Sample records for puva inhibits degranulation

  1. Quercetin inhibits degranulation and superoxide generation in PMA stimulated neutrophils

    PubMed Central

    Ma?I?ková, Tatiana; Sviteková, Klára; Nosá?, Radomír

    2012-01-01

    Activated neutrophils represent the main source of myeloperoxidase (MPO), superoxide (SO) and subsequently derived oxygen metabolites. They have important microbicidal activities, however in inflammatory conditions they may secondarily attack surrounding tissues. Overproduction of reactive oxygen species, prolonged or excessive liberation of MPO and other effective yet also toxic substances from neutrophils may participate in disturbed apoptosis, intensify the inflammatory processes and result in serious human diseases. The inhibitory effect of quercetin on PMA stimulated SO generation in isolated human neutrophils was found to be dose-dependent, without affecting the activity of intact isolated neutrophils. At comparable conditions, quercetin was more potent in inhibiting MPO release than SO generation. Our results indicate that quercetin could support resolution of inflammation through decreased activity of neutrophils, i.e. respiratory burst and degranulation. PMID:23118592

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

    SciTech Connect

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

    2011-05-01

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

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

    PubMed

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

    2012-01-01

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

  4. Creme-PUVA-Photochemotherapie

    Microsoft Academic Search

    Helger Stege; Mark Berneburg; Thomas Ruzicka; Jean Krutmann

    1997-01-01

    Zusammenfassung  \\u000a Trotz unbestrittener Vorteile wie z.B. dem Fehlen systemischer Nebenwirkungen oder niedriger kumulativer UVA-Dosen wird die\\u000a Durchführung der Bade-PUVA-Photochemotherapie in der dermatologischen Praxis durch die mit dem Badevorgang verknüpften räumlichen\\u000a und personellen Anforderungen erschwert. Wir haben daher eine topische Photochemotherapie entwickelt, bei der 8-Methoxypsoralen\\u000a (8-MOP) in einer Konzentration von 0.0006% in einer Wasser-in-Öl Emulsion (30% Wasser) angewendet wird (Creme-PUVA- Photochemotherapie).

  5. Cardiovascular stress of photochemotherapy (PUVA)

    SciTech Connect

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

    1980-11-01

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

  6. Effects of PUVA on the eye

    SciTech Connect

    Backman, H.A.

    1982-01-01

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

  7. Naloxone-induced morphine withdrawal increases the number and degranulation of mast cells in the thalamus of the mouse

    Microsoft Academic Search

    Oludare B. Taiwo; Katalin J. Kovács; Lauren C. Sperry; Alice A. Larson

    2004-01-01

    Naloxone-induced jumping in morphine-dependent mice is inhibited by cromolyn, a mast cell stabilizer, suggesting that this characteristic withdrawal behavior results from degranulation of mast cells. Because withdrawal is considered as a central phenomenon, degranulation of mast cells located within the CNS may influence aspects of opioid withdrawal. The present study evaluates histologically whether naloxone, injected into opioid dependent mice, induces

  8. Treatment of stable vitiligo with autologous epidermal grafting and PUVA

    Microsoft Academic Search

    Seung Kyung Hann; Sungbin Im; Ha Wook Bong; Yoon-Kee Park

    1995-01-01

    Background: Previous reports have shown the benefits of epidermal grafting for vitiligo.Objective: Our purpose was to evaluate the effectiveness and complications of epidermal grafting in combination with PUVA on stable vitiligo refractory to conventional treatments.Methods: In 100 patients with stable refractory vitiligo we performed epidermal grafting with suction blisters followed by PUVA treatment. The grafted sites were examined for repigmentation

  9. Mathematical model of laser PUVA psoriasis treatment

    NASA Astrophysics Data System (ADS)

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

    1991-05-01

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

  10. Microvascular leakage of plasma proteins after PUVA and UVA

    SciTech Connect

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

    1982-04-01

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

  11. The histamine H4 receptor is a potent inhibitor of adhesion-dependent degranulation in human neutrophils.

    PubMed

    Dib, Karim; Perecko, Tomas; Jenei, Veronika; McFarlane, Cheryl; Comer, David; Brown, Vanessa; Katebe, Mwape; Scheithauer, Torsten; Thurmond, Robin L; Chazot, Paul L; Ennis, Madeleine

    2014-09-01

    The histamine H4 receptor regulates the inflammatory response. However, it is not known whether this receptor has a functional role in human neutrophils. We found that fMLP (1 ?M), but not histamine (0.1-1 ?M), induced Mac-1-dependent adhesion, polarization, and degranulation (release of lactoferrin). A pretreatment of neutrophils with histamine (0.001-1 ?M) or JNJ 28610244 (0.1-10 ?M), a specific H4 receptor agonist, led to inhibition of degranulation. Total inhibition of degranulation was obtained with 0.1 ?M histamine and 10 ?M JNJ 28610244. Furthermore, such inhibition by histamine of degranulation was reversed by JNJ 7777120 and JNJ 28307474, two selective H4 receptor antagonists. However, neither histamine nor the H4 receptor agonist JNJ 28610244 prevented fMLP-induced, Mac-1-dependent adhesion, indicating that the H4 receptor may block signals emanating from Mac-1-controlling degranulation. Likewise, engagement of the H4 receptor by the selective agonist JNJ 28610244 blocked Mac-1-dependent activation of p38 MAPK, the kinase that controls neutrophil degranulation. We also show expression of the H4 receptor at the mRNA level in ultrapure human neutrophils and myeloid leukemia PLB-985 cells. We concluded that engagement of this receptor by selective H4 receptor agonists may represent a good, therapeutic approach to accelerate resolution of inflammation. PMID:24799603

  12. Mathematical modeling for laser PUVA treatment of psoriasis

    NASA Astrophysics Data System (ADS)

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

    1991-06-01

    The justifaction of method of the laser PUVA (LPUVA) therapy, the description of an UVA therapeutic system, the preliminary results of using the nitrogen gas laser as an UVA source for LPUVA chamber and in some other fields of application in dermatology are given.

  13. Treatment of Recalcitrant Idiopathic Leukocytoclastis Vasculitis with PUVA

    Microsoft Academic Search

    Surangkana Nawapuntu; Rutsanee Akaraphanth; Pimonpun Gritiyarangsan

    Leukocytoclastic vasculitis (LCV) is a small-vessel inflammatory disease mediated by deposition of immune complexes. Idiopathic LCV is defined as LCV with negative or normal laboratory findings. Some of these patients were recalcitrant to conventional therapy especially patients who showed livedo reticularis and livedoid vasculitis clinically. Several studies reported good response to PUVA treating conditions which showed evidence of LCV in

  14. Inhibitory effects of guarana seed extract on passive cutaneous anaphylaxis and mast cell degranulation.

    PubMed

    Jippo, Tomoko; Kobayashi, Yuko; Sato, Harumi; Hattori, Atsushi; Takeuchi, Hiroaki; Sugimoto, Keiichiro; Shigekawa, Munekazu

    2009-09-01

    This study investigated the effects of guarana seed extract (GSE) on an anti-allergic mechanism. GSE orally administered inhibited the anti-dinitrophenol IgE-induced passive cutaneous anaphylaxis reaction in mice. Furthermore, it inhibited the degranulation of rat basophilic leukemia RBL-2H3 cells. It had no cytotoxicity on RBL-2H3 cells. These results show that GSE is a candidate for effective therapeutic material for allergic diseases. PMID:19734657

  15. MOTION PICTURE STUDIES ON DEGRANULATION OF HORSE EOSINOPHILS DURING PHAGOCYTOSIS

    PubMed Central

    Archer, Gordon T.; Hirsch, James G.

    1963-01-01

    Horse eosinophil function has been studied in vitro by means of phase contrast cinemicrophotography. Locomotion of horse eosinophils was inhibited by serum factors reacting with glass surfaces. Under appropriate conditions which eliminated this inhibitory effect, eosinophils moved about and ingested some particles as rapidly as did neutrophils. Eosinophils were attracted to and readily engulfed such diverse materials as yeast cell walls, foreign erythrocytes, and antigen-antibody precipitates. Specific antibody was required for phagocytosis of red cells, and greatly accelerated the uptake of yeast cell walls. Horse eosinophil granules situated adjacent to material being engulfed disrupted with discharge of granule contents into or alongside the phagocytic vacuole. Granule disruption resulted in a clear zone and deposition of amorphous, phase-dense material. A heat-labile serum factor was required for degranulation of eosinophils ingesting foreign red cells, but not for degranulation during engulfment of yeast cell walls or antigen-antibody precipitates. Horse eosinophils were incapable under these conditions of engulfing an entire human red cell. The eosinophil commonly put out a large pseudopod to surround about half the red cell, and then appeared to constrict this pseudopod distally to cut the erythrocyte in half. It is concluded that eosinophils are phagocytic cells, resembling neutrophils in many of their properties. Any specific functions of eosinophils, distinguishing them from other phagocytes, remain to be discovered. PMID:14074392

  16. MOTION PICTURE STUDIES ON DEGRANULATION OF HORSE EOSINOPHILS DURING PHAGOCYTOSIS.

    PubMed

    ARCHER, G T; HIRSCH, J G

    1963-08-01

    Horse eosinophil function has been studied in vitro by means of phase contrast cinemicrophotography. Locomotion of horse eosinophils was inhibited by serum factors reacting with glass surfaces. Under appropriate conditions which eliminated this inhibitory effect, eosinophils moved about and ingested some particles as rapidly as did neutrophils. Eosinophils were attracted to and readily engulfed such diverse materials as yeast cell walls, foreign erythrocytes, and antigen-antibody precipitates. Specific antibody was required for phagocytosis of red cells, and greatly accelerated the uptake of yeast cell walls. Horse eosinophil granules situated adjacent to material being engulfed disrupted with discharge of granule contents into or alongside the phagocytic vacuole. Granule disruption resulted in a clear zone and deposition of amorphous, phase-dense material. A heat-labile serum factor was required for degranulation of eosinophils ingesting foreign red cells, but not for degranulation during engulfment of yeast cell walls or antigen-antibody precipitates. Horse eosinophils were incapable under these conditions of engulfing an entire human red cell. The eosinophil commonly put out a large pseudopod to surround about half the red cell, and then appeared to constrict this pseudopod distally to cut the erythrocyte in half. It is concluded that eosinophils are phagocytic cells, resembling neutrophils in many of their properties. Any specific functions of eosinophils, distinguishing them from other phagocytes, remain to be discovered. PMID:14074392

  17. Effects of fibrinogen receptor antagonist GR144053F and aurintricarboxylic acid on platelet activation and degranulation 1 1 Abbreviations: ACD, citric acid\\/trisodium citrate\\/glucose (recipe A), blood anticoagulant; ATA, aurintricarboxylic acid; CT CADP, closure (occlusion) time determined with the use of collagen\\/ADP cassettes in PFA100; GPIb-IX-V, a complex of glycoproteins Ib, IX, and V, a vWF receptor; GPIIb-IIIa, a complex of glycoproteins IIb and IIIa, a fibrinogen receptor; ic 50, the concentration of an inhibitor, at which 50% of the maximal estimated inhibition occurred; the extent of maximal inhibition was calculated based on the mathematical resolving of the equation describing the inhibition of platelet aggregation; PE, R-phycoerythrin; PFA100™, platelet function analyzer; PRP, platelet-rich plasma; RGD, Arg-Gly-Asp; PBS, phosphate-buffered saline; TRAP, thrombin receptor activating peptide, SFLLRNPNDKYEPF; and vWF, von Willebrand factor

    Microsoft Academic Search

    Marcin Rozalski; Magdalena Boncler; Jacek Golanski; Cezary Watala

    2001-01-01

    Activated blood platelets play crucial role in restenosis due to their fundamental significance in thrombus formation. Therefore, platelets are attractive targets for the inhibition with a variety of antagonists. In this study, we present direct evidence that GR144053F [non-peptide antagonist of glycoprotein IIb-IIIa complex (GPIIb-IIIa)] inhibits activation and degranulation of human platelets, and opposes the action of aurintricarboxylic acid (ATA),

  18. PUVA-Treatment for solar urticaria and persistent light reaction

    Microsoft Academic Search

    Erhard Hölzle; Cornelia Hofmann; Gerd Plewig

    1980-01-01

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

  19. Effect of fruits of Opuntia elatior Mill on mast cell degranulation

    PubMed Central

    Chauhan, Sanjay P.; Sheth, N. R.; Suhagia, B. N.

    2015-01-01

    Background: The presence of potentially active nutrients and their multifunctional properties make prickly pear a perfect candidate for the production of phytopharmaceutical products. Among the numerous Opuntia species, bioactive compounds have been isolated and characterized primarily from Opuntia ficus-indica, Opuntia polycantha, Opuntia stricta, Opuntia dilleni for various medicinal properties. Objective: Based on the traditional use of prickly pear for enhancement of immune function, the objective of the present study to evaluate the effect of prickly pear on mast cell degranulation function. Materials and Methods: The Opuntia fruit juice (OFJ) (10-200 ?l/ml) were studied for the effect on sensitized rat peritoneal mast cell degranulation induced by immunological (egg albumin), and nonimmunological (compound 48/80) stimuli and compared with that of the reference standard, sodium cromoglycate and ketotifen (10 ?g/ml). Results and Conclusion: The OFJ exhibited significantly (P < 0.001) concentration dependent inhibition of mast cell degranulation. The IC50 value of OFJ was found 12.24 and 18 ?l/ml for immunological and nonimmunological induced mast cell degranulation, respectively. The betacyanin is an active principle compound in prickly pear that may responsible for mast cell stabilizing action. PMID:25883521

  20. Modulation of Basophils' Degranulation and Allergy-Related Enzymes by Monomeric and Dimeric Naphthoquinones

    PubMed Central

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

    2014-01-01

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

  1. Treatment of chronic graft-versus-host disease with ultraviolet irradiation and psoralen (PUVA).

    PubMed

    Vogelsang, G B; Wolff, D; Altomonte, V; Farmer, E; Morison, W L; Corio, R; Horn, T

    1996-06-01

    Chronic graft-versus-host disease (GVHD) remains a difficult clinical problem to treat and manage. We have reviewed our treatment of 40 patients treated at a single institution with PUVA (ultraviolet irradiation and psoralen) over a 14 year period. Thirty-five patients were treated for refractory chronic GVHD and five patients were treated at presentation of high-risk chronic GVHD. Overall, 31 of 40 patients improved on PUVA treatment. Sixteen patients achieved a complete response to PUVA added to their GVHD regimen. Four of the 15 partial responders had complete resolution of cutaneous GVHD but persistence of other systemic manifestations. The remaining partial responders had at least a 50% improvement in GVHD. We have also used PUVA with a glass fiber extension to treat intra-oral GVHD. PUVA is well tolerated with a high rate of response in the skin and mild side effects except for three patients who had therapy discontinued after phototoxicity (burn). PMID:8807115

  2. Anti-degranulating activity in rat basophil leukemia RBL-2H3 cells of flavanone glycosides and their aglycones in citrus fruits.

    PubMed

    Murata, Kazuya; Takano, Seiya; Masuda, Megumi; Iinuma, Munekazu; Matsuda, Hideaki

    2013-07-01

    The anti-degranulating activity of flavonoids present in Citrus fruits was comprehensively evaluated. Among these, hesperetin and naringenin, respectively aglycones of hesperidin and narirutin, showed significant activity. The targets of hesperetin and naringenin were found: hesperetin inhibited phosphorylation of Syk and Akt, while naringenin suppressed the expression of Lyn and inhibited the phosphorylation of Akt. These results suggest that hesperetin and naringenin inhibit degranulation by suppression of pathway signals and reduce the symptoms of allergy by inhibiting phosphorylation of Akt, which leads to the suppression of cytokines. In addition, hesperetin showed inhibitory activity against the degranulation induced by calcium ionophores, indicating that hesperetin exerts its inhibitory activity by stabilizing the membrane structure. PMID:22903244

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

    PubMed Central

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

    2014-01-01

    Despite the fact that glucocorticoids and long acting beta agonists are effective treatments for asthma, their effects on human mast cells (MC) appear to be modest. Although MC are one of the major effector cells in the underlying inflammatory reactions associated with asthma, their regulation by these drugs is not yet fully understood and, in some cases, controversial. Using a human immortalized MC line (LAD2), we studied the effects of fluticasone propionate (FP) and salmeterol (SM), on the release of early and late phase mediators. LAD2 cells were pretreated with FP (100 nM), SM (1 µM), alone and in combination, at various incubation times and subsequently stimulated with agonists substance P, C3a and IgE/anti-IgE. Degranulation was measured by the release of ?-hexosaminidase. Cytokine and chemokine expression were measured using quantitative PCR, ELISA and cytometric bead array (CBA) assays. The combination of FP and SM synergistically inhibited degranulation of MC stimulated with substance P (33% inhibition compared to control, n?=?3, P<.05). Degranulation was inhibited by FP alone, but not SM, when MC were stimulated with C3a (48% inhibition, n?=?3, P<.05). As previously reported, FP and SM did not inhibit degranulation when MC were stimulated with IgE/anti-IgE. FP and SM in combination inhibited substance P-induced release of tumor necrosis factor (TNF), CCL2, and CXCL8 (98%, 99% and 92% inhibition, respectively, n?=?4, P<.05). Fluticasone and salmeterol synergistically inhibited mediator production by human MC stimulated with the neuropeptide substance P. This synergistic effect on mast cell signaling may be relevant to the therapeutic benefit of combination therapy in asthma. PMID:24819142

  4. Human umbilical cord blood mesenchymal stem cell-derived PGE2 and TGF-?1 alleviate atopic dermatitis by reducing mast cell degranulation.

    PubMed

    Kim, Hyung-Sik; Yun, Jun-Won; Shin, Tae-Hoon; Lee, Sung-Hoon; Lee, Byung-Chul; Yu, Kyung-Rok; Seo, Yoojin; Lee, Seunghee; Kang, Tae-Wook; Choi, Soon Won; Seo, Kwang-Won; Kang, Kyung-Sun

    2015-04-01

    Mesenchymal stem cell (MSC) is a promising tool for the therapy of immune disorders. However, their efficacy and mechanisms in treating allergic skin disorders are less verified. We sought to investigate the therapeutic efficacy of human umbilical cord blood-derived MSCs (hUCB-MSCs) against murine atopic dermatitis (AD) and to explore distinct mechanisms that regulate their efficacy. AD was induced in mice by the topical application of Dermatophagoides farinae. Naïve or activated-hUCB-MSCs were administered to mice, and clinical severity was determined. The subcutaneous administration of nucleotide-binding oligomerization domain 2 (NOD2)-activated hUCB-MSCs exhibited prominent protective effects against AD, and suppressed the infiltration and degranulation of mast cells (MCs). A ?-hexosaminidase assay was performed to evaluate the effect of hUCB-MSCs on MC degranulation. NOD2-activated MSCs reduced the MC degranulation via NOD2-cyclooxygenase-2 signaling. In contrast to bone marrow-derived MSCs, hUCB-MSCs exerted a cell-to-cell contact-independent suppressive effect on MC degranulation through the higher production of prostaglandin E2 (PGE2 ). Additionally, transforming growth factor (TGF)-?1 production from hUCB-MSCs in response to interleukin-4 contributed to the attenuation of MC degranulation by downregulating Fc?RI expression in MCs. In conclusion, the subcutaneous application of NOD2-activated hUCB-MSCs can efficiently ameliorate AD, and MSC-derived PGE2 and TGF-?1 are required for the inhibition of MC degranulation. PMID:25522163

  5. Oxidative requirement for degranulation of human peripheral blood eosinophils.

    PubMed Central

    Baskar, P; Pincus, S H

    1988-01-01

    Eosinophils possess both oxygen-dependent and oxygen-independent mechanisms for damaging helminthic parasites such as schistosomula. We have studied the release of the granular enzymes beta-glucuronidase and arylsulfatase to evaluate the oxidative requirement for degranulation. Both ionophore-mediated and immunoglobulin G-mediated release of granular enzymes were enhanced in the presence of oxygen (P less than or equal to 0.05). Calcium ionophore-mediated degranulation under aerobic conditions was reduced by the addition of the degradative enzymes catalase and superoxide dismutase, suggesting that active oxygen products enhance degranulation. In contrast, oxygen products did not appear to contribute to degranulation induced by immunoglobulin G-coated beads. PMID:2840397

  6. Munc18-2 and Syntaxin 3 control distinct essential steps in mast cell degranulation1

    PubMed Central

    Vita, Francesca; Soranzo, Maria Rosa; Claver, Julien; Madjene, Lydia Celia; Attout, Tarik; Vitte, Joana; Varin-Blank, Nadine; Zabucchi, Giuliano; Rivera, Juan; Blank, Ulrich

    2013-01-01

    Mast cell degranulation requires N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs)6 and mammalian unc18 (Munc18) fusion accessory proteins for membrane fusion. However, it is still unknown how their interaction supports fusion. Here we found that siRNA-mediated silencing of the isoform Munc18-2 in mast cells inhibits cytoplasmic secretory granule (SG) release but not CCL2 chemokine secretion. Silencing of its SNARE binding partner Syntaxin 3 (STX3) also markedly inhibited degranulation, while combined knock-down produced an additive inhibitory effect. Strikingly, while Munc18-2 silencing impaired SG translocation, silencing of STX3 inhibited fusion demonstrating unique roles of each protein. Immunogold studies showed that both Munc18-2 and STX3 are located on the granule surface, but also within the granule matrix and in small nocodazole-sensitive clusters of the cytoskeletal meshwork surrounding SG. After stimulation clusters containing both effectors were detected at fusion sites. In resting cells, Munc18-2, but not STX3, interacted with tubulin. This interaction was sensitive to nocodazole treatment and decreased after stimulation. Our results indicate that Munc18-2 dynamically couples the membrane fusion machinery to the microtubule cytoskeleton and demonstrate that Munc18-2 and STX3 perform distinct, but complementary, functions to support, respectively, SG translocation and membrane fusion in mast cells. PMID:24323579

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

    SciTech Connect

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

    2010-01-22

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

  8. Randomized controlled observer-blinded treatment of chronic foot eczema with iontophoresis and bath-PUVA.

    PubMed

    Tupker, Ron A; Coenraads, Pieter J; Zanen, Pieter; Schuttelaar, Marie Louise A

    2013-07-01

    The aim of this study was to investigate the effect of iontophoresis combined with local psoralen plus ultraviolet A (PUVA) therapy in chronic foot eczema. A randomized, observer-blinded, multi-centre study was conducted in 48 patients with chronic moderate-to-severe foot eczema randomized to one of 3 groups: In the iontophoresis group local bath-PUVA was preceded by iontophoresis. In the PUVA group only local PUVA was given. The corticosteroid group was treated with fluticasone. All treatments were given for 8 weeks, with an 8-week follow-up period. The primary efficacy parameter was eczema score described by Rosén et al. Secondary efficacy parameters were a global impression by the patient, and the Dermatology Life Quality Index (DLQI). The eczema score and the DLQI decreased significantly over time. There were no significant differences in the decrease in eczema score (p=0.053) and DLQI values (p=0.563) between the 3 treatments. The DLQI values in our chronic foot eczema patients were high. There was no obvious advantage of local bath-PUVA with or with-out iontophoresis over local steroid therapy. PMID:23420314

  9. Silver nanoparticle-induced degranulation observed with quantitative phase microscopy

    NASA Astrophysics Data System (ADS)

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

    2010-07-01

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

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

    PubMed Central

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

    2014-01-01

    Galectin-9 (Gal-9), a lectin having a ?-galactoside-binding domain, can induce apoptosis of Th1 cells by binding to TIM-3. In addition, Gal-9 inhibits IgE/Ag-mediated degranulation of mast cell/basophilic cell lines by binding to IgE, thus blocking IgE/Ag complex formation. However, the role of Gal-9 in mast cell function in the absence of IgE is not fully understood. Here, we found that recombinant Gal-9 directly induced phosphorylation of Erk1/2 but not p38 MAPK in a human mast cell line, HMC-1, which does not express Fc?RI. Gal-9 induced apoptosis and inhibited PMA/ionomycin-mediated degranulation of HMC-1 cells. On the other hand, Gal-9 induced cytokine and/or chemokine production by HMC-1 cells, dependent on activation of ERK1/2 but not p38 MAPK. In addition, the lectin activity of Gal-9 was required for Gal-9-mediated cytokine secretion by HMC-1 cells. These observations suggest that Gal-9 has dual properties as both a regulator and an activator of mast cells. PMID:24465902

  11. Aspergillus fumigatus Induces Immunoglobulin E–Independent Mast Cell Degranulation

    Microsoft Academic Search

    Mirjam Urb; Philippe Pouliot; Martin Olivier

    2009-01-01

    Background. Pulmonary colonization by Aspergillus fumigatus in chronic lung disease is associated with pro- gressive decline in lung function even in the absence of specific allergic response. We hypothesized that A. fumigatus contributes to this decline by inducing pulmonary mast cell degranulation even in the absence of antigen-specific immunoglobulin E (IgE). Therefore, we investigated whether A. fumigatus can induce mast

  12. PUVA-induced Repigmentation of Vitiligo: Scanning Electron Microscopy of Hair Follicles

    Microsoft Academic Search

    J. P. Ortonne; D. Schmitt; J. Thivolet

    1980-01-01

    PUVA-induced repigmentation of vitiligo was studied using both the split-dopa reaction and scanning electron microscopy. Proliferation of hypertrophic, Dopa-positive melanocytes were observed in the lower portion of some hair follicles, whereas other giant melanocytes were observed along the middle portion. The existence of a melanocyte reservoir in human hair follicles is postulated.

  13. Flow cytometric detection of degranulation reveals phenotypic heterogeneity of degranulating CMV-specific CD8+ T lymphocytes in rhesus macaques

    PubMed Central

    Chan, Kenneth S.; Kaur, Amitinder

    2007-01-01

    Flow-cytometric conditions for detection of lysosomal-associated membrane proteins (LAMPs) on the surface of recently degranulated cells were optimized for rhesus macaques and used to investigate the functional properties of rhesus cytomegalovirus (rhCMV)-specific CD8+ T lymphocytes with regards to cytotoxicity and interferon (IFN)-? secretion in six asymptomatic CMV-seropositive rhesus macaques. Unlike humans, the rhesus macaque LAMP-1 protein CD107a underwent little or no endocytosis over a six to 18 hour stimulation period. Following in vitro stimulation, rhCMV-specific CD8+ T lymphocytes were heterogeneous with regards to the composition of cells positive for CD107a and/or IFN-?, time to reach peak degranulation, and kinetics of IFN-? secretion relative to degranulation. Responder CD8+ T lymphocytes that underwent degranulation without IFN-? production (CD107a+IFN-??) were predominantly composed of terminally differentiated effectors (CD28?CD45RA+). Moreover, they had significantly lower frequencies of effector memory (CD28?CD45RA?) cells compared to the IFN-?-secreting cells that did or did not undergo degranulation (CD107a+IFN-?+ or CD107a?IFN-?+). The perforin content of effector CD8+ T lymphocytes was significantly greater than that of effector memory CD8+ T lymphocytes in rhesus macaques, suggesting that they were more cytolytic. Our findings suggest that the composition of rhCMV-specific CD8+ T lymphocytes with regards to CD107a+IFN-?? responders may be an important determinant of their ability to control CMV replication. PMID:17628586

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

    NASA Astrophysics Data System (ADS)

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

    1994-07-01

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

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

    SciTech Connect

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

    1985-04-01

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

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

    SciTech Connect

    Bredberg, A.

    1981-06-01

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

  17. DNA Damage in Human Skin Fibroblasts Exposed to UVA Light Used in Clinical PUVA Treatment

    Microsoft Academic Search

    Anders Bredberg

    1981-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2009-08-01

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

  19. 'High single-dose' European PUVA regimen also causes an excess of non-melanoma skin cancer.

    PubMed

    Bruynzeel, I; Bergman, W; Hartevelt, H M; Kenter, C C; Van de Velde, E A; Schothorst, A A; Suurmond, D

    1991-01-01

    We report the results of a long-term (12.8 years) follow-up study of the detection of malignant and benign skin tumours in patients with psoriasis, who were treated with PUVA according to the European, 'high single-dose' regimen. A total of 13 squamous cell carcinomas (SCC) and 24 basal cell carcinomas (BCC) were diagnosed in 11 of 260 patients. The incidence of both SCC and BCC was increased in comparison with the general Dutch population. The ratio of SCC to BCC in the general population was 1:8 but was 1:2.5 in our study group. A positive correlation was observed between the development of SCC and the total UVA dosage, the age of the patient at the start of the PUVA treatment and a history of arsenic use. This dose-related increase in the incidence of SCC, reported in studies from the U.S.A., has not been found in earlier European studies. The average time period between the start of PUVA therapy and the diagnosis of the first malignant skin tumour was 6.0 years for SCC and 4.7 years for BCC. Among the 49 benign skin tumours were actinic keratoses, a keratoacanthoma and 'PUVA keratoses', a newly described hyperkeratotic lesion, especially found in PUVA-treated patients. PMID:1993145

  20. Molecular Mechanisms of N-Formyl-Methionyl-Leucyl-Phenylalanine-Induced Superoxide Generation and Degranulation in Mouse Neutrophils: Phospholipase D Is Dispensable

    PubMed Central

    Sato, Takanobu; Hongu, Tsunaki; Sakamoto, Megumi; Funakoshi, Yuji

    2013-01-01

    Phospholipase D (PLD), which produces the lipid messenger phosphatidic acid (PA), has been implicated in superoxide generation and degranulation in neutrophils. The basis for this conclusion is the observation that primary alcohols, which interfere with PLD-catalyzed PA production, inhibit these neutrophil functions. However, off-target effects of primary alcohols cannot be totally excluded. Here, we generated PLD?/? mice in order to reevaluate the involvement of PLD in and investigate the molecular mechanisms of these neutrophil functions. Surprisingly, N-formyl-methionyl-leucyl-phenylalanine (fMLP) induced these functions in PLD?/? neutrophils, and these functions were suppressed by ethanol. These results indicate that PLD is dispensable for these neutrophil functions and that ethanol nonspecifically inhibits them, warning against the use of primary alcohols as specific inhibitors of PLD-mediated PA formation. The calcium ionophore ionomycin and the membrane-permeative compound 1-oleoyl-2-acetyl-sn-glycerol (OADG) synergistically induced superoxide generation. On the other hand, ionomycin alone induced degranulation, which was further augmented by OADG. These results demonstrate that conventional protein kinase C (cPKC) is crucial for superoxide generation, and a Ca2+-dependent signaling pathway(s) and cPKC are involved in degranulation in mouse neutrophils. PMID:23109426

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

    SciTech Connect

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

    2012-01-01

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

  2. CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction

    PubMed Central

    Gri, Giorgia; Piconese, Silvia; Frossi, Barbara; Manfroi, Vanessa; Merluzzi, Sonia; Tripodo, Claudio; Viola, Antonella; Odom, Sandra; Rivera, Juan; Colombo, Mario P.; Pucillo, Carlo E.

    2008-01-01

    Summary CD4+CD25+ T regulatory cells (Tregs) play a central role in the suppression of immune responses thus serving to induce tolerance and to control persistent immune responses that can lead to autoimmunity. Here we explore if Tregs also play a role in controlling the immediate hypersensitivity response of mast cells (MCs). Tregs directly inhibit the Fc?RI-dependent degranulation of MCs through cell-cell contact involving OX40-OX40L interactions between Tregs and MCs, respectively. MCs show increased cAMP levels and reduced Ca2+ influx, independent of PLC-?2 or Ca2+ release from intracellular stores. Antagonism of cAMP in MCs reverses the inhibitory effects of Tregs restoring normal Ca2+ responses and degranulation. Importantly, the in vivo depletion or inactivation of Tregs causes enhancement of the anaphylactic response. The demonstrated cross-talk between Tregs and MCs defines a previously unrecognized mechanism controlling MCs degranulation. Loss of this interaction may contribute to the severity of allergic responses. PMID:18993084

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

    SciTech Connect

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

    1990-07-01

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

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

    Microsoft Academic Search

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

    1998-01-01

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

  5. Studies on the Specific Degranulation of Mast Cell Sensitized by Several Allergens in Vitro

    PubMed Central

    Guo, Yongchao; Li, Zhenxing; Lin, Hong; Samee, Haider; Khalid, Jamil

    2009-01-01

    Food allergy is a major health issue worldwide. Mast cells play a very important role in the immediate hypersensitivity for which mast cell degranulation needs to be studied extensively. In this study, an approach was taken to study the characteristics of sensitized mast cell degranulation in vitro, which associated with the study of mast cells and animal models. BALB/c mice were immunized respectively by several food allergens, then blood and peritoneal mast cells were collected at different time points. A dynamic determination was carried out between mast cells and serumal IgE. Comparative analysis on sequential time points showed that there was a close coincidence between mast cell degranulation and IgE antibody titers in sensitized BALB/c mice. Furthermore, it is interesting that sensitized mast cells could implement specific degranulation against the challenges in vitro, but the closely tropomyosins induced mast cell degranulation displayed cross reactions. This is very similar to IgE resisting the allergens in vivo. The study disclosed some characteristics on mast cells, coming from sensitized BALB/c mice, degranulation in vitro. PMID:19403066

  6. Suppressive effects of carotenoids on the antigen-induced degranulation in RBL-2H3 rat basophilic leukemia cells.

    PubMed

    Manabe, Yuki; Hirata, Takashi; Sugawara, Tatsuya

    2014-01-01

    In this study, the anti-degranulation effects of fifteen carotenoids were evaluated using RBL-2H3 rat basophilic leukemia cell line as a mast cell model. Nine carotenoids, fucoxanthin, zeaxanthin, ?-carotene, astaxanthin, 3-hydroxyechinenone, fucoxanthinol, lycopene, ?-cryptoxanthin, and siphonaxanthin significantly suppressed antigen-induced mast cell degranulation. Under the same conditions, the cellular carotenoid contents were quantified using high performance liquid chromatography-photodiode array (HPLC-PDA). There was no correlation between the cellular carotenoid contents and their anti-degranulation activities. These results indicate that the differences in the anti-degranulation activities of carotenoids were not related to their uptake by the cells. PMID:24492380

  7. Flow microfluorometric analysis of phagocyte degranulation in bacteria-infected whole human blood cell cultures

    NASA Astrophysics Data System (ADS)

    Kravtsov, Alexander L.; Bobyleva, Elena V.; Grebenyukova, Tatyana P.; Kuznetsov, Oleg S.; Kulyash, Youri V.

    2002-07-01

    A quantitative flow microfluorometric method was used to study the intensity of human blood phagocyte degranulation in response to viable staphylococcus aureus or Yersinia pestis cells. Microorganisms were added directly to defibrinated whole blood. Uninfected and infected blood samples were incubated at 37 degrees C to 8 h. The results were recorded in dynamics after the staining of whole blood with acridine orange solution. Lymphocytes with a low azurophilic granule per cell content were discriminated from phagocytes by the measurement of single cell red cytoplasmic granule fluorescence. 30,000 cells in each sample were examined. S. aureus cells caused a dose-dependent decrease in the number of phagocytes having a high red cytoplasmic fluorescence intensity and a corresponding increase in the weakly fluorescence cell population. In the presence of an initial S. aureus-to-phagocyte ratio more than 1:1, degranulation was measured after 3 h of incubation and to 8 h the percentage of degranulated phagocytes was at least 100 percent Y. pestis cells grown for 48 h at 28 degrees C caused at same condition as the degranulation only about 50 percent of cells. Y.pestis EV cells preincubated in broth for 12 h at 37 degrees C did no stimulate the phahocyte degranulation. The results of these studies suggest that analysis of cell populations via flow microfluorimeter technology may be a powerful tool in analysis bacterial infection.

  8. A Combination of Screening and Computational Approaches for the Identification of Novel Compounds That Decrease Mast Cell Degranulation.

    PubMed

    McShane, Marisa P; Friedrichson, Tim; Giner, Angelika; Meyenhofer, Felix; Barsacchi, Rico; Bickle, Marc; Zerial, Marino

    2015-07-01

    High-content screening of compound libraries poses various challenges in the early steps in drug discovery such as gaining insights into the mode of action of the selected compounds. Here, we addressed these challenges by integrating two biological screens through bioinformatics and computational analysis. We screened a small-molecule library enriched in amphiphilic compounds in a degranulation assay in rat basophilic leukemia 2H3 (RBL-2H3) cells. The same library was rescreened in a high-content image-based endocytosis assay in HeLa cells. This assay was previously applied to a genome-wide RNAi screen that produced quantitative multiparametric phenotypic profiles for genes that directly or indirectly affect endocytosis. By correlating the endocytic profiles of the compounds with the genome-wide siRNA profiles, we identified candidate pathways that may be inhibited by the compounds. Among these, we focused on the Akt pathway and validated its inhibition in HeLa and RBL-2H3 cells. We further showed that the compounds inhibited the translocation of the Akt-PH domain to the plasma membrane. The approach performed here can be used to integrate chemical and functional genomics screens for investigating the mechanism of action of compounds. PMID:25838434

  9. Tocotrienol (unsaturated vitamin E) suppresses degranulation of mast cells and reduces allergic dermatitis in mice.

    PubMed

    Tsuduki, Tsuyoshi; Kuriyama, Keiko; Nakagawa, Kiyotaka; Miyazawa, Teruo

    2013-01-01

    In this study, we examined whether tocotrienol (T3) reduces allergic dermatitis in mice and suppresses degranulation of mast cells. First, allergic dermatitis was examined in the atopic dermatitis model NC/Nga mouse. Allergic dermatitis was induced using picryl chloride in mice with and without administration of T3 (1 mg/day/mouse). Increases in scratching behavior, dermal thickening, and the serum histamine level were greatly reduced in mice treated with T3, indicating that T3 reduces allergic dermatitis in vivo. Next, the effect of T3 on degranulation of mast cells was examined, since these cells release bioactive substances such as histamine. T3 significantly suppressed degranulation of mast cells and significantly reduced histamine release. The effect of T3 on protein kinase C (PKC) activity was also measured, since suppression of this activity may be associated with the mechanism underlying the antidegranulation effect of T3. T3 significantly suppressed PKC activity. Therefore, we conclude that T3 suppresses degranulation of mast cells and reduces allergic dermatitis in mice through reduction of PKC activity. PMID:24088520

  10. Diesel exhaust particulates enhance eosinophil adhesion to nasal epithelial cells and cause degranulation.

    PubMed

    Terada, N; Maesako, K; Hiruma, K; Hamano, N; Houki, G; Konno, A; Ikeda, T; Sai, M

    1997-10-01

    Diesel exhaust particulates (DEP) are a common air pollutant from diesel-engine-powered car exhaust and are thought to cause chronic airway diseases. On the other hand, eosinophils are major components of allergic inflammatory disorders such as asthma, nasal allergy and atopic dermatitis. We examined the effects of DEP and DEP extract (extract of polyaromatic hydrocarbons) on eosinophil adhesion, survival rate and degranulation. Eosinophils, human mucosal microvascular endothelial cells (HMMECs) and human nasal epithelial cells (HNECs) were preincubated in the presence or absence of DEP and DEP extract. 35S-labeled eosinophils were allowed to adhere to monolayers of HMMECs and HNECs. After washing, 35S radioactivity was determined and numbers of adherent eosinophils were calculated using each standard curve. The effects of DEP and DEP extract on eosinophil survival rate and degranulation were also determined. Although neither DEP nor DEP extract affected the adhesiveness of HMMECs and HNECs to eosinophils, 5 ng/ml of DEP extract and 50 ng/ml of DEP extract each significancy increased eosinophil adhesiveness to HNECs (134+/-9 and 143+/-8%, respectively; p<0.01 vs. control), but neither effected eosinophil adhesiveness to HMMECs. DEP extract also induced eosinophil degranulation without changing the eosinophil survival rate. Given that eosinophil-derived lipid mediators and toxic proteins play important roles in the development of nasal allergy, the above findings strongly suggest that DEP plays an important role in promoting the nasal hypersensitivity induced by enhanced eosinophil infiltration of epithelium and eosinophil degranulation. PMID:9338611

  11. Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation

    PubMed Central

    Siegel, Andrea M.; Stone, Kelly D.; Cruse, Glenn; Lawrence, Monica G.; Olivera, Ana; Jung, Mi-yeon; Barber, John S.; Freeman, Alexandra F.; Holland, Steven M.; O’Brien, Michelle; Jones, Nina; Wisch, Laura B.; Kong, Heidi H.; Desai, Avanti; Farber, Orly; Gilfillan, Alasdair M.; Rivera, Juan; Milner, Joshua D.

    2013-01-01

    Background Severe atopic conditions associated with elevated serum IgE are heterogeneous with few known causes. Nearly every patient with autosomal-dominant hyper-IgE syndrome (AD-HIES) due to signal transducer and activator of transcription 3 (STAT3) mutations has a history of eczematous dermatitis and elevated IgE; however, clinical atopy has never been systematically studied. Objective Understanding of genetic determinants of allergic disease may lead to novel therapies in controlling allergic disease. Methods We conducted clinical evaluation of the rates of food allergies and anaphylaxis in patients with AD-HIES, a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis, and healthy volunteers with no history of atopy. Morphine skin prick testing, ImmunoCAP assays for allergen-specific IgE, and basophil activation were measured. A model of systemic anaphylaxis was studied in transgenic mice carrying an AD-HIES mutation. STAT3 was silenced in LAD2 and primary human mast cells to study the role of STAT3 in signaling and degranulation after IgE cross-linking. Results Food allergies and anaphylaxis were markedly diminished in patients with AD-HIES compared with a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis. Morphine skin prick testing and basophil activation were diminished in patients with AD-HIES, whereas mice carrying an AD-HIES mutation were hyporesponsive to systemic anaphylaxis models. Rapid mast cell STAT3 serine727 phosphorylation was noted after IgE cross-linking, and inhibition of STAT3 signaling in mast cells lead to impaired Fc?RI-mediated proximal and distal signaling, as well as reduced degranulation. Conclusion This study serves as an example for how mutations in specific atopic pathways can lead to discrete allergic phenotypes, encompassing increased risk of some phenotypes but a relative protection from others. PMID:24184145

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

    PubMed Central

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

    2004-01-01

    Background Broad-band UVA, long-wave UVA1 and PUVA treatment have been described as an alternative/adjunct therapeutic option in a number of inflammatory and malignant skin diseases. Nevertheless, controlled studies investigating the efficacy of UVA irradiation in connective tissue diseases and related disorders are rare. Methods Searching the PubMed database the current article systematically reviews established and innovative therapeutic approaches of broad-band UVA irradiation, UVA1 phototherapy and PUVA photochemotherapy in a variety of different connective tissue disorders. Results Potential pathways include immunomodulation of inflammation, induction of collagenases and initiation of apoptosis. Even though holding the risk of carcinogenesis, photoaging or UV-induced exacerbation, UVA phototherapy seems to exhibit a tolerable risk/benefit ratio at least in systemic sclerosis, localized scleroderma, extragenital lichen sclerosus et atrophicus, sclerodermoid graft-versus-host disease, lupus erythematosus and a number of sclerotic rarities. Conclusions Based on the data retrieved from the literature, therapeutic UVA exposure seems to be effective in connective tissue diseases and related disorders. However, more controlled investigations are needed in order to establish a clear-cut catalogue of indications. PMID:15380024

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

    Microsoft Academic Search

    Anne-Marie Coelho; Jean Fioramonti; Lionel Bueno

    1998-01-01

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

  14. Evaluation of PUVA-Induced Skin Side Effects in Patients Referred to the Imam Reza Hospital of Mashhad in 2005-2007

    PubMed Central

    Maleki, Masoud; Yazdanpanah, Mohammad Javad; Hamidi, Hamid; Jokar, Leila

    2014-01-01

    Background: Systemic oral psoralens plus UVA therapy (PUVA) is a therapeutic method used with considerable success in many different skin disorders. PUVA therapy causes some cutaneous and noncutaneous side effects and in the present research we deal with cutaneous side effects. Aims: Evaluation of patients to know the different skin side effects of PUVA and their importance. Materials and Methods: All patients referred to the phototherapy unit of Imam Reza Hospital of Mashhad entered the research and skin examination was taken place initially and every 3 months thereafter. Whenever any side effect appeared, it was recorded in the information sheet. Results: One hundred and twenty-eight patients were included in the research, 61 were male between 15 and 75 years and 67 were female between 10 and 61 years of age. Age of female patients at the time of cutaneous side effect appearance was less than male patients. The most common early side effect was pruritus (34.3%) and the rarest was telangiectasia (0.7%). One case of late side effect in the form of squamous cell carcinoma was observed in a patient who had received other carcinogenic drugs as well. Complications such as skin dryness, pruritus, erythema and burning sensation occurred at low doses of UVA, while dermatitis, severe limb pain and acne at moderate doses and PUVA lentigines, hypertrichosis and lichenoid lesions appeared at high doses of UVA. Conclusion: Considering the significant therapeutic effects and few serious side effects, PUVA therapy is a suitable and safe method for treatment of certain skin diseases. PMID:24700955

  15. Stimulation of neutrophil actin polymerization and degranulation by opsonized and unopsonized Candida albicans hyphae and zymosan.

    PubMed Central

    Kolotila, M P; Diamond, R D

    1988-01-01

    We previously showed that unopsonized Candida albicans hyphae stimulated a delayed rise in the putative neutrophil second messengers Ca2+ and inositol 1,4,5-trisphosphate and subsequent O2- release, as compared with opsonized hyphae or zymosan. Therefore, cytoskeletal and degranulation temporal responses to these stimuli were examined. Unopsonized zymosan elicited no neutrophil responses under the experimental condition used. Neutrophil actin polymerization (quantitated by fluorescent measurements of NBD phallacidin) was rapid after stimulation by opsonized hyphae or zymosan (peaking at 1 and 2 min, respectively). This corresponded to observed changes in microscopic actin polymerization, measured with rhodamine phalloidin, which progressed from initially diffuse to collarlike to cylinderlike staining patterns surrounding the hyphae. Compared with opsonized hyphae, unopsonized hyphae resulted in a delayed appearance of the last two visible patterns (P less than 0.05) and in quantitative actin polymerization despite similarly rapid initial contact and spreading over the hyphae by neutrophils. Unlike other neutrophil responses, degranulation did not follow the delayed patterns of responses to stimulation with unopsonized hyphae. In the absence of the release of the cytoplasmic marker lactate dehydrogenase, the release of beta-glucuronidase, an azurophil granule marker, gradually and progressively rose in response to all of the stimuli but unopsonized zymosan. The low but significant levels observed were within a range consistent with published results for degranulation responses to particulate stimuli without cytochalasin B. A quantitative immunoassay of lactoferrin, a specific granule marker, detected no release into supernatants, and immunofluorescent staining indicated concomitant depletion of lactoferrin from neutrophil granules and binding to hyphal and neutrophil surfaces after stimulation by unopsonized hyphae. Thus, the delayed actin polymerization response to unopsonized hyphae occurred subsequent to neutrophil attachment and spreading and resembled the temporal sequence of other neutrophil responses linked to the respiratory burst. In contrast, the degranulation responses to all stimuli appeared to begin and progress gradually after observed attachment and spreading of the neutrophil over hyphal surfaces without a clear temporal relationship to rises in cytoplasmic Ca2+ or F-actin. In addition, the avid binding of released lactoferrin to cell surfaces eliminates its value as a quantitative marker of enzyme release but raises the possibility that it might participate in fungicidal activity.(ABSTRACT TRUNCATED AT 400 WORDS) Images PMID:3294183

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

    Microsoft Academic Search

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

    1998-01-01

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

  17. Hydroxycarbamide reduces eosinophil adhesion and degranulation in sickle cell anaemia patients.

    PubMed

    Pallis, Flavia Rubia; Conran, Nicola; Fertrin, Kleber Yotsumoto; Olalla Saad, Sara Terezinha; Costa, Fernando Ferreira; Franco-Penteado, Carla Fernanda

    2014-01-01

    Inflammation, leucocyte and red cell adhesion to the endothelium contribute to the pathogenesis of sickle cell anaemia. Neutrophils appear to be important for vaso-occlusion, however, eosinophils may also participate in this phenomenon. The role of eosinophils in the pathophysiology of sickle cell anaemia (SCA) and the effect of hydroxycarbamide (HC) therapy on the functional properties of these cells are not understood. Patients with SCA and those on HC therapy (SCAHC) were included in the study. SCAHC individuals presented significantly lower absolute numbers of eosinophils than SCA. Furthermore, SCAHC eosinophils demonstrated significantly lower adhesive properties, compared to SCA eosinophils. SCA and SCAHC eosinophils presented greater spontaneous migration when compared with control eosinophils. Baseline eosinophil peroxidase and reactive oxygen species release was higher for SCA individuals than for control individuals, as were plasma levels of eosinophil derived neurotoxin. SCAHC eosinophil degranulation was lower than that of SCA eosinophil degranulation. Eotaxin-1 and RANTES levels were higher in the plasma of SCA and SCAHC individuals, when compared with controls. These data suggest that eosinophils exist in an activated state in SCA and indicate that these cells play a role in the vaso-occlusive process. The exact mechanism by which HC may alter SCA eosinophil properties is not clear. PMID:24383847

  18. Overhauser-Enhanced MRI of Elastase Activity from In Vitro Human Neutrophil Degranulation

    PubMed Central

    Parzy, Elodie; Bouchaud, Véronique; Massot, Philippe; Voisin, Pierre; Koonjoo, Neha; Moncelet, Damien; Franconi, Jean-Michel; Thiaudière, Eric; Mellet, Philippe

    2013-01-01

    Background Magnetic resonance imaging can reveal exquisite anatomical details. However several diseases would benefit from an imaging technique able to specifically detect biochemical alterations. In this context protease activity imaging is one of the most promising areas of research. Methodology/Principal Findings We designed an elastase substrate by grafting stable nitroxide free radicals on soluble elastin. This substrate generates a high Overhauser magnetic resonance imaging (OMRI) contrast upon digestion by the target proteases through the modulation of its rotational correlation time. The sensitivity is sufficient to generate contrasted images of the degranulation of neutrophils induced by a calcium ionophore from 2×104 cells per milliliter, well under the physiological neutrophils concentrations. Conclusions/Significance These ex-vivo experiments give evidence that OMRI is suitable for imaging elastase activity from neutrophil degranulation. Provided that a fast protease-substrate is used these results open the door to better diagnoses of a number of important pathologies (cystic fibrosis, inflammation, pancreatitis) by OMRI or Electron Paramagnetic Resonance Imaging in vivo. It also provides a long-expected method to monitor anti-protease treatments efficiency and help pharmaceutical research. PMID:23469112

  19. Syntaxin 11 is required for NK and CD8? T-cell cytotoxicity and neutrophil degranulation.

    PubMed

    D'Orlando, Orietta; Zhao, Fang; Kasper, Brigitte; Orinska, Zane; Müller, Jürgen; Hermans-Borgmeyer, Irm; Griffiths, Gillian M; Zur Stadt, Udo; Bulfone-Paus, Silvia

    2013-01-01

    Syntaxin 11 (STX11) controls vesicular trafficking and is a key player in exocytosis. Since Stx11 mutations are causally associated with a familial hemophagocytic lymphohistio-cytosis, we wanted to clarify whether STX11 is functionally important for key immune cell populations. This was studied in primary cells obtained from newly generated Stx11(-/-) mice. Our data revealed that STX11 is not only widely expressed in different immune cells, but also induced upon LPS or IFN-? treatment. However, Stx11 deficiency does not affect macrophage phagocytic function and cytokine secretion, mast cell activation, or antigen presentation by DCs. Instead, STX11 selectively controls lymphocyte cytotoxicity in NK and activated CD8(+) T cells and degranulation in neutrophils. Stx11(-/-) NK cells and CTLs show impaired degranulation, despite a comparable activation, maturation and expression of the complex-forming partners MUNC18-2 and VTI1B. In addition, Stx11(-/-) CTLs and NK cells produce abnormal levels of IFN-?. Since functional reconstitution rescues the defective phenotype of Stx11(-/-) CTLs, we suggest a direct, specific and key role of STX11 in controlling lymphocyte cytotoxicity, cytokine production and secretion. Finally, we show that these mice are a very useful tool for dissecting the role of STX11 in vesicular trafficking and secretion. PMID:23042080

  20. p21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics

    PubMed Central

    Allen, Jayme D.; Jaffer, Zahara M.; Park, Su-Jung; Burgin, Sarah; Hofmann, Clemens; Sells, Mary Ann; Chen, Shi; Derr-Yellin, Ethel; Michels, Elizabeth G.; McDaniel, Andrew; Bessler, Waylan K.; Ingram, David A.; Atkinson, Simon J.; Travers, Jeffrey B.

    2009-01-01

    Mast cells are key participants in allergic diseases via activation of high-affinity IgE receptors (Fc?RI) resulting in release of proinflammatory mediators. The biochemical pathways linking IgE activation to calcium influx and cytoskeletal changes required for intracellular granule release are incompletely understood. We demonstrate, genetically, that Pak1 is required for this process. In a passive cutaneous anaphylaxis experiment, Wsh/Wsh mast cell–deficient mice locally reconstituted with Pak1?/? bone marrow–derived mast cells (BMMCs) experienced strikingly decreased allergen-induced vascular permeability compared with controls. Consistent with the in vivo phenotype, Pak1?/? BMMCs exhibited a reduction in Fc?RI-induced degranulation. Further, Pak1?/? BMMCs demonstrated diminished calcium mobilization and altered depolymerization of cortical filamentous actin (F-actin) in response to Fc?RI stimulation. These data implicate Pak1 as an essential molecular target for modulating acute mast cell responses that contribute to allergic diseases. PMID:19124833

  1. Degranulating Stimuli Decrease the Negative Surface Charge and Increase the Adhesiveness of Human Neutrophils

    PubMed Central

    Gallin, John I.

    1980-01-01

    Chemotactic factors decrease the negative surface charge of neutrophils (polymorphonuclear leukocytes [PMN]) and this has been speculated to be important in PMN margination and aggregation in vivo. PMN adherence and aggregation are also enhanced by degranulation of lysosomal enzymes. To further assess the possible relationship between degranulation, surface charge, adherence, and aggregation, human peripheral blood PMN (isolated by Hypaque-Ficoll and dextran sedimentation) were exposed to the secretagogues ionophore A23187, phorbol myristate acetate, concanavalin A, and chemotactic factors (partially purified C5a or the synthetic peptide f-met-leu-phe) plus cytochalasin B. Surface charge was measured in a cytopherometer. After incubation of PMN with secretagogues, PMN surface charge was decreased to a greater extent than incubation of PMN with chemotactic factors. The decreased surface charge induced by f-met-leu-phe plus cytochalasin B required both extracellular calcium and magnesium. The ionophore A23187-induced surface charge changes were dependent on extracellular calcium but not magnesium whereas the phorbol myristate acetate effect was only partially dependent on Ca++ and Mg++. The surface charge changes induced by secretagogues were related to both the amount of lysozyme released and to the increased adhesiveness of cells to plastic surfaces. These observations indicate exocytosis of lysosomal granule contents is associated with decreases in neutrophil surface charge, and there appears to be a correlation between decreases in surface charge and facilitation of neutrophil aggregation and adhesiveness. However, a causal relationship between these events has not been established, and the relationship may be simply temporal. PMID:6243307

  2. Hemichannels Are Required for Amyloid ?-Peptide-Induced Degranulation and Are Activated in Brain Mast Cells of APPswe/PS1dE9 Mice.

    PubMed

    Harcha, Paloma A; Vargas, Aníbal; Yi, Chenju; Koulakoff, Annette A; Giaume, Christian; Sáez, Juan C

    2015-06-24

    Mast cells (MCs) store an array of proinflammatory mediators in secretory granules that are rapidly released upon activation by diverse conditions including amyloid beta (A?) peptides. In the present work, we found a rapid degranulation of cultured MCs through a pannexin1 hemichannel (Panx1 HC)-dependent mechanism induced by A?25-35 peptide. Accordingly, A?25-35 peptide also increased membrane current and permeability, as well as intracellular Ca(2+) signal, mainly via Panx1 HCs because all of these responses were drastically inhibited by Panx1 HC blockers and absent in the MCs of Panx1(-/-) mice. Moreover, in acute coronal brain slices of control mice, A?25-35 peptide promoted both connexin 43 (Cx43)- and Panx1 HC-dependent MC dye uptake and histamine release, responses that were only Cx43 HC dependent in Panx1(-/-) mice. Because MCs have been found close to amyloid plaques of patients with Alzheimer's disease (AD), their distribution in brain slices of APPswe/PS1dE9 mice, a murine model of AD, was also investigated. The number of MCs in hippocampal and cortical areas increased drastically even before amyloid plaque deposits became evident. Therefore, MCs might act as early sensors of amyloid peptide and recruit other cells to the neuroinflammatory response, thus playing a critical role in the onset and progression of AD. PMID:26109673

  3. Degranulation of mast cells in the trachea and bronchi of the rat following stimulation of the vagus nerve.

    PubMed

    Kiernan, J A

    1990-01-01

    In the trachea and bronchi of the atropinized rat, the proportion of degranulating mast cells (defined as having one or more granules outside the body of the cell in a 10-microns thick section) was increased from 35-40% to 48-55% following electrical stimulation of one or both vagus nerves for 3 min. The increase occurred bilaterally, though it was greater on the stimulated side. The degranulation of mast cells was prevented by transection of the nerve rostral to the nodose ganglion 8-10 days before stimulation. Pre-treatment of rats with capsaicin also prevented the degranulation of mast cells that otherwise would have followed stimulation of the vagus nerve. These observations indicate that tracheo-bronchial mast cells discharge their granules in response to the activity of capsaicin-sensitive axons of neurons whose cell bodies are rostral to the nodose ganglion. These are probably substance P-containing polymodal nociceptive neurons of the jugular ganglion. If similar neurons exist in man, axon reflexes in their intrabronchial branches would be expected to stimulate the release of mast cell-derived agents that cause bronchoconstriction in asthma. PMID:2210875

  4. Early CD8 T-cell memory precursors and terminal effectors exhibit equipotent in vivo degranulation.

    PubMed

    Yuzefpolskiy, Yevgeniy; Baumann, Florian M; Kalia, Vandana; Sarkar, Surojit

    2015-07-01

    Early after priming, effector CD8 T cells are distinguished into memory precursor and short-lived effector cell subsets (MPECs and SLECs). Here, we delineated a distinct in vivo heterogeneity in killer cell lectin-like receptor G1 (KLRG-1) expression, which was strongly associated with diverse MPEC and SLEC fates. These in vivo MPECs and SLECs expressed equivalent levels of cytotoxic molecules and effector cytokines. Using a unique in vivo degranulation assay, we found that the MPECs and SLECs similarly encountered infected target cells and elaborated equivalent levels of cytotoxicity in vivo. These data provide direct in vivo evidence that memory-fated cells pass through a robust effector phase. Additionally, the preferential localization of the MPECs in the lymph nodes, where a lesser degree of cytotoxicity was elaborated, suggests that the MPECs may be protected from excessive stimulation and terminal differentiation by virtue of their differential tissue localization. These data provide novel mechanistic insights into the linear decreasing potential model of memory differentiation.Cellular & Molecular Immunology advance online publication, 28 July 2014; doi:10.1038/cmi.2014.48. PMID:25066419

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

    USGS Publications Warehouse

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

    2013-01-01

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

  6. Cyclical mechanical stretch enhances degranulation and IL-4 secretion in RBL-2H3 mast cells.

    PubMed

    Komiyama, Hidenori; Miyake, Koichi; Asai, Kuniya; Mizuno, Kyoichi; Shimada, Takashi

    2014-01-01

    Mast cells are widely distributed in the body and affect their surrounding environment through degranulation and secretion of cytokines. Conversely, mast cells are influenced by environmental stimuli such as cyclical mechanical stretch (CMS), such as that induced by heartbeat and respiration. Peripherally distributed mast cells are surrounded by extracellular matrix, where they bind IgE on their surface by expressing the high-affinity Fc receptor for IgE (Fc?RI), and they release mediators after cross-linking of surface-bound IgE by allergen. To analyse how CMS affects mast cell responses, we examined the effect of applying CMS on the behaviour of IgE-bound mast cells (RBL-2H3 cell line) adhering to fibronectin as a substitute for extracellular matrix. We found that CMS enhanced Fc?RI-mediated secretion in the presence of antigen (2,4-dinitrophenol-bovine serum albumin). CMS increased expression of IL-4 mRNA and secretion of IL-4 protein. Western blot analysis showed that CMS changes the signal transduction in mitogen-activated protein kinases and AKT, which in turn alters the regulation of IL-4 and increases the secretion of IL-4. These results suggest that CMS modulates the effect of mast cells on inflammation and resultant tissue remodelling. Understanding how CMS affects mast cell responses is crucial for developing therapies to treat mast cell-related diseases. PMID:23584980

  7. Degranulated mast cells in the skin of adults with self-injurious behavior and neurodevelopmental disorders.

    PubMed

    Symons, Frank J; Wendelschafer-Crabb, Gwen; Kennedy, William; Heeth, William; Bodfish, James W

    2009-03-01

    The role of nociceptive processes in relation to chronic, tissue-damaging self-injury among individuals with neurodevelopmental disorders is poorly understood. Scientific investigation has been limited, in part, by the clinical reality that the majority of individuals with severe intellectual impairments have co-morbid communicative impairments making it difficult to ascertain information regarding pain. Recently, we found abnormal patterns of peripheral epidermal nerve fiber (ENF) innervation and increased neuropeptide (substance P; SP) content among a subset of individuals with chronic self-injury. Here, we provide initial evidence for peripheral neuro-immune activity specific to self-injury. Skin samples from non-injury body-matched sites were compared between non-verbal adults with and without self-injury matched on gender and disability level. Relative to disability-matched controls, individuals with chronic self-injury had significantly more degranulated mast cells and were more responsive to tactile stimulation during a sensory testing procedure. Thus, nociceptive mechanisms and peripheral afferent sensitization may play a part in mediating and maintaining chronic self-injury. PMID:19084591

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

    PubMed

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

    2013-11-01

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

  9. Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I–associated neurologic disease

    PubMed Central

    Enose-Akahata, Yoshimi; Oh, Unsong; Grant, Christian

    2008-01-01

    CD8+ T cells contribute to central nervous system inflammation in human T-cell lymphotropic virus type I (HTLV-I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP). We analyzed CD8+ T-cell dysfunction (degranulation and IFN-? production) and have demonstrated that CD8+ T cells of patients with HAM/TSP (HAM/TSP patients) spontaneously degranulate and express IFN-? in ex vivo unstimulated culture. CD8+ T cells of HTLV-I asymptomatic carriers and healthy donors did not. Spontaneous degranulation was detected in Tax11-19/HLA-A*201 tetramer+ cells, but not in CMV pp65 tetramer+ cells. Interestingly, degranulation and IFN-? production in CD8+ T cells was induced by coculture with autologous CD14+ cells, but not CD4+ T cells, of HAM/TSP patients, which correlated with proviral DNA load in CD14+ cells of infected patients. Moreover, the expression of IL-15, which induced degranulation and IFN-? production in infected patients, was enhanced on surface of CD14+ cells in HAM/TSP patients. Blockade of MHC class I and IL-15 confirmed these results. Thus, CD8+ T-cell dysregulation was mediated by both virus infection and enhanced IL-15 on CD14+ cells in HAM/TSP patients. Despite lower viral expression than in CD4+ T cells, HTLV-I–infected or –activated CD14+ cells may be a heretofore important but under recognized reservoir particularly in HAM/TSP patients. PMID:18509087

  10. Increased counts and degranulation of duodenal mast cells and eosinophils in functional dyspepsia- a clinical study.

    PubMed

    Song, Shijun; Song, Yan; Zhang, Haishan; Li, Gaiqin; Li, Xiaopei; Wang, Xiaohong; Liu, Zhen

    2015-02-01

    The above article published in Medicinski Glasnik online on 26 June 2014 by the Medical Association of Zenica-Doboj Canton (http://www.ljkzedo.com.ba/index.php/u-sljedecem-broju) and in Volume 11, Issue 2, pages 276-282, has been retracted by agreement between the authors, the journal Editor-in-Chief, Professor Selma Uzunovi?, and the Medical Association of Zenica-Doboj Canton. The reasons for this retraction are as follows: The work reported in the paper was about the role of duodenal eosinophils and mast cells in the pathogenesis of functional dyspepsia. Most of the experiments were carried out by a former member of the authors' team named Yuan Haipeng, who has left the team for more than two years. A high proportion of data in the paper had been reported in the doctoral dissertation of Yuan Haipeng in 2012, and the paper was published without the knowledge or permission of Yuan. Besides the data previously reported in the doctoral dissertation of Yuan Haipeng, the authors calculated the other data in the paper before the submission. However, it has come to the authors' attention that they had made quite a few mistakes due to a loss of the original data, which was not described in details in the dissertation. REFERENCE Shijun Song, Yan Song, Haishan Zhang, Gaiqin Li, Xiaopei Li, Xiaohong Wang, Zhen Liu. Increased counts and degranulation of duodenal mast cells and eosinophils in functional dyspepsia- a clinical study. Med Glas (Zenica) 2014; 11(2):276-82. PMID:25669347

  11. Structure and biological activities of eumenine mastoparan-AF (EMP-AF), a new mast cell degranulating peptide in the venom of the solitary wasp ( Anterhynchium flavomarginatum micado)

    Microsoft Academic Search

    Katsuhiro Konno; Miki Hisada; Hideo Naoki; Yasuhiro Itagaki; Nobufumi Kawai; Akiko Miwa; Tadashi Yasuhara; Yukiko Morimoto; Yoshihiro Nakata

    2000-01-01

    A new mast cell degranulating peptide, eumenine mastoparan-AF (EMP-AF), was isolated from the venom of the solitary wasp Anterhynchium flavomarginatum micado, the most common eumenine wasp found in Japan. The structure was analyzed by FAB-MS\\/MS together with Edman degradation, which was corroborated by solid-phase synthesis. The sequence of EMP-AF, Ile–Asn–Leu–Leu–Lys–Ile–Ala–Lys–Gly–Ile–Ile–Lys–Ser–Leu–NH2, was similar to that of mastoparan, a mast cell degranulating

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

    SciTech Connect

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

    2012-11-01

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

  13. CpG-containing oligodeoxynucleotides induce TNF-a and IL6 production but not degranulation from murine bone marrow-derived mast cells

    Microsoft Academic Search

    Fu-Gang Zhu; Jean S. Marshall

    Mast cells are sentinel cells critical to the initiation of innate immune and inflammatory responses, particularly at mucosal surfaces. To ful- fill this function they can be activated by several pathogen-associated stimuli to produce cytokines with or without concurrent degranulation. We ex- amined the ability of immunostimulatory DNA se- quences including CpG motifs, which are found in increased quantities in

  14. Effects of Thaumetopoea pityocampa (Lepidoptera: Thaumetopoeidae) larvae on the degranulation of dermal mast cells in mice; an electron microscopic study.

    PubMed

    Kalender, Yusuf; Kalender, Suna; Uzunhisarcikli, Meltem; Ogutcu, Ay?e; Açikgoz, Fatma

    2004-01-01

    The pine caterpillar Thaumetopoea pityocampa (Lepidoptera: Thaumetopoeidae) is found in pine woods. Hairs of the T. pityocampa caterpillar cause a cutaneous reaction in humans and animals. Mast cells are responsible for allergic reactions in mammals. In this study male swiss albino mice were divided into two groups: 5 mice in the control group and 25 mice in the experimental group. The dorsal skin of mice was shaved. The mice in the experimental group and T. pityocampa larvae (fifth instar, approximately n=100) were put in the same cage. Dermal mast cells of mice exposed to T. pityocampa were examined with a transmission electron microscope and compared to the control group 1, 3, 6, 12 and 24 hours after exposure. Dermal mast cell degranulation in mice was observed 12 and 24 hours after exposure. PMID:15521642

  15. Human immunoglobulin G potentiates superoxide production induced by chemotactic peptides and causes degranulation in isolated human neutrophils.

    PubMed

    Aaku, E; Sorsa, T; Wilkström, M

    1990-05-01

    Neutrophils are major cellular mediators of host defense and inflammation. They can be activated to produce superoxide and to release the contents of their granules to the extracellular space. We observed that monomeric human immunoglobulin G (IgG) sensitizes these cells to the chemotactic peptide N-formylmethionylleucylphenylalanine (fMLP). In cells submaximally stimulated by fMLP this enhancement was especially prominent. With saturating fMLP concentrations, the rate of O2- production was still about twice that in the control. No synergy with other activators (phorbol myristate acetate, concanavalin A) was observed. Binding of fMLP to the cells was decreased by IgG, resembling the effect of cytochalasin B. IgG did not induce O2- production on its own, but it stimulated degranulation of the neutrophils. PMID:2159345

  16. Thrombomodulin inhibits the activation of eosinophils and mast cells.

    PubMed

    Roeen, Ziaurahman; Toda, Masaaki; D'Alessandro-Gabazza, Corina N; Onishi, Masahiro; Kobayashi, Tetsu; Yasuma, Taro; Urawa, Masahito; Taguchi, Osamu; Gabazza, Esteban C

    2015-01-01

    Eosinophils and mast cells play critical roles in the pathogenesis of bronchial asthma. Activation of both cells leads to the release of pro-inflammatory mediators in the airway of asthmatic patients. Recently, we have shown that inhaled thrombomodulin inhibits allergic bronchial asthma in a mouse model. In the present study, we hypothesize that thrombomodulin can inhibit the activation of eosinophils and mast cells. The effect of thrombomodulin on the activation and release of inflammatory mediators from eosinophils and mast cells was evaluated. Thrombomodulin inhibited the eotaxin-induced chemotaxis, upregulation of CD11b and degranulation of eosinophils. Treatment with thrombomodulin also significantly suppressed the degranulation and synthesis of inflammatory cytokines and chemokines in eosinophils and mast cells. Mice treated with a low-dose of inhaled thrombomodulin have decreased number of eosinophils and activated mast cells and Th2 cytokines in the lungs compared to untreated mice. The results of this study suggest that thrombomodulin may modulate allergic responses by inhibiting the activation of both eosinophils and mast cells. PMID:25497974

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

    PubMed Central

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

    2014-01-01

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

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

    Microsoft Academic Search

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

    2009-01-01

    Sesquiterpene lactones (SQTLs) have been shown to suppress the degranulation as inferred by histamine release in rat basophilic leukemia RBL-2H3 cells. In this study, we isolated the 9 kinds of SQTLs from Eupatorium chinense L. and examined the effects of these SQTLs on the degranulation in RBL-2H3 cells. The chemical structures of two novel compounds (SQTL-3 and 8) were determined.

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

    PubMed

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

    2013-07-31

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

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

    PubMed Central

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

    2006-01-01

    Mast cells are pivotal effector cells in IgE-mediated allergic inflammatory diseases. Central for mast cell activation are signals from the IgE receptor Fc?RI, which induce cell degranulation with the release of preformed mediators and de novo synthesis of proinflammatory leukotrienes and cytokines. How these individual mast cell responses are differentially controlled is still unresolved. We identify B cell lymphoma 10 (Bcl10) and mucosa-associated lymphoid tissue 1 (Malt1) as novel key regulators of mast cell signaling. Mice deficient for either protein display severely impaired IgE-dependent late phase anaphylactic reactions. Mast cells from these animals neither activate nuclear factor ?B (NF-?B) nor produce tumor necrosis factor ? or interleukin 6 upon Fc?RI ligation even though proximal signaling, degranulation, and leukotriene secretion are normal. Thus, Bcl10 and Malt1 are essential positive mediators of Fc?RI-dependent mast cell activation that selectively uncouple NF-?B–induced proinflammatory cytokine production from degranulation and leukotriene synthesis. PMID:16432253

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

    PubMed

    Klemm, Stefanie; Gutermuth, Jan; Hültner, Lothar; Sparwasser, Tim; Behrendt, Heidrun; Peschel, Christian; Mak, Tak W; Jakob, Thilo; Ruland, Jürgen

    2006-02-20

    Mast cells are pivotal effector cells in IgE-mediated allergic inflammatory diseases. Central for mast cell activation are signals from the IgE receptor FcepsilonRI, which induce cell degranulation with the release of preformed mediators and de novo synthesis of proinflammatory leukotrienes and cytokines. How these individual mast cell responses are differentially controlled is still unresolved. We identify B cell lymphoma 10 (Bcl10) and mucosa-associated lymphoid tissue 1 (Malt1) as novel key regulators of mast cell signaling. Mice deficient for either protein display severely impaired IgE-dependent late phase anaphylactic reactions. Mast cells from these animals neither activate nuclear factor kappaB (NF-kappaB) nor produce tumor necrosis factor alpha or interleukin 6 upon FcepsilonRI ligation even though proximal signaling, degranulation, and leukotriene secretion are normal. Thus, Bcl10 and Malt1 are essential positive mediators of FcepsilonRI-dependent mast cell activation that selectively uncouple NF-kappaB-induced proinflammatory cytokine production from degranulation and leukotriene synthesis. PMID:16432253

  2. ADP-ribose/TRPM2-mediated Ca(2+) signaling is essential for cytolytic degranulation and antitumor activity of natural killer cells.

    PubMed

    Rah, So-Young; Kwak, Jae-Yong; Chung, Yun-Jo; Kim, Uh-Hyun

    2015-01-01

    Natural killer (NK) cells are essential for immunosurveillance against transformed cells. Transient receptor potential melastatin 2 (TRPM2) is a Ca(2+)-permeable cation channel gated by ADP-ribose (ADPR). However, the role of TRPM2-mediated Ca(2+) signaling in the antitumor response of NK cells has not been explored. Here, we show that ADPR-mediated Ca(2+) signaling is important for cytolytic granule polarization and degranulation but not involved in target cell recognition by NK cells. The key steps of this pathway are: 1) the activation of intracellular CD38 by protein kinase A following the interaction of the NK cell with a tumor cell results in the production of ADPR, 2) ADPR targets TRPM2 channels on cytolytic granules, and 3) TRPM2-mediated Ca(2+) signaling induces cytolytic granule polarization and degranulation, resulting in antitumor activity. NK cells treated with 8-Br-ADPR, an ADPR antagonist, as well as NK cells from Cd38(-/-) mice showed reduced tumor-induced granule polarization, degranulation, granzyme B secretion, and cytotoxicity of NK cells. Furthermore, TRPM2-deficient NK cells showed an intrinsic defect in tumoricidal activity. These results highlight CD38, ADPR, and TRPM2 as key players in the specialized Ca(2+) signaling system involved in the antitumor activity of NK cells. PMID:25879940

  3. Involvement of Pacific oyster CgPGRP-S1S in bacterial recognition, agglutination and granulocyte degranulation.

    PubMed

    Iizuka, Masao; Nagasaki, Toshihiro; Takahashi, Keisuke G; Osada, Makoto; Itoh, Naoki

    2014-03-01

    Peptidoglycan recognition protein (PGRP) recognizes invading bacteria through their peptidoglycans (PGN), a component of the bacterial cell wall. Insect PGRPs contribute to effective immune systems as inducers of other host defense responses, while this function has not been reported from PGRP of bivalves. In this study, recombinant CgPGRP-S1S (rCgPGRP-S1S), produced in the mantle and the gill, was synthesized and used to elucidate the immunological function of CgPGRP-S1S. rCgPGRP-S1S bound specifically to DAP-type PGN and to Escherichia coli cells, but not to other DAP-type PGN-containing bacterial species, Vibrio anguillarum, or Bacillus subtilis. Antibacterial activity was not detected, but E. coli cells were agglutinated. Moreover, in addition to these direct interactions with bacterial cells, rCgPGRP-S1S induced secretion of granular contents by hemocyte degranulation. Taken together, these results suggest for the first time that a PGRP of bivalves is, just as in insects, involved in host defense, not only by direct interaction with bacteria, but also by triggering other defense pathways. PMID:24201133

  4. Ultrastructure of mast cell degranulation induced by eosinophil peroxidase: Use of diaminobenzidine cytochemistry by scanning electron microscopy.

    PubMed

    Chi, E Y; Henderson, W R

    1984-03-01

    It has been previously demonstrated that eosinophil peroxidase (EPO) when supplemented with hydrogen peroxide and a halide induces noncytotoxic mast cell degranulation. Using a more highly purified EPO preparation, the ultrastructure of EPO-induced mast cell secretion has been studied using transmission and scanning electron microscopy and freeze-fracture techniques. At relatively low EPO concentrations, secretory changes were comparable to those caused by other mast cell secretagogues. Swollen and less electron-dense granules were seen in intracellular channels, some of which opened to the outside of the cell. EPO stimulation led to bulging of the surface membrane by submembranous granules and formation of pores in the cell surface that also contained fewer villous projections than control cells. During the secretory process, plasma membrane bulges were depleted of intramembranous particles in both the E and P faces of the apical regions of the perigranular and plasma membranes. Higher EPO concentrations caused a marked cytotoxic disruption of the mast cells. Diaminobenzidine cytochemistry was used to detect EPO reaction products on the mast cell surface by scanning electron microscopy; this technique should prove useful in detecting peroxidase reaction products on a variety of target cells. PMID:6420461

  5. Involvement of Class II Phosphoinositide 3-Kinase ?-Isoform in Antigen-Induced Degranulation in RBL-2H3 Cells

    PubMed Central

    Nigorikawa, Kiyomi; Hazeki, Kaoru; Guo, Ying; Hazeki, Osamu

    2014-01-01

    In this study, we present findings that suggest that PI3K-C2?, a member of the class II phosphoinositide 3-kinase (PI3K) subfamily, regulates the process of Fc?RI-triggered degranulation. RBL-2H3 cells were transfected with shRNA targeting PI3K-C2?. The knockdown impaired the Fc?RI-induced release of a lysosome enzyme, ?-hexosaminidase, without affecting the intracellular Ca2+ mobilization. The release of mRFP-tagged neuropeptide-Y, a reporter for the regulated exocytosis, was also decreased in the PI3K-C2?-deficient cells. The release was increased significantly by the expression of the siRNA-resistant version of PI3K-C2?. In wild-type cells, Fc?RI stimulation induced the formation of large vesicles, which were associated with CD63, a marker protein of secretory granules. On the vesicles, the existence of PI3K-C2? and PtdIns(3,4)P2 was observed. These results indicated that PI3K-C2? and its product PtdIns(3,4)P2 may play roles in the secretory process. PMID:25357130

  6. PI3Kgamma adaptor subunits define coupling to degranulation and cell motility by distinct PtdIns(3,4,5)P3 pools in mast cells.

    PubMed

    Bohnacker, Thomas; Marone, Romina; Collmann, Emilie; Calvez, Ronan; Hirsch, Emilio; Wymann, Matthias P

    2009-01-01

    Phosphoinositide 3-kinase gamma (PI3Kgamma) plays a major role in chronic inflammation and allergy. It is a heterodimer of a catalytic p110gamma subunit and an adaptor protein, either p101 or the p101 homolog p84 (p87(PIKAP)). It is unclear whether both PI3Kgamma complexes specifically modulate responses such as chemotaxis and degranulation. In mast cells, the p84:p110gamma complex synergizes with immunoglobulin E (IgE)- and antigen-clustered FcepsilonRI receptor signaling and is required to achieve maximal degranulation. During this process, PI3Kgamma is activated by ligands of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs), in particular adenosine receptors, through autocrine and paracrine pathways. Here, we show that p110gamma needs p84 to relay signals from GPCRs to formation of phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)], phosphorylation of Akt, migration of cells, and synergistic adenosine-enforced degranulation. Furthermore, the absence of adaptor subunits could not be compensated for by increased p110gamma abundance. Differentiated, p110gamma null cells also lost adaptor proteins. Complementation of p110gamma null mast cells with p101 and p110gamma restored the activation of Akt and cell migration, but failed to support degranulation. Lack of degranulation was attributed to a change in the spatiotemporal localization of PI3Kgamma-derived PtdIns(3,4,5)P(3); although both p84:p110gamma and p101:p110gamma complexes initially deposited PtdIns(3,4,5)P(3) at the plasma membrane, p101:p110gamma-derived PtdIns(3,4,5)P(3) was rapidly endocytosed to motile, microtubule-associated vesicles. In addition, p84:p110gamma, but not p101:p110gamma signaling was sensitive to disruption of lipid rafts. Our results demonstrate a nonredundant function for the p101 and p84 PI3Kgamma adaptor proteins and show that distinct pools of PtdIns(3,4,5)P(3) at the plasma membrane can elicit specific cell responses. PMID:19509406

  7. Tyrosol Suppresses Allergic Inflammation by Inhibiting the Activation of Phosphoinositide 3-Kinase in Mast Cells

    PubMed Central

    Kim, Sung-Wan; Lee, Soyoung; Lee, Hyun-Shik; Park, Eui Kyun; Khang, Dongwoo; Kim, Sang-Hyun

    2015-01-01

    Allergic diseases such as atopic dermatitis, rhinitis, asthma, and anaphylaxis are attractive research areas. Tyrosol (2-(4-hydroxyphenyl)ethanol) is a polyphenolic compound with diverse biological activities. In this study, we investigated whether tyrosol has anti-allergic inflammatory effects. Ovalbumin-induced active systemic anaphylaxis and immunoglobulin E-mediated passive cutaneous anaphylaxis models were used for the immediate-type allergic responses. Oral administration of tyrosol reduced the allergic symptoms of hypothermia and pigmentation in both animal models. Mast cells that secrete allergic mediators are key regulators on allergic inflammation. Tyrosol dose-dependently decreased mast cell degranulation and expression of inflammatory cytokines. Intracellular calcium levels and activation of inhibitor of ?B kinase (IKK) regulate cytokine expression and degranulation. Tyrosol blocked calcium influx and phosphorylation of the IKK complex. To define the molecular target for tyrosol, various signaling proteins involved in mast cell activation such as Lyn, Syk, phosphoinositide 3-kinase (PI3K), and Akt were examined. Our results showed that PI3K could be a molecular target for tyrosol in mast cells. Taken together, these findings indicated that tyrosol has anti-allergic inflammatory effects by inhibiting the degranulation of mast cells and expression of inflammatory cytokines; these effects are mediated via PI3K. Therefore, we expect tyrosol become a potential therapeutic candidate for allergic inflammatory disorders. PMID:26068872

  8. The Subunit of the Type I Fc Receptor Is a Target for Peptides Inhibiting IgE-Mediated Secretory Response of Mast Cells1

    Microsoft Academic Search

    Marton Andrasfalvy; Hajna Peterfy; Janos Matko ´; Jakub Abramson; Krisztina Kerekes; Gyorgy Vamosi; Israel Pecht; Anna Erdei

    Peptides originally derived from complement component C3a were earlier shown to inhibit the type I FcR (FcRI)-mediated degranulation of mucosal type mast cells. In the present study, we show that C3a7, a peptide with a natural sequence, and its modified derivative, C3a9, are powerful inhibitors of the above response of both serosal and mucosal type mastocytes. We demonstrate that these

  9. Comparison of Mast Cells and Inflammatory Cells within Periapical Lesions and Comparison of Degranulated Mast Cells Between Fibrous and Inflamed Area in Radicular Cysts: An Immunohistochemical Study

    PubMed Central

    Sood, Rahul; Akifuddin, Syed; Sidhu, Gagandeep Kaur; Khan, Nadia; Singla, Kapil

    2014-01-01

    Objective: The role of mast cells as the key effector of allergic inflammation, anaphylactic inflammatory reactions and in the pathogenesis of chronic inflammation, is well-known. The present study is adopted to compare mast cells and inflammatory cells within periapical granuloma and cysts and localize the mast cells and quantify their number in the periapical cysts so as to propose a role of mast cells in the pathogenesis of this lesion. Materials and Methods: Biopsy specimens of 30 periapical lesions were stained with hematoxylin–eosin, and immunohistochemical Mast Cell Tryptase from Bio SB (IHC detection system kit) antibody. The tryptase positive mast cells and mononuclear inflammatory cells were counted in 10 consecutive high power fields (100X) using the binocular microscope from Motic attached to a computer with Motic Advanced Images 3.2 software. Results: Comparative microscopic analysis indicated that periapical cyst shows more percentage of mast cells and less percentage of inflammatory cell than periapical granuloma (comparison of mean and standard deviation of total number of mast cells and inflammatory cells, mast cells 3.15±1.39 in the granuloma group and 4.43±1.91in the cyst group, inflammatory cells, 67.11±1.2 in the granuloma group and 52.66±0.8 in the cyst group). Numerous degranulated mast cells were observed in the fibrous wall than the inflammatory infiltrate of the periapical cysts. The mean and standard deviation of degranulated mast cells between the inflammatory and fibrous zone within the cyst group, being 0.95±1.10 and1.68±1.34 respectively. The values varied significantly between the two zones. Conclusion: The number of inflammatory cells in the cyst group is less than periapical granuloma and total number of mast cells in the cyst group is more as compared to periapical granuloma. The degranulated cells were quantified and they were higher in the fibrous area of the cysts than the inflammatory zone. This study could support the fact that the various mediators released on degranulation play a role in the connective tissue remodeling, chronicity and expansion of the periapical lesion. PMID:25654034

  10. Cultured Peripheral Blood Mast Cells from Chronic Idiopathic Urticaria Patients Spontaneously Degranulate Upon IgE Sensitization: Relationship to Expression of Syk and SHIP-2

    PubMed Central

    Saini, Sarbjit S.; Paterniti, Miya; Vasagar, Kavitha; Gibbons, Scott P.; Sterba, Patricia M.; Vonakis, Becky M.

    2009-01-01

    Recently, signaling changes in the Fc?RI pathway involving inositol lipid phosphatases have been identified in the basophils of chronic idiopathic urticaria (CIU) subjects. Based on the profile of basophil Fc?RI-mediated histamine degranulation, we have segregated CIU subjects into two groups, CIU Responder (CIU R) or CIU Nonresponder (CIU NR). In the present study, we compared expression of SHIP-1, SHIP-2, and Syk protein to histamine release (HR) from mast cells (MC) cultured from the peripheral blood of CIU R, CIU NR, and normal subjects. The MC of CIU R donors contained significantly increased Syk and decreased SHIP-2 as compared to CIU NR (Syk: p=0.038: SHIP-2: p=0.038) and normals (Syk: p=0.042: SHIP-2: p=0.027). Spontaneous HR from CIU donors was increased two-fold compared to normals (p=0.04). In summary, our results suggest a possible predilection for urticarial MC to spontaneously degranulate upon IgE sensitization contributing to the increased pruritis associated with CIU. PMID:19477690

  11. Neisserial Porins Inhibit Human Neutrophil Actin Polymerization, Degranulation, Opsonin Receptor Expression, and Phagocytosis but Prime the Neutrophils To Increase Their Oxidative Burst

    Microsoft Academic Search

    ROBERT BJERKNES; HILDE-KARI GUTTORMSEN; CLAUS OLA SOLBERG; ANDLEE M. WETZLER

    Porins are trimeric proteins that constitute water-filled pores that allow transmembrane diffusion of small solutes through the outer membrane layer of gram-negative bacteria. The porins are capable of inserting into the membranes of eucaryotic cells, and in the present study we have examined the in vitro effects on neutrophil functions of the following purified porins: meningococcal outer membrane protein classes

  12. The ?-1,3-glucan-binding protein from the crayfish Pacifastacus leniusculus , when reacted with a ?-1,3-glucan, induces spreading and degranulation of crayfish granular cells

    Microsoft Academic Search

    Margherita A. Barracco; Bernard Duvic; Kenneth Söderhäll

    1991-01-01

    A ß-1,3-glucan-binding protein (ßGBP) was purified from crayfish plasma, and incubated with laminarin (L), a ß-1,3-glucan. The ßGBP reacted with laminarin (ßGBP-L) induced strong spreading and partial degranulation of isolated and separated crayfish granular haemocytes. However, neither the ßGBP nor laminarin alone induced any changes in the crayfish granular cells. When monolayers of granular haemocytes were incubated with 20 µg

  13. Release of leukotriene B4 from human neutrophils and its relationship to degranulation induced by N-formyl-methionyl-leucyl-phenylalanine, serum-treated zymosan and the ionophore A23187.

    PubMed Central

    Palmer, R M; Salmon, J A

    1983-01-01

    The release of leukotriene B4 (LTB4) from human neutrophils and its relationship to degranulation induced by the divalent cation ionophore A23187, serum-treated zymosan (STZ), N-formyl-methionyl-leucyl-phenylalanine (FMLP) and arachidonic acid (AA) have been studied. Greatest release of LTB4, measured by specific radioimmunoassay, occurred in response to A23187 (5-10 ng/10(6) cells); lower concentrations were obtained after incubation with STZ (0.2-0.8 ng/10(6) cells) and AA (0.3-2.6 ng/10(6) cells) and low (0.02 ng/10(6) cells) or not detectable amounts from cells incubated with FMLP. Release of LTB4 induced by STZ, FMLP and submaximal concentrations of A23187 was potentiated by simultaneous addition of AA. Lower amounts (0.06-0.3 ng/10(6) cells) of thromboxane B2 (TXB2) were also released by these stimuli, however this release of TXB2 was not potentiated by exogenous AA. The secretion of beta-glucuronidase induced by A23187, STZ and FMLP was not quantitatively related to release of LTB4 or TXB2 and was not potentiated by exogenous AA. Furthermore, FMLP induced degranulation was cytochalasin B (Cyt B)-dependent, whereas LTB4 release in response to this stimulus was only marginally increased by pretreatment of the cells with Cyt B. These data indicate that LTB4 does not mediate degranulation induced by these stimuli. PMID:6309653

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

    PubMed

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

    2012-10-01

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

  15. Mechanism of photobiological effects of psoralens: the involvement of photo-oxidized psoralens as reactive intermediate species in induction of photosensitized hemolysis and skin erythema

    NASA Astrophysics Data System (ADS)

    Lysenko, Eugene P.; Kyagova, Alla A.; Potapenko, Alexander Y.

    2002-07-01

    Psoralens combined with UVA irradiation are used for the treatment of skin and autoimmune diseases. In the present paper the involvement of psoralen photooxidation products (POP) into induction of PUVA-erythema was studied. Under low fluence rate (LFR) UVA-irradiation and/or at low psoralen concentrations POP-products were predominantly formed, which were detected by spin trp method and possessed immunosuppressive activity. Under high fluence rate (HFR) UVA-irradiation and/or at high psoralen concentrations POP2-products were predominantly formed, which could be detected by Fe(II)-induced chemiluminescence and possessed hemolytic activity. Both PUVA- and POP-induced hemolysis of erythrocytes as well as PUVA-erythema were strongly activated with the increase in UVA-fluence rate. Both LFR and HFR PUVA-hemolysis as well as POP-hemolysis were strongly activated by Fe(II)-ions, bivalent cation chelators produced different effects on these processes depending on UVA fluence rate. Ethylenediaminetetraacetate (EDTA), and o- fenanthroline were found to inhibit LFT PUVA-erythema and enhanced HFR PUVA-erythema. Similar regulatory effects of EDTA were found for PUVA- and POP-induced hemolysis. EDTA inhibited LFT PUVA-hemolysis and activated HFR PUVA- and POP-hemolysis that suggests a participation of POP1- products in induction of LFR PUVA-hemolysis and LFT PUVA- erythema and POP2-products in induction of HFR PUVA- hemolysis and HFR PUVA-erythema.

  16. Probing the mystery of Chinese medicine meridian channels with special emphasis on the connective tissue interstitial fluid system, mechanotransduction, cells durotaxis and mast cell degranulation.

    PubMed

    Fung, Peter Chin Wan

    2009-01-01

    This article hypothesizes that the Chinese medicine meridian system is a special channel network comprising of skin with abundant nerves and nociceptive receptors of various types, and deeper connective tissues inside the body with the flowing interstitial fluid system. These meridian channels provide efficient migratory tracks mainly due to durotaxis (also including chemotaxis) for mast cells, fibroblasts and other cells to migrate and carry out a number of physiological functions. Acupuncture acting on meridian channel causes cytoskeletal remodeling through mechanotransduction, leading to regulation of gene expression and the subsequent production of related proteins. Also, stimulation on cell surface can trigger Ca2+ activities, resulting in a cascade of intra- and inter-cellular signaling. Moreover, nerve endings in the meridian channels interact with mast cells and induce the degranulation of these cells, leading to the release of many specific biomolecules needed for homeostasis, immune surveillance, wound healing and tissue repair. Acupoint along a meridian channel is a functional site to trigger the above functions with specificity and high efficiency. PMID:19480699

  17. Mountain cedar pollen induces IgE-independent mast cell degranulation, IL-4 production, and intracellular reactive oxygen species generation

    PubMed Central

    Endo, Shuichiro; Hochman, Daniel J.; Midoro-Horiuti, Terumi; Goldblum, Randall M.; Brooks, Edward G.

    2011-01-01

    Cedar pollens cause severe allergic disease throughout the world. We have previously characterized allergenic pollen glycoproteins from mountain cedar (Juniperus ashei) that bind to allergen-specific immunoglobulin E (IgE). In the present report, we investigated an alternative pathway of mast cell activation by mountain cedar pollen extract through IgE-independent mechanisms. We show that mountain cedar pollen directly induces mast cell serotonin and IL-4 release and enhances release induced by IgE cross-linking. Concomitant with mediator release, high levels of intracellular reactive oxygen species (ROS) were generated, and both ROS and serotonin release were inhibited by anti-oxidants. These findings suggest that alternative mechanisms exist whereby pollen exposure enhances allergic inflammatory mediator release through mechanisms that involve ROS. These mechanisms have the potential for enhancing the allergenic potency of pollens. PMID:21944563

  18. Once Phosphorylated, Tyrosines in Carboxyl Terminus of Protein-tyrosine Kinase Syk Interact with Signaling Proteins, Including TULA-2, a Negative Regulator of Mast Cell Degranulation*

    PubMed Central

    de Castro, Rodrigo Orlandini; Zhang, Juan; Groves, Jacqueline R.; Barbu, Emilia Alina; Siraganian, Reuben P.

    2012-01-01

    Activation of the high affinity IgE-binding receptor (Fc?RI) results in the tyrosine phosphorylation of two conserved tyrosines located close to the COOH terminus of the protein-tyrosine kinase Syk. Synthetic peptides representing the last 10 amino acids of the tail of Syk with these two tyrosines either nonphosphorylated or phosphorylated were used to precipitate proteins from mast cell lysates. Proteins specifically precipitated by the phosphorylated peptide were identified by mass spectrometry. These included the adaptor proteins SLP-76, Nck-1, Grb2, and Grb2-related adaptor downstream of Shc (GADS) and the protein phosphatases SHIP-1 and TULA-2 (also known as UBASH3B or STS-1). The presence of these in the precipitates was further confirmed by immunoblotting. Using the peptides as probes in far Western blots showed direct binding of the phosphorylated peptide to Nck-1 and SHIP-1. Immunoprecipitations suggested that there were complexes of these proteins associated with Syk especially after receptor activation; in these complexes are Nck, SHIP-1, SLP-76, Grb2, and TULA-2 (UBASH3B or STS-1). The decreased expression of TULA-2 by treatment of mast cells with siRNA increased the Fc?RI-induced tyrosine phosphorylation of the activation loop tyrosines of Syk and the phosphorylation of phospholipase C-?2. There was parallel enhancement of the receptor-induced degranulation and activation of nuclear factor for T cells or nuclear factor ?B, indicating that TULA-2, like SHIP-1, functions as a negative regulator of Fc?RI signaling in mast cells. Therefore, once phosphorylated, the terminal tyrosines of Syk bind complexes of proteins that are positive and negative regulators of signaling in mast cells. PMID:22267732

  19. Once phosphorylated, tyrosines in carboxyl terminus of protein-tyrosine kinase Syk interact with signaling proteins, including TULA-2, a negative regulator of mast cell degranulation.

    PubMed

    de Castro, Rodrigo Orlandini; Zhang, Juan; Groves, Jacqueline R; Barbu, Emilia Alina; Siraganian, Reuben P

    2012-03-01

    Activation of the high affinity IgE-binding receptor (Fc?RI) results in the tyrosine phosphorylation of two conserved tyrosines located close to the COOH terminus of the protein-tyrosine kinase Syk. Synthetic peptides representing the last 10 amino acids of the tail of Syk with these two tyrosines either nonphosphorylated or phosphorylated were used to precipitate proteins from mast cell lysates. Proteins specifically precipitated by the phosphorylated peptide were identified by mass spectrometry. These included the adaptor proteins SLP-76, Nck-1, Grb2, and Grb2-related adaptor downstream of Shc (GADS) and the protein phosphatases SHIP-1 and TULA-2 (also known as UBASH3B or STS-1). The presence of these in the precipitates was further confirmed by immunoblotting. Using the peptides as probes in far Western blots showed direct binding of the phosphorylated peptide to Nck-1 and SHIP-1. Immunoprecipitations suggested that there were complexes of these proteins associated with Syk especially after receptor activation; in these complexes are Nck, SHIP-1, SLP-76, Grb2, and TULA-2 (UBASH3B or STS-1). The decreased expression of TULA-2 by treatment of mast cells with siRNA increased the Fc?RI-induced tyrosine phosphorylation of the activation loop tyrosines of Syk and the phosphorylation of phospholipase C-?2. There was parallel enhancement of the receptor-induced degranulation and activation of nuclear factor for T cells or nuclear factor ?B, indicating that TULA-2, like SHIP-1, functions as a negative regulator of Fc?RI signaling in mast cells. Therefore, once phosphorylated, the terminal tyrosines of Syk bind complexes of proteins that are positive and negative regulators of signaling in mast cells. PMID:22267732

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

    PubMed

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

    2013-09-01

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

  1. 2-O-Sulfated Domains in Syndecan-1 Heparan Sulfate Inhibit Neutrophil Cathelicidin and Promote Staphylococcus aureus Corneal Infection.

    PubMed

    Hayashida, Atsuko; Amano, Shiro; Gallo, Richard L; Linhardt, Robert J; Liu, Jian; Park, Pyong Woo

    2015-06-26

    Ablation of syndecan-1 in mice is a gain of function mutation that enables mice to significantly resist infection by several bacterial pathogens. Syndecan-1 shedding is induced by bacterial virulence factors, and inhibition of shedding attenuates bacterial virulence, whereas administration of purified syndecan-1 ectodomain enhances virulence, suggesting that bacteria subvert syndecan-1 ectodomains released by shedding for their pathogenesis. However, the pro-pathogenic functions of syndecan-1 ectodomain have yet to be clearly defined. Here, we examined how syndecan-1 ectodomain enhances Staphylococcus aureus virulence in injured mouse corneas. We found that syndecan-1 ectodomain promotes S. aureus corneal infection in an HS-dependent manner. Surprisingly, we found that this pro-pathogenic activity is dependent on 2-O-sulfated domains in HS, indicating that the effects of syndecan-1 ectodomain are structure-based. Our results also showed that purified syndecan-1 ectodomain and heparan compounds containing 2-O-sulfate motifs inhibit S. aureus killing by antimicrobial factors secreted by degranulated neutrophils, but does not affect intracellular phagocytic killing by neutrophils. Immunodepletion of antimicrobial factors with staphylocidal activities demonstrated that CRAMP, a cationic antimicrobial peptide, is primarily responsible for S. aureus killing among other factors secreted by degranulated neutrophils. Furthermore, we found that purified syndecan-1 ectodomain and heparan compounds containing 2-O-sulfate units potently and specifically inhibit S. aureus killing by synthetic CRAMP. These results provide compelling evidence that a specific subclass of sulfate groups, and not the overall charge of HS, permits syndecan-1 ectodomains to promote S. aureus corneal infection by inhibiting a key arm of neutrophil host defense. PMID:25931123

  2. Damnacanthal inhibits IgE receptor-mediated activation of mast cells.

    PubMed

    Garcia-Vilas, Javier A; Medina, Miguel A; Melo, Fabio R; Pejler, Gunnar; Garcia-Faroldi, Gianni

    2015-05-01

    Damnacanthal, an anthraquinone obtained from the noni fruit (Morinda citrifolia L.), has been described to possess anti-cancer and anti-inflammatory properties. Since mast cells are key players in various inflammatory conditions as well as in cancer, we considered the possibility that the biological actions of damnacanthal, at least partly, could be due to effects on mast cells. Many of the biological activities of mast cells are mediated by IgE receptor cross-linking, which results in degranulation with release of preformed granule mediators, as well as de novo synthesis and release of additional compounds. Here we show that damnacanthal has profound inhibitory activity on mast cell activation through this pathway. The release of the granule compounds beta-hexosaminidase and tryptase release was completely abrogated by damnacanthal at doses that were non-toxic to mast cells. In addition, damnacanthal inhibited activation-dependent pro-inflammatory gene induction, as well as cytokine/chemokine release in response to mast cell stimulation. The mechanism underlying damnacanthal inhibition was linked to impaired phosphorylation of Syk and Akt. Furthermore, damnacanthal inhibited mast cell activation in response to calcium ionophore A23187. Altogether, the data presented here demonstrate that damnacanthal inhibits mast cell activation induced by different stimuli and open a new window for the use of this compound as a mast cell stabilizer. PMID:25656801

  3. Spiraeoside inhibits mast cells activation and IgE-mediated allergic responses by suppressing phospholipase C-?-mediated signaling.

    PubMed

    Kim, Jung Kuk; Seo, Young-Kyo; Park, Sehoon; Park, Soo-Ah; Lim, Seyoung; Lee, Susie; Kwon, Ohman; Seo, Jeong Kon; Choi, Ung-Kyu; Ryu, Sung Ho; Suh, Pann-Ghill

    2015-06-01

    Mast cells are responsible for IgE-mediated allergic responses through the secretion of various inflammatory cytokines and mediators. Therefore, the pharmacological regulation of mast cell activation is an important goal in the development of novel anti-allergic drugs. In this study, we found that spiraeoside (SP) inhibits mast cell activation and allergic responses in vivo. SP dose-dependently inhibited the degranulation induced by IgE-antigen (Ag) stimulation in RBL-2H3 mast cells without cytotoxic effects. At the molecular level, SP reduced the Ag-induced phosphorylation and subsequent activation of phospholipase C-?2 (PLC-?2). Moreover, SP inhibited the phosphorylation of spleen tyrosine kinase (Syk), linker for activation of T cells (LAT), and downstream MAPKs, such as ERK1/2, p38, and JNK, eventually attenuating expression of TNF-? and IL-4. Finally, we found that SP significantly inhibited IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. Taken together, our results strongly suggest that SP suppresses IgE-mediated mast cell activation and allergic responses by inhibiting Lyn-induced PLC-?2/MAPK signaling in mast cells. PMID:25781488

  4. IgE–mediated mast cell responses are inhibited by thymol-mediated, activation-induced cell death in skin inflammation

    PubMed Central

    Wechsler, Joshua B.; Hsu, Chia-Lin; Bryce, Paul J.

    2014-01-01

    Background Mast cells play a critical role in inflammatory skin diseases through releasing pro-inflammatory mediators; however, few therapies directly target these cells. In 1878, the use of topical Thymol, a now recognized potent agonist for Transient Receptor Potential (TRP) channels, was first described to treat eczema and psoriasis. Objective We sought to determine the mechanisms through which thymol may alter skin inflammation. Methods We examined the effect of topical thymol on IgE-dependent responses using a mast cell–dependent passive cutaneous anaphylaxis (PCA) model as well as in vitro cultured mast cells. Results Thymol dose-dependently inhibited PCA when administered topically 24 hours prior to antigen challenge but provoked an ear swelling response directly on application. This direct effect was associated with local mast cell degranulation and was absent in histamine-deficient mice. However, unlike with PCA responses, there was no late phase swelling. In vitro, thymol directly trigged calcium flux in mast cells via TRP-channel activation, along with degranulation and cytokine transcription. However, no cytokine protein was produced. Instead, thymol induced a significant increase in apoptotic cell death that was seen both in vitro and in vivo. Conclusions We propose that the efficacy of thymol in reducing IgE-dependent responses is through promotion of activation-induced apoptotic cell death of mast cells and that this likely explains the clinical benefits observed in early clinical reports. PMID:24486068

  5. Cheonggukjang Ethanol Extracts Inhibit a Murine Allergic Asthma via Suppression of Mast Cell-Dependent Anaphylactic Reactions

    PubMed Central

    Bae, Min-Jung; Shin, Hee Soon; See, Hye-Jeong

    2014-01-01

    Abstract Cheonggukjang (CGJ), a traditional Korean fermented soybean food, exerts immunomodulatory effects. Asthma is the most common chronic allergic disease to be associated with immune response to environmental allergens. In the pathogenesis of asthma, histamine is one of the important inflammatory mediators released from granules of mast cells. In this study, we evaluated the therapeutic effect of CGJ on a mouse model of ovalbumin (OVA)-induced asthma via the suppression of histamine release. C57BL/6 mice were sensitized by intraperitoneal injection of OVA or a phosphate-buffered saline (PBS) control and then challenged with OVA inhalation. Mice were treated intraperitoneally with either 70% ethanol-extracted CGJ (CGJE) (100?mg/kg/day) or equivalent PBS. Asthma-related inflammation was assessed by bronchoalveolar lavage fluid cell counts and histopathological and immunohistochemical analysis of lung tissues. To elucidate the mechanisms of asthma inhibition by CGJE treatment, we also examined degranulation and histamine release of compound 48/80-induced rat peritoneal mast cells (RPMCs). Treatment with CGJE downregulated the number of eosinophils and monocytes in the lungs of mice challenged with OVA and suppressed histopathological changes, such as eosinophil infiltration, mucus accumulation, goblet cell hyperplasia, and collagen fiber deposits. Moreover, CGJE alleviated compound 48/80-induced mast cell degranulation and histamine release from RPMCs through inhibition of calcium (Ca2+) uptake as well as ear swelling by infiltration of inflammatory cells. These findings demonstrated that CGJE can be used as an antiasthmatic dietary supplements candidate for histamine-mediated asthma. PMID:24456365

  6. Corrosion inhibiting organic coatings

    SciTech Connect

    Sasson, E.

    1984-10-16

    A corrosion inhibiting coating comprises a mixture of waxes, petroleum jelly, a hardener and a solvent. In particular, a corrosion inhibiting coating comprises candelilla wax, carnauba wax, microcrystalline waxes, white petrolatum, an oleoresin, lanolin and a solvent.

  7. Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a.

    PubMed

    Vego, Heidi; Sand, Kristin L; Høglund, Rune A; Fallang, Lars-Egil; Gundersen, Glenn; Holmøy, Trygve; Maghazachi, Azzam A

    2014-12-01

    Dimethyl fumarate (DMF) is a new drug used to treat multiple sclerosis (MS) patients. Here, we examined the effects of DMF and the DMF metabolite monomethyl fumarate (MMF) on various activities of natural killer (NK) cells. We demonstrated that MMF augments the primary CD56(+), but not CD56(-), NK cell lysis of K562 and RAJI tumor cells. MMF induced NKp46 expression on the surface of CD56(+), but not CD56(-), NK cells after incubation for 24 h. This effect was closely correlated with the upregulation of CD107a expression on the surface of CD56(+) NK cells and the induction of Granzyme B release from these cells through this metabolite. An anti-NKp46 antibody inhibited the MMF-induced upregulation of CD107a and the lysis of tumor cells through CD56(+) NK cells. Thus, these results are the first to show that MMF augments CD56(+) NK cell lysis of tumor target cells, an effect mediated through NKp46. This novel effect suggests the use of MMF for therapeutic and/or preventive protocols in cancer.Cellular & Molecular Immunology advance online publication, 1 December 2014; doi:10.1038/cmi.2014.114. PMID:25435072

  8. Natural killer cells in perinatally HIV-1-infected children exhibit less degranulation compared to HIV-1-exposed uninfected children and their expression of KIR2DL3, NKG2C, and NKp46 correlates with disease severity.

    PubMed

    Ballan, Wassim M; Vu, Bien-Aimee N; Long, Brian R; Loo, Christopher P; Michaëlsson, Jakob; Barbour, Jason D; Lanier, Lewis L; Wiznia, Andrew A; Abadi, Jacobo; Fennelly, Glenn J; Rosenberg, Michael G; Nixon, Douglas F

    2007-09-01

    NK cells play an integral role in the innate immune response by targeting virally infected and transformed cells with direct killing and providing help to adaptive responses through cytokine secretion. Whereas recent studies have focused on NK cells in HIV-1-infected adults, the role of NK cells in perinatally HIV-1-infected children is less studied. Using multiparametric flow cytometric analysis, we assessed the number, phenotype, and function of NK cell subsets in the peripheral blood of perinatally HIV-1-infected children on highly active antiretroviral therapy and compared them to perinatally exposed but uninfected children. We observed an increased frequency of NK cells expressing inhibitory killer Ig-like receptors in infected children. This difference existed despite comparable levels of total NK cells and NK cell subpopulations between the two groups. Additionally, NK cell subsets from infected children expressed, with and without stimulation, significantly lower levels of the degranulation marker CD107, which correlates with NK cell cytotoxicity. Lastly, increased expression of KIR2DL3, NKG2C, and NKp46 on NK cells correlated with decreased CD4+ T-lymphocyte percentage, an indicator of disease severity in HIV-1- infected children. Taken together, these results show that HIV-1-infected children retain a large population of cytotoxically dysfunctional NK cells relative to perinatally exposed uninfected children. This reduced function appears concurrently with distinct NK cell surface receptor expression and is associated with a loss of CD4+ T cells. This finding suggests that NK cells may have an important role in HIV-1 disease pathogenesis in HIV-1-infected children. PMID:17709553

  9. Natural Killer Cells in Perinatally HIV-1-Infected Children Exhibit Less Degranulation Compared to HIV-1-Exposed Uninfected Children and Their Expression of KIR2DL3, NKG2C, and NKp46 Correlates with Disease Severity1

    PubMed Central

    Ballan, Wassim M.; Vu, Bien-Aimee N.; Long, Brian R.; Loo, Christopher P.; Michaëlsson, Jakob; Barbour, Jason D.; Lanier, Lewis L.; Wiznia, Andrew A.; Abadi, Jacobo; Fennelly, Glenn J.; Rosenberg, Michael G.; Nixon, Douglas F.

    2014-01-01

    NK cells play an integral role in the innate immune response by targeting virally infected and transformed cells with direct killing and providing help to adaptive responses through cytokine secretion. Whereas recent studies have focused on NK cells in HIV-1-infected adults, the role of NK cells in perinatally HIV-1-infected children is less studied. Using multiparametric flow cytometric analysis, we assessed the number, phenotype, and function of NK cell subsets in the peripheral blood of perinatally HIV-1-infected children on highly active antiretroviral therapy and compared them to perinatally exposed but uninfected children. We observed an increased frequency of NK cells expressing inhibitory killer Ig-like receptors in infected children. This difference existed despite comparable levels of total NK cells and NK cell subpopulations between the two groups. Additionally, NK cell subsets from infected children expressed, with and without stimulation, significantly lower levels of the degranulation marker CD107, which correlates with NK cell cytotoxicity. Lastly, increased expression of KIR2DL3, NKG2C, and NKp46 on NK cells correlated with decreased CD4+ T-lymphocyte percentage, an indicator of disease severity in HIV-1-infected children. Taken together, these results show that HIV-1-infected children retain a large population of cytotoxically dysfunctional NK cells relative to perinatally exposed uninfected children. This reduced function appears concurrently with distinct NK cell surface receptor expression and is associated with a loss of CD4+ T cells. This finding suggests that NK cells may have an important role in HIV-1 disease pathogenesis in HIV-1-infected children. PMID:17709553

  10. Sevoflurane ameliorates intestinal ischemia-reperfusion-induced lung injury by inhibiting the synergistic action between mast cell activation and oxidative stress

    PubMed Central

    LUO, CHENFANG; YUAN, DONGDONG; ZHAO, WEICHENG; CHEN, HUIXIN; LUO, GANGJIAN; SU, GUANGJIE; HEI, ZIQING

    2015-01-01

    Preconditioning with sevoflurane (SEV) can protect against ischemia-reperfusion injury in several organs, however, the benefits of SEV against acute lung injury (ALI), induced by intestinal ischemia-reperfusion (IIR), and the underlying mechanisms remain to be elucidated. The present study was designed to investigate the effects of SEV preconditioning on IIR-mediated ALI and the associated mechanisms in a rat model. Female Sprague-Dawley rats treated with 2.3% SEV or apocynin (AP), an inhibitor of NADPH oxidase, were subjected to 75 min superior mesenteric artery occlusion followed by 2 h reperfusion in the presence or absence of the mast cell degranulator compound 48/80 (CP). SEV and AP were observed to downregulate the protein expression levels of p47phox and gp91phox in the lungs of normal rats. IIR resulted in severe lung injury, characterized by significant increases in pathological injury scores, lung wet/dry weight ratio, protein expression levels of p47phox, gp91phox and ICAM-1, the presence of hydrogen peroxide, malondydehyde and interleukin-6, and the activity of myeloperoxidase. In addition, significant reductions were observed in the expression of prosurfactant protein C, accompanied by an increase in MC degranulation, demonstrated by significant elevations in the number of mast cells, expression levels of tryptase and the concentration of ?-hexosaminidase. These changes were further augmented in the presence of CP. In addition, SEV and AP preconditioning significantly alleviated the above alterations induced by IIR alone or in combination with CP. These findings suggested that SEV and AP attenuated IIR-induced ALI by inhibiting NADPH oxidase and the synergistic action between oxidative stress and mast cell activation. PMID:25815524

  11. Histamine H4-Receptors Inhibit Mast Cell Renin Release in Ischemia/Reperfusion via Protein Kinase C?-Dependent Aldehyde Dehydrogenase Type-2 Activation

    PubMed Central

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

    2014-01-01

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

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

    SciTech Connect

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

    2010-05-14

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

  13. Inhibition of selectin binding

    DOEpatents

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

    1999-01-01

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

  14. Inhibition of selectin binding

    DOEpatents

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

    2001-10-09

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

  15. Human renin inhibiting dipeptide.

    PubMed

    Toda, N; Miyazaki, M; Etoh, Y; Kubota, T; Iizuka, K

    1986-10-01

    KRI-1177, a dipeptide containing nor-statine inhibited renin activity in human and Japanese monkey plasma to a markedly greater extent than that in dog, rabbit and rat plasma. The systemic blood pressure of anesthetized monkeys was lowered by intravenous injections of this compound which also reduced plasma renin activity and concentration of angiotensins. KRI-1177 appears to selectively inhibit primate renin activity, thereby producing hypotension. PMID:3536533

  16. Psychotherapy by reciprocal inhibition

    Microsoft Academic Search

    Joseph Wolpe

    1968-01-01

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

  17. Modulation of neutrophil degranulation by hypoxia

    E-print Network

    Hoenderdos, Kim

    2015-02-03

    -immunity; Systemic Lupus Erythematosus (SLE) patients make antibodies against histones and neutrophil 1. Introduction 26 | Figure 1.5: NETs A. Neutrophil extracellular traps (NETs) are characterised by long strands of DNA (blue) decorated...

  18. Antigen-specific inhibition of high-avidity T cell target lysis by low-avidity T cells via trogocytosis.

    PubMed

    Chung, Brile; Stuge, Tor B; Murad, John P; Beilhack, Georg; Andersen, Emily; Armstrong, Brian D; Weber, Jeffrey S; Lee, Peter P

    2014-08-01

    Current vaccine conditions predominantly elicit low-avidity cytotoxic T lymphocytes (CTLs), which are non-tumor-cytolytic but indistinguishable by tetramer staining or enzyme-linked immunospot from high-avidity CTLs. Using CTL clones of high or low avidity for melanoma antigens, we show that low-avidity CTLs can inhibit tumor lysis by high-avidity CTLs in an antigen-specific manner. This phenomenon operates in vivo: high-avidity CTLs control tumor growth in animals but not in combination with low-avidity CTLs specific for the same antigen. The mechanism involves stripping of specific peptide-major histocompatibility complexes (pMHCs) via trogocytosis by low-avidity melanoma-specific CTLs without degranulation, leading to insufficient levels of specific pMHC on target cell surface to trigger lysis by high-avidity CTLs. As such, peptide repertoire on the cell surface is dynamic and continually shaped by interactions with T cells. These results describe immune regulation by low-avidity T cells and have implications for vaccine design. PMID:25088413

  19. Specific Inhibition of Obligate Anaerobes

    Microsoft Academic Search

    Herbert N. Prince

    1960-01-01

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

  20. Inhibition of the IgE-Mediated Activation of RBL-2H3 Cells by TIPP, a Novel Thymic Immunosuppressive Pentapeptide

    PubMed Central

    Lian, Qianqian; Cheng, Yanna; Zhong, Chuanqing; Wang, Fengshan

    2015-01-01

    TIPP is a novel thymic immunosuppressive pentapeptide originally obtained from calf thymic immunosuppressive extract. The present study aimed to investigate the inhibitory activity of TIPP on IgE-mediated activation of RBL-2H3 cells. Release of ?-hexosaminidase and histamine, intracellular calcium, membrane ruffling, mRNA levels of cytokines, cyclooxygenase-2 (COX-2) expression, and activation of mitogen-activated protein kinases (MAP kinases) and NF-?B were determined by colorimetric assay, fluorescence spectrophotometer, confocal fluorescence microscope, quantification PCR, and Western blot, respectively. The results showed that TIPP significantly inhibited the degranulation in IgE-antigen complex-stimulated RBL-2H3 cells without cytotoxicity. TIPP significantly suppressed the increase of intracellular calcium and the rearrangement of F-actin, attenuated the transcription of pro-inflammatory cytokines (IL-3, -4, -6, -13, TNF-?, and monocyte chemotactic protein-1 (MCP-1)), and decreased the expression of COX-2. Western blot analysis showed that TIPP had an inhibitory activity on the phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and ERK kinase 1/2 (MEK1/2), and inhibited the activation of NF-?B. The data suggested that TIPP effectively suppressed IgE-mediated activation of RBL-2H3 cells via blocking MEK/ERK and NF-?B signaling pathways. PMID:25608657

  1. Inhibition of the IgE-mediated activation of RBL-2H3 cells by TIPP, a novel thymic immunosuppressive pentapeptide.

    PubMed

    Lian, Qianqian; Cheng, Yanna; Zhong, Chuanqing; Wang, Fengshan

    2015-01-01

    TIPP is a novel thymic immunosuppressive pentapeptide originally obtained from calf thymic immunosuppressive extract. The present study aimed to investigate the inhibitory activity of TIPP on IgE-mediated activation of RBL-2H3 cells. Release of ?-hexosaminidase and histamine, intracellular calcium, membrane ruffling, mRNA levels of cytokines, cyclooxygenase-2 (COX-2) expression, and activation of mitogen-activated protein kinases (MAP kinases) and NF-?B were determined by colorimetric assay, fluorescence spectrophotometer, confocal fluorescence microscope, quantification PCR, and Western blot, respectively. The results showed that TIPP significantly inhibited the degranulation in IgE-antigen complex-stimulated RBL-2H3 cells without cytotoxicity. TIPP significantly suppressed the increase of intracellular calcium and the rearrangement of F-actin, attenuated the transcription of pro-inflammatory cytokines (IL-3, -4, -6, -13, TNF-?, and monocyte chemotactic protein-1 (MCP-1)), and decreased the expression of COX-2. Western blot analysis showed that TIPP had an inhibitory activity on the phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and ERK kinase 1/2 (MEK1/2), and inhibited the activation of NF-?B. The data suggested that TIPP effectively suppressed IgE-mediated activation of RBL-2H3 cells via blocking MEK/ERK and NF-?B signaling pathways. PMID:25608657

  2. Cooperation for Better Inhibiting.

    PubMed

    Novoa, Eva Maria; Ribas de Pouplana, Lluís

    2015-06-18

    Cladosporin is an antimalarial drug that acts as an ATP-mimetic to selectively inhibit Plasmodium lysyl-tRNA synthetase. Using multiple crystal structures, Fang et al. (2015) reveal in this issue of Chemistry & Biology the fascinating mechanism responsible for cladosporin selectivity. PMID:26091164

  3. Microbial Inhibition by Erythrosin

    Microsoft Academic Search

    W. J. Begue; R. C. Bard; G. W. Koehne

    1966-01-01

    SYNOPSIS IN INTERLINGUA INHIBITION DE MICROBIOS PER ERYTHROSINA.-Erythrosina, un substantia colorante que es includite in oblatas detectori usate in le cavitate oral possede cognoscitemente le capacitate de inhibir certe microorganismos. Viste que le spectro del microorganismos sensibile pro erythrosina non es cognoscite, un studio esseva interprendite pro clarificar iste question. Esseva usate 16 microorganismos de occurrentia satis corn mun. Le

  4. Renin inhibition with aliskiren.

    PubMed

    Wuerzner, Grégoire; Azizi, Michel

    2008-04-01

    1. Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modelling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors, such as aliskiren. 2. Aliskiren has a low bioavailability (between 2.6 and 5.0%) compensated by its high potency to inhibit renin (IC50: 0.6 nmol/L) and a long plasma half-life (23-36 h), which makes it suitable for once-daily dosing. 3. The once-daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 (AT1) receptor blockers (losartan, valsartan, irbesartan), hydrochlorothiazide, angiotensin converting enzyme inhibitors (ramipril and lisinopril) or long acting calcium channel blockers (amlodipine). In combination therapy, aliskiren further decreases blood pressure when combined with either hydrochlorothiazide, amlodipine, irbesartan or ramipril. 4. The biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme (ACE) inhibition and Ang II antagonism, particularly in terms of angiotensin profiles and interactions with the bradykinin-nitric oxide-cyclic guanosine monophosphate pathway and possibly the (pro)renin receptor. 5. Blockade of the renin angiotensin system (RAS) with ACE inhibitors, AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine. However, it remains unclear how to optimize RAS blockade to maximize cardiovascular and renal benefits. In this context, renin inhibition to render the RAS fully quiescent is a new possibility requiring further study. PMID:18307734

  5. Human polymorphonuclear leukocytes inhibit Aspergillus fumigatus conidial growth by lactoferrin-mediated iron depletion.

    PubMed

    Zarember, Kol A; Sugui, Janyce A; Chang, Yun C; Kwon-Chung, Kyung J; Gallin, John I

    2007-05-15

    Aspergillus fumigatus, a common mold, rarely infects humans, except during prolonged neutropenia or in cases of chronic granulomatous disease (CGD), a primary immunodeficiency caused by mutations in the NADPH oxidase that normally produces fungicidal reactive oxygen species. Filamentous hyphae of Aspergillus are killed by normal, but not CGD polymorphonuclear leukocytes (PMN); however, the few studies on PMN-mediated host defenses against infectious conidia (spores) of this organism have yielded conflicting results, some showing that PMN do not inhibit conidial growth, with others showing that they do, most likely using reactive oxygen species. Given that CGD patients are exposed daily to hundreds of viable A. fumigatus conidia, yet considerable numbers of them survive years without infection, we reasoned that PMN use ROS-independent mechanisms to combat Aspergillus. We show that human PMN from both normal controls and CGD patients are equipotent at arresting the growth of Aspergillus conidia in vitro, indicating the presence of a reactive oxygen species-independent factor(s). Cell-free supernatants of degranulated normal and CGD neutrophils both suppressed fungal growth and were found to be rich in lactoferrin, an abundant PMN secondary granule protein. Purified iron-poor lactoferrin at concentrations occurring in PMN supernatants (and reported in human mucosal secretions in vivo) decreased fungal growth, whereas saturation of lactoferrin or PMN supernatants with iron, or testing in the presence of excess iron in the form of ferritin, completely abolished activity against conidia. These results demonstrate that PMN lactoferrin sequestration of iron is important for host defense against Aspergillus. PMID:17475866

  6. 4-Chlorotetrazolo[1,5-a]quinoxaline inhibits activation of Syk kinase to suppress mast cells in vitro and mast cell-mediated passive cutaneous anaphylaxis in mice

    SciTech Connect

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

    2011-12-15

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

  7. Subsea corrosion inhibition applications

    SciTech Connect

    Jovancicevic, V.

    2000-04-01

    Subsea wells are hard to treat--and mistakes carry high penalties. This article describes some difficulties that beset corrosion inhibition programs and the ways in which computer modeling and laboratory protocols can be used to select optimum products for particular wells and flowlines. In addition, test results are shown for a new inhibitor with dramatic capabilities to control corrosion even in severe slug-flow conditions.

  8. Method for decreasing radiation load in puva therapy

    SciTech Connect

    Wolff, K.

    1987-02-10

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

  9. Innovative Therapy of CTCL: Beyond PUVA and Nitrogen Mustard

    PubMed Central

    Heald, Peter

    2010-01-01

    Synopsis Cutaneous T Cell Lymphoma is a malignancy of skin homing T cells. This unique population of lymphocytes requires alternative therapies than those used in nodal lymphomas. Although phototherapy and nitrogen mustard have been standard treatments for decades, newer therapies have been arriving with increased frequency. Moreover some therapies, currently used to treat other disease, have been used in CTCL with good effect. These innovative therapies in CTCL are discussed, with review of current data and examples of how these therapies may be utilized today. PMID:20510760

  10. Livedo reticularis and livedoid vasculitis responding to PUVA therapy

    Microsoft Academic Search

    Hyun-Joo Choi; Seung-Kyung Hann

    1999-01-01

    Livedo reticularis is a mottled blue discoloration of the skin, which occurs in a netlike pattern. Livedoid vasculitis is a chronic disorder clinically manifested by recurrent painful ulcerations of the lower extremities and is characterized by the presence of smooth or depressed ivory-white lesions surrounded by hyperpigmentation and telangiectasia. We describe two patients with livedo reticularis and livedoid vasculitis who

  11. A Soluble Fragment of the Tumor Antigen BCL2-associated Athanogene 6 (BAG-6) Is Essential and Sufficient for Inhibition of NKp30 Receptor-dependent Cytotoxicity of Natural Killer Cells*

    PubMed Central

    Binici, Janina; Hartmann, Jessica; Herrmann, Julia; Schreiber, Christine; Beyer, Steffen; Güler, Günnur; Vogel, Vitali; Tumulka, Franz; Abele, Rupert; Mäntele, Werner; Koch, Joachim

    2013-01-01

    Immunosurveillance of tumor cells depends on NKp30, a major activating receptor of human natural killer (NK) cells. The human BCL2-associated athanogene 6 (BAG-6, also known as BAT3; 1126 amino acids) is a cellular ligand of NKp30. To date, little is known about the molecular details of this receptor ligand system. Within the current study, we have located the binding site of NKp30 to a sequence stretch of 250 amino acids in the C-terminal region of BAG-6 (BAG-6686–936). BAG-6686–936 forms a noncovalent dimer of 57–59 kDa, which is sufficient for high affinity interaction with NKp30 (KD < 100 nm). As our most important finding, BAG-6686–936 inhibits NKp30-dependent signaling, interferon-? release, and degranulation of NK cells in the presence of malignantly transformed target cells. Based on these data, we show for the first time that BAG-6686–936 comprises a subdomain of BAG-6, which is sufficient for receptor docking and inhibition of NKp30-dependent NK cell cytotoxicity as part of a tumor immune escape mechanism. These molecular insights provide an access point to restore tumor immunosurveillance by NK cells and to increase the efficacy of cellular therapies. PMID:24133212

  12. Chemical limits to flame inhibition

    Microsoft Academic Search

    V. Babushok; W. Tsang; G. T. Linteris; D. Reinelt

    1998-01-01

    This paper deals with the ultimate limits of chemical contributions to flame inhibition. Particular attention is focussed on the inhibition cycles which regenerate the inhibitor. This leads to the definition of an idealized “perfect” inhibition cycle. It is demonstrated that for such an inhibitor in a stoichiometric methane\\/air flame, additive levels in the 0.001–0.01 mole percent range will lead to

  13. Probing distractor inhibition in visual search: Inhibition of return

    Microsoft Academic Search

    Hermann J. Müller; Adrian von Miihlenen

    2000-01-01

    The mle of inhibition of retum (IOR) in serial visual search was reinvestigated using R. Klein's (1988) paradigm of a seatvh task followed by a probe-detection task. Robes were presented at either the location of a potentially inhibited mh distractor or an empty location. No evidence of IOR was obtained when the search objects were removed after the search-task response.

  14. Protoporphyrinogen Oxidase-Inhibiting Herbicides

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Protoporphyrinogen oxidase-inhibiting herbicides (also referred to as Protox- or PPO-inhibiting herbicides) were commercialized in the 1960s and their market share reached approximately 10% (total herbicide active ingredient output) in the late 1990’s. The wide-spread adoption of glyphosate-resista...

  15. 5-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3,7-dimethoxy-4H-chromen-4-one (MSF-2) suppresses fMLP-mediated respiratory burst in human neutrophils by inhibiting phosphatidylinositol 3-kinase activity.

    PubMed

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

    2011-06-01

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

  16. Calcitonin gene-related peptide (CGRP) activates human neutrophils--inhibition by chemotactic peptide antagonist BOC-MLP.

    PubMed Central

    Richter, J; Andersson, R; Edvinsson, L; Gullberg, U

    1992-01-01

    The effect of the neuropeptides substance P, neurokinin A and alpha-calcitonin gene-related peptide (CGRP) on human neutrophil granulocytes was investigated. Substance P induced secondary granule secretion at a concentration of 100 microM. CGRP induced a significant secretory response at 10 microM and thus appeared to be about 10 times more potent than substance P. Calcitonin and a fragment of CGRP, CGRP(8-37), had no effect on neutrophil degranulation. The chemotactic peptide antagonist BOC-MLP (100 microM) inhibited lactoferrin secretion mediated both by CGRP and chemotactic peptide FMLP almost completely, while secretion in response to tumour necrosis factor (TNF) was unaffected. Results from receptor binding studies showed that CGRP and N-formyl-methionyl-leucyl-phenylalanine (FMLP) do not compete for binding. This indicates that CGRP does not exert its effects by binding to the chemotactic peptide receptor. CGRP induced a rapid increase in the cytosolic-free calcium concentration and this increase was not, unlike that induced by FMLP, abolished by preincubation of the cells with pertussis toxin (1000 ng/ml). Therefore CGRP signal transduction in neutrophils appears to involve rapid changes in the cytosolic-free calcium concentration but not a pertussis toxin-sensitive G-protein. In summary, this is the first report to show that CGRP can directly activate neutrophil granulocytes, and this probably occurs via a cell surface receptor which is distinct from that of FMLP although both the CGRP and FMLP-mediated effects can be blocked by BOC-MLP. Images Figure 3 PMID:1282494

  17. 1,25(OH)2 vitamin D3-dependent inhibition of platelet Ca2+ signaling and thrombus formation in klotho-deficient mice.

    PubMed

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

    2014-05-01

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

  18. Inhibition of MMPs by alcohols

    PubMed Central

    Tezvergil-Mutluay, Arzu; Agee, Kelli A.; Hoshika, Tomohiro; Uchiyama, Toshikazu; Tjäderhane, Leo; Breschi, Lorenzo; Mazzoni, Annalisa; Thompson, Jeremy M.; McCracken, Courtney E.; Looney, Stephen W.; Tay, Franklin R.; Pashley, David H.

    2011-01-01

    Objectives While screening the activity of potential inhibitors of matrix metalloproteinases (MMPs), due to the limited water solubility of some of the compounds, they had to be solubilized in ethanol. When ethanol solvent controls were run, they were found to partially inhibit MMPs. Thus, the purpose of this study was to compare the MMP-inhibitory activity of a series of alcohols. Methods The possible inhibitory activity of a series of alcohols was measured against soluble rhMMP-9 and insoluble matrix-bound endogenous MMPs of dentin in completely demineralized dentin. Increasing concentrations (0.17, 0.86, 1.71 and 4.28 moles/L) of a homologous series of alcohols (i.e. methanol, ethanol, propanols, butanols, pentanols, hexanols, the ethanol ester of methacrylic acid, heptanols and octanol) were compared to ethanediol, and propanediol by regression analysis to calculate the molar concentration required to inhibit MMPs by 50% (i.e. the IC50). Results Using two different MMP models, alcohols were shown to inhibit rhMMP-9 and the endogenous proteases of dentin matrix in a dose-dependent manner. The degree of MMP inhibition by alcohols increased with chain length up to 4 methylene groups. Based on the molar concentration required to inhibit rhMMP-9 fifty percent, 2-hydroxyethylmethacrylate (HEMA), 3-hexanol, 3-heptanol and 1-octanol gave the strongest inhibition. Significance The results indicate that alcohols with 4 methylene groups inhibit MMPs more effectively than methanol or ethanol. MMP inhibition was inversely related to the Hoy's solubility parameter for hydrogen bonding forces of the alcohols (i.e. to their hydrophilicity). PMID:21676453

  19. Presynaptic inhibition of elicited neurotransmitter release

    Microsoft Academic Search

    Ling-Gang Wu; Peter Saggau

    1997-01-01

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

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

    PubMed Central

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

    1997-01-01

    In mouse mast cells, both Fc epsilonRI and Fc gammaRIII are alpha beta gamma2 tetrameric complexes in which different alpha chains confer IgE or IgG ligand recognition while the signaling FcR beta and gamma chains are identical. We used primarily noninvasive techniques (changes in body temperature, dye extravasation) to assess systemic anaphylactic responses in nonanesthetized wild-type, Fc epsilonRI alpha chain -/- and FcR gamma chain -/- mice. We confirm that systemic anaphylaxis in mice can be mediated largely through IgG1 and Fc gammaRIII and we provide direct evidence that these responses reflect activation of Fc gammaRIII rather than Fc gammaRI. Furthermore, we show that Fc gammaRIII-dependent responses are more intense in normal than in congenic mast cell-deficient KitW/KitW-v mice, indicating that Fc gammaRIII responses have mast cell-dependent and -independent components. Finally, we demonstrate that the upregulation of cell surface expression of Fc gammaRIII seen in Fc epsilonRI alpha chain -/- mice corresponds to an increased association of Fc gammaRIII alpha chains with FcR beta and gamma chains and is associated with enhanced Fc gammaRIII-dependent mast cell degranulation and systemic anaphylactic responses. Therefore, the phenotype of the Fc epsilonRI alpha chain -/- mice suggests that expression of Fc epsilonRI and Fc gammaRIII is limited by availability of the FcR beta and gamma chains and that, in normal mice, changes in the expression of one receptor (Fc epsilonRI) may influence the expression of functional responses dependent on the other (Fc gammaRIII). PMID:9062349

  1. Bacterial Inhibition by Electrical Stimulation

    PubMed Central

    Asadi, Mohammad Reza; Torkaman, Giti

    2014-01-01

    Significance: Much evidence shows that electrical stimulation (ES) promotes the wound healing process. The inhibitory effect of ES on bacterial growth has been proposed as a mechanism to explain the useful effects of ES on wound healing. Bacterial burden has been associated with chronic wounds. The extensive use of antibiotics can lead to the spread of multiple drug resistant bacteria. Whether biophysical energies, such as ES, can be used as a treatment modality against pathogenic microorganisms remains an open question. Recent Advances: The research literature provides evidence for useful effects of ES in terms of inhibition of bacterial growth. The type of ES, its polarity, and the intensity of the current play a major role in establishment of antibacterial effects. Both direct current (DC) and high voltage pulse current are more effective at inhibiting bacterial growth than are other types of ES. The exact mechanism underlying the antibacterial effects of ES is not clear. Critical Issues: Available evidence indicates that microampere DC (?ADC) is better than other ES types for inhibition of bacterial growth. The results of most studies also support the application of cathodal current for bacterial growth inhibition. The current intensity of ES would appear to be tolerable by humans if used clinically for treatment of infected wounds. Future Directions: The cathodal ?ADC appears to be more effective for inhibition of microorganism growth. Further research, especially in vivo, is necessary to clarify the inhibitory effects of ES on wound bacterial infections. PMID:24761349

  2. Remote inhibition of polymer degradation.

    SciTech Connect

    Clough, Roger Lee; Celina, Mathias Christopher

    2005-08-01

    Polymer degradation has been explored on the basis of synergistic infectious and inhibitive interaction between separate materials. A dual stage chemiluminescence detection system with individually controlled hot stages was applied to probe for interaction effects during polymer degradation in an oxidizing environment. Experimental confirmation was obtained that volatile antioxidants can be transferred over a relatively large distance. The thermal degradation of a polypropylene (PP) sample receiving traces of inhibitive antioxidants from a remote source is delayed. Similarly, volatiles from two stabilized elastomers were also capable of retarding a degradation process remotely. This observation demonstrates inhibitive cross-talk as a novel interactive phenomenon between different polymers and is consequential for understanding general polymer interactions, fundamental degradation processes and long-term aging effects of multiple materials in a single environment.

  3. Type A Behavior Pattern, Inhibited Power Motivation, and Activity Inhibition

    Microsoft Academic Search

    Alan F. Fontana; Roberta L. Rosenberg; Jonathan L. Marcus; Robert D. Kerns

    1987-01-01

    The constructs of the Type A behavior pattern and the Inhibited Power Motive Syndrome (IPMS) have many features in common. The empirical relation between the two constructs was investigated in this study with 45 employed, male medical and surgical patients. Four different measures of the Type A pattern were examined. Results showed that, of the four measures, the Structured Interview

  4. Post-Stop-Signal Adjustments: Inhibition Improves Subsequent Inhibition

    ERIC Educational Resources Information Center

    Bissett, Patrick G.; Logan, Gordon D.

    2012-01-01

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

  5. Inhibition among olfactory receptor neurons

    PubMed Central

    Van der Goes van Naters, Wynand

    2013-01-01

    Often assumed to be epiphenomena of a cell’s activity, extracellular currents and resulting potential changes are increasingly recognized to influence the function of other cells in the vicinity. Experimental evidence shows that even small electric fields can modulate spike timing in neurons. Moreover, when neurons are brought close together experimentally or in pathological conditions, activity in one neuron can excite its neighbors. Inhibitory ephaptic mechanisms, however, may depend on more specialized coupling among cells. Recent studies in the Drosophila olfactory system have shown that excitation of a sensory neuron can inhibit its neighbor, and it was speculated that this interaction was ephaptic. Here we give an overview of ephaptic interactions that effect changes in spike timing, excitation or inhibition in diverse systems with potential relevance to human neuroscience. We examine the mechanism of the inhibitory interaction in the Drosophila system and that of the well-studied ephaptic inhibition of the Mauthner cell in more detail. We note that both current towards and current away from the local extracellular environment of a neuron can inhibit it, but the mechanism depends on the specific architecture of each system. PMID:24167484

  6. Infant Predictors of Behavioural Inhibition

    ERIC Educational Resources Information Center

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

    2008-01-01

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

  7. Azide inhibition of urate oxidase.

    PubMed

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

    2014-07-01

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

  8. Direct renin inhibition: clinical pharmacology.

    PubMed

    Azizi, Michel

    2008-06-01

    Initial attempts to inhibit renin in humans have faced numerous difficulties. Molecular modeling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors such as aliskiren. Aliskiren has a low bioavailability (2.6% to 5%) compensated by its high potency to inhibit renin and a long plasma half-life (24 to 40 h), which makes it suitable for once-daily dosing. The once-daily administration of aliskiren to hypertensive patients lowers blood pressure as strongly as standard doses of established AT1 receptor blockers (losartan, valsartan, and irbesartan), angiotensin-converting enzyme inhibitors (ramipril and lisnopril), hydrochlorothiazide, or long-acting calcium channel blockers (amlodipine). In combination therapy, aliskiren further decreases blood pressure when combined with either hydrochlorothiazide, amlodipine, valsartan, irbesartan, or ramipril. However, the biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme inhibition and angiotensin II antagonism, particularly in terms of angiotensin profiles and interactions with the bradykinin-NO-cGMP pathway. Blockade of the renin-angiotensin system with angiotensin I-converting enzyme inhibitors, AT1 receptor blockers, or a combination of these drugs has become one of the most successful therapeutic approaches in medicine. However, it remains unclear how to optimize renin-angiotensin system blockade to maximize cardiovascular and renal benefits. In this context, renin inhibition to render the renin-angiotensin system fully quiescent is a new possibility requiring further study. Preliminary results show that short-term administration of aliskiren has beneficial anti-albuminuric effects in diabetic patients with chronic nephropathy and favorable neurohormonal effects in patients with chronic heart failure. PMID:18368379

  9. The toxicology of chemokine inhibition.

    PubMed

    Schroff, Robert W; Touvay, Caroline; Culler, Michael D; Dong, Jesse Z; Taylor, John E; Thurieau, Christophe; McKilligin, Elaine

    2005-09-01

    The dividing line between essential physiological inflammatory processes and excessive pathological inflammation is often very thin - in some circumstances, indeed, it may be non-existent. Devising anti-inflammatory medications that effectively target only the pathological component therefore remains a central challenge for the pharmaceutical industry. At present, the general rule is that the more powerful the anti-inflammatory effect of a drug, the greater the side-effects that accompany it. Steroids, for example, are potent anti-inflammatory medications, but they have a diverse array of side effects that substantially limit their use. Since chemokines play a central role in regulating the immune system, and in particular, the trafficking of leukocytes, inhibiting their action may represent a powerful new therapeutic strategy for treating diseases with an inflammatory component. However, this potential will only be realized if it is possible to interfere with chemokine signaling networks, without inducing unacceptable side effects. Although very little, direct human toxicology has been carried out using chemokine inhibitors, there is now a sufficient body of indirect and circumstantial evidence (for example, from genetically modified mice and from animal model studies using chemokine inhibitors) to allow a tentative assessment of the biological impact of chemokine inhibition. The purpose of this review is to outline the available data and to speculate on the likely toxicological profile resulting from chemokine inhibition. The tentative conclusion is that anti-inflammatory therapy achieved through chemokine inhibition may have fewer side effects than originally expected, even when the actions of multiple chemokines are inhibited simultaneously. PMID:16178726

  10. Inhibition of Hsp90 in Streptomyces coelicolor

    E-print Network

    Wu, Katherine A. (Katherine Ann)

    2005-01-01

    Inhibition of the chaperone protein Hsp90 in plants and insects has been found to result in drastic changes in phenotype. We investigated the effect of Hsp90 inhibition on the bacteria Streptomyces coelicolor. These changes ...

  11. Myc inhibition impairs autophagosome formation

    PubMed Central

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

    2013-01-01

    Autophagy, a major clearance route for many long-lived proteins and organelles, has long been implicated in cancer development. Myc is a proto-oncogene often found to be deregulated in many cancers, and thus is an attractive target for design of cancer therapy. Therefore, understanding the relationship between anti-Myc strategies and autophagy will be important for development of effective therapy. Here, we show that Myc depletion inhibits autophagosome formation and impairs clearance of autophagy substrates. Myc suppression has an inhibitory effect on autophagy via reduction of c-Jun N-terminal kinase 1 (JNK1) and B-cell lymphoma 2 (Bcl2) phosphorylation. Additionally, the decrease in JNK1 phosphorylation observed with Myc knockdown is associated with a reduction in ROS production. Our data suggest that targeting Myc in cancer therapy might have the additional benefit of inhibiting autophagy in the case of therapy resistance associated with chemotherapy-induced autophagy. PMID:23933736

  12. 8, 87438771, 2008 Inhibition of ice

    E-print Network

    Paris-Sud XI, Université de

    ACPD 8, 8743­8771, 2008 Inhibition of ice crystallisation B. J. Murray Title Page Abstract Chemistry and Physics Discussions Inhibition of ice crystallisation in highly viscous aqueous organic acid­8771, 2008 Inhibition of ice crystallisation B. J. Murray Title Page Abstract Introduction Conclusions

  13. Do vanadate polyanions inhibit phosphotransferase enzymes?

    PubMed

    Boyd, D W; Kustin, K; Niwa, M

    1985-03-01

    Decavanadate inhibits hexokinase, adenylate kinase and phosphofructokinase; neither mono-, tri nor tetrameric vanadate anion is an inhibitor. Decavanadate inhibits phosphofructokinase obtained from bacterial and protistic sources. No form of vanadium(V) anion inhibits galacto-, glycero-, pyruvate and creatine kinase, or inorganic pyrophosphatase. Decavanadate appears to be a non-competitive inhibitor of both hexokinase substrates. PMID:2982413

  14. Time-dependent inhibited spontaneous emission

    Microsoft Academic Search

    D. Branning; Y. H. Shin; S. Khanal; A. L. Migdall

    2011-01-01

    The spontaneous emission rate of photon pairs in a parametric downconverter can be inhibited by a cavity mirror. Using a fast switch, we detect photons within the cavity during times when the emission was inhibited. In the process of inhibited spontaneous emission, an excited atom is prevented from spontaneously emitting radiation by a reflecting cavity that surrounds it. Quantum theory

  15. Behavioral inhibition: A neurobiological perspective

    Microsoft Academic Search

    Barak E. Morgan

    2006-01-01

    Behavioral inhibition (BI) during early childhood has been associated with subsequent development of anxiety disorders. However,\\u000a understanding of the neuroanatomical substrates of BI in humans generally has not kept pace with that of anxiety disorders.\\u000a Recent interpretations and implementations of Gray’s and Kagan’s concepts of BI are examined from the perspective of current\\u000a neurobiological models. Particular attention is given to

  16. Th2 Cytokines Inhibit Lymphangiogenesis

    PubMed Central

    Savetsky, Ira L.; Ghanta, Swapna; Gardenier, Jason C.; Torrisi, Jeremy S.; García Nores, Gabriela D.; Hespe, Geoffrey E.; Nitti, Matthew D.; Kataru, Raghu P.; Mehrara, Babak J.

    2015-01-01

    Lymphangiogenesis is the process by which new lymphatic vessels grow in response to pathologic stimuli such as wound healing, inflammation, and tumor metastasis. It is well-recognized that growth factors and cytokines regulate lymphangiogenesis by promoting or inhibiting lymphatic endothelial cell (LEC) proliferation, migration and differentiation. Our group has shown that the expression of T-helper 2 (Th2) cytokines is markedly increased in lymphedema, and that these cytokines inhibit lymphatic function by increasing fibrosis and promoting changes in the extracellular matrix. However, while the evidence supporting a role for T cells and Th2 cytokines as negative regulators of lymphatic function is clear, the direct effects of Th2 cytokines on isolated LECs remains poorly understood. Using in vitro and in vivo studies, we show that physiologic doses of interleukin-4 (IL-4) and interleukin-13 (IL-13) have profound anti-lymphangiogenic effects and potently impair LEC survival, proliferation, migration, and tubule formation. Inhibition of these cytokines with targeted monoclonal antibodies in the cornea suture model specifically increases inflammatory lymphangiogenesis without concomitant changes in angiogenesis. These findings suggest that manipulation of anti-lymphangiogenic pathways may represent a novel and potent means of improving lymphangiogenesis. PMID:26039103

  17. Inhibition of Hendra Virus Fusion

    PubMed Central

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

    2006-01-01

    Hendra virus (HeV) is a recently identified paramyxovirus that is fatal in humans and could be used as an agent of bioterrorism. The HeV receptor-binding protein (G) is required in order for the fusion protein (F) to mediate fusion, and analysis of the triggering/activation of HeV F by G should lead to strategies for interfering with this key step in viral entry. HeV F, once triggered by the receptor-bound G, by analogy with other paramyxovirus F proteins, undergoes multistep conformational changes leading to a six-helix bundle (6HB) structure that accomplishes fusion of the viral and cellular membranes. The ectodomain of paramyxovirus F proteins contains two conserved heptad repeat regions (HRN and HRC) near the fusion peptide and the transmembrane domains, respectively. Peptides derived from the HRN and HRC regions of F are proposed to inhibit fusion by preventing F, after the initial triggering step, from forming the 6HB structure that is required for fusion. HeV peptides have previously been found to be effective at inhibiting HeV fusion. However, we found that a human parainfluenza virus 3 F-peptide is more effective at inhibiting HeV fusion than the comparable HeV-derived peptide. PMID:16973588

  18. A Fusion-Inhibiting Peptide against Rift Valley Fever Virus Inhibits Multiple, Diverse Viruses

    E-print Network

    A Fusion-Inhibiting Peptide against Rift Valley Fever Virus Inhibits Multiple, Diverse Viruses (Class I, II, and III) based on the protein sequence and structure. For Rift Valley fever virus (RVFV KW, Taylor SL, et al. (2013) A Fusion-Inhibiting Peptide against Rift Valley Fever Virus Inhibits

  19. Honokiol inhibits lung tumorigenesis through inhibition of mitochondrial function.

    PubMed

    Pan, Jing; Zhang, Qi; Liu, Qian; Komas, Steven M; Kalyanaraman, Balaraman; Lubet, Ronald A; Wang, Yian; You, Ming

    2014-11-01

    Honokiol is an important bioactive compound found in the bark of Magnolia tree. It is a nonadipogenic PPAR? agonist and capable of inhibiting the growth of a variety of tumor types both in vitro and in xenograft models. However, to fully appreciate the potential chemopreventive activity of honokiol, a less artificial model system is required. To that end, this study examined the chemopreventive efficacy of honokiol in an initiation model of lung squamous cell carcinoma (SCC). This model system uses the carcinogen N-nitroso-trischloroethylurea (NTCU), which is applied topically, reliably triggering the development of SCC within 24 to 26 weeks. Administration of honokiol significantly reduced the percentage of bronchial that exhibit abnormal lung SCC histology from 24.4% bronchial in control to 11.0% bronchial in honokiol-treated group (P = 0.01) while protecting normal bronchial histology (present in 20.5% of bronchial in control group and 38.5% of bronchial in honokiol-treated group. P = 0.004). P63 staining at the SCC site confirmed the lung SCCs phenotype. In vitro studies revealed that honokiol inhibited lung SCC cells proliferation, arrested cells at the G1-S cell-cycle checkpoint, while also leading to increased apoptosis. Our study showed that interfering with mitochondrial respiration is a novel mechanism by which honokiol changed redox status in the mitochondria, triggered apoptosis, and finally leads to the inhibition of lung SCC. This novel mechanism of targeting mitochondrial suggests honokiol as a potential lung SCC chemopreventive agent. PMID:25245764

  20. Self-regulation, ego depletion, and inhibition.

    PubMed

    Baumeister, Roy F

    2014-12-01

    Inhibition is a major form of self-regulation. As such, it depends on self-awareness and comparing oneself to standards and is also susceptible to fluctuations in willpower resources. Ego depletion is the state of reduced willpower caused by prior exertion of self-control. Ego depletion undermines inhibition both because restraints are weaker and because urges are felt more intensely than usual. Conscious inhibition of desires is a pervasive feature of everyday life and may be a requirement of life in civilized, cultural society, and in that sense it goes to the evolved core of human nature. Intentional inhibition not only restrains antisocial impulses but can also facilitate optimal performance, such as during test taking. Self-regulation and ego depletion- may also affect less intentional forms of inhibition, even chronic tendencies to inhibit. Broadly stated, inhibition is necessary for human social life and nearly all societies encourage and enforce it. PMID:25149821

  1. Inhibition of human napsin A.

    PubMed

    Cronshaw, Rebecca F; Schauer-Vukasinovic, Vesna; Powell, David J; Giller, Thomas; Bur, Daniel; Kay, John

    2003-02-01

    The newly-discovered human aspartic proteinase, napsin A was not susceptible to protein inhibitors from potato, squash or yeast but was weakly inhibited by the 17 kDa polypeptide from Ascaris lumbricoides and potently by isovaleryl and lactoyl-pepstatins. A series of synthetic inhibitors was also investigated which contained in the P(1)-P(1)' positions the dipeptide analogue statine or its phenylalanine or cyclohexylalanine homologues and in which the residues occupying P(4)-P(3)' were varied systematically. On this basis, the active site of napsin A can be readily distinguished from other human aspartic proteinases. PMID:12625824

  2. Respiratory Syncytial Virus Stimulates Neutrophil Degranulation and Chemokine Release

    Microsoft Academic Search

    Patarin Jaovisidha; Mark E. Peeples; Abbi A. Brees; Laura R. Carpenter; James N. Moy

    Neutrophil infiltration of the airways is a common finding in respiratory syncytial virus (RSV) bronchiolitis. Neutrophil-derived chemokines and neutrophil granule contents can cause further inflammation, hyperresponsiveness, and damage of the airways. In this study, peripheral blood neutrophils incubated with RSV (multiplicity of infection (MOI) 5 10) induced IL-8, macrophage inflammatory protein (MIP)-1 a, MIP-1b, and myeloperoxidase (MPO) release. In contrast,

  3. Eosinophil Degranulation in the Presence of Lung Fibroblasts

    Microsoft Academic Search

    Shigeru Takafuji; Shunsuke Shoji; Koji Ito; Kazuhiko Yamamoto; Takemasa Nakagawa

    1998-01-01

    Background: Although eosinophils (Eos) and fibroblasts (Fb) are closely approximated in the bronchial submucosae of asthmatics, and are believed to play important roles in the pathogenesis of bronchial asthma, the interaction between Eos and Fb has not been thoroughly elucidated. In this study, we have examined eosinophil cationic protein (ECP) release from human Eos cultured in the presence of human

  4. Graphene: corrosion-inhibiting coating.

    PubMed

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

    2012-02-28

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

  5. Pharmacological inhibition of poly(ADP-ribose) polymerase inhibits angiogenesis

    SciTech Connect

    Rajesh, Mohanraj [Section On Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, NIAAA, National Institutes of Health, 5625 Fishers Lane, MSC-9413, Bethesda, MD 20892-9413 (United States); Mukhopadhyay, Partha [Section On Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, NIAAA, National Institutes of Health, 5625 Fishers Lane, MSC-9413, Bethesda, MD 20892-9413 (United States); Batkai, Sandor [Section On Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, NIAAA, National Institutes of Health, 5625 Fishers Lane, MSC-9413, Bethesda, MD 20892-9413 (United States); Godlewski, Grzegorz [Section On Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, NIAAA, National Institutes of Health, 5625 Fishers Lane, MSC-9413, Bethesda, MD 20892-9413 (United States); Hasko, Gyoergy [Department of Surgery, UMDNJ-New Jersey Medical School, Newark, NJ 07103 (United States); Liaudet, Lucas [Department of Intensive Care Medicine, University Hospital, 1011 Lausanne (Switzerland); Pacher, Pal [Section On Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, NIAAA, National Institutes of Health, 5625 Fishers Lane, MSC-9413, Bethesda, MD 20892-9413 (United States)]. E-mail: pacher@mail.nih.gov

    2006-11-17

    Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which plays an important role in regulating cell death and cellular responses to DNA repair. Pharmacological inhibitors of PARP are being considered as treatment for cancer both in monotherapy as well as in combination with chemotherapeutic agents and radiation, and were also reported to be protective against untoward effects exerted by certain anticancer drugs. Here we show that pharmacological inhibition of PARP with 3-aminobenzamide or PJ-34 dose-dependently reduces VEGF-induced proliferation, migration, and tube formation of human umbilical vein endothelial cells in vitro. These results suggest that treatment with PARP inhibitors may exert additional benefits in various cancers and retinopathies by decreasing angiogenesis.

  6. Selective inhibition of factor inhibiting hypoxia-inducible factor.

    PubMed

    McDonough, Michael A; McNeill, Luke A; Tilliet, Melanie; Papamicaël, Cyril A; Chen, Qiu-Yun; Banerji, Biswadip; Hewitson, Kirsty S; Schofield, Christopher J

    2005-06-01

    A set of four non-heme iron(II) and 2-oxoglutarate-dependent enzymes catalyze the post-translational modification of a transcription factor, hypoxia inducible factor (HIF), that mediates the hypoxic response in animals. Hydroxylation of HIF both causes its degradation and limits its activity. We describe how the use of structural data coupled to solid-phase synthesis led to the discovery of a selective inhibitor of one of the HIF hydroxylases. The inhibitor N-oxalyl-d-phenylalanine was shown to inhibit the HIF asparaginyl hydroxylase (FIH) but not a HIF prolyl hydroxylase. A crystal structure of the inhibitor complexed to FIH reveals that it binds in the 2OG and, likely, in the dioxygen binding site. The results will help to enable the modulation of the hypoxic response for the up-regulation of specific genes of biomedical importance, such as erythropoietin and vascular endothelial growth factor. PMID:15913349

  7. Genistein Treatment of Cells Inhibits Arenavirus Infection

    PubMed Central

    Vela, Eric M.; Bowick, Gavin C.; Herzog, Norbert K.; Aronson, Judith F.

    2008-01-01

    Arenaviridae is a family of enveloped viruses some of which are capable of causing hemorrhagic fever syndromes in humans. In this report, we demonstrate that treatment of host cells with the tyrosine kinase inhibitor genistein inhibits infection of cells with the New World arenavirus Pichindé (PICV). The greatest degree of inhibition was observed in pre-treated target cells, but modest inhibition of infection was also seen when drug was added to cultures up to 48 hours after infection. We show that PICV induced phosphorylation of the activating transcription factor-2 protein (ATF-2) and cyclic adenosine monophosphate response element-binding protein (CREB) is inhibited following genistein treatment. Lastly, genistein treatment also inhibited transduction of cells with pseudotyped retrovirus particles expressing envelope proteins of the Old World arenavirus Lassa virus. These results demonstrate that kinase activity is required for arenavirus infection and that therapeutics designed to inhibit kinase activity should be explored. PMID:17961732

  8. DISULFIRAM INHIBITS TNF-?-INDUCED CELL DEATH

    Microsoft Academic Search

    Aiping Zhao; Zheng-Qi Wu; Matthew Pollack; Florence M Rollwagen; Przemyslaw Hirszel; Xiaoming Zhou

    2000-01-01

    Disulfiram, a clinically employed alcohol deterrent, was recently discovered to inhibit caspase-3 and DNA fragmentation. Using LLC-PK1 cells and murine liver as models, we examined if the drug inhibited TNF-?-induced cell death. Disulfiram produced dose-dependent inhibition of TNF-?-induced cell death as well as caspase-3-like activity. Disulfiram retained 80% of its effect when added 4h after TNF-?. Disulfiram protected the cells

  9. Tetrahydrocannabinol inhibition of macrophage nitric oxide production

    Microsoft Academic Search

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

    1996-01-01

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

  10. Inhibition of cortiocosteroidogenesis by delta-9-tetrahydrocannabinol.

    PubMed

    Warner, W; Harris, L S; Carchman, R A

    1977-12-01

    ACTH, cholera toxin, cyclic AMP but not pregnenolone-induced steroidogenesis in Y-1 functional mouse adrenal tumor cells was significantly inhibited by delta-9-tetrahydrocannabinol, cannabidiol, and cannabinol. The inhibition of steroidogenesis could not be correlated with a general depression in cell function or viability. The data suggest that cannabinoids inhibit corticosteroidogenesis at a site between the synthesis of cAMP and of pregnenolone. PMID:201449

  11. Inhibition of the dorsal premotor cortex does not repair surround inhibition in writer's cramp patients.

    PubMed

    Veugen, Lidwien C; Hoffland, Britt S; Stegeman, Dick F; van de Warrenburg, Bart P

    2013-03-01

    Writer's cramp is a task-specific form of focal dystonia, characterized by abnormal movements and postures of the hand and arm during writing. Two consistent abnormalities in its pathophysiology are a loss of surround inhibition and overactivity of the dorsal premotor cortex (PMd). This study aimed to assess a possible link between these two phenomena by investigating whether PMd inhibition leads to an improvement of surround inhibition, in parallel with previously demonstrated writing improvement. Fifteen writer's cramp patients and ten controls performed a simple motor hand task during which surround inhibition was measured using transcranial magnetic stimulation. Motor cortical excitability was measured of the active and surround muscles at three phases of the task. Surround inhibition and writing performance were assessed before and after PMd inhibitory continuous theta burst stimulation. In contrast to healthy controls, patients did not show inhibition of the abductor digiti minimi muscle during movement initiation of the first dorsal interosseus muscle, confirming the loss of surround inhibition. PMd inhibition led to an improvement of writing speed in writer's cramp patients. However, in both groups, no changes in surround inhibition were observed. The results confirm a role for the PMd in the pathophysiology of writer's cramp. We show that PMd inhibition does not lead to restoration of the surround inhibition defect in writer's cramp, despite the improvement in writing. This questions the involvement of the PMd in the loss of surround inhibition, and perhaps also the direct link between surround inhibition and dystonia. PMID:23192337

  12. Inhibition drives early feature-based attention

    PubMed Central

    Moher, Jeff; Lakshmanan, Balaji M.; Egeth, Howard E.; Ewen, Joshua B.

    2013-01-01

    Attention can modulate processing of visual input according to task-relevant features, even as early as ~100 ms after stimulus presentation. In the present study, ERP and behavioral data reveal that inhibition of distractor features, rather than activation of target features, is the primary driver of early feature-based selection in human observers. This discovery of inhibition consistent with task goals during early visual processing suggests that inhibition plays a much larger role at an earlier stage of target selection than previously recognized, and highlights the importance of understanding the role of inhibition (in addition to activation) in attention. PMID:24390823

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

    PubMed Central

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

    2014-01-01

    Photo-activation of psoralen with UVA irradiation, referred to as PUVA, is used in the treatment of proliferative skin disorders. The anti-proliferative effects of PUVA have been largely attributed to psoralen intercalation of DNA, which upon UV treatment, triggers the formation of interstrand DNA crosslinks (ICL) that inhibit transcription and DNA replication. Here, we show that PUVA exerts antitumor effects in models of human breast cancer that overexpress the ErbB2 receptor tyrosine kinase oncogene, through a new mechanism. Independent of ICL formation, the antitumor effects of PUVA in ErbB2+ breast cancer models can instead be mediated through inhibition of ErbB2 activation and signaling. Using a mass spectroscopy-based approach, we show for the first time that photo-activated 8MOP (8-methoxypsoralen) interacts with the ErbB2 catalytic autokinase domain. Furthermore, PUVA can reverse therapeutic resistance to lapatinib and other ErbB2 targeted therapies, including resistance mediated via expression of a phosphorylated, truncated form of ErbB2 (p85ErbB2) that is preferentially expressed in tumor cell nuclei. Current ErbB2 targeted therapies, small molecule kinase inhibitors or antibodies, do not block the phosphorylated, activated state of p85ErbB2. Here we show that PUVA reduced p85ErbB2 phosphorylation leading to tumor cell apoptosis. Thus, in addition to its effects on DNA and the formation of ICL, PUVA represents a novel ErbB2 targeted therapy for the treatment of ErbB2+ breast cancers, including those that have developed resistance to other ErbB2 targeted therapies. PMID:24551203

  14. Well having inhibited microbial growth

    DOEpatents

    Lee, Brady D.; Dooley, Kirk J.

    2006-08-15

    The invention includes methods of inhibiting microbial growth in a well. A packing material containing a mixture of a first material and an antimicrobial agent is provided to at least partially fill a well bore. One or more access tubes are provided in an annular space around a casing within the well bore. The access tubes have a first terminal opening located at or above a ground surface and have a length that extends from the first terminal opening at least part of the depth of the well bore. The access tubes have a second terminal opening located within the well bore. An antimicrobial material is supplied into the well bore through the first terminal opening of the access tubes. The invention also includes well constructs.

  15. Magnetic Catalysis vs Magnetic Inhibition

    E-print Network

    Kenji Fukushima; Yoshimasa Hidaka

    2012-09-06

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

  16. Mechanisms of inhibition of calcification.

    PubMed

    Blumenthal, N C

    1989-10-01

    Mineralization processes in the body are controlled by physicochemical and cellular regulation of hydroxyapatite (HA) nucleators and inhibitors. The chemical mechanism of action of HA inhibitors has been studied in vitro using solution pH-stat techniques or Types I and II collagen gel diffusion systems. Three biologically relevant systems are used with these methodologies: (1) transformation of amorphous calcium phosphate (ACP) to crystalline HA; (2) direct formation of HA; and (3) growth of HA crystals. Several different mechanisms have been identified for HA inhibition. Condensed phosphates (containing P-O-P linkages) and diphosphonates (containing P-C-P linkages) bind strongly to the surface of forming HA nuclei and crystals and poison growth sites at concentrations as low as 10(-6) M, blocking HA formation. From this in vitro work, diphosphonates have been developed for the treatment of Paget's disease. Proteoglycans, found in cartilage, delay HA formation by a steric effect whereby large volumes of solution become unavailable for HA formation and growth as these enormous macromolecules tumble about. Mg ions enter the structure of forming HA nuclei by replacing Ca, resulting in a distorted atomic structure that slows subsequent growth to HA. Al ions delay HA formation, not by entering the structure of forming HA nuclei, but by adsorbing on the surface of growing HA crystals. Serum proteins slow the transformation of ACP to HA by adsorbing on the ACP surface, which decreases its dissolution rate. Metal-citrate complexes can inhibit HA formation and growth at concentrations as low as 10(-5) to 10(-6) M. Phosphorylated molecules such as acidic proline-rich phosphoproteins and statherins found in saliva suppress HA crystal growth on tooth surfaces by adsorbing on active surface sites. Future research in this field lies in the study of interactions of HA inhibitors found together in calcifying tissues. PMID:2676300

  17. Inhibition of Return Arises from Inhibition of Response Processes: An Analysis of Oscillatory Beta Activity

    Microsoft Academic Search

    Bernhard Pastötter; Simon Hanslmayr; Karl-heinz Bäuml

    2008-01-01

    In the orienting of attention paradigm, inhibition of return (IOR) refers to slowed responses to targets presented at the same location as a preceding stimulus. No consensus has yet been reached regarding the stages of information processing underlying the inhibition. We report the results of an electro-encephalogram experiment designed to examine the involvement of response inhibition in IOR. Using a

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

    ERIC Educational Resources Information Center

    Adams, Nena C.; Jarrold, Christopher

    2012-01-01

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

  19. Hydrogen production from inhibited anaerobic composters

    Microsoft Academic Search

    R. Sparling; D. Risbey; H. M. Poggi-Varaldo

    1997-01-01

    This paper investigated hydrogen production from a model lignocellulosic waste in inhibited solid substrate anaerobic digesters. Acetylene at 1% vv in the headspace was as effective as bromoethanesulfonate in inhibiting methanogenic activity in batch anaerobic composters containing 25% (wv) total organic solids inoculated with an undefined cellulotytic consortium derived from anaerobic digesters. Acetylene also had no effect on the rate

  20. A Qualitative Approach to Enzyme Inhibition

    ERIC Educational Resources Information Center

    Waldrop, Grover L.

    2009-01-01

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

  1. Inhibition and Facilitation of Nucleic Acid Amplification

    Microsoft Academic Search

    IAN G. WILSON

    1997-01-01

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

  2. Inhibited and Uninhibited Types of Children.

    ERIC Educational Resources Information Center

    Kagan, Jerome; And Others

    1989-01-01

    Investigates the preservation of inhibited and uninhibited behaviors in 100 children of 14, 20, 32, and 48 months. Children who had been extremely inhibited or uninhibited at 14 and 20 months differed significantly at 4 years of age in behavior and cardiac acceleration. (RJC)

  3. Optimal Decision Making in Neural Inhibition Models

    ERIC Educational Resources Information Center

    van Ravenzwaaij, Don; van der Maas, Han L. J.; Wagenmakers, Eric-Jan

    2012-01-01

    In their influential "Psychological Review" article, Bogacz, Brown, Moehlis, Holmes, and Cohen (2006) discussed optimal decision making as accomplished by the drift diffusion model (DDM). The authors showed that neural inhibition models, such as the leaky competing accumulator model (LCA) and the feedforward inhibition model (FFI), can mimic the…

  4. Carbon Dioxide Corrosion and Inhibition Studies

    E-print Network

    Petta, Jason

    · Corrosion inhibition very important in the oil industry · Film forming inhibitors containing nitrogen inhibitor for CO2 corrosion · Electrochemistry provides useful ways to study corrosion · At room temperatureCarbon Dioxide Corrosion and Inhibition Studies Kristin Gilida #12;Outline · Background

  5. Factors Impacting the Child with Behavioral Inhibition

    ERIC Educational Resources Information Center

    Hornbuckle, Suzanne R.

    2010-01-01

    Various factors influence the developmental course of the behaviorally inhibited child. These factors include reciprocating, contextual factors, such as the child's own traits, the environment, the maternal characteristics, and the environment. Behaviorally inhibited children show physiological and behavioral signs of fear and anxiety when…

  6. Inhibition of Experimental Dental Caries by Antibiotics

    PubMed Central

    Fitzgerald, Robert J.

    1972-01-01

    A variety of antibiotic and chemotherapeutic agents were tested for their ability to inhibit the development of dental caries in Sprague-Dawley rats receiving the drugs in a coarse-particle sucrose-containing diet. Drugs which inhibit gram-positive microorganisms were effective inhibitors of caries, whereas agents which are active solely against gram-negative bacteria did not inhibit caries development. In vivo efficacy of the agents tested generally, but not invariably, paralleled in vitro inhibition of the growth of Streptococcus mutans strain FA-1, an organism which was isolated from carious Sprague-Dawley rats and which is known to induce caries in gnotobiotic Sprague-Dawley rats. Caries was significantly inhibited when 1-ephenamine penicillin (20 units/mg) was administered intermittently in the diet, 1 day per week or 1 week of every 4 weeks, but protection against caries was greatest when the same amount of the drug was fed continuously. PMID:4670694

  7. Tetrahydrocannabinol inhibition of macrophage nitric oxide production.

    PubMed

    Coffey, R G; Yamamoto, Y; Snella, E; Pross, S

    1996-09-13

    delta 9-Tetrahydrocannabinol (THC) inhibited nitric oxide (NO) production by mouse peritoneal macrophages activated by bacterial endotoxin lipopolysaccharide (LPS) and interferon-gamma (IFN)-gamma). Inhibition of NO production was noted at THC concentrations as low as 0.5 microgram/mL, and was nearly total at 7 micrograms/mL. Inhibition was greatest if THC was added 1-4 hr before induction of nitric oxide synthase (NOS) by LPS and IFN-gamma, and declined with time after addition of the inducing agents. This suggested that an early step such as NOS gene transcription or NOS synthesis, rather than NOS activity, was affected by THC. Steady-state levels of mRNA for NOS were not affected by THC. In contrast, protein synthesis was inhibited as indicated by immunoblotting. NOS activity was also decreased in the cytosol of cells pretreated with THC. Addition of excess cofactors did not restore activity. Inhibition of NO production was greater at low levels of IFN-gamma, indicating the ability of the cytokine to overcome inhibition. The effectiveness of various THC analogues, in decreasing order of potency, was delta 8-THC > delta 9-THC > cannabidiol > or = 11-OH-THC > cannabinol. The presumably inactive stereoisomer, (+)delta 9-THC, and the endogenous ligand for cannabinoid receptors, anandamide, were weakly inhibitory. Inhibition may be mediated by a process that depends partly on stereoselective receptors and partly on a nonselective process. LPS, IFN-gamma, hormone receptor agonists, and forskolin increased macrophage cyclic AMP levels. THC inhibited this increase, indicating functional cannabinoid receptors. Addition of 8-bromocyclic AMP increased NO 2-fold, and partially restored NO production that had been inhibited by THC. This occurred only under conditions of limited NOS induction, suggesting that the effect of THC on cyclic AMP was responsible for only a small portion of the inhibition of NO. PMID:8765472

  8. Cytokinin inhibition of leaf senescence

    PubMed Central

    Zwack, Paul J.; Rashotte, Aaron M.

    2013-01-01

    The senescence delaying effect of cytokinin is well known, however, the details behind how this process occurs remain unclear. Efforts to improve understanding of this phenomenon have led to the identification in Arabidopsis of specific cytokinin signaling components through which senescence signal responses are regulated. These include the cytokinin receptor (AHK3), the type-B response regulator (ARR2) and the recently identified cytokinin response factor (CRF6). At the mechanistic end of this process, it was found that increased cell-wall invertase activity which occurs in response to cytokinin is both necessary and sufficient for the inhibition of senescence. Yet, a direct link between the signaling and mechanistic steps of a cytokinin regulated senescence process has yet to be demonstrated. This may be in part because the relationship between senescence and primary metabolism implied by the key role of cell-wall invertase is the subject of two apparently opposing bodies of evidence. Here we briefly summarize and propose a model in which cytokinin mediated changes in sink/source relationships leads to delayed senescence which is consistent with existing evidence both for and against sugars as a trigger for developmental senescence. PMID:23656876

  9. Allosteric Inhibition Through Core Disruption

    SciTech Connect

    Horn, James R.; Shoichet, Brian K. (NWU); (UCSF)

    2010-03-05

    Although inhibitors typically bind pre-formed sites on proteins, it is theoretically possible to inhibit by disrupting the folded structure of a protein or, in the limit, to bind preferentially to the unfolded state. Equilibria defining how such molecules act are well understood, but structural models for such binding are unknown. Two novel inhibitors of {beta}-lactamase were found to destabilize the enzyme at high temperatures, but at lower temperatures showed no preference for destabilized mutant enzymes versus stabilized mutants. X-ray crystal structures showed that both inhibitors bound to a cryptic site in {beta}-lactamase, which the inhibitors themselves created by forcing apart helixes 11 and 12. This opened up a portion of the hydrophobic core of the protein, into which these two inhibitors bind. Although this binding site is 16 {angstrom} from the center of the active site, the conformational changes were transmitted through a sequence of linked motions to a key catalytic residue, Arg244, which in the complex adopts conformations very different from those in catalytically competent enzyme conformations. These structures offer a detailed view of what has heretofore been a theoretical construct, and suggest the possibility for further design against this novel site.

  10. Inhibition of muscle force by vanadate.

    PubMed Central

    Wilson, G J; Shull, S E; Cooke, R

    1995-01-01

    Vanadate (Vi), an analogue of inorganic phosphate (Pi), is known to bind tightly with a long half life to the myosin MgATPase site, producing a complex which inhibits force. Both of these ligands bind to an actin.myosin.ADP state that follows the release of Pi in the enzymatic cycle, and their effects on muscle fibers and proteins in solution provide information on the properties of this state. The inhibition of active force generation began to occur at a [Vi] of 5 microM and was 90% complete at a [Vi] of 1 mM. Hill plots of the inhibition of force by Vi approximated that expected for a simple binding isotherm. Similar plots were obtained at both 25 degrees C and 5 degrees C. A simple binding isotherm is not expected to occur in a muscle fiber where steric constraints imposed by the intact filaments should introduce more complexity into the energetics of ligand binding. The inhibition of MgATPase activity for acto-subfragment-1 to 50% of controls occurred at a [Vi] which was only 20-fold higher than that required to inhibit force generation in fibers to the same level. Some models of actomyosin interactions would predict that the range of [Vi] required for complete force inhibition in fibers and the difference in the [Vi] required for inhibition in fibers and of myosin in solution would both be much larger. PMID:7711244

  11. Acetylcholinesterase inhibition by pitofenone: a spasmolytic compound.

    PubMed

    Punekar, N S; Kulkarni, A V

    1991-12-01

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

  12. Benzimidazole analogs inhibit human herpesvirus 6.

    PubMed

    Prichard, Mark N; Frederick, Samuel L; Daily, Shannon; Borysko, Katherine Z; Townsend, Leroy B; Drach, John C; Kern, Earl R

    2011-05-01

    Several benzimidazole nucleoside analogs, including 1H-?-D-ribofuranosyl-2-bromo-5,6-dichlorobenzimidazole (BDCRB) and 1H-?-L-ribofuranosyl-2-isopropylamino-5,6-dichlorobenzimidazole (maribavir [MBV]), inhibit the replication of human cytomegalovirus. Neither analog inhibited the related betaherpesvirus human herpesvirus 6 (HHV-6). Additional analogs of these compounds were evaluated against both variants of HHV-6, and two L-analogs of BDCRB had good antiviral activity against HHV-6A, as well as more modest inhibition of HHV-6B replication. PMID:21300829

  13. Habituation, latent inhibition, and extinction.

    PubMed

    Jordan, Wesley P; Todd, Travis P; Bucci, David J; Leaton, Robert N

    2015-06-01

    In two conditioned suppression experiments with a latent inhibition (LI) design, we measured the habituation of rats in preexposure, their LI during conditioning, and then extinction over days. In the first experiment, lick suppression, the preexposed group (PE) showed a significant initial unconditioned response (UR) to the target stimulus and significant long-term habituation (LTH) of that response over days. The significant difference between the PE and nonpreexposed (NPE) groups on the first conditioning trial was due solely to the difference in their URs to the conditioned stimulus (CS)-a habituated response (PE) and an unhabituated response (NPE). In the second experiment, bar-press suppression, little UR to the target stimulus was apparent during preexposure, and no detectable LTH. Thus, there was no difference between the PE and NPE groups on the first conditioning trial. Whether the UR to the CS confounds the interpretation of LI (Exp. 1) or not (Exp. 2) can only be known if the UR is measured. In both experiments, LI was observed in acquisition. Also in both experiments, rats that were preexposed and then conditioned to asymptote were significantly more resistant to extinction than were the rats not preexposed. This result contrasts with the consistently reported finding that preexposure either produces less resistance to extinction or has no effect on extinction. The effect of stimulus preexposure survived conditioning to asymptote and was reflected directly in extinction. These two experiments provide a cautionary procedural note for LI experiments and have shown an unexpected extinction effect that may provide new insights into the interpretation of LI. PMID:25678396

  14. Hydrogen sulfide inhibits amyloid formation.

    PubMed

    Rosario-Alomar, Manuel F; Quiñones-Ruiz, Tatiana; Kurouski, Dmitry; Sereda, Valentin; Ferreira, Eduardo B; Jesús-Kim, Lorraine De; Hernández-Rivera, Samuel; Zagorevski, Dmitri V; López-Garriga, Juan; Lednev, Igor K

    2015-01-29

    Amyloid fibrils are large aggregates of misfolded proteins, which are often associated with various neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and vascular dementia. The amount of hydrogen sulfide (H2S) is known to be significantly reduced in the brain tissue of people diagnosed with Alzheimer's disease relative to that of healthy individuals. These findings prompted us to investigate the effects of H2S on the formation of amyloids in vitro using a model fibrillogenic protein hen egg white lysozyme (HEWL). HEWL forms typical ?-sheet rich fibrils during the course of 70 min at low pH and high temperatures. The addition of H2S completely inhibits the formation of ?-sheet and amyloid fibrils, as revealed by deep UV resonance Raman (DUVRR) spectroscopy and ThT fluorescence. Nonresonance Raman spectroscopy shows that disulfide bonds undergo significant rearrangements in the presence of H2S. Raman bands corresponding to disulfide (RSSR) vibrational modes in the 550-500 cm(-1) spectral range decrease in intensity and are accompanied by the appearance of a new 490 cm(-1) band assigned to the trisulfide group (RSSSR) based on the comparison with model compounds. The formation of RSSSR was proven further using a reaction with TCEP reduction agent and LC-MS analysis of the products. Intrinsic tryptophan fluorescence study shows a strong denaturation of HEWL containing trisulfide bonds. The presented evidence indicates that H2S causes the formation of trisulfide bridges, which destabilizes HEWL structure, preventing protein fibrillation. As a result, small spherical aggregates of unordered protein form, which exhibit no cytotoxicity by contrast with HEWL fibrils. PMID:25545790

  15. Response facilitation and inhibition in subliminal priming.

    PubMed

    Eimer, Martin; Schlaghecken, Friederike

    2003-10-01

    The research reviewed in this article has investigated with behavioural, electrophysiological, and functional imaging methods how subliminally presented masked prime stimuli affect response-related processes. An initial response activation triggered by these primes was found to be followed by an inhibition of this response tendency, provided that the initial activation was strong enough to exceed an 'inhibition threshold'. This biphasic pattern is assumed to reflect the presence of self-inhibitory circuits in motor control. In contrast to endogenous response inhibition, observed when response-relevant signals are consciously perceived, this exogenous mode of response inhibition appears to be mediated by corticostriate rather than by prefrontal mechanisms. Overall, results demonstrate that inhibitory mechanisms are involved in the control of response processes, even when motor activations are triggered by stimuli that are not accessible to conscious awareness. PMID:14602353

  16. Inhibition of serine proteinases by squash inhibitors.

    PubMed

    Otlewski, J; Zbyryt, T; Krokoszy?ska, I; Wilusz, T

    1990-07-01

    The squash inhibitors of serine proteinases have been discovered as proteins, which inhibit the catalytic activity of bovine trypsin. In this report we show, that three human enzymes of trypsin-like specificity - i.e. plasmin, plasma kallikrein and thrombin - are also inhibited by squash inhibitors. Moreover, rather strong inhibition was demonstrated for human cathepsin G. Lower association constants were found for Streptomyces griseus proteinase B (SGPB) and subtilisin BPN'. No association was detected for bovine chymotrypsin, even at millimolar concentrations of the inhibitors. Porcine pancreatic elastase showed extremely weak inhibition by squash inhibitors. Most of the enzymes examined did not exhibit a clear discrimination between P1 Arg and P1 Lys inhibitors. However, human plasma kallikrein and human thrombin formed much stronger complexes with CMTI I (P1-Arg) than with CPTI II (P1-Lys). PMID:2145863

  17. BROMODICHLOROMETHANE INHIBITS HUMAN PLACENTAL TROPHOBLAST DIFFERENTIATION

    EPA Science Inventory

    BROMODICHLOROMETHANE INHIBITS HUMAN PLACENTAL TROPHOBLAST DIFFERENTIATION Jiangang Chen, Twanda L. Thirkill, Peter N. Lohstroh, Susan R. Bielmeier, Michael G. Narotsky, Deborah S. Best, Randy A. Harrison, Kala Natarajan, Rex A. Pegram, Bill L. Lasley, and Gordon C. Do...

  18. CANNABINOIDS INHIBIT CALCIUM UPTAKE BY BRAIN SYNAPTOSOMES

    Microsoft Academic Search

    R. ADRON HARRIS; JAMES A. STOKES

    The depolarization-dependent uptake of calcium was studied in synaptosomes isolated from whole mouse brain and regions of rat brain. In vitro addition of A'-tetrahydrocannabinol (THC) inhibited calcium uptake. The brainstem was most sensitive to this effect-a lo-@ M THC concentration was sufficient to inhibit uptake by synaptosomes from this region. Cannabidiol produced effects similar to those of THC. Cannabinol was

  19. Seed extracts inhibiting protein synthesis in vitro.

    PubMed Central

    Gasperi-Campani, A; Barbieri, L; Morelli, P; Stirpe, F

    1980-01-01

    Of 33 seed extracts examined, 12 inhibited protein synthesis in a rabbit reticulocyte lysate. This activity seems to be due to a protein, since (i) it was recovered with the (NH4)2SO4 precipitate, (ii) it was retained by dialysis membranes, and (iii) in all cases but one was destroyed by boiling. Only the extracts from the seeds of Adenia digitata and, to a lower extent, of Euonymus europaeus inhibited protein synthesis in intact cells. PMID:7378060

  20. INHIBITION OF LEUKOCYTE LOCOMOTION BY HYALURONIC ACID

    Microsoft Academic Search

    J. V. FORRESTER; P. C. WILKINSONf

    1981-01-01

    SUMMARY The effect of hyaluronate on neutrophil motility in vitro was studied by the micropore filter technique and by direct visual analysis of the locomotion of neutrophils on glass. Both directed and random locomotion of neutrophils were inhibited by physiological concentrations (0-5-6-0 mgml'^o f hyaluronate in a dose-and molecular weight-dependent manner. Inhibition of cell movement was more pronounced for high

  1. Corrosion inhibition of steel by bacteria

    SciTech Connect

    Hernandez, G.; Kucera, V.; Thierry, D.; Pedersen, A. (Swedish Corrosion Inst., Stockholm (Sweden)); Hermansson, M. (Univ. of Gothenburg (Sweden). Dept. of General and Marine Microbiology)

    1994-08-01

    Mild steel was exposed to Pseudomonas sp. S9 or Serratia marcescens in synthetic seawater. An increase in corrosion resistance over that i natural seawater was monitored by electrochemical techniques. Biological analyses were performed to characterize the system. The inhibition effect also was observed when mild steel was coated with bacteria and then immersed in synthetic seawater. When specimens coated with bacteria were transferred to a natural seawater flow system, the inhibition effect disappeared during the first 2 weeks.

  2. Inflammasome inhibition: putting out the fire.

    PubMed

    Netea, Mihai G; Joosten, Leo A B

    2015-04-01

    NLRP3-inflammasome activates caspase-1 and processes pro-IL-1? and pro-IL-18 into the active cytokines. Two recent studies describe specific inhibitors of NLRP3 inflammasome that inhibit IL-1? release and inflammation. The specificity and potency of these compounds gives hope that a targeted approach to inhibit NLRP3-driven inflammation may be just around the corner. PMID:25863243

  3. Chemical Defoliation and Regrowth Inhibition in Cotton. 

    E-print Network

    Lane, H. C.; Truchelut, G. B.; Hall, W. C.

    1953-01-01

    during the past decade. In 1947, Steinberg (25) investigated the use of synthetic auxins to inhibit axillary growth to tobacco plants following topping. He continued this work in the greenhouse and published his ------Its in 1950 (26). His data showed...,4-dichlorophenoxyacetic acid and their derivatives. Scofield and Anderson (19) repokted the successful use of white min- eral oils to inhibit "suckers" of flue-cured tobacco varieties when the oil was applied at the time of terminal bud removal. Maleic hydrazide...

  4. Inhibition of tumor specific angiogenesis by amentoflavone

    Microsoft Academic Search

    C. Guruvayoorappan; G. Kuttan

    2008-01-01

    The formation of new capillaries from existing blood vessels is critical for tumor growth and metastasis. In this study we\\u000a report that amentoflavone, a biflavonoid from Biophytum sensitivum, could inhibit the process of angiogenesis. Amentoflavone at nontoxic concentrations (0.05–0.2 ?g\\/ml) showed significant\\u000a inhibition in the proliferation, migration, and tube formation of endothelial cells, which are key events in the process

  5. Quorum sensing inhibition, relevance to periodontics.

    PubMed

    Yada, Sudheer; Kamalesh, B; Sonwane, Siddharth; Guptha, Indra; Swetha, R K

    2015-01-01

    Quorum sensing helps bacteria to communicate with each other and in coordinating their behavior. Many diseases of human beings, plants, and animals are mediated by quorum sensing. Various approaches are being tried to inhibit this communication to control the diseases caused by bacteria. Periodontal pathogens also communicate through quorum sensing and new approaches to treat periodontal disease using quorum sensing inhibition need to explored. PMID:25709373

  6. Modelling Myc inhibition as a cancer therapy

    PubMed Central

    Soucek, Laura; Whitfield, Jonathan; Martins, Carla P.; Finch, Andrew J.; Murphy, Daniel J.; Sodir, Nicole M.; Karnezis, Anthony N.; Swigart, Lamorna Brown; Nasi, Sergio; Evan, Gerard I.

    2015-01-01

    Myc is a pleiotropic basic helix–loop–helix leucine zipper transcription factor that coordinates expression of the diverse intracellular and extracellular programs that together are necessary for growth and expansion of somatic cells1. In principle, this makes inhibition of Myc an attractive pharmacological approach for treating diverse types of cancer. However, enthusiasm has been muted by lack of direct evidence that Myc inhibition would be therapeutically efficacious, concerns that it would induce serious side effects by inhibiting proliferation of normal tissues, and practical difficulties in designing Myc inhibitory drugs. We have modelled genetically both the therapeutic impact and the side effects of systemic Myc inhibition in a preclinical mouse model of Ras-induced lung adenocarcinoma by reversible, systemic expression of a dominant-interfering Myc mutant. We show that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Our data demonstrate the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient and tumour-specific cancer therapy. PMID:18716624

  7. Activin inhibits telomerase activity in cancer

    SciTech Connect

    Katik, Indzi; Mackenzie-Kludas, Charley; Nicholls, Craig [Department of Immunology, Monash University, Melbourne (Australia)] [Department of Immunology, Monash University, Melbourne (Australia); Jiang, Fang-Xu [Centre for Diabetes Research, Western Australian Institute for Medical Research and The University of Western Australia, Perth (Australia)] [Centre for Diabetes Research, Western Australian Institute for Medical Research and The University of Western Australia, Perth (Australia); Zhou, Shufeng [School of Health Sciences, RMIT University, Melbourne (Australia)] [School of Health Sciences, RMIT University, Melbourne (Australia); Li, He [Department of Immunology, Monash University, Melbourne (Australia)] [Department of Immunology, Monash University, Melbourne (Australia); Liu, Jun-Ping, E-mail: jun-ping.liu@med.monash.edu.au [Department of Immunology, Monash University, Melbourne (Australia)] [Department of Immunology, Monash University, Melbourne (Australia)

    2009-11-27

    Activin is a pleiotropic cytokine with broad tissue distributions. Recent studies demonstrate that activin-A inhibits cancer cell proliferation with unknown mechanisms. In this report, we demonstrate that recombinant activin-A induces telomerase inhibition in cancer cells. In breast and cervical cancer cells, activin-A resulted in telomerase activity in a concentration-dependent manner. Significant inhibition was observed at 10 ng/ml of activin-A, with a near complete inhibition at 80 ng/ml. Consistently, activin-A induced repression of the telomerase reverse transcriptase (hTERT) gene, with the hTERT gene to be suppressed by 60-80% within 24 h. In addition, activin-A induced a concomitant increase in Smad3 signaling and decrease of the hTERT gene promoter activity in a concentration-dependent fashion. These data suggest that activin-A triggered telomerase inhibition by down-regulating hTERT gene expression is involved in activin-A-induced inhibition of cancer cell proliferation.

  8. Characterization of acetylcholinesterase-inhibition by itopride.

    PubMed

    Iwanaga, Y; Kimura, T; Miyashita, N; Morikawa, K; Nagata, O; Itoh, Z; Kondo, Y

    1994-11-01

    Itopride is a gastroprokinetic benzamide derivative. This agent inhibited both electric eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE). The IC50 of itopride with AChE (2.04 +/- 0.27 microM) was, however, 100-fold less than that with BuChE, whereas in the case of neostigmine with AChE (11.3 +/- 3.4 nM), it was 10-fold less. The recovery of AChE activity inhibited by 10(-7) M neostigmine was partial, but that inhibited by up to 3 x 10(-5) M itopride was complete when the reaction mixture was subjected to ultrafiltration. Double reciprocal plots of the experimental data showed that both Km and Vmax were affected by itopride, suggesting that the inhibition is a "mixed" type, although primarily being an uncompetitive one. The inhibitory effect of itopride on cholinesterase (ChE) activity in guinea pig gastrointestine was much weaker than that on pure AChE. However, in the presence of a low dose of diisopropyl fluorophosphate, just enough to inhibit BuChE but not AChE, the IC50s of itopride against ChE activities were found to be about 0.5 microM. In conclusion, itopride exerts reversible and a "mixed" type of inhibition preferably against AChE. The IC50 of itopride for electric eel and guinea pig gastrointestinal AChE inhibition was 200 times and 50 times as large as that of neostigmine, respectively. PMID:7869618

  9. Evidence that dimethyl sulfoxide inhibits defects of copper deficiency by inhibition of glycation

    Microsoft Academic Search

    Jack T. Saari

    1996-01-01

    Prior studies have indicated that dimethyl sulfoxide (DMSO), when fed to rats, can inhibit the cardiac enlargement and anemia of a concurrent dietary copper (Cu) deficiency. Because DMSO is capable of chemically destroying the hydroxyl radical, its inhibition of defects of Cu deficiency was taken as evidence that those defects resulted from oxidative stress. To examine this conclusion further, rats

  10. Ampligen inhibits human herpesvirus-6 in vitro.

    PubMed

    Ablashi, D V; Berneman, Z N; Williams, M; Strayer, D R; Kramarsky, B; Suhadolnik, R J; Reichenbach, N; Hiltzges, P; Komaroff, A L

    1994-01-01

    The recently discovered human herpesvirus-6 (HHV-6) is being associated with an increasing number of conditions in which there is evidence of immunologic dysfunction. A number of widely available antiviral agents have shown little or no activity against the virus. We found that Ampligen [Poly (1): Poly (C12U), a synthetic, mismatched, double-stranded RNA, has potent, previously unexpected antiviral effects. Cells known to allow replication of HHV-6 were infected with the virus and treated with Ampligen under various conditions. When cells were pretreated with Ampligen (concentrations of 100 or 200 micrograms/ml) prior to infection or treated shortly after infection, viral replication was inhibited by 46-98%. At 100 and 200 micrograms/ml, Ampligen also inhibited the DNA polymerase activity of HHV-6 by 42-98%. When lower concentrations of Ampligen (10 and 50 micrograms/ml) were used, only pretreatment of cells, with Ampligen, followed by virus infection and carrying the infected cells with Ampligen, significantly inhibited HHV-6 infection (83.7 and 89.1% respectively). Indirect evidence suggests that Ampligen may inhibit viral attachment to cellular receptors and/or inhibit intracellular maturation of the virus. The above concentrations of Ampligen were not toxic to the cells used in the study. Given these in vitro findings, and the low frequency of toxicity reported with the use of Ampligen, clinical trials of this drug in patients with evidence of reactivated HHV-6 infection would seem to be warranted. PMID:7893986

  11. Inhibition of tumor specific angiogenesis by amentoflavone.

    PubMed

    Guruvayoorappan, C; Kuttan, G

    2008-02-01

    The formation of new capillaries from existing blood vessels is critical for tumor growth and metastasis. In this study we report that amentoflavone, a biflavonoid from Biophytum sensitivum, could inhibit the process of angiogenesis. Amentoflavone at nontoxic concentrations (0.05-0.2 microg/ml) showed significant inhibition in the proliferation, migration, and tube formation of endothelial cells, which are key events in the process of angiogenesis. In vivo studies in C57BL/6 mice using amentoflavone showed remarkable inhibition (52.9%) of tumor directed capillary formation. Amentoflavone showed inhibitory effect on the production of various endogenous factors such as IL-1beta, IL-6, TNF-alpha, GM-CSF, and VEGF that control the process of angiogenesis. Amentoflavone treatment could increase the production of IL-2 and TIMP-1, which could successfully shift the equilibrium towards an angiostatic condition. The antiangiogenic activity of amentoflavone was supported by its remarkable suppression in sprouting of microvessels from rat aorta. Our results also show that amentoflavone could inhibit the production of VEGF mRNA in B16-F10 cells. These findings indicate that amentoflavone inhibits angiogenesis by disrupting the integrity of endothelial cells and by altering the endogenous factors that are required for the process of neovascularization. PMID:18298378

  12. Inhibition and Agglutination of Arthrobacters by Pseudomonads

    PubMed Central

    Sieburth, John McN.

    1967-01-01

    The bacterial flora of water in Narragansett Bay, R.I., was observed semimonthly from 1962 to 1964. Dominant isolates were keyed to genus, and the isolates for each genus were expressed as percentage of total isolates. There was a consistent inverse relationship between arthrobacters and the dominant pseudomonads. Pseudomonad growth on agar plates markedly inhibited arthrobacter cross-streaks. Agar from inhibition zones as well as supernatant fluids from pseudomonad broth cultures inhibited arthrobacter motility and caused the cells to agglutinate. Gummy pseudomonad residues from vacuum-evaporated broth cultures readily passed a G-25 Sephadex column. This material agglutinated arthrobacter cells, but failed to cause arthrobacter inhibition in filter-pad assays. In contrast, sterile medium inside a dialysis sac, inoculated externally with a pseudomonad, was inhibitory to arthrobacters in pad assay but failed to agglutinate arthrobacter cells. Pseudomonad isolates from soil showed similar inhibiting and agglutinating activities for both soil and seawater arthrobacter isolates. The inhibitory and agglutinating activities of pseudomonad isolates appeared to diminish on prolonged laboratory cultivation. Images PMID:6025306

  13. Response Inhibition in Motor Conversion Disorder

    PubMed Central

    Voon, Valerie; Ekanayake, Vindhya; Wiggs, Edythe; Kranick, Sarah; Ameli, Rezvan; Harrison, Neil A.; Hallett, Mark

    2014-01-01

    Conversion disorders (CDs) are unexplained neurological symptoms presumed to be related to a psychological issue. Studies focusing on conversion paralysis have suggested potential impairments in motor initiation or execution. Here we studied CD patients with aberrant or excessive motor movements and focused on motor response inhibition. We also assessed cognitive measures in multiple domains. We compared 30 CD patients and 30 age-, sex-, and education-matched healthy volunteers on a motor response inhibition task (go/no go), along with verbal motor response inhibition (color-word interference) and measures of attention, sustained attention, processing speed, language, memory, visuospatial processing, and executive function including planning and verbal fluency. CD patients had greater impairments in commission errors on the go/no go task (P <.001) compared with healthy volunteers, which remained significant after Bonferroni correction for multiple comparisons and after controlling for attention, sustained attention, depression, and anxiety. There were no significant differences in other cognitive measures. We highlight a specific deficit in motor response inhibition that may play a role in impaired inhibition of unwanted movement such as the excessive and aberrant movements seen in motor conversion. Patients with nonepileptic seizures, a different form of conversion disorder, are commonly reported to have lower IQ and multiple cognitive deficits. Our results point toward potential differences between conversion disorder subgroups. PMID:23554084

  14. Inhibition of Camellia sinensis (L.) O. Kuntze on Microcystis aeruginosa and isolation of the inhibition factors.

    PubMed

    Lu, Yaping; Wang, Jin; Yu, Yang; Su, Wen; Kong, Fanxiang

    2013-07-01

    Low concentration of tea (Camellia sinensis (L.) O. Kuntze) was shown to inhibit the growth of the toxic cyanobacterium Microcystis aeruginosa. The inhibition efficiency was 40% at 0.1 g dry tea/L and 90% at 0.2 g/L after a 12-day culture. All varieties of tea used in the test could inhibit Microcystis growth, in which the inhibitory effect of green tea was greater than that of black tea. Antialgal allelochemicals were isolated from tea by solvent extraction, gel-chromatography and high performance liquid chromatography. Two algal-inhibition compounds were identified by liquid chromatography/mass spectrometry as epigallocatechin-3-gallate, epicatechin-3-gallate respectively. These are the main polyphenols in tea that have inhibitory effects on the growth of cyanobacteria. The combined effect of these polyphenols makes tea a promising source of algicide to inhibit the growth of algal blooms. PMID:23584804

  15. Audio-visual integration and saccadic inhibition.

    PubMed

    Makovac, Elena; Buonocore, Antimo; McIntosh, Robert D

    2015-07-01

    Saccades operate a continuous selection between competing targets at different locations. This competition has been mostly investigated in the visual context, and it is well known that a visual distractor can interfere with a saccade toward a visual target. Here, we investigated whether multimodal, audio-visual targets confer stronger resilience against visual distraction. Saccades to audio-visual targets had shorter latencies than saccades to unisensory stimuli. This facilitation exceeded the level that could be explained by simple probability summation, indicating that multisensory integration had occurred. The magnitude of inhibition induced by a visual distractor was comparable for saccades to unisensory and multisensory targets, but the duration of the inhibition was shorter for multimodal targets. We conclude that multisensory integration can allow a saccade plan to be reestablished more rapidly following saccadic inhibition. PMID:25599266

  16. Zerumbone, Sesquiterpene Photochemical from Ginger, Inhibits Angiogenesis.

    PubMed

    Park, Ju-Hyung; Park, Geun Mook; Kim, Jin-Kyung

    2015-07-01

    Here, we investigated the role of zerumbone, a natural cyclic sesquiterpene of Zingiber zerumbet Smith, on angiogenesis using human umbilical vein endothelial cells (HUVECs). Zerumbone inhibited HUVECs proliferation, migration and tubule formation, as well as angiogenic activity by rat aorta explants. In particular, zerumbone inhibited phosphorylation of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1, which are key regulators of endothelial cell function and angiogenesis. In vivo matrigel plug assay in mice demonstrated significant decrease in vascularization and hemoglobin content in the plugs from zerumbone-treated mice, compared with control mice. Overall, these results suggest that zerumbone inhibits various attributes of angiogenesis, which might contribute to its reported antitumor effects. PMID:26170737

  17. Zerumbone, Sesquiterpene Photochemical from Ginger, Inhibits Angiogenesis

    PubMed Central

    Park, Ju-Hyung; Park, Geun Mook

    2015-01-01

    Here, we investigated the role of zerumbone, a natural cyclic sesquiterpene of Zingiber zerumbet Smith, on angiogenesis using human umbilical vein endothelial cells (HUVECs). Zerumbone inhibited HUVECs proliferation, migration and tubule formation, as well as angiogenic activity by rat aorta explants. In particular, zerumbone inhibited phosphorylation of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1, which are key regulators of endothelial cell function and angiogenesis. In vivo matrigel plug assay in mice demonstrated significant decrease in vascularization and hemoglobin content in the plugs from zerumbone-treated mice, compared with control mice. Overall, these results suggest that zerumbone inhibits various attributes of angiogenesis, which might contribute to its reported antitumor effects.

  18. Mapuche Herbal Medicine Inhibits Blood Platelet Aggregation

    PubMed Central

    Falkenberg, Susan Skanderup; Tarnow, Inge; Guzman, Alfonso; Mølgaard, Per; Simonsen, Henrik Toft

    2012-01-01

    12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0??M) and collagen- (2.0??g/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H2O), Amomyrtus luma (DCM?:?MeOH 1?:?1) and Cestrum parqui (DCM?:?MeOH 1?:?1). The platelet aggregating inhibitory effects of A. luma (DCM?:?MeOH 1?:?1), and L. apiculata (H2O) were substantial and confirmed by inhibition of platelet surface activation markers. PMID:22028732

  19. Mapuche herbal medicine inhibits blood platelet aggregation.

    PubMed

    Falkenberg, Susan Skanderup; Tarnow, Inge; Guzman, Alfonso; Mølgaard, Per; Simonsen, Henrik Toft

    2012-01-01

    12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0??M) and collagen- (2.0??g/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H(2)O), Amomyrtus luma (DCM?:?MeOH 1?:?1) and Cestrum parqui (DCM?:?MeOH 1?:?1). The platelet aggregating inhibitory effects of A. luma (DCM?:?MeOH 1?:?1), and L. apiculata (H(2)O) were substantial and confirmed by inhibition of platelet surface activation markers. PMID:22028732

  20. Vanadium inhibition of serine and cysteine proteases.

    PubMed

    Guerrieri, N; Cerletti, P; De Vincentiis, M; Salvati, A; Scippa, S

    1999-03-01

    A study was made on the effect of vanadium, in both the tetravalent state in vanadyl sulphate and in the pentavalent state in sodium meta-vanadate, and ortho-vanadate, on the proteolysis of azocasein by two serine proteases, trypsin and subtilisin and two cysteine proteases bromelain and papain. Also the proteolysis of bovine azoalbumin by serine proteases was considered. An inhibitory effect was present in all cases, except meta-vanadate with subtilisin. The oxidation level of vanadium by itself did not determine the inhibition kinetics, which also depended on the type and composition of the vanadium containing molecule and on the enzyme assayed. The pattern of inhibition was similar for proteases belonging to the same class. The highest inhibition was obtained with meta-vanadate on papain and with vanadyl sulphate on bromelain. PMID:10356762

  1. Complete corrosion inhibition through graphene defect passivation.

    PubMed

    Hsieh, Ya-Ping; Hofmann, Mario; Chang, Kai-Wen; Jhu, Jian Gang; Li, Yuan-Yao; Chen, Kuang Yao; Yang, Chang Chung; Chang, Wen-Sheng; Chen, Li-Chyong

    2014-01-28

    Graphene is expected to enable superior corrosion protection due to its impermeability and chemical inertness. Previous reports, however, demonstrate limited corrosion inhibition and even corrosion enhancement of graphene on metal surfaces. To enable the reliable and complete passivation, the origin of the low inhibition efficiency of graphene was investigated. Combining electrochemical and morphological characterization techniques, nanometer-sized structural defects in chemical vapor deposition grown graphene were found to be the cause for the limited passivation effect. Extremely fast mass transport on the order of meters per second both across and parallel to graphene layers results in an inhibition efficiency of only ?50% for Cu covered with up to three graphene layers. Through selective passivation of the defects by atomic layer deposition (ALD) an enhanced corrosion protection of more than 99% was achieved, which compares favorably with commercial corrosion protection methods. PMID:24359599

  2. Maintenance of Prior Associations and Proactive Inhibition

    ERIC Educational Resources Information Center

    Postman, Leo; Gray, Wayne

    1977-01-01

    The method of transfer learning was manipulated in a study of proactive inhibition. Results suggest that the joint recall of two lists during transfer increases list differentiation and reduces competition between alternative sets of responses on the retention test. (Editor/RK)

  3. Hemagglutinin inhibition assay with swine sera

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hemagglutination is based on the ability of certain viruses to agglutinate red blood cells (RBC) of certain animal species by formation of cross-linking lattices between RBC. Antibodies that have the ability to inhibit the hemagglutination property of influenza A viruses are generally thought to pro...

  4. Motivational Influences on Response Inhibition Measures

    ERIC Educational Resources Information Center

    Leotti, Lauren A.; Wager, Tor D.

    2010-01-01

    Psychological research has placed great emphasis on inhibitory control due to its integral role in normal cognition and clinical disorders. The stop-signal task and associated measure--stop-signal reaction time (SSRT)--provides a well-established paradigm for measuring response inhibition. However, motivational influences on stop-signal…

  5. Nickel inhibits mitochondrial fatty acid oxidation.

    PubMed

    Uppala, Radha; McKinney, Richard W; Brant, Kelly A; Fabisiak, James P; Goetzman, Eric S

    2015-08-01

    Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation-the pathway by which fatty acids are catabolized for energy-in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with l-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 h), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1? (HIF1?). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1? knockout fibroblasts, implicating HIF1? as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis. PMID:26051273

  6. Theobromine inhibits sensory nerve activation and cough

    Microsoft Academic Search

    Omar S. Usmani; Maria G. Belvisi; Hema J. Patel; Natascia Crispino; Mark A. Birrell; Márta Korbonits; Peter J. Barnes

    2004-01-01

    Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid- induced cough in guinea-pigs in vivo. Furthermore,

  7. Illustrating Enzyme Inhibition Using Gibbs Energy Profiles

    ERIC Educational Resources Information Center

    Bearne, Stephen L.

    2012-01-01

    Gibbs energy profiles have great utility as teaching and learning tools because they present students with a visual representation of the energy changes that occur during enzyme catalysis. Unfortunately, most textbooks divorce discussions of traditional kinetic topics, such as enzyme inhibition, from discussions of these same topics in terms of…

  8. Sphingolipids inhibit vimentin-dependent cell migration.

    PubMed

    Hyder, Claire L; Kemppainen, Kati; Isoniemi, Kimmo O; Imanishi, Susumu Y; Goto, Hidemasa; Inagaki, Masaki; Fazeli, Elnaz; Eriksson, John E; Törnquist, Kid

    2015-06-01

    The sphingolipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), can induce or inhibit cellular migration. The intermediate filament protein vimentin is an inducer of migration and a marker for epithelial-mesenchymal transition. Given that keratin intermediate filaments are regulated by SPC, with consequences for cell motility, we wanted to determine whether vimentin is also regulated by sphingolipid signalling and whether it is a determinant for sphingolipid-mediated functions. In cancer cells where S1P and SPC inhibited migration, we observed that S1P and SPC induced phosphorylation of vimentin on S71, leading to a corresponding reorganization of vimentin filaments. These effects were sphingolipid-signalling-dependent, because inhibition of either the S1P2 receptor (also known as S1PR2) or its downstream effector Rho-associated kinase (ROCK, for which there are two isoforms ROCK1 and ROCK2) nullified the sphingolipid-induced effects on vimentin organization and S71 phosphorylation. Furthermore, the anti-migratory effect of S1P and SPC could be prevented by expressing S71-phosphorylation-deficient vimentin. In addition, we demonstrated, by using wild-type and vimentin-knockout mouse embryonic fibroblasts, that the sphingolipid-mediated inhibition of migration is dependent on vimentin. These results imply that this newly discovered sphingolipid-vimentin signalling axis exerts brake-and-throttle functions in the regulation of cell migration. PMID:25908861

  9. Aromatase Inhibition in a Transcriptional Network Context

    EPA Science Inventory

    A variety of chemicals in the environment have the potential to inhibit aromatase, an enzyme critical to estrogen synthesis. We examined the responses of female fathead minnow ovaries (FHM, Pimephales promelas) to a model aromatase inhibitor, fadrozole, using a transcriptional ne...

  10. Inhibiting Adaptation 1 Kathleen M. Carley

    E-print Network

    Sadeh, Norman M.

    Inhibiting Adaptation 1 Kathleen M. Carley Social and Decision Sciences and H.J. Heinz III School forces or coalition forces, the "organization" must be adaptive. Unanticipated changes in mission to create forces that can respond rapidly, accurately and can readily adapt to new situations. Over the past

  11. Nitric oxide synthases: structure, function and inhibition

    Microsoft Academic Search

    Wendy K. ALDERTON; Chris E. COOPER; Richard G. KNOWLES

    2001-01-01

    This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family. There is now in- formation on the enzyme structure at all levels from primary (amino acid sequence) to quaternary (dimerization, association with other proteins) structure.

  12. Psychiatric drugs and inhibited female orgasm

    Microsoft Academic Search

    R. T. Segraves

    1988-01-01

    The available evidence concerning sexual side effects of psychiatric drugs suggests that inhibited female orgasm may be associated with the use of heterocyclic antidepressants, monoamine oxidase inhibitors, benzodiazepines, and neuroleptics. Possible mechanisms of action including anticholinergic, alpha adrenergic blockade, and serotonergic effects are discussed.

  13. Product Inhibition in Native-State Proteolysis

    PubMed Central

    Kasper, Joseph R.; Andrews, Elizabeth C.; Park, Chiwook

    2014-01-01

    The proteolysis kinetics of intact proteins by nonspecific proteases provides valuable information on transient partial unfolding of proteins under native conditions. Native-state proteolysis is an approach to utilize the proteolysis kinetics to assess the energetics of partial unfolding in a quantitative manner. In native-state proteolysis, folded proteins are incubated with nonspecific proteases, and the rate of proteolysis is determined from the disappearance of the intact protein. We report here that proteolysis of intact proteins by nonspecific proteases, thermolysin and subtilisin deviates from first-order kinetics. First-order kinetics has been assumed for the analysis of native-state proteolysis. By analyzing the kinetics of proteolysis with varying concentrations of substrate proteins and also with cleavage products, we found that the deviation from first-order kinetics results from product inhibition. A kinetic model including competitive product inhibition agrees well with the proteolysis time course and allows us to determine the uninhibited rate constant for proteolysis as well as the apparent inhibition constant. Our finding suggests that the likelihood of product inhibition must be considered for quantitative assessment of proteolysis kinetics. PMID:25360755

  14. Behavioral Inhibition in Children with Learning Disabilities

    ERIC Educational Resources Information Center

    De Weerdt, Frauke; Desoete, Annemie; Roeyers, Herbert

    2013-01-01

    Children with reading disabilities (RD, n = 17), mathematical disabilities (MD, n = 22), combined reading and mathematical disabilities (RD + MD, n = 28) and control peers (n = 45) were tested on behavioral inhibition with a Go/no-go task in a picture, letter and digit-modality. In contrast to children without RD, children with RD made…

  15. Target Predictability, Sustained Attention, and Response Inhibition

    ERIC Educational Resources Information Center

    Carter, Leonie; Russell, Paul N.; Helton, William S.

    2013-01-01

    We examined whether the sustained attention to response task is a better measure of response inhibition or sustained attention. Participants performed a number detection task for 37.3 min using either a Sustained Attention to Response Task (SART; high Go low No-Go) or a more traditionally formatted vigilance task (TFT; high No-Go low Go) response…

  16. Temporal Preparation, Response Inhibition and Impulsivity

    ERIC Educational Resources Information Center

    Correa, Angel; Trivino, Monica; Perez-Duenas, Carolina; Acosta, Alberto; Lupianez, Juan

    2010-01-01

    Temporal preparation and impulsivity involve overlapping neural structures (prefrontal cortex) and cognitive functions (response inhibition and time perception), however, their interrelations had not been investigated. We studied such interrelations by comparing the performance of groups with low vs. high non-clinical trait impulsivity during a…

  17. Biodegradable implant strategies for inhibition of restenosis

    Microsoft Academic Search

    Lisa A. Orloff; Abraham J. Domb; Doron Teomim; Ilia Fishbein; Gershon Golomb

    1997-01-01

    Restenosis of coronary arteries within 6 months of angioplasty has severely limited the long-term success of this procedure. As with any procedure that involves vascular manipulation, thrombosis and stenosis due to intimal proliferation and blood vessel remodeling are the processes that interfere with prolonged patency. This review explores the latest strategies in the form of biodegradable implants designed to inhibit

  18. Notch Receptor Activation Inhibits Oligodendrocyte Differentiation

    Microsoft Academic Search

    Songli Wang; Andrei D Sdrulla; Guy diSibio; Gay Bush; Donna Nofziger; Carol Hicks; Gerry Weinmaster; Ben A Barres

    1998-01-01

    In this study, we show that oligodendrocyte differentiation is powerfully inhibited by activation of the Notch pathway. Oligodendrocytes and their precursors in the developing rat optic nerve express Notch1 receptors and, at the same time, retinal ganglion cells express Jagged1, a ligand of the Notch1 receptor, along their axons. Jagged1 expression is developmentally regulated, decreasing with a time course that

  19. Product inhibition in native-state proteolysis.

    PubMed

    Kasper, Joseph R; Andrews, Elizabeth C; Park, Chiwook

    2014-01-01

    The proteolysis kinetics of intact proteins by nonspecific proteases provides valuable information on transient partial unfolding of proteins under native conditions. Native-state proteolysis is an approach to utilize the proteolysis kinetics to assess the energetics of partial unfolding in a quantitative manner. In native-state proteolysis, folded proteins are incubated with nonspecific proteases, and the rate of proteolysis is determined from the disappearance of the intact protein. We report here that proteolysis of intact proteins by nonspecific proteases, thermolysin and subtilisin deviates from first-order kinetics. First-order kinetics has been assumed for the analysis of native-state proteolysis. By analyzing the kinetics of proteolysis with varying concentrations of substrate proteins and also with cleavage products, we found that the deviation from first-order kinetics results from product inhibition. A kinetic model including competitive product inhibition agrees well with the proteolysis time course and allows us to determine the uninhibited rate constant for proteolysis as well as the apparent inhibition constant. Our finding suggests that the likelihood of product inhibition must be considered for quantitative assessment of proteolysis kinetics. PMID:25360755

  20. RGD-Tachyplesin Inhibits Tumor Growth1

    Microsoft Academic Search

    Yixin Chen; Xueming Xu; Shuigen Hong; Jinguo Chen; Ningfei Liu; Charles B. Underhill; Karen Creswell; Lurong Zhang

    2001-01-01

    Tachyplesin is an antimicrobial peptide present in leukocytes of the horseshoe crab (Tachypleus tridentatus). In this study, a synthetic tachyplesin conjugated to the integrin homing domain RGD was tested for antitumor activity. The in vitro results showed that RGD-tachyplesin inhibited the proliferation of both cultured tumor and endothelial cells and reduced the colony formation of TSU prostate cancer cells. Staining

  1. Scale and corrosion inhibition by thermal polyaspartates

    SciTech Connect

    Bains, D.I.; Fan, G.; Fan, J.; Ross, R.J. [Donlar Corp., Bedford Park, IL (United States)

    1999-11-01

    Organic polymers have found wide spread use as inhibitors for the prevention of mineral scales in heat transfer equipment. Recently a biodegradable organic polymer has been developed which provides both scale and corrosion control. The development of the polymeric inhibitor and laboratory evaluations of scale and corrosion inhibition is discussed together with its potential application in open recirculating cooling systems.

  2. INHIBITION OF PANCREATIC LIPASE BY TETRACYCLINES

    Microsoft Academic Search

    Alan R. Shalita; Victor Wheatley

    1970-01-01

    The effect of various antibiotics on the rate of hydrolysis of an olive oil emulsion by hog pancreatic lipase was studied by potentiometric titration. Tetracycline, demethyl-chlortetracycline and doxycycline were able to inhibit this lipase system completely, at appropriate drug concentrations. None of the other drugs tested were able to affect this enzyme system significantly. These included penicillin G, ampicillin, oxacillin,

  3. Kinetics of ethanol inhibition in alcohol fermentation

    Microsoft Academic Search

    J. H. T. Luong; J. H. T

    1985-01-01

    The inhibitory effect of ethanol on yeast growth and fermentation has been studied for the strain Saccharo-myces cerevisiae ATCC No. 4126 under anaerobic batch conditions. The results obtained reveal that there is no striking difference between the response of growth and ethanol fermentation. Two kinetic models are also proposed to describe the kinetic pattern of ethanol inhibition on the specific

  4. Erotic stimuli and aggression: Facilitation or inhibition

    Microsoft Academic Search

    Edward Donnerstein; Marcia Donnerstein; Ronald Evans

    1975-01-01

    Attempted to reconcile previous results on the relationship of erotic stimuli and aggression. 81 male undergraduates were either insulted or not insulted prior or subsequent to observing erotic stimuli of varying levels of arousal inducements. It was found, in support of prior research, that mildly erotic stimuli had an inhibiting effect on aggression when viewed subsequent to anger arousal, whereas

  5. Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

    SciTech Connect

    Szkudlarek-Mikho, Maria; Saunders, Rudel A. [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States)] [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States); Yap, Sook Fan [Faculty of Medicine and Health Sciences, Department of Pre-Clinical Sciences, University of Tunku Abdul Rahman (Malaysia)] [Faculty of Medicine and Health Sciences, Department of Pre-Clinical Sciences, University of Tunku Abdul Rahman (Malaysia); Ngeow, Yun Fong [Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603 (Malaysia)] [Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603 (Malaysia); Chin, Khew-Voon, E-mail: khew-voon.chin@utoledo.edu [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States)] [Department of Medicine, Biochemistry and Cancer Biology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43614 (United States)

    2012-11-30

    Highlights: Black-Right-Pointing-Pointer Salinomycin inhibits preadipocyte differentiation into adipocytes. Black-Right-Pointing-Pointer Salinomycin inhibits transcriptional regulation of adipogenesis. Black-Right-Pointing-Pointer Pharmacological effects of salinomycin suggest toxicity in cancer therapy. -- Abstract: The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor {gamma}. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy.

  6. Neprilysin inhibition in chronic kidney disease

    PubMed Central

    Judge, Parminder; Haynes, Richard; Landray, Martin J.; Baigent, Colin

    2015-01-01

    Despite current practice, patients with chronic kidney disease (CKD) are at increased risk of progression to end-stage renal disease and cardiovascular events. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. NEPi enhances the activity of natriuretic peptide systems leading to natriuresis, diuresis and inhibition of the renin–angiotensin system (RAS), which could act as a potentially beneficial counter-regulatory system in states of RAS activation such as chronic heart failure (HF) and CKD. Early NEPi drugs were combined with angiotensin-converting enzyme inhibitors but were associated with unacceptable rates of angioedema and, therefore, withdrawn. However, one such agent (omapatrilat) showed promise of NEP/RAS inhibition in treating CKD in animal models, producing greater reductions in proteinuria, glomerulosclerosis and tubulointerstitial fibrosis compared with isolated RAS inhibition. A new class of drug called angiotensin receptor neprilysin inhibitor (ARNi) has been developed. One such drug, LCZ696, has shown substantial benefits in trials in hypertension and HF. In CKD, HF is common due to a range of mechanisms including hypertension and structural heart disease (including left ventricular hypertrophy), suggesting that ARNi could benefit patients with CKD by both retarding the progression of CKD (hence delaying the need for renal replacement therapy) and reducing the risk of cardiovascular disease. LCZ696 is now being studied in a CKD population. PMID:25140014

  7. Curcumin inhibition of angiogenesis and adipogenesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The growth of new blood vessels or angiogenesis is necessary for the growth of adipose tissue. Adipokines produced by fat cells stimulate this process. Some dietary polyphenols with antiangiogenic activity may suppress adipose tissue growth not only by inhibiting angiogenesis, but also by interferin...

  8. T-2 mycotoxin inhibits mitochondrial protein synthesis

    SciTech Connect

    Pace, J.G.; Watts, M.R.; Canterbury, W.J.

    1988-01-01

    The authors investigated the effect of T-2 toxin on rat liver mitochondrial protein synthesis. Isolated rat liver mitochondria were supplemented with an S-100 supernatant from rat liver and an external ATP-generating system. An in-vitro assay employing cycloheximide, and inhibitor of cytoplasmic protein synthesis, and chloramphenicol, and inhibitor of mitochondrial protein synthesis, to distinguish mitochondrial protein synthesis from the cytoplasmic process. Amino acid incorporation into mitochondria was dependent on the concentration of mitochondria and was inhibited by chloramphenicol. The rate of uptake of tritium leucine into mitochondrial protein was unaffected by the addition of T-2 toxin and was not a rate-limiting step in incorporation. However, 0.02 micrograms/ml of T-2 toxin decreased the rate of protein synthesis inhibition correlated with the amount of T-2 toxin taken up by the mitochondria. While T-2 toxin is known to inhibit eukaryotic protein synthesis, this is the first time T-2 was shown to inhibit mitochondrial protein synthesis.

  9. Helicobacter pylori inhibits gastric cell cycle progression

    Microsoft Academic Search

    Amel Ahmed; Duane Smoot; George Littleton; Robert Tackey; Curla S. Walters; Fatah Kashanchi; Cornell R. Allen; Hassan Ashktorab

    2000-01-01

    Helicobacter pylori infection of the gastric mucosa is associated with changes in gastric epithelial cell proliferation. In vitro studies have shown that exposure to H. pylori inhibits proliferation of gastric cells. This study sought to investigate the cell cycle progression of gastric epithelial cell lines in the presence and absence of H. pylori. Unsynchronized and synchronized gastric epithelial cell lines

  10. The Mechanism Underlying Inhibition of Saccadic Return

    ERIC Educational Resources Information Center

    Ludwig, Casimir J. H.; Farrell, Simon; Ellis, Lucy A.; Gilchrist, Iain D.

    2009-01-01

    Human observers take longer to re-direct gaze to a previously fixated location. Although there has been some exploration of the characteristics of inhibition of saccadic return (ISR), the exact mechanisms by which ISR operates are currently unknown. In the framework of accumulation models of response times, in which evidence is integrated over…

  11. Gold Nanoparticles Inhibit Matrix Metalloproteases without Cytotoxicity.

    PubMed

    Hashimoto, M; Sasaki, J I; Yamaguchi, S; Kawai, K; Kawakami, H; Iwasaki, Y; Imazato, S

    2015-08-01

    Nanoparticles (NPs) are currently the focus of considerable attention for dental applications; however, their biological effects have not been fully elucidated. The long-term, slow release of matrix metalloproteases (MMPs) digests collagen fibrils within resin-dentin bonds. Therefore, MMP inhibitors can prolong the durability of resin-dentin bonds. However, there have been few reports evaluating the combined effect of MMP inhibition and the cytotoxic effects of NPs for dentin bonding. The aim of this study was to evaluate MMP inhibition and cytotoxic responses to gold (AuNPs) and platinum nanoparticles (PtNPs) stabilized by polyvinylpyrrolidone (PVP) in cultured murine macrophages (RAW264) by using MMP inhibition assays, measuring cell viability and inflammatory responses (quantitative reverse transcription polymerase chain reaction [RT-qPCR]), and conducting a micromorphological analysis by fluorescence and transmission electron microscopy. Cultured RAW264 cells were exposed to metal NPs at various concentrations (1, 10, 100, and 400 µg/mL). AuNPs and PtNPs markedly inhibited MMP-8 and MMP-9 activity. Although PtNPs were cytotoxic at high concentrations (100 and 400 µg/mL), no cytotoxic effects were observed for AuNPs at any concentration. Transmission electron microscopy images showed a significant nonrandom intercellular distribution for AuNPs and PtNPs, which were mostly observed to be localized in lysosomes but not in the nucleus. RT-qPCR analysis demonstrated inflammatory responses were not induced in RAW264 cells by AuNPs or PtNPs. The cytotoxicity of nanoparticles might depend on the core metal composition and arise from a "Trojan horse" effect; thus, MMP inhibition could be attributed to the surface charge of PVP, which forms the outer coating of NPs. The negative charge of the surface coating of PVP binds to Zn(2+) from the active center of MMPs by chelate binding and results in MMP inhibition. In summary, AuNPs are attractive NPs that effectively inhibit MMP activity without cytotoxicity or inflammatory responses. PMID:26040283

  12. Angiostatin inhibits activation and migration of neutrophils.

    PubMed

    Aulakh, Gurpreet K; Balachandran, Yadu; Liu, Lixin; Singh, Baljit

    2014-02-01

    There is a critical need to identify molecules that modulate the biology of neutrophils because activated neutrophils, though necessary for host defense, cause exuberant tissue damage through production of reactive oxygen species and increased lifespan. Angiostatin, an endogenous anti-angiogenic cleavage product of plasminogen, binds to integrin ?v?3, ATP synthase and angiomotin and its expression is increased in inflammatory conditions. We test the hypothesis that angiostatin inhibits neutrophil activation, induces apoptosis and blocks recruitment in vivo and in vitro. The data show immuno-reactivity for plasminogen/angiostatin in resting neutrophils. Angiostatin conjugated to FITC revealed that angiostatin was endocytozed by activated mouse and human neutrophils in a lipid raft-dependent fashion. Co-immunoprecipitation of human neutrophil lysates, confocal microscopy of isolated mouse and human neutrophils and functional blocking experiments showed that angiostatin complexes with flotillin-1 along with integrin ?v?3 and ATP synthase. Angiostatin inhibited fMLP-induced neutrophil polarization, as well as caused inhibition of hsp-27 phosphorylation and stabilization of microtubules. Angiostatin treatment, before or after LPS-induced neutrophil activation, inhibited phosphorylation of p38 and p44/42 MAPKs, abolished reactive oxygen species production and released the neutrophils from suppressed apoptosis, as indicated by expression of activated caspase-3 and morphological evidence of apoptosis. Finally, intravital microscopy and myeloperoxidase assay showed inhibition of neutrophil recruitment in post-capillary venules of TNF?-treated cremaster muscle in mouse. These in vitro and in vivo data demonstrate angiostatin as a broad deactivator and silencer of neutrophils and an inhibitor of their migration. These data potentially open new avenues for the development of anti-inflammatory drugs. PMID:24297047

  13. Documento de consenso sobre fototerapia: terapias PUVA y UVB de banda estrecha

    Microsoft Academic Search

    José M. Carrascosa; Jesús Gardeazábal; Amparo Pérez-Ferriols; Agustín Alomar; Pilar Manrique; María Jones-Caballero; Mario Lecha; José Aguilera; Jesús de la Cuadra

    2005-01-01

    It is essential to develop a consensus document on phototherapy in order to adapt this procedure to the specific characteristics, needs and reality of our milieu.Using a review of existing literature on the subject and the experience of its own members as a reference, the Spanish Photobiology Group (GEF) of the Spanish Academy of Dermatology and Venereology (AEDV) has developed

  14. VISUALIZATION-BASED ANALYSIS FOR A MIXED-INHIBITION BINARY PBPK MODEL: DETERMINATION OF INHIBITION MECHANISM

    EPA Science Inventory

    A physiologically-based pharmacokinetic (PBPK) model incorporating mixed enzyme inhibition was used to determine mechanism of the metabolic interactions occurring during simultaneous inhalation exposures to the organic solvents chloroform and trichloroethylene (TCE). V...

  15. VISUALIZATION-BASED ANALYSIS FOR A MIXED-INHIBITION BINARY PBPK MODEL: DETERMINATION OF INHIBITION MECHANISM

    EPA Science Inventory

    A physiologically-based pharmacokinetic (PBPK) model incorporating mixed enzyme inhibition was used to determine the mechanism of metabolic interactions occurring during simultaneous exposures to the organic solvents chloroform and trichloroethylene (TCE). Visualization-based se...

  16. The temporal dynamic of response inhibition in early childhood: an ERP study of partial and successful inhibition.

    PubMed

    Chevalier, Nicolas; Kelsey, Kathleen M; Wiebe, Sandra A; Espy, Kimberly Andrews

    2014-01-01

    Event-related potentials were recorded while five-year-old children completed a Go/No-Go task that distinguished between partial inhibition (i.e., response is initiated but cancelled before completion) and successful inhibition (i.e., response is inhibited before it is initiated). Partial inhibition trials were characterized by faster response initiation and later latency of the lateral frontal negativity than successful Go and successful inhibition trials. The speed of response initiation was influenced by the response speed on previous trials and influenced the response speed on subsequent trials. Response initiation and action decision dynamically influenced each other, and their temporal interplay determined response inhibition success. PMID:25470223

  17. Dietary linoleic acid, immune inhibition and disease

    PubMed Central

    Sammon, A.

    1999-01-01

    Review of the evidence available in published literature supports a radical change in viewpoint with respect to disease in countries where maize is the predominant dietary component. In these countries, the pattern of disease is largely determined by a change in immune profile caused by metabolites of dietary linoleic acid. High intake of linoleic acid in a diet deficient in other polyunsaturated fatty acids and in riboflavin results in high tissue production of prostaglandin E2, which in turn causes inhibition of the proliferation and cytokine production of Th1 cells, mediators of cellular immunity. Tuberculosis, measles, hepatoma, secondary infection in HIV and kwashiorkor are all favoured by this reduction in cellular immunity. Diet-associated inhibition of the Th1 subset is a major contributor to the high prevalence of these diseases found in areas of sub-Saharan Africa where maize is the staple.???Keywords: maize; linoleic acid; prostaglandin E2; cellular immunity; kwashiorkor; diet PMID:10448487

  18. Inhibition of lymphocyte proliferative responses by ribavirin.

    PubMed Central

    Peavy, D L; Koff, W C; Hyman, D S; Knight, V

    1980-01-01

    When added to cultures of human peripheral blood lymphocytes, ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) inhibited antigen- and mitogen-induced proliferative responses as determined by [3H]thymidine incorporation. Dose-dependent suppressive effects were obtained when concentrations of 5 to 60 microgram of ribavirin per ml were added at culture initiation or up to 96 h thereafter. Ribavirin inhibited [3H]uridine and [3H]leucine incorporation by concanavalin A-activated and normal lymphocytes although not as severely as deoxyribonucleic acid synthesis. The capacity of ribavirin to interfere with lymphoproliferative responses was entirely reversed by guanosine and, to a lesser extent, by adenosine and xanthosine. These studies demonstrate that ribavirin is a reversible inhibitor of lymphocyte nucleic acid synthesis and suggest that the drug may be immunosuppressive when administered in vivo. PMID:7216427

  19. Theobromine inhibits sensory nerve activation and cough.

    PubMed

    Usmani, Omar S; Belvisi, Maria G; Patel, Hema J; Crispino, Natascia; Birrell, Mark A; Korbonits, Márta; Korbonits, Dezso; Barnes, Peter J

    2005-02-01

    Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of theobromine appear to be peripherally mediated. We conclude theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs. PMID:15548587

  20. Evaluation of tankyrase inhibition in whole cells.

    PubMed

    Ohishi, Tomokazu; Tsuruo, Takashi; Seimiya, Hiroyuki

    2007-01-01

    The telomeric poly(ADP-ribose) polymerase (PARP), tankyrase 1, modulates the impact of telomerase inhibition on human cancer cells. Thus, overexpression of tankyrase 1 in telomerase-positive cancer cells confers resistance to telomerase inhibitors, such as MST-312, whereas pharmacological inhibition of tankyrase 1 enhances telomere shortening by MST-312. These facts indicate that tankyrase 1 could be a target for telomere-directed molecular cancer therapy. Here, the authors describe a convenient method to monitor the telomeric function of tankyrase 1. This protocol takes much less time than the telomere Southern blot analysis and can be utilized as a rapid screening system for tankyrase 1 inhibitors that are effective in intact cells. For direct monitoring of tankyrase 1 PARP activity, a protocol for the in vitro enzyme assay is also described. PMID:18369822

  1. Hyaluronan inhibits BMP-induced osteoblast differentiation.

    PubMed

    Kaneko, Keiko; Higuchi, Chikahisa; Kunugiza, Yasuo; Yoshida, Kiyoshi; Sakai, Takashi; Yoshikawa, Hideki; Nakata, Ken

    2015-02-13

    Hyaluronan (HA), one of the major structural extracellular components in cartilage, regulates cellular responses via receptors such as CD44. However, the direct effects of HA on osteoblastic differentiation has not been studied in detail. Here, we investigated the effects of HA (molecular weight: 900-1200 kDa) on osteoblastic differentiation that was induced by bone morphogenetic protein (BMP) in C2C12 cells (mouse myoblastic cells) and ST2 cells (mouse bone marrow cells). BMP-induced osteoblastic differentiation and Smad1/Smad5/Smad8 phosphorylation were downregulated by HA. Use of the CD44-blocking antibody restored HA-induced inhibition of osteoblastic differentiation and Smad1/Smad5/Smad8 phosphorylation. Our results indicate that HA inhibits BMP-induced osteoblastic differentiation through the CD44 receptor. PMID:25592835

  2. Inhibition of acetylcholinesterase activity by essential oil from Citrus paradisi.

    PubMed

    Miyazawa, M; Tougo, H; Ishihara, M

    2001-01-01

    Inhibition of acetylcholinesterase (AChE) activity by essential oils of Citrus paradisi (grapefruit pink in USA) was studied. Inhibition of AChE was measured by the colorimetric method. Nootkatone and auraptene were isolated from C. paradisi oil and showed 17-24% inhibition of AChE activity at the concentration of 1.62 microg/mL. PMID:11858553

  3. Eye Blink Startle Responses in Behaviorally Inhibited and Uninhibited Children

    ERIC Educational Resources Information Center

    van Brakel, Anna M. L.; Muris, Peter; Derks, Wendy

    2006-01-01

    The present study examined the startle reflex as a physiological marker of behavioral inhibition. Participants were 7 to 12-year-old children who had been previously identified as inhibited or uninhibited as part of an ongoing longitudinal study on the role of behavioral inhibition in the development of anxiety disorders. Analysis of their scores…

  4. Differential sensitivity of rice pathogens to growth inhibition by flavonoids

    Microsoft Academic Search

    Manchikanti Padmavati; Natarajan Sakthivel; K. V. Thara; Arjula R. Reddy

    1997-01-01

    Differential sensitivity of the major pathogens of rice, Xanthomonas oryzae pv. oryzae, Pyricularia oryzae and Rhizoctonia solani to inhibition by certain flavonoids was tested using paper disc\\/liquid culture and spore germination assays. Naringenin, the first intermediate of the flavonoid pathway, displayed growth inhibition of Xanthomonas strains and spore germination of P. oryzae. On the other hand, no such inhibition was

  5. Mechanism of zinc-mediated inhibition of caspase-9

    E-print Network

    Hardy, Jeanne

    Mechanism of zinc-mediated inhibition of caspase-9 Kristen L. Huber and Jeanne A. Hardy* Department; Accepted 25 April 2012 DOI: 10.1002/pro.2090 Published online 9 May 2012 proteinscience.org Abstract: Zinc-mediated inhibition is implicated in global caspase regulation, with relief of zinc- mediated inhibition central

  6. Original article Heat-killed Lactobacillus acidophilus inhibits

    E-print Network

    Paris-Sud XI, Université de

    Original article Heat-killed Lactobacillus acidophilus inhibits adhesion of Escherichia coli B41-105 °C) Lactobacillus acidophilus (Lact6ol strain) was found to inhibit this adhe- sion in a doseLa cells, and for the inhibition of adhesion of E coli to these cells. Escherichia coliJ Lactobacillus

  7. Studies on the detergent inhibition of pancreatic lipase activity

    Microsoft Academic Search

    Y. Gargouri; R. Julien; A. G. Bois; R. Verger; L. Sarda

    Pancreatic lipase requires colipase, a protein cofac- tor, to counteract the in vitro inhibition by bile salt. Lipase activity is inhibited by nonsteroidic detergents regardless of their charge and structure. Detergent-inhibited lipase is reac- tivated by colipase but in all cases activation is limited to a narrow range of detergent concentration. Complementary studies on the bile salt and detergent effect

  8. Inhibition of SN38 glucuronidation by ketoconazole

    Microsoft Academic Search

    W. Yong; J. Ramirez; F. Innocenti; M. J. Ratain

    2005-01-01

    Background\\/Aims: Ketoconazole has been shown to inhibit the glucuronidation of the UGT2B7 substrates AZT and lorazepam. Its effect on UGT1A substrates is unknown. A recent study (Kehrer et al, JClin Oncol, 2002) found that co-administration of irinotecan and ketoconazole led to a significant increase in the formation of SN-38. This study investigates whether ketoconazole contributes to the increase in SN-38

  9. Octreotide Inhibits Choroidal Neovascularization in Rats

    Microsoft Academic Search

    Yi Qu; Shuihua Zhang; Xiaoyi Xu; Hong Wang; Jinghai Li; Fang Zhou; Fengcai Wei

    2009-01-01

    Aims: Octreotide exhibits anti-angiogenic activity in animal models of retinopathy of prematurity and in clinical cases of proliferative diabetic retinopathy. In this study, we tested the applicability of using octreotide for inhibiting experimental choroidal neovascularization (CNV) in rats. Methods: Of 15 adult rats used, 3 served as non-laser-treated controls. CNV was induced in the right eye of the remaining 12

  10. Lipoproteins inhibit macrophage activation by lipoteichoic acid

    Microsoft Academic Search

    Carl Grunfeld; Maureen Marshall; Judy K. Shigenaga; Arthur H. Moser; Peter Tobias; Kenneth R. Feingold

    Regulation of lipid metabolism during infection is thought to be part of host defense, as lipoproteins neu- tralize endotoxin (LPS) and viruses. Gram-positive infec- tions also induce disturbances in lipid metabolism. There- fore, we investigated whether lipoproteins could inhibit the toxic effects of lipoteichoic acid (LTA), a fragment of gram- positive bacteria. LTA activated RAW264.7 macrophage cells, stimulating production of

  11. Inhibition of Precipitation and Aggregation of Metacinnabar

    E-print Network

    Ryan, Joe

    (black HgS) was inhibited in the presence of low concentrations (g3 mg C/L) of humic fractions(SH)2, HgS2H- , HgS2 2-] or insoluble mercuric sulfide (HgS) solids depending on the pH, sulfide, and Hg concentrations. Generally, formation of solid HgS is favored at low pH and low sulfide concentrations, while

  12. Caffeine inhibits acetylcholinesterase, but not butyrylcholinesterase.

    PubMed

    Pohanka, Miroslav; Dobes, Petr

    2013-01-01

    Caffeine is an alkaloid with a stimulant effect in the body. It can interfere in transmissions based on acetylcholine, epinephrine, norepinephrine, serotonin, dopamine and glutamate. Clinical studies indicate that it can be involved in the slowing of Alzheimer disease pathology and some other effects. The effects are not well understood. In the present work, we focused on the question whether caffeine can inhibit acetylcholinesterase (AChE) and/or, butyrylcholinesterase (BChE), the two enzymes participating in cholinergic neurotransmission. A standard Ellman test with human AChE and BChE was done for altering concentrations of caffeine. The test was supported by an in silico examination as well. Donepezil and tacrine were used as standards. In compliance with Dixon's plot, caffeine was proved to be a non-competitive inhibitor of AChE and BChE. However, inhibition of BChE was quite weak, as the inhibition constant, Ki, was 13.9 ± 7.4 mol/L. Inhibition of AChE was more relevant, as Ki was found to be 175 ± 9 µmol/L. The predicted free energy of binding was -6.7 kcal/mol. The proposed binding orientