plays roles in the induction of allergic inflammation by activating eosinophils, mast cells, basophils, and Th2 cells via histamine H4 receptor (H4R). H4R, in addition to H1R, is expressed on sensory neurons, and a decrease in scratching behaviors was observed in H4R-deficient mice and mice treated with a H4R antagonist. We found that the combined administration of H1R and H4R antagonists inhibited the itch response and chronic allergic inflammation, and had a pharmacological effect similar to that of prednisolone. Although the oral administration of H1R antagonists is widely used to treat AD, it is not very effective. In contrast, JNJ39758979, a novel H4R antagonist, had marked effects against pruritus in Japanese patients with AD in a phase II clinical trial. Next generation antihistaminic agents possessing H1R and H4R antagonistic actions may be a potent therapeutic drug for AD. PMID:25249063

  6. Quality assurance of histamine analysis in fresh and canned fish.

    PubMed

    Evangelista, Warlley P; Silva, Tarliane M; Guidi, Letícia R; Tette, Patrícia A S; Byrro, Ricardo M D; Santiago-Silva, Paula; Fernandes, Christian; Gloria, Maria Beatriz A

    2016-11-15

    Histamine determination is relevant for fish safety, quality and trade. Recently a study by the European Union (EU) compared the Codex and the EU mandated methods for the analysis of histamine and observed that they underestimated and overestimated the results, respectively. To solve this problem, a simple and efficient procedure for the extraction and quantification of histamine by ion-pair HPLC method with post-column derivatization and fluorimetric detection is proposed. It was optimized and validated for the analysis of histamine in fish. The method attended the performance criteria established by Commission Decision 2002/657/CE. The method was also submitted to proficiency testing; uncertainty was calculated; and the stability of solutions and standards was investigated. There was no matrix effect. The LOD, LOQ, CCα and CCβ were fit for the purpose. The method was successfully used in the analyses of freshwater fish and fresh and canned tuna. PMID:27283612

  7. Release of basic fibroblast growth factor-heparan sulfate complexes from endothelial cells by plasminogen activator-mediated proteolytic activity

    PubMed Central

    1990-01-01

    Cultured bovine capillary endothelial (BCE) cells synthesize heparan sulfate proteoglycans (HSPG), which are both secreted into the culture medium and deposited in the cell layer. The nonsoluble HSPGs can be isolated as two predominant species: a larger 800-kD HSPG, which is recovered from preparations of extracellular matrix, and a 250-kD HSPG, which is solubilized by nonionic detergent extraction of the cells. Both HSPG species bind bFGF. 125I-bFGF bound to BCE cell cultures is readily released by either heparinase or plasmin. When released by plasmin, the growth factor is recovered from the incubation medium as a complex with the partly degraded high molecular mass HSPG. Endogenous bFGF activity is released by a proteolytic treatment of cultured BCE cells. The bFGF-binding HSPGs are also released when cultures are incubated with the inactive proenzyme plasminogen. Under such experimental conditions, the release of the extracellular proteoglycans can be enhanced by treating the cells either with bFGF, which increases the plasminogen activating activity expressed by the cells, or decreased by treating the cells with transforming growth factor beta, which decreases the plasminogen activating activity of the cells. Specific immune antibodies raised against bovine urokinase also block the release of HSPG from BCE cell cultures. We propose that this plasminogen activator-mediated proteolysis provides a mechanism for the release of biologically active bFGF-HSPG complexes from the extracellular matrix and that bFGF release can be regulated by the balance between factors affecting the pericellular proteolytic activity. PMID:2137829

  8. Histamine modulates thalamocortical activity by activating a chloride conductance in ferret perigeniculate neurons.

    PubMed

    Lee, Kendall H; Broberger, Christian; Kim, Uhnoh; McCormick, David A

    2004-04-27

    In the mammalian central nervous system only gamma-aminobutyric acid (GABA) and glycine have been firmly linked to inhibition of neuronal activity through increases in membrane Cl(-) conductance, and these responses are mediated by ionotropic receptors. Iontophoretic application of histamine can also cause inhibitory responses in vivo, although the mechanisms of this inhibition are unknown and may involve pre- or postsynaptic factors. Here, we report that application of histamine to the GABAergic neurons of the thalamic perigeniculate nucleus (PGN), which is innervated by histaminergic fibers from the tuberomammillary nucleus of the hypothalamus, causes a slow membrane hyperpolarization toward a reversal potential of -73 mV through a relatively small increase in membrane conductance to Cl(-). This histaminergic action appears to be mediated by the H(2) subclass of histaminergic receptors and inhibits the single-spike activity of these PGN GABAergic neurons. Application of histamine to the PGN could halt the generation of spindle waves, indicating that increased activity in the tuberomammillary histaminergic system may play a functional role in dampening thalamic oscillations in the transition from sleep to arousal.

  9. Histamine-dependent prolongation by aldosterone of vasoconstriction in isolated small mesenteric arteries of the mouse.

    PubMed

    Schjerning, Jeppe; Uhrenholt, Torben R; Svenningsen, Per; Vanhoutte, Paul M; Skøtt, Ole; Jensen, Boye L; Hansen, Pernille B L

    2013-04-15

    In arterioles, aldosterone counteracts the rapid dilatation (recovery) following depolarization-induced contraction. The hypothesis was tested that this effect of aldosterone depends on cyclooxygenase (COX)-derived products and/or nitric oxide (NO) synthase (NOS) inhibition. Recovery of the response to high K(+) was observed in mesenteric arteries of wild-type and COX-2(-/-) mice but it was significantly diminished in preparations from endothelial NOS (eNOS)(-/-) mice. Aldosterone pretreatment inhibited recovery from wild-type and COX-2(-/-) mice. The NO donor sodium nitroprusside (SNP) restored recovery in arteries from eNOS(-/-) mice, and this was inhibited by aldosterone. Actinomycin-D abolished the effect of aldosterone, indicating a genomic effect. The effect was blocked by indomethacin and by the COX-1 inhibitor valeryl salicylate but not by NS-398 (10(-6) mol/l) or the TP-receptor antagonist S18886 (10(-7) mol/l). The effect of aldosterone on recovery in arteries from wild-type mice and the SNP-mediated dilatation in arteries from eNOS(-/-) mice was inhibited by the histamine H2 receptor antagonist cimetidine. RT-PCR showed expression of mast cell markers in mouse mesenteric arteries. The adventitia displayed granular cells positive for toluidine blue vital stain. Confocal microscopy of live mast cells showed loss of quinacrine fluorescence and swelling after aldosterone treatment, indicating degranulation. RT-PCR showed expression of mineralocorticoid receptors in mesenteric arteries and in isolated mast cells. These findings suggest that aldosterone inhibits recovery by stimulation of histamine release from mast cells along mesenteric arteries. The resulting activation of H2 receptors decreases the sensitivity to NO of vascular smooth muscle cells. Aldosterone may chronically affect vascular function through paracrine release of histamine.

  10. Molecular and biochemical pharmacology of the histamine H4 receptor

    PubMed Central

    Leurs, Rob; Chazot, Paul L; Shenton, Fiona C; Lim, Herman D; de Esch, Iwan JP

    2009-01-01

    The elucidation of the human genome has had a major impact on histamine receptor research. The identification of the human H4 receptor by several groups has been instrumental for a new appreciation of the role of histamine in the modulation of immune function. In this review, we summarize the historical developments and the molecular and biochemical pharmacology of the H4 receptor. PMID:19413568

  11. The role of histamine in the cardiovascular system.

    PubMed

    Cabanié, M; Godfraind, T

    1988-01-01

    This article reviews briefly the role of histamine through its H1 and H2 receptors on the cardiovascular system and its action on calcium and catecholamines. The analogy between the adrenergic and the histaminergic systems is well demonstrated and there is evidence that histamine participates in myocardial damage and arrythmias, but the question of its exact role in the early stages of cardiovascular diseases, such as myocardial ischaemia and atherosclerosis, requires further study.

  12. Cloning, characterization and expression of the polypeptide release factor gene, eRF1, of Blepharisma japonicum.

    PubMed

    Wang, Wei; Chai, Bao-Feng; Heckmann, Klaus; Liang, Ai-Hua

    2004-06-01

    The polypeptide release factor gene, eRF1, of Blepharisma japonicum (Bj-eRF1) was cloned and sequenced. Its coding region was 1314 base pairs and encodes a protein of 437 amino acids. The cloned gene was expressed in Escherichia coli and the recombinant Bj-eRF1 polypeptide was purified by Ni2+-nitrilotriacetic acid agarose and Superose12 chromatography. Pull-down analysis showed that the recombinant Bj-eRF1 interacts with the heterologously-expressed release factor, eRF3C, of Euplotes octocarinatus.

  13. Rapid quantification of histamine in human psoriatic plaques using microdialysis and ultra high performance liquid chromatography with fluorescence detection.

    PubMed

    Guihen, Elizabeth; Ho, Wen Lyn; Hogan, Anna-Marie; O'Connell, Marie-Louise; Leahy, Martin J; Ramsay, Bart; O'Connor, William T

    2012-01-01

    Psoriasis is a chronic skin disease resulting from abnormal immune function and is characterized by the presence of scaly psoriatic plaques which are areas of inflammation and excessive skin production. The psoriatic plaques contain mast cells which are increased in number in the uppermost dermis of the psoriatic lesion and which may play a role in the initiation and maintenance of the lesion. These processes are thought to be mediated via the local release of histamine along with other mediators from the mast cells; however their precise role still remains a mystery. Our study involved the development of a rapid and ultra-sensitive liquid chromatographic method for the separation and detection of histamine. To this end a state-of-the-art ultra high pressure liquid chromatography (UHPLC) system incorporating the latest technology in fluorescence detection system was employed which allowed for the rapid and reliable trace level detection of histamine in human derived microdialysate samples. This new reverse phase method utilized a sub-two-micron packed C(18) stationary phase (50 mm × 4.6 mm, 1.8 μm particle size) and a polar mobile phase of ACN:H(2)O:acetic acid (70:30:0.05) (v/v). The column temperature was maintained at (30±2°C), the injection volume was (8 μl), with a flow rate of (1.1 ml/min). Dermal microdialysis was used to collect (20 μl) samples from healthy, peri-lesional and lesional skin regions, in the forearms of a small cohort of subjects (n=6), and the ultra sensitive liquid chromatographic method allowed for nanomolar quantitation of histamine in 6.7 min. To date this represents one of the fastest reported separations of histamine using fluorescence detection with very high chromatographic efficiency (258,000/m) and peak symmetry of (0.88). Prior to sample analysis being performed method linearity, precision and limit of detection (LOD) were investigated. The results showed that intracutaneous histamine measured at 70 min after catheter

  14. Histamine N-methyl transferase: inhibition by drugs.

    PubMed Central

    Pacifici, G M; Donatelli, P; Giuliani, L

    1992-01-01

    1. Histamine N-methyl transferase activity was measured in samples of human liver, brain, kidney, lung and intestinal mucosa. The mean (+/- s.d.) rate (nmol min-1 mg-1 protein) of histamine N-methylation was 1.78 +/- 0.59 (liver, n = 60), 1.15 +/- 0.38 (renal cortex, n = 8), 0.79 +/- 0.14 (renal medulla, n = 8), 0.35 +/- 0.08 (lung, n = 20), 0.47 +/- 0.18 (human intestine, n = 30) and 0.29 +/- 0.14 (brain, n = 13). 2. Inhibition of histamine N-methyl transferase by 15 drugs was investigated in human liver. The IC50 for the various drugs ranged over three orders of magnitude; chloroquine was the most potent inhibitor. 3. The average IC50 values for chloroquine were 12.6, 22.0, 19.0, 21.6 microM in liver, renal cortex, brain and colon, respectively. These values are lower than the Michaelis-Menten constant for histamine N-methyltransferase in liver (43.8 microM) and kidney (45.5 microM). Chloroquine carried a mixed non-competitive inhibition of hepatic histamine N-methyl transferase. Some side-effects of chloroquine may be explained by inhibition of histamine N-methyl transferase. PMID:1457266

  15. Histamine inhibits differentiation of skin fibroblasts into myofibroblasts.

    PubMed

    Lin, Lin; Yamagata, Kaoru; Nakayamada, Shingo; Sawamukai, Norifumi; Yamaoka, Kunihiro; Sakata, Kei; Nakano, Kazuhisa; Tanaka, Yoshiya

    2015-07-31

    Histamine and TGF-β, major mediators secreted by mast cells, are involved in skin inflammation and play critical roles in the pathogenesis of systemic sclerosis. However, the roles of signaling mechanisms in the development of skin fibrosis remain largely unclear. Here we show that histamine suppressed the expression of α smooth muscle actin (αSMA), a marker of myofibroblasts, induced by TGF-β1 in skin fibroblasts. Histamine H1-receptor (H1R), but not H2-receptor (H2R) or H4-receptor (H4R), was expressed on skin fibroblasts at both mRNA and protein levels. Interestingly, an H1R antagonist, but not H2R or H4R antagonists, antagonized the histamine-mediated suppression of αSMA expression by TGF-β1. Correspondingly, phosphorylated Smad2 was detected after treatment with TGF-β1, whereas the addition of histamine inhibited this phosphorylation. Taken together, histamine-H1R decreased TGF-β1-mediated Smad2 phosphorylation and inhibited differentiation of skin fibroblasts into myofibroblasts.

  16. Organic cation transporter 3 modulates murine basophil functions by controlling intracellular histamine levels

    PubMed Central

    Schneider, Elke; Machavoine, François; Pléau, Jean-Marie; Bertron, Anne-France; Thurmond, Robin L.; Ohtsu, Hiroshi; Watanabe, Takehiko; Schinkel, Alfred H.; Dy, Michel

    2005-01-01

    In this study, we identify the bidirectional organic cation transporter 3 (OCT3/Slc22a3) as the molecule responsible for histamine uptake by murine basophils. We demonstrate that OCT3 participates in the control of basophil functions because exogenous histamine can inhibit its own synthesis—and that of interleukin (IL)-4, IL-6, and IL-13—through this means of transport. Furthermore, ligands of H3/H4 histamine receptors or OCT3 inhibit histamine uptake, and outward transport of newly synthesized histamine. By doing so, they increase the histamine content of basophils, which explains why they mimic the effect of exogenous histamine. These drugs were no longer effective in histamine-free histidine decarboxylase (HDC)-deficient mice, in contrast with histamine itself. Histamine was not taken up and lost its inhibitory effect in mice deficient for OCT3, which proved its specific involvement. Intracellular histamine levels were increased strongly in IL-3–induced OCT3−/− bone marrow basophils, and explained why they generated fewer cytokines than their wild-type counterpart. Their production was enhanced when histamine synthesis was blocked by the specific HDC inhibitor α-fluoro-methyl histidine, and underscored the determinant role of histamine in the inhibitory effect. We postulate that pharmacologic modulation of histamine transport might become instrumental in the control of basophil functions during allergic diseases. PMID:16061728

  17. PABP enhances release factor recruitment and stop codon recognition during translation termination

    PubMed Central

    Ivanov, Alexandr; Mikhailova, Tatyana; Eliseev, Boris; Yeramala, Lahari; Sokolova, Elizaveta; Susorov, Denis; Shuvalov, Alexey; Schaffitzel, Christiane; Alkalaeva, Elena

    2016-01-01

    Poly(A)-binding protein (PABP) is a major component of the messenger RNA–protein complex. PABP is able to bind the poly(A) tail of mRNA, as well as translation initiation factor 4G and eukaryotic release factor 3a (eRF3a). PABP has been found to stimulate translation initiation and to inhibit nonsense-mediated mRNA decay. Using a reconstituted mammalian in vitro translation system, we show that PABP directly stimulates translation termination. PABP increases the efficiency of translation termination by recruitment of eRF3a and eRF1 to the ribosome. PABP's function in translation termination depends on its C-terminal domain and its interaction with the N-terminus of eRF3a. Interestingly, we discover that full-length eRF3a exerts a different mode of function compared to its truncated form eRF3c, which lacks the N-terminal domain. Pre-association of eRF3a, but not of eRF3c, with pre-termination complexes (preTCs) significantly increases the efficiency of peptidyl–tRNA hydrolysis by eRF1. This implicates new, additional interactions of full-length eRF3a with the ribosomal preTC. Based on our findings, we suggest that PABP enhances the productive binding of the eRF1–eRF3 complex to the ribosome, via interactions with the N-terminal domain of eRF3a which itself has an active role in translation termination. PMID:27418677

  18. Factors controlling nitrogen release from two forested catchments with contrasting hydrochemical responses

    USGS Publications Warehouse

    Christopher, S.F.; Mitchell, M.J.; McHale, M.R.; Boyer, E.W.; Burns, Douglas A.; Kendall, C.

    2008-01-01

    Quantifying biogeochemical cycles of nitrogen (N) and the associated fluxes to surface waters remains challenging, given the need to deal with spatial and temporal variability and to characterize complex and heterogeneous landscapes. We focused our study on catchments S14 and S15 located in the Adirondack Mountains of New York, USA, which have similar topographic and hydrologic characteristics but contrasting stream nitrate (NO3- ) concentrations. We characterized the mechanisms by which NO3- reaches the streams during hydrological events in these catchments, aiming to reconcile our field data with our conceptual model of factors that regulate nutrient exports from forested catchments. Combined hydrometric, chemical and isotopic (??18O-H2O) data showed that the relative contributions of both soil and ground water sources were similar between the two catchments. Temporal patterns of stream chemistry were markedly different between S14 and S15, however, because the water sources in the two catchments have different solute concentrations. During late summer/fall, the largest source of NO3- in S14 was till groundwater, whereas shallow soil was the largest NO3- source in S15. NO3- concentrations in surface water decreased in S14, whereas they increased in S15 because an increasing proportion of stream flow was derived from shallow soil sources. During snowmelt, the largest sources of NO3- were in the near-surface soil in both catchments. Concentrations of NO3- increased as stream discharge increased and usually peaked before peak discharge, when shallow soil water sources made the largest contribution to stream discharge. The timing of peaks in stream NO3- concentrations was affected by antecedent moisture conditions. By elucidating the factors that affect sources and transport of N, including differences in the soil nutrient cycling and hydrological characteristics of S14 and S15, this study contributes to the overall conceptualization of NO3- release from temperate

  19. Hypothalamic corticotropin-releasing factor is centrally involved in learning under moderate stress.

    PubMed

    Lucas, Morgan; Chen, Alon; Richter-Levin, Gal

    2013-08-01

    The corticotropin-releasing factor (CRF) neuropeptide is found to have a pivotal role in the regulation of the behavioral and neuroendocrine responses to stressful challenges. Here, we studied the involvement of the hypothalamic CRF in learning under stressful conditions. We have used a site-specific viral approach to knockdown (KD) CRF expression in the paraventricular nucleus of the hypothalamus (PVN). The two-way shuttle avoidance (TWSA) task was chosen to assess learning and memory under stressful conditions. Control animals learned to shuttle from one side to the other to avoid electrical foot shock by responding to a tone. Novel object and social recognition tasks were used to assess memory under less stressful conditions. KD of PVN-CRF expression decreased the number of avoidance responses in a TWSA session under moderate (0.8 mA), but not strong (1.5 mA), stimulus intensity compared to control rats. On the other hand, KD of PVN-CRF had no effect on memory performance in the less stressful novel object or social recognition tasks. Interestingly, basal or stress-induced corticosterone levels in CRF KD rats were not significantly different from controls. Taken together, the data suggest that the observed impairment was not a result of alteration in HPA axis activity, but rather due to reduced PVN-CRF activity on other brain areas. We propose that hypothalamic CRF is centrally involved in learning under moderate stressful challenge. Under 'basal' (less stressful) conditions or when the intensity of the stress is more demanding, central CRF ceases to be the determinant factor, as was indicated by performances in the TWSA with higher stimulus intensity or in the less stressful tasks of object and social recognition.

  20. The Bladder-Brain Connection: Putative Role of Corticotropin-releasing Factor

    PubMed Central

    Valentino, Rita J.; Wood, Susan K.; Wein, Alan J.; Zderic, Stephen A.

    2013-01-01

    The coordination of pelvic visceral activity with appropriate elimination behaviors is a complex task that requires reciprocal communication between the brain and pelvic viscera. Barrington’s nucleus in the pons is central to a circuit involved in this function. Barrington’s nucleus neurons diverge to project to pelvic visceral motoneurons and brain norepinephrine neurons that modulate behavior. This circuit is adaptively designed to coordinate the descending limb of the micturition reflex with a central limb that initiates arousal and shifts the focus of attention to facilitate elimination behavior. Although it serves an adaptive function, this same circuitry that links the bladder and brain allows for pathological processes at one end of the circuit to be expressed at the other. Here we show how urologic disorders can have cognitive and behavioral consequences by affecting components of this circuit. In the opposing direction, psychosocial stressors can produce voiding dysfunctions and bladder pathology through this circuit. The stress-related neuropeptide, corticotropin-releasing factor, which is prominent in Barrington’s nucleus neurons, is a potential mediator of these effects. Together, the studies reviewed highlight the potential for co-morbid bladder and neurobehavioral symptoms and suggest how this information can guide new cognitive and pharmacotherapies for urologic disorders. PMID:21135878

  1. Fluoxetine inhibits corticotropin-releasing factor (CRF)-induced behavioural responses in rats.

    PubMed

    Lowry, Christopher A; Hale, Matthew W; Plant, Andrea; Windle, Richard J; Shanks, Nola; Wood, Susan A; Ingram, Colin D; Renner, Kenneth J; Lightman, Stafford L; Summers, Cliff H

    2009-05-01

    Corticotropin-releasing factor (CRF) is a potent neuromodulator of stress-related behaviour but the neural mechanisms underlying these effects are not clear. Studies were designed to test the hypothesis that CRF-induced behavioural arousal involves interactions with brainstem serotonergic systems. To examine interactions between CRF and serotonergic systems in the regulation of behaviour, CRF (1 microg, intracerebroventricular (i.c.v.)) or vehicle was infused in the presence or absence of the selective serotonin re-uptake inhibitor fluoxetine (0, 0.1, 1 or 10 mg/kg, intravenous (i.v.)). Fluoxetine was used at these doses because it is known to decrease serotonin cell firing rates while increasing extracellular serotonin concentrations in select forebrain regions. We then measured behavioural, neurochemical and endocrine responses. CRF increased locomotion and spontaneous non-ambulatory motor activity (SNAMA) in the home cages. Fluoxetine decreased tissue 5-hydroxyindoleacetic acid concentrations, a measure of serotonin metabolism, in specific limbic brain regions of CRF-treated rats (nucleus accumbens shell region, entorhinal cortex, central nucleus of the amygdala). Furthermore, fluoxetine inhibited CRF-induced SNAMA. CRF and fluoxetine independently increased plasma corticosterone concentrations, but the responses had distinct temporal profiles. Overall, these data are consistent with the hypothesis that CRF-induced facilitation of behavioural activity is dependent on brainstem serotonergic systems. Therefore, fluoxetine may attenuate or alleviate some behavioural responses to stress by interfering with CRF-induced responses. PMID:18951247

  2. Autogenous suppression of an opal mutation in the gene encoding peptide chain release factor 2.

    PubMed Central

    Kawakami, K; Nakamura, Y

    1990-01-01

    The peptide chain release factor 2 (RF2) gene, prfB, was cloned from Salmonella typhimurium by DNA hybridization using the Escherichia coli prfB probe. The nucleotide and amino acid sequences of prfB are 87.0% and 95.6% homologous between E. coli and S. typhimurium, respectively, including an in-frame premature UGA stop codon at position 26, the site of +1 frameshift for mature RF2 synthesis. The supK584 mutation, which had been isolated as a recessive UGA suppressor in S. typhimurium, caused an opal (UGA) substitution at amino acid position 144 in the prfB gene. Complementation, reversion, and gene fusion analyses led to the conclusion that supK is a S. typhimurium RF2 mutation and this opal RF2 mutation generates a UGA suppressor activity, presumably because of inefficient translation termination due to the reduced cellular level of RF2. In fact, suppression of the supK opal mutation results from a form of autogenous control of RF2 synthesis. Images PMID:2236050

  3. Two soluble antigens of Plasmodium falciparum induce tumor necrosis factor release from macrophages.

    PubMed Central

    Taverne, J; Bate, C A; Kwiatkowski, D; Jakobsen, P H; Playfair, J H

    1990-01-01

    The production of cytokines such as tumor necrosis factor (TNF) may contribute to the pathology of malaria. We showed previously that crude preparations of heat-stable exoantigens from parasite cultures induce the release of TNF in vitro and in vivo. When separated from the culture medium by affinity chromatography, in which immune immunoglobulin G was used as ligand, the mixture of exoantigens of Plasmodium falciparum retained the capacity to induce the secretion of TNF, both by human monocytes from Gambian children and by mouse macrophages. Two individual antigens, Ag1 and Ag7, further purified by affinity chromatography and identified by crossed immunoelectrophoresis, also stimulated TNF production by both types of cell but differed in other functional properties. Thus, the activity of Ag7, but not that of Ag1, was inhibited by polymyxin B, and antisera made against boiled exoantigens of the rodent parasite Plasmodium yoelii which blocked the ability of these antigens to induce the production of TNF also inhibited the activity of Ag7 without affecting Ag1. Since the prevalence of antibody against Ag7 in sera from children in endemic areas appears to correlate with the development of immunity against the manifestations of the disease, this antigen may be one cause of pathology, perhaps through its ability to induce the production of TNF. Its serological relationship with rodent exoantigens suggests that it might be a candidate for an anti-disease vaccine which has the advantage that its active moiety is not subject to significant antigen polymorphism. PMID:2201638

  4. Detecting transforming growth factorrelease from liver cells using an aptasensor integrated with microfluidics.

    PubMed

    Matharu, Zimple; Patel, Dipali; Gao, Yandong; Haque, Amranul; Zhou, Qing; Revzin, Alexander

    2014-09-01

    We developed a cell-culture/biosensor platform consisting of aptamer-modified Au electrodes integrated with reconfigurable microfluidics for monitoring of transforming growth factor-beta 1 (TGF-β1), an important inflammatory and pro-fibrotic cytokine. Aptamers were thiolated, labeled with redox reporters, and self-assembled on gold surfaces. The biosensor was determined to be specific for TGF-β1 with an experimental detection limit of 1 ng/mL and linear range extending to 250 ng/mL. Upon determining figures of merit, aptasensor was miniaturized and integrated with human hepatic stellate cells inside microfluidic devices. Reconfigurable microfluidics were developed to ensure that seeding of "sticky" stromal cells did not foul the electrode and compromise sensor performance. This microsystem with integrated aptasensors was used to monitor TGF-β1 release from activated stellate cells over the course of 20 h. The electrochemical response went down upon infusing anti-TGF-β1 antibodies into the microfluidic devices containing activated stellate cells. To further validate aptasensor responses, stellate cells were stained for markers of activation (e.g., alpha smooth muscle actin) and were also tested for presence of TGF-β1 using enzyme linked immunosorbent assay (ELISA). Given the importance of TGF-β1 as a fibrogenic signal, a microsystem with integrated biosensors for local and continuous detection of TGF-β1 may prove to be an important tool to study fibrosis of the liver and other organs.

  5. Maternal profiling of corticotropin-releasing factor receptor 2 deficient mice in association with restraint stress

    PubMed Central

    D’Anna, Kimberly L.; Stevenson, Sharon A.; Gammie, Stephen C.

    2008-01-01

    Mice deficient in corticotropin releasing factor receptor 2 (CRF2) (C57BL/6J:129Sv background) exhibit impaired maternal defense (protection of offspring) and are more reactive to stressors than wild-type mice. To further understand CRF2’s role in maternal behavior, we crossed the knockout mice with a line bred for high maternal defense that also has elevated maternal care relative to inbred lines. Maternal care was normal in knockout mice (relative to wild-type). Maternal defense was impaired as previously observed. Exposure to a mild stressor (15 min restraint) did not trigger deficits in maternal defense in either genotype as determined by a two-way repeated measures ANOVA analysis. However, when examining difference scores between unrestrained and restrained conditions, knockout mice exhibited significant decreases in maternal defense with stress, suggesting knockouts are more susceptible to a mild stressor’s effects. To gain possible insights into brain activity differences between WT and KO mice, we examined c-Fos expression in association with stress. Unrestrained KO mice exhibited significantly lower c-Fos levels relative to unrestrained WT mice in 9 regions, including lateral septum and periaqueductal gray. For WT mice, restraint stress triggered c-Fos activity increases in 3 regions while for KO mice, restraint stress triggered c-Fos increases in 16 regions. Taken together, our results suggest both altered behavioral and c-Fos responses to stress in lactating CRF2 KO mice. PMID:18817761

  6. Corticotropin-releasing factor CRF1, but not CRF2, receptors mediate anxiogenic-like behavior.

    PubMed

    Heinrichs, S C; Lapsansky, J; Lovenberg, T W; De Souza, E B; Chalmers, D T

    1997-07-23

    The recent identification and differential localization in brain of three binding sites for corticotropin-releasing factor (CRF)-like peptides (CRF1 and CRF2 receptors as well as CRF-binding protein) suggest the existence of functionally distinct neurobiological systems which mediate CRF activation. For instance, evidence from receptor knockdown and pharmacological studies suggest involvement of the CRF1 receptor in anxiogenic-like behavior and the CRF-binding protein in learning and memory processes. The present studies examined the potential functional significance of the CRF2 receptor in relation to the CRF1 receptor using two animal models of anxiety and endocrine reactivity to a stressor. CRF1 and CRF2 receptor knockdown was achieved and confirmed autoradiographically within brain regions relevant to behavioral reactivity to stressors by chronic, central administration of antisense oligonucleotides. CRF1 but not CRF2, know down produced a significant anxiolytic-like effect in the Defensive Withdrawal relative to vehicle-treated and two missense oligonucleotide negative control groups. In contrast, neither antisense treatment altered endocrine or behavioral reactivity to a swim stressor. Thus, the present data support the reported role of CRF1 receptors in the mediation of anxiogenic-like behavior and suggest a functionally distinct for role for CRF2 receptors in brain.

  7. Molecular Recognition of Corticotropin releasing Factor by Its G protein-coupled Receptor CRFR1

    SciTech Connect

    Pioszak, Augen A.; Parker, Naomi R.; Suino-Powell, Kelly; Xu, H. Eric

    2009-01-15

    The bimolecular interaction between corticotropin-releasing factor (CRF), a neuropeptide, and its type 1 receptor (CRFR1), a class B G-protein-coupled receptor (GPCR), is crucial for activation of the hypothalamic-pituitary-adrenal axis in response to stress, and has been a target of intense drug design for the treatment of anxiety, depression, and related disorders. As a class B GPCR, CRFR1 contains an N-terminal extracellular domain (ECD) that provides the primary ligand binding determinants. Here we present three crystal structures of the human CRFR1 ECD, one in a ligand-free form and two in distinct CRF-bound states. The CRFR1 ECD adopts the alpha-beta-betaalpha fold observed for other class B GPCR ECDs, but the N-terminal alpha-helix is significantly shorter and does not contact CRF. CRF adopts a continuous alpha-helix that docks in a hydrophobic surface of the ECD that is distinct from the peptide-binding site of other class B GPCRs, thereby providing a basis for the specificity of ligand recognition between CRFR1 and other class B GPCRs. The binding of CRF is accompanied by clamp-like conformational changes of two loops of the receptor that anchor the CRF C terminus, including the C-terminal amide group. These structural studies provide a molecular framework for understanding peptide binding and specificity by the CRF receptors as well as a template for designing potent and selective CRFR1 antagonists for therapeutic applications.

  8. The epidural and intrathecal administration of somatotrophin-release inhibiting factor: native and synthetic analogues.

    PubMed

    Beltrutti, D P; Moessinger, S; Varrassi, G

    2000-01-01

    It is well-known that morphine is the king of analgesics. It is widely used, and administered in various ways for the control of acute and chronic pain states. There are, however, certain types of pain and certain clinical conditions in which morphine cannot be used due to the risk of possible complications. These are usually pain states associated with intracranial hypertension, the presence of serious respiratory problems, the onset of major opioid tolerance, persistent vomiting, and so on. The search for "alternative analgesics" has been in progress for a decade, alternatives that could be used alone or in combination for spinal administration in the treatment of complex chronic pain states and with a low incidence of secondary effects. Today, research is carefully assessing the clinical effectiveness and the side effects of a series of drugs for spinal administration, that is, epidural or intrathecal, such as the new narcotics, alpha-2 agonists, central muscle relaxants, calcitonin, and local anesthetics. In this alternative analgesic category we have to mention the somatotrophin-release inhibiting factor (SRIF), which is an ubiquitous native hormone with widespread, predominantly inhibitory actions, and octreotide, its synthetic analogue. In this article we review the literature on the natural drug and its synthetic analogue, paying particular attention to the problems connected with intraspinal administration and analgesic properties.

  9. Stop codon recognition in ciliates: Euplotes release factor does not respond to reassigned UGA codon

    PubMed Central

    Kervestin, Stéphanie; Frolova, Ludmila; Kisselev, Lev; Jean-Jean, Olivier

    2001-01-01

    In eukaryotes, the polypeptide release factor 1 (eRF1) is involved in translation termination at all three stop codons. However, the mechanism for decoding stop codons remains unknown. A direct interaction of eRF1 with the stop codons has been postulated. Recent studies focus on eRF1 from ciliates in which some stop codons are reassigned to sense codons. Using an in vitro assay based on mammalian ribosomes, we show that eRF1 from the ciliate Euplotes aediculatus responds to UAA and UAG as stop codons and lacks the capacity to decipher the UGA codon, which encodes cysteine in this organism. This result strongly suggests that in ciliates with variant genetic codes eRF1 does not recognize the reassigned codons. Recent hypotheses describing stop codon discrimination by eRF1 are not fully consistent with the set of eRF1 sequences available so far and require direct experimental testing. PMID:11463747

  10. Two-step model of stop codon recognition by eukaryotic release factor eRF1

    PubMed Central

    Kryuchkova, Polina; Grishin, Alexander; Eliseev, Boris; Karyagina, Anna; Frolova, Ludmila; Alkalaeva, Elena

    2013-01-01

    Release factor eRF1 plays a key role in the termination of protein synthesis in eukaryotes. The eRF1 consists of three domains (N, M and C) that perform unique roles in termination. Previous studies of eRF1 point mutants and standard/variant code eRF1 chimeras unequivocally demonstrated a direct involvement of the highly conserved N-domain motifs (NIKS, YxCxxxF and GTx) in stop codon recognition. In the current study, we extend this work by investigating the role of the 41 invariant and conserved N-domain residues in stop codon decoding by human eRF1. Using a combination of the conservative and non-conservative amino acid substitutions, we measured the functional activity of >80 mutant eRF1s in an in vitro reconstituted eukaryotic translation system and selected 15 amino acid residues essential for recognition of different stop codon nucleotides. Furthermore, toe-print analyses provide evidence of a conformational rearrangement of ribosomal complexes that occurs during binding of eRF1 to messenger RNA and reflects stop codon decoding activity of eRF1. Based on our experimental data and molecular modelling of the N-domain at the ribosomal A site, we propose a two-step model of stop codon decoding in the eukaryotic ribosome. PMID:23435318

  11. Stress and addiction: contribution of the corticotropin releasing factor (CRF) system in neuroplasticity

    PubMed Central

    Haass-Koffler, Carolina L.; Bartlett, Selena E.

    2012-01-01

    Corticotropin releasing factor (CRF) has been shown to induce various behavioral changes related to adaptation to stress. Dysregulation of the CRF system at any point can lead to a variety of psychiatric disorders, including substance use disorders (SUDs). CRF has been associated with stress-induced drug reinforcement. Extensive literature has identified CRF to play an important role in the molecular mechanisms that lead to an increase in susceptibility that precipitates relapse to SUDs. The CRF system has a heterogeneous role in SUDs. It enhances the acute effects of drugs of abuse and is also responsible for the potentiation of drug-induced neuroplasticity evoked during the withdrawal period. We present in this review the brain regions and circuitries where CRF is expressed and may participate in stress-induced drug abuse. Finally, we attempt to evaluate the role of modulating the CRF system as a possible therapeutic strategy for treating the dysregulation of emotional behaviors that result from the acute positive reinforcement of substances of abuse as well as the negative reinforcement produced by withdrawal. PMID:22973190

  12. [Gastroprotective action of corticotropin-releasing factor (CRF): involvement of glucocorticoids and CRF receptors type 2].

    PubMed

    Filaretova, L P; Bagaeva, T R; Morozova, O Iu

    2012-12-01

    The stress response involves the activation of two corticotropin-releasing factor (CRF) receptors types 1 and 2. The pituitary type 1 CRF receptors represent the primary receptors to activate the hypothalamic-pituitary-adrenocortical axis and, consequently, glucocorticoid production. Exogenous CRF induces an increase in glucocorticoid production and may protect the gastric mucosa against stress-induced injury. Here we examined contribution of glucocorticoids and CRF receptors type 2 to gastroprotective effect of exogenous CRF. Gastric injury was induced by 3 him-mobilization (at 10 degrees C) in conscious rats or 3.5 h gastric ischemia-reperfusion in anaesthetized rats. Intraperitoneal administration of CRF at the doses of 1.25 or 2.5 Mg/kg increased plasma corticosterone levels and suppressed the occurrence of gastric erosion induced by each stimulus. Metyrapone injected before CRF caused an inhibition of CRF-induced corticosterone response and prevented the protective effect of CRF on the gastric mucosa against erosion caused by immobilization (at 10 degrees C). However, metyrapone injection did not influence the protective effect of CRF on the gastric mucosa against ischemia-reperfusion-induced lesion. The protective effect of CRF on the gastric mucosa against ischemia-reperfusion-induced lesion was prevented by the nonselective CRF receptor antagonist astressin and selective type 2 CRF receptor antagonist astressin2-B. The results obtained suggest that exogenous CRF may protect the gastric mucosa against injury through involvement of glucocorticoids and also through CRF receptors type 2.

  13. Preclinical evidence implicating corticotropin-releasing factor signaling in ethanol consumption and neuroadaptation

    PubMed Central

    Phillips, T. J.; Reed, C.; Pastor, R.

    2016-01-01

    The results of many studies support the influence of the corticotropin-releasing factor (CRF) system on ethanol (EtOH) consumption and EtOH-induced neuroadaptations that are critical in the addiction process. This review summarizes the preclinical data in this area after first providing an overview of the components of the CRF system. This complex system involves hypothalamic and extra-hypothalamic mechanisms that play a role in the central and peripheral consequences of stressors, including EtOH and other drugs of abuse. In addition, several endogenous ligands and targets make up this system and show differences in their involvement in EtOH drinking and in the effects of chronic or repeated EtOH treatment. In general, genetic and pharmacological approaches paint a consistent picture of the importance of CRF signaling via type 1 CRF receptors (CRF1) in EtOH-induced neuroadaptations that result in higher levels of intake, encourage alcohol seeking during abstinence and alter EtOH sensitivity. Furthermore, genetic findings in rodents, non-human primates and humans have provided some evidence of associations of genetic polymorphisms in CRF-related genes with EtOH drinking, although additional data are needed. These results suggest that CRF1 antagonists have potential as pharmacotherapeutics for alcohol use disorders. However, given the broad and important role of these receptors in adaptation to environmental and other challenges, full antagonist effects may be too profound and consideration should be given to treatments with modulatory effects. PMID:25565358

  14. Entrapment of basic fibroblast growth factor (bFGF) in a succinylated chitosan nanoparticle delivery system and release profile.

    PubMed

    Butko, Alison; Bonat Celli, Giovana; Paulson, Allan; Ghanem, Amyl

    2016-07-01

    Basic fibroblast growth factor (bFGF) helps to regulate the proliferation and migration of fibroblasts, the proliferation of endothelial cells, and aids the development of angiogenesis. Its in vivo half-life is on the order of minutes due to extensive degradation and inactivation, which could be potentially reduced by controlled release vehicles. In this study, bFGF was entrapped into chitosan (CS) and N-succinyl-chitosan (SC) nanoparticles, with and without heparin, at two levels of initial loading, followed by further characterization of the particles. Release studies were conducted using radiolabeled bFGF-loaded nanoparticles. Both types of nanoparticles loaded similar amounts of bFGF (60.2 and 68.6% for CS and SC, respectively). The release profile varied greatly among the samples, and a burst release was observed in most cases, with the release amount approaching its final value in the first 6 h. The final amount released varied from 1.5 to 18% of the amount of bFGF-entrapped. The concomitant encapsulation of heparin and the use of SC as a nanoparticle matrix contributed to the largest amount of bFGF release (18%) over the time investigated.

  15. Von-Willebrand Factor Influences Blood Brain Barrier Permeability and Brain Inflammation in Experimental Allergic Encephalomyelitis

    PubMed Central

    Noubade, Rajkumar; del Rio, Roxana; McElvany, Benjamin; Zachary, James F.; Millward, Jason M.; Wagner, Denisa D.; Offner, Halina; Blankenhorn, Elizabeth P.; Teuscher, Cory

    2008-01-01

    Weibel-Palade bodies within endothelial cells are secretory granules known to release von Willebrand Factor (VWF), P-selectin, chemokines, and other stored molecules following histamine exposure. Mice with a disrupted VWF gene (VWFKO) have endothelial cells that are deficient in Weibel-Palade bodies. These mice were used to evaluate the role of VWF and/or Weibel-Palade bodies in Bordetella pertussis toxin-induced hypersensitivity to histamine, a subphenotype of experimental allergic encephalomyelitis, the principal autoimmune model of multiple sclerosis. No significant differences in susceptibility to histamine between wild-type and VWFKO mice were detected after 3 days; however, histamine sensitivity persisted significantly longer in VWFKO mice. Correspondingly, encephalomyelitis onset was earlier, disease was more severe, and blood brain barrier (BBB) permeability was significantly increased in VWFKO mice, as compared with wild-type mice. Moreover, inflammation was selectively increased in the brains, but not spinal cords, of VWFKO mice as compared with wild-type mice. Early increases in BBB permeability in VWFKO mice were not due to increased encephalitogenic T-cell activity since BBB permeability did not differ in adjuvant-treated VWFKO mice as compared with littermates immunized with encephalitogenic peptide plus adjuvant. Taken together, these data indicate that VWF and/or Weibel-Palade bodies negatively regulate BBB permeability changes and autoimmune inflammatory lesion formation within the brain elicited by peripheral inflammatory stimuli. PMID:18688020

  16. Histamine H(3) receptor-mediated modulation of perivascular nerve transmission in rat mesenteric arteries.

    PubMed

    Sun, Pengyuan; Takatori, Shingo; Jin, Xin; Koyama, Toshihiro; Tangsucharit, Panot; Li, Simin; Zamami, Yoshito; Kitamura, Yoshihisa; Kawasaki, Hiromu

    2011-03-25

    The rat mesenteric artery has been shown to be innervated by adrenergic vasoconstrictor nerves and calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves. The present study was designed to investigate the involvement of histamine H(3) receptors in the neurotransmission of perivascular adrenergic and CGRPergic nerves. The mesenteric vascular beds without an endothelium isolated from male Wistar rats were perfused with Krebs solution and perfusion pressure was measured. In preparations with resting tension, the selective H(3) receptor agonist (R)-α-methylhistamine (α-methylhistamine; 10-100nM) significantly reduced periarterial nerve stimulation (2-8Hz)-induced vasoconstriction and noradrenaline release in the perfusate without an effect on the vasoconstriction induced by exogenously injected noradrenaline (0.5, 1.0nmol). In preparations with active tone produced by methoxamine (2μM) and in the presence of guanethidine (5μM), the periarterial nerve stimulation (1, 2Hz)-induced vasodilator response was inhibited by α-methylhistamine (0.1-1μM) perfusion without affecting vasodilation induced by exogenously injected CGRP (5pmol). Clobenpropit (histamine H(3) receptor antagonist, 1μM) canceled the α-methylhistamine-induced decrease in the periarterial nerve stimulation-induced vasoconstriction and noradrenaline release and periarterial nerve stimulation-induced vasodilation. These results suggest that the stimulation of H(3) receptors located in rat perivascular nerves inhibits presynaptically the neurotransmission of not only adrenergic nerves, but also CGRP nerves, by decreasing neurotransmitters.

  17. Histamine dehydrogenase from Rhizobium sp.: gene cloning, expression in Escherichia coli, characterization and application to histamine determination.

    PubMed

    Bakke, Mikio; Sato, Tsuneo; Ichikawa, Keiichi; Nishimura, Ikuko

    2005-09-29

    The gene encoding histamine dehydrogenase in Rhizobium sp. 4--9 has been cloned and overexpressed in Escherichia coli. The coding region of the gene was 2,079 bp and encoded a protein of 693 amino acids with a calculated molecular mass of 76,732 Da. This histamine dehydrogenase was related to histamine dehydrogenase from Nocardioides simplex (54.5% identical), trimethylamine dehydrogenase from Methylophilus methylotrophus (39.3% identical) and dimethylamine dehydrogenase from Hyphomicrobium X (38.1% identical), which have a covalent 6-S-cysteinyl flavin mononucleotide and a [4Fe--4S] cluster as redox cofactors. Sequence alignment and a UV-visible absorption spectrum supported the presence of these cofactors in this histamine dehydrogenase. The investigation of the enzymatic properties suggested that this enzyme exhibited the most excellent substrate specificity toward histamine among all amine oxidases or dehydrogenases found to date. The recombinant enzyme was able to be used for the colorimetric determination of histamine, which gave a linear calibration curve and identical data with conventional methods. PMID:15964650

  18. The histamine H3 receptor: from discovery to clinical trials with pitolisant

    PubMed Central

    Schwartz, Jean-Charles

    2011-01-01

    The third histamine receptor was discovered in 1983 by a traditional pharmacological approach, consisting of assessing the inhibitory effect of histamine on its own release from depolarized rat brain slices. The same in vitro test was used to design, in 1987, the first highly selective and potent H3-autoreceptor ligands, the antagonist thioperamide and the agonist (R)alphamethylhistamine which enhances and inhibits, respectively, the activity of histaminergic neurons in brain. The use of these research tools was instrumental in establishing the main functions of cerebral histaminergic neurons, namely their role in maintenance of wakefulness, attention, learning and other cognitive processes. In 1990, the cloning of the gene of the H3-receptor, a member of the superfamily of heptahelical receptors coupled to G proteins, paved the way to the demonstration of the high constitutive activity of the receptor, including its native form, and its participation in the tonic control of histamine release; it also facilitated the development of H3-receptor inverse agonist programs in many drug companies. Pitolisant (BF2.649, 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride) is the first inverse agonist to be introduced in the clinics. Its wake-promotion activity was evidenced in excessive diurnal sleepiness of patients with narcolepsy, Parkinson's disease or Obstructive Sleep Apnea/Hypopnea, in which this activity is characterized by a mean decrease of the Epworth Sleepiness Scale by about five units. The procognitive activity of this novel class of drugs may also find therapeutic applications in dementias, schizophrenia or attention deficit hyperactivity disorder. LINKED ARTICLES This review is dedicated to the memory of Sir James Black who recently passed away and whose achievements in classical pharmacology and drug design have been examples to the author throughout his career. BJP published an issue in 2010 on Analytical Receptor Pharmacology in Drug

  19. Efficient Approaches to S-alkyl-N-alkylisothioureas and Application to Novel Histamine H3R Antagonists.

    PubMed

    Yoneyama, Hiroki; Yamamoto, Daisuke; Yamatodani, Atsushi; Harusawa, Shinya

    2016-01-01

    S-Alkyl-N-alkylisothiourea compounds, which contain various cyclic amines, were synthesized using 3-phenylpropionyl isothiocyanate (PPI) to discover novel non-imidazole histamine H3 receptor (H3R) antagonists. The synthetic route was improved remarkably by using 2-nitrophenylacetyl isothiocyanate (NPAI). Among the synthesized compounds, N-[4-(4-chlorophenyl)butyl]-S-[3-piperidin-1-yl)propyl]isothiourea (1k, OUP-186) exhibited potent and selective antagonism against human H3R but not human H4R, in vitro. Of particular interest, they did not show antagonism for the histamine release in rat brain microdialysis in vivo, suggesting species-selective differences in antagonist affinities. Furthermore, in silico docking studies of OUP-186 and its C2-homolog (OUP-181) in human/rat H3Rs suggested that the structural difference of antagonist-docking sites between human and rat H3Rs was attributable to the Ala122/Val122 mutation. PMID:27592826

  20. Serum histamine in Alzheimer's disease and multi-infarct dementia.

    PubMed

    Cacabelos, R; Fernández-Novoa, L; Pérez-Trullén, J M; Franco-Maside, A; Alvarez, X A

    1992-11-01

    Recent data indicate that a neuroimmune reaction might be responsible in part for neuronal death and cognitive deterioration in senile dementia. The potential involvement of brain histamine (HA) and interleukin-1 (IL-1) in this process has been previously documented. We have studied the concentration of serum HA in patients with Alzheimer's disease (AD) or multi-infarct dementia (MID) and in age-matched control subjects. Serum HA levels were significantly higher in AD (10.935 +/- 5.692 nM) and MID (8.521 +/- 3.44 nM) than in controls (5.533 +/- 2.567 nM) and correlated with mental performance as evaluated with the Mini-Mental State Examination (MMSE) (r = +0.493, p < 0.009). No correlation was found with cardiovascular parameters, cerebrovascular risk factors or age. Hyperactivation of the histaminergic system in AD at central and peripheral levels might reflect a neuroimmune reaction to brain tissue damage, a neurotrophic response, and/or a reactive process to regulate the IL-1 induced amyloid precursor protein (APP) overproduction. PMID:1294859

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

    PubMed

    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

    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-α as well as the activation of their transcription factors NF-κB, AP-1 and p38 in histamine-stimulated skin tissues. They also inhibited the expression of IL-4 and TNF-α and the activation of NF-κB 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-κB and AP-1 via PKC.

  2. Histamine H3 and H4 receptor ligands modify vascular histamine levels in normal and arthritic large blood vessels in vivo.

    PubMed

    Kyriakidis, Konstantinos; Zampeli, Evangelia; Palaiologou, Marina; Tiniakos, Dina; Tiligada, Ekaterini

    2015-01-01

    Growing evidence associates histamine with arthritis, but its implication in shaping vascular function in chronic inflammation remains largely elusive. This study explored the involvement of vascular histamine in the extra-articular responses in peripheral large blood vessels using a rat model of adjuvant-induced arthritis. Histamine levels were increased in the abdominal aorta and the inferior vena cava of arthritic animals. Contrary to the H1 receptor antagonist dimetindene, histamine induction was observed following administration of the H3 and H4 receptor ligands GSK334429 and JNJ7777120, respectively. In arthritis, prophylactic treatment with GSK334429 partially attenuated the clinical signs and restored basal histamine levels only in the abdominal aorta. This study is the first to implicate the H3 and H4 receptors in a concerted constitutive regulation of basal vascular histamine in the rat large blood vessels and to identify the H3 receptor as a component that may influence arterial histamine during the onset of arthritis.

  3. Increased tau phosphorylation and aggregation in the hippocampus of mice overexpressing corticotropin-releasing factor.

    PubMed

    Campbell, Shannon N; Zhang, Cheng; Monte, Louise; Roe, Allyson D; Rice, Kenner C; Taché, Yvette; Masliah, Eliezer; Rissman, Robert A

    2015-01-01

    Clinical and basic science research suggests that stress and/or changes in central stress signaling intermediates may be involved in Alzheimer's disease (AD) pathogenesis. Although the links between stress and AD remain unsettled, data from our group and others have established that stress exposure in rodents may confer susceptibility to AD pathology by inducing hippocampal tau phosphorylation (tau-P). Work in our laboratory has shown that stress-induced tau-P requires activation of the type-1 corticotropin-releasing factor receptor (CRFR1). CRF overexpressing (CRF-OE) mice are a model of chronic stress that display cognitive impairment at 9-10 month of age. In this study we used 6-7 month old CRF-OE mice to examine whether sustained exposure to CRF and stress steroids would impact hippocampal tau-P and kinase activity in the presence or absence of the CRFR1-specific antagonist, R121919, given daily for 30 days. CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK). Examination of hippocampal extracts from CRF-OE mice at the ultrastructural level revealed negatively stained round/globular aggregates that were positively labeled by PHF-1. These data suggest critical roles for CRF and CRFR1 in tau-P and aggregation and may have implications for the development of AD cognitive decline.

  4. Corticotropin-releasing factor enhances locomotion and medullary neuronal firing in an amphibian.

    PubMed

    Lowry, C A; Rose, J D; Moore, F L

    1996-03-01

    Corticotropin-releasing factor (CRF) administration has been shown to act centrally to enhance locomotion in rats and amphibians. In the present study we used an amphibian, the roughskin newt (Taricha granulosa), to characterize changes in medullary neuronal activity associated with CRF-induced walking and swimming in animals chronically implanted with fine-wire microelectrodes. Neuronal activity was recorded from the raphe and adjacent reticular region of the rostral medulla. Under baseline conditions most of the recorded neurons showed low to moderate amounts of neuronal activity during periods of immobility and pronounced increases in firing that were time-locked with episodes of walking. These neurons sometimes showed further increases in discharge during swimming. Injections of CRF but not saline into the lateral ventricle produced a rapidly appearing increase in walking and pronounced changes (mostly increases) in firing rates of the medullary neurons. CRF produced diverse changes in patterns of firing in different neurons, but for these neurons as a group, the effects of CRF showed a close temporal association with the onset and expression of the peptide's effect on locomotion. In neurons that were active exclusively during movement prior to CRF treatment, the post-CRF increase in firing was evident during episodes of walking; in other neurons that also were spontaneously active during immobility prior to CRF infusion, post-CRF activity changes were evident during immobility as well as during episodes of locomotion. Thus, a principal effect of CRF was to potentiate the level of neuronal firing in a population of medullary neurons with locomotor-related properties. Due to the route of administration CRF may have acted on multiple central nervous system sites to enhance locomotion, but the results are consistent with neurophysiological effects involving medullary locomotion-regulating neurons.

  5. A Transgenic Rat for Investigating the Anatomy and Function of Corticotrophin Releasing Factor Circuits

    PubMed Central

    Pomrenze, Matthew B.; Millan, E. Zayra; Hopf, F. Woodward; Keiflin, Ronald; Maiya, Rajani; Blasio, Angelo; Dadgar, Jahan; Kharazia, Viktor; De Guglielmo, Giordano; Crawford, Elena; Janak, Patricia H.; George, Olivier; Rice, Kenner C.; Messing, Robert O.

    2015-01-01

    Corticotrophin-releasing factor (CRF) is a 41 amino acid neuropeptide that coordinates adaptive responses to stress. CRF projections from neurons in the central nucleus of the amygdala (CeA) to the brainstem are of particular interest for their role in motivated behavior. To directly examine the anatomy and function of CRF neurons, we generated a BAC transgenic Crh-Cre rat in which bacterial Cre recombinase is expressed from the Crh promoter. Using Cre-dependent reporters, we found that Cre expressing neurons in these rats are immunoreactive for CRF and are clustered in the lateral CeA (CeL) and the oval nucleus of the BNST. We detected major projections from CeA CRF neurons to parabrachial nuclei and the locus coeruleus, dorsal and ventral BNST, and more minor projections to lateral portions of the substantia nigra, ventral tegmental area, and lateral hypothalamus. Optogenetic stimulation of CeA CRF neurons evoked GABA-ergic responses in 11% of non-CRF neurons in the medial CeA (CeM) and 44% of non-CRF neurons in the CeL. Chemogenetic stimulation of CeA CRF neurons induced Fos in a similar proportion of non-CRF CeM neurons but a smaller proportion of non-CRF CeL neurons. The CRF1 receptor antagonist R121919 reduced this Fos induction by two-thirds in these regions. These results indicate that CeL CRF neurons provide both local inhibitory GABA and excitatory CRF signals to other CeA neurons, and demonstrate the value of the Crh-Cre rat as a tool for studying circuit function and physiology of CRF neurons. PMID:26733798

  6. Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression.

    PubMed

    Bangasser, D A; Reyes, B A S; Piel, D; Garachh, V; Zhang, X-Y; Plona, Z M; Van Bockstaele, E J; Beck, S G; Valentino, R J

    2013-02-01

    Stress-related psychiatric disorders are more prevalent in women than men. As hypersecretion of the stress neuromediator, corticotropin-releasing factor (CRF) has been implicated in these disorders, sex differences in CRF sensitivity could underlie this disparity. Hyperarousal is a core symptom that is shared by stress-related disorders and this has been attributed to CRF regulation of the locus ceruleus (LC)-norepinephrine arousal system. We recently identified sex differences in CRF(1) receptor (CRF(1)) signaling and trafficking that render LC neurons of female rats more sensitive to CRF and potentially less able to adapt to excess CRF compared with male rats. The present study used a genetic model of CRF overexpression to test the hypothesis that females would be more vulnerable to LC dysregulation by conditions of excess CRF. In both male and female CRF overexpressing (CRF-OE) mice, the LC was more densely innervated by CRF compared with wild-type controls. Despite the equally dense CRF innervation of the LC in male and female CRF-OE mice, LC discharge rates recorded in slices in vitro were selectively elevated in female CRF-OE mice. Immunoelectron microscopy revealed that this sex difference resulted from differential CRF(1) trafficking. In male CRF-OE mice, CRF(1) immunolabeling was prominent in the cytoplasm of LC neurons, indicative of internalization, a process that would protect cells from excessive CRF. However, in female CRF-OE mice, CRF(1) labeling was more prominent on the plasma membrane, suggesting that the compensatory response of internalization was compromised. Together, the findings suggest that the LC-norepinephrine system of females will be particularly affected by conditions resulting in elevated CRF because of differences in receptor trafficking. As excessive LC activation has been implicated in the arousal components of stress-related psychiatric disorders, this may be a cellular mechanism that contributes to the increased incidence of

  7. Sex-biased stress signaling: the corticotropin-releasing factor receptor as a model.

    PubMed

    Valentino, Rita J; Bangasser, Debra; Van Bockstaele, Elisabeth J

    2013-04-01

    Sex differences in the prevalence or severity of many diseases and in the response to pharmacological agents are well recognized. Elucidating the biologic bases of these differences can advance our understanding of the pathophysiology of disease and facilitate the development of treatments. Despite the importance to medicine, this has been an area of limited research. Here, we review physiologic, cellular, and molecular findings supporting the idea that there are sex differences in receptor signaling and trafficking that can be determinants of pathology. The focus is on the receptor for corticotropin-releasing factor (CRF), the orchestrator of the stress response, which has been implicated in diverse stress-related diseases that show a female prevalence. Data are reviewed that show sex differences in the association of the CRF receptor (CRF1) with the Gs protein and β-arrestin 2 that would render females more responsive to acute stress and less able to adapt to chronic stress as a result of compromised CRF1 internalization. Because β-arrestin 2 serves to link CRF1 to Gs-independent signaling pathways, this sex-biased signaling is proposed to result in distinct cellular responses to stress that are translated to different physiologic and behavioral coping mechanisms and that can have different pathologic consequences. Because stress has been implicated in diverse medical and psychiatric diseases, these sex differences in CRF1 signaling could explain sex differences in a multitude of disorders. The possibility that analogous sex differences may occur with other G-protein-coupled receptors underscores the impact of this effect and is discussed. PMID:23239826

  8. Corticotropin-releasing factor receptor densities vary with photoperiod and sociality.

    PubMed

    Beery, Annaliese K; Vahaba, Daniel M; Grunberg, Diana M

    2014-11-01

    Life in social groups relies on prosocial behaviors as well as on reduction of antisocial behaviors such as aggression and territoriality. The mechanisms supporting variation in behaviors that give rise to group living (sociality) are largely unknown. Female meadow voles exhibit natural seasonal variation in sociality: females are aggressive and territorial in summer, while in winter they share burrows and nest in mixed-sex groups. This behavioral shift is paralleled in the lab by day length-dependent variation in partner preference formation and social huddling. We exploit natural variation in meadow vole sociality in order to examine changes in neural pathways that coincide with environmental and behavioral variations. Mounting evidence suggests that the corticotropin-releasing factor system, encompassing multiple peptides and two receptor subtypes (CRF1 and CRF2), may play an important role in regulating social behaviors. We report day-length dependent variation in CRF1 and CRF2 receptor binding in female meadow voles, and relate these findings to previously collected oxytocin receptor (OTR) binding data and behavioral data for the same individuals. CRF1 receptor binding was greater in summer-like long day lengths (LD), particularly in the hippocampus, while CRF2 receptor binding was greater in winter-like short day lengths (SD) in the cingulate cortex and hippocampus. OTR varied with day length in the bed nucleus of the stria terminalis, nucleus accumbens, and hippocampus. SD voles huddled more extensively than LD voles, and greater huddling time was associated with more CRF1 receptor binding and less CRF2 receptor binding in subregions of the lateral septum. CRF2 receptor associations with behavior mirrored those of OTR in the lateral septum. Finally, estradiol treatment affected density of CRF receptors in multiple brain regions. CRF receptors and their ligands are promising candidates for enhancing understanding of the regulation of non-sexual social

  9. Molecular mechanisms of corticotropin-releasing factor receptor-induced calcium signaling.

    PubMed

    Gutknecht, Eric; Van der Linden, Ilse; Van Kolen, Kristof; Verhoeven, Kim F C; Vauquelin, Georges; Dautzenberg, Frank M

    2009-03-01

    The molecular mechanisms governing calcium signal transduction of corticotropin-releasing factor (CRF) receptors CRF(1) and CRF(2(a)) stably expressed in human embryonic kidney (HEK) 293 cells were investigated. Calcium signaling strictly depended on intracellular calcium sources, and this is the first study to establish a prominent contribution of the three major G-protein families to CRF receptor-mediated calcium signaling. Overexpression of Galpha(q/11) and Galpha(16) led to leftward shifts of the agonist concentration-response curves. Blockade of Galpha(q/11) proteins by the small interfering RNA (siRNA) technology partially reduced agonist-mediated calcium responses in CRF(1)- and CRF(2(a))-expressing HEK293 cells, thereby proving a contribution of the G(q) protein family. A small but significant inhibition of calcium signaling was recorded by pharmacological inhibition of G(i/o) proteins with pertussis toxin treatment. This effect was mediated by direct binding of Gbetagamma subunits to phospholipase C. G(i/o) inhibition also elevated cAMP responses in CRF receptor-overexpressing HEK293 cells and in Y79 retinoblastoma cells endogenously expressing human CRF(1) and CRF(2(a)) receptors, thereby demonstrating natural coupling of G(i) proteins to both CRF receptors. The strongest reduction of CRF receptor-mediated calcium mobilization was noted when blocking the G(s) signaling protein either by cholera toxin or by siRNA. It is noteworthy that simultaneous inhibition of two G-proteins shed light on the additive effects of G(s) and G(q) on the calcium signaling and, hence, that they act in parallel. On the other hand, G(i) coupling required prior G(s) activation. PMID:19098121

  10. Coevolution between Stop Codon Usage and Release Factors in Bacterial Species

    PubMed Central

    Wei, Yulong; Wang, Juan; Xia, Xuhua

    2016-01-01

    Three stop codons in bacteria represent different translation termination signals, and their usage is expected to depend on their differences in translation termination efficiency, mutation bias, and relative abundance of release factors (RF1 decoding UAA and UAG, and RF2 decoding UAA and UGA). In 14 bacterial species (covering Proteobacteria, Firmicutes, Cyanobacteria, Actinobacteria and Spirochetes) with cellular RF1 and RF2 quantified, UAA is consistently over-represented in highly expressed genes (HEGs) relative to lowly expressed genes (LEGs), whereas UGA usage is the opposite even in species where RF2 is far more abundant than RF1. UGA usage relative to UAG increases significantly with PRF2 [=RF2/(RF1 + RF2)] as expected from adaptation between stop codons and their decoders. PRF2 is > 0.5 over a wide range of AT content (measured by PAT3 as the proportion of AT at third codon sites), but decreases rapidly toward zero at the high range of PAT3. This explains why bacterial lineages with high PAT3 often have UGA reassigned because of low RF2. There is no indication that UAG is a minor stop codon in bacteria as claimed in a recent publication. The claim is invalid because of the failure to apply the two key criteria in identifying a minor codon: (1) it is least preferred by HEGs (or most preferred by LEGs) and (2) it corresponds to the least abundant decoder. Our results suggest a more plausible explanation for why UAA usage increases, and UGA usage decreases, with PAT3, but UAG usage remains low over the entire PAT3 range. PMID:27297468

  11. Plasticity in the brainstem vagal circuits controlling gastric motor function triggered by corticotropin releasing factor.

    PubMed

    Browning, Kirsteen N; Babic, Tanja; Toti, Luca; Holmes, Gregory M; Coleman, F Holly; Travagli, R Alberto

    2014-10-15

    Stress impairs gastric emptying, reduces stomach compliance and induces early satiety via vagal actions. We have shown recently that the ability of the anti-stress neuropeptide oxytocin (OXT) to modulate vagal brainstem circuits undergoes short-term plasticity via alterations in cAMP levels subsequent to vagal afferent fibre-dependent activation of metabotropic glutamate receptors. The aim of the present study was to test the hypothesis that the OXT-induced gastric response undergoes plastic changes in the presence of the prototypical stress hormone, corticotropin releasing factor (CRF). Whole cell patch clamp recordings showed that CRF increased inhibitory GABAergic synaptic transmission to identified corpus-projecting dorsal motor nucleus of the vagus (DMV) neurones. In naive brainstem slices, OXT perfusion had no effect on inhibitory synaptic transmission; following exposure to CRF (and recovery from its actions), however, re-application of OXT inhibited GABAergic transmission in the majority of neurones tested. This uncovering of the OXT response was antagonized by pretreatment with protein kinase A or adenylate cyclase inhibitors, H89 and di-deoxyadenosine, respectively, indicating a cAMP-mediated mechanism. In naive animals, OXT microinjection in the dorsal vagal complex induced a NO-mediated corpus relaxation. Following CRF pretreatment, however, microinjection of OXT attenuated or, at times reversed, the gastric relaxation which was insensitive to l-NAME but was antagonized by pretreatment with a VIP antagonist. Immunohistochemical analyses of vagal motoneurones showed an increased number of oxytocin receptors present on GABAergic terminals of CRF-treated or stressed vs. naive rats. These results indicate that CRF alters vagal inhibitory circuits that uncover the ability of OXT to modulate GABAergic currents and modifies the gastric corpus motility response to OXT. PMID:25128570

  12. Magnetic field-responsive release of transforming growth factor beta 1 from heparin-modified alginate ferrogels.

    PubMed

    Kim, Hwi; Park, Honghyun; Lee, Jae Won; Lee, Kuen Yong

    2016-10-20

    Stimuli-responsive polymeric systems have been widely used for various drug delivery and tissue engineering applications. Magnetic stimulation can be also exploited to regulate the release of pharmaceutical drugs, growth factors, and cells from hydrogels in a controlled manner, on-demand. In the present study, alginate ferrogels containing iron oxide nanoparticles were fabricated via ionic cross-linking, and their various characteristics were investigated. The deformation of the ferrogels was dependent on the polymer concentration, calcium concentration, iron oxide concentration, and strength of magnetic field. To modulate the release of transforming growth factor beta 1 (TGF-β1) under magnetic stimulation, alginate was chemically modified with heparin, as TGF-β1 has a heparin-binding domain. Alginate was first modified with ethylenediamine, and heparin was then conjugated to the ethylenediamine-modified alginate via carbodiimide chemistry. Conjugation of heparin to alginate was confirmed by infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. Sustained release of TGF-β1 from alginate-g-heparin ferrogels was achieved, and application of a magnetic field to the ferrogels regulated TGF-β1 release, resultantly enhancing chondrogenic differentiation of ATDC5 cells, which were used as a model chondrogenic cell line. Alginate-based ferrogels that release drugs in a controlled manner may therefore be useful in many biomedical applications. PMID:27474590

  13. Sustained release of vascular endothelial growth factor from calcium-induced alginate hydrogels reinforced by heparin and chitosan.

    PubMed

    Lee, K W; Yoon, J J; Lee, J H; Kim, S Y; Jung, H J; Kim, S J; Joh, J W; Lee, H H; Lee, D S; Lee, S K

    2004-10-01

    A possible alternative for immunosuppression is a microencapsulation technique using hydrogels, which have been utilized for cell immobilization and drug delivery systems. Angiogenesis is crucial for delivery of the metabolic products to the host tissues as well as to supply oxygen and nutrients to cells. The local delivery of angiogenic growth factors, such as VEGF and basic FGF, has been recently studied to enhance angiogenesis on peripheral tissue of graft. In this study, we evaluated sustained VEGF release with a model using hydrogels coated with chitosan and heparin in vitro. We fabricated calcium alginate gels and chitosan-coated calcium alginate gels. Heparinized chitosan-coated calcium-induced alginate hydrogel beads were prepared by soaking chitosan-coated calcium alginate gels in heparin solution. We compared the stability and VEGF release manner between three kinds of hydrogels. To compare the stability, 5 mL of each hydrogel was incubated with 20 mL PBS under the rotational culture. Compression forces were measured using a rheometer. The amount of VEGF released from the gels was measured by ELISA. The heparin-coated chitosan alginate hydrogels showed the highest surface stability among the three hydrogels. VEGF from the heparinized gel was released in sustained manner up to 10 days in vitro. Chitosan-coated alginate gels released 90% of loaded VEGF within 5 days. These results suggest that local delivery of VEGF using a heparinized hydrogel may provide a long-term supply of angiogenic growth factor that might induce new vessel formation in vivo.

  14. Spontaneous and stimulated release of tumor necrosis factor-alpha (TNF) from blood monocytes of miners with coal workers' pneumoconiosis

    SciTech Connect

    Borm, P.J.; Palmen, N.; Engelen, J.J.; Buurman, W.A.

    1988-12-01

    It is generally accepted that fibrotic lung diseases are mediated by macrophage-derived cytokines. We investigated the release of the monokine tumor necrosis factor-alpha (TNF) from blood monocytes in a group of 66 coal miners and 12 non-dust-exposed individuals. Twenty-seven miners had simple Coal Workers' Pneumoconiosis (CWP). Control miners (n = 39) were matched with respect to age, years underground, and smoking. Monocytes were assayed for TNF release, spontaneously or in response to soluble (endotoxin) or particulate (coal mine dust, silica) stimulation. TNF was measured with a TNF-specific ELISA. Monocytes of all subjects responded to stimulants by the release of TNF. Dust-exposed controls' monocytes revealed higher TNF release as compared to normal controls. The greatest discriminator between control miners and cases (CWP) was coal mine dust-induced TNF release. Interestingly, the largest difference was observed between controls and those cases with a small number of opacities (0/1, 1/0, 1/1, and 1/2), giving an odds ratio of 6.3 to find an individual with a high dust-induced TNF release in the patient group.

  15. Histamine H3 receptor in primary mouse microglia inhibits chemotaxis, phagocytosis, and cytokine secretion.

    PubMed

    Iida, Tomomitsu; Yoshikawa, Takeo; Matsuzawa, Takuro; Naganuma, Fumito; Nakamura, Tadaho; Miura, Yamato; Mohsen, Attayeb S; Harada, Ryuichi; Iwata, Ren; Yanai, Kazuhiko

    2015-07-01

    Histamine is a physiological amine which initiates a multitude of physiological responses by binding to four known G-protein coupled histamine receptor subtypes as follows: histamine H1 receptor (H1 R), H2 R, H3 R, and H4 R. Brain histamine elicits neuronal excitation and regulates a variety of physiological processes such as learning and memory, sleep-awake cycle and appetite regulation. Microglia, the resident macrophages in the brain, express histamine receptors; however, the effects of histamine on critical microglial functions such as chemotaxis, phagocytosis, and cytokine secretion have not been examined in primary cells. We demonstrated that mouse primary microglia express H2 R, H3 R, histidine decarboxylase, a histamine synthase, and histamine N-methyltransferase, a histamine metabolizing enzyme. Both forskolin-induced cAMP accumulation and ATP-induced intracellular Ca(2+) transients were reduced by the H3 R agonist imetit but not the H2 R agonist amthamine. H3 R activation on two ubiquitous second messenger signalling pathways suggests that H3 R can regulate various microglial functions. In fact, histamine and imetit dose-dependently inhibited microglial chemotaxis, phagocytosis, and lipopolysaccharide (LPS)-induced cytokine production. Furthermore, we confirmed that microglia produced histamine in the presence of LPS, suggesting that H3 R activation regulate microglial function by autocrine and/or paracrine signalling. In conclusion, we demonstrate the involvement of histamine in primary microglial functions, providing the novel insight into physiological roles of brain histamine.

  16. Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors

    PubMed Central

    Carlin, Jesse Lea; Tosh, Dilip K.; Xiao, Cuiying; Piñol, Ramón A.; Chen, Zhoumou; Salvemini, Daniela; Gavrilova, Oksana; Jacobson, Kenneth A.

    2016-01-01

    Adenosine can induce hypothermia, as previously demonstrated for adenosine A1 receptor (A1AR) agonists. Here we use the potent, specific A3AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A3AR. The hypothermic effect of A3AR agonists is independent of A1AR activation, as the effect was fully intact in mice lacking A1AR but abolished in mice lacking A3AR. A3AR agonist–induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A3AR hypothermia is mediated, at least in part, via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a non–brain-penetrant agonist caused hypothermia, suggesting that peripheral A3AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H1 (but not H2 or H4) receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A3AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A3AR agonists act on peripheral mast cells, causing histamine release, which stimulates central histamine H1 receptors to induce hypothermia. This mechanism suggests that A3AR agonists will probably not be useful for clinical induction of hypothermia. PMID:26606937

  17. Fc alpha receptors mediate release of tumour necrosis factor-alpha and interleukin-6 by human monocytes following receptor aggregation.

    PubMed Central

    Patry, C; Herbelin, A; Lehuen, A; Bach, J F; Monteiro, R C

    1995-01-01

    The functional capacity of the human monocyte receptor for the Fc portion of IgA (Fc alpha R) in mediating signal transduction was evaluated by cytokine release. F(ab')2 fragments of anti-Fc alpha R monoclonal antibodies (mAb) were used as specific probes to induce release of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Multivalent cross-linking by a secondary anti-mouse antibody [F(ab')2 fragments] induced a significant release of TNF-alpha and IL-6 by human blood mononuclear cells, indicating requirements for Fc alpha R aggregation on the cell surface to transmit signals. Both cytokines were released exclusively by adherent cells, identifying monocytes as the responding cells within the mononuclear cell population. This cytokine release could not be due to contaminating endotoxins, because it was not abolished by polymyxin B, a lipopolysaccharide (LPS) inhibitor. Moreover, purified recombinant soluble Fc alpha R inhibited the anti-Fc alpha R mAb-mediated cytokine release from blood monocytes, demonstrating that TNF-alpha and IL-6 were released in a receptor-specific manner. Our data suggest that Fc alpha R, through its capacity to mediate secretion of IL-6, may play an important role in B-cell proliferation and immunoglobulin production. On the other hand, release of TNF-alpha following stimulation of Fc alpha R molecules directly implicates these receptors in amplification and regulation of the inflammatory process occurring during IgA-mediated host defence. PMID:7590867

  18. The tumour necrosis factor superfamily ligand APRIL (TNFSF13) is released upon platelet activation and expressed in atherosclerosis.

    PubMed

    Sandberg, Wiggo J; Otterdal, Kari; Gullestad, Lars; Halvorsen, Bente; Ragnarsson, Asgrimur; Frøland, Stig S; Damås, Jan K; Oie, Erik; Aukrust, Pål; Hansson, Göran K; Yndestad, Arne

    2009-10-01

    Activated platelets release a wide range of inflammatory mediators, including members of the tumour necrosis factor (TNF) superfamily (e.g. CD40 ligand [CD40L] and LIGHT). Such platelet-mediated inflammation could be involved in atherogenesis and plaque destabilisation. In the present study we investigated whether APRIL, another member of the TNF superfamily that has been detected in megakaryocytes, could be released from platelets upon activation. The release of APRIL was studied in thrombin receptor (SFLLRN) activated platelets, and the expression of APRIL was examined in plasma and within the atherosclerotic lesion in patients with carotid and coronary atherosclerosis. Upon SFLLRN activation, there was a gradual release of APRIL, reaching maximum after 90 minutes. While this pattern is similar to that of CD40L and LIGHT, the release of APRIL was quite differently regulated. Thus, prostaglandin E1, but not inhibitors of metal-dependent proteases and actin polymerisation or the lack of GP IIb/IIIa, blocks APRIL release in activated platelets. With relevance to atherogenesis, we found that patients with coronary artery disease (n=80) had raised plasma levels of APRIL as compared with controls (n=20), and APRIL immunoreactivity was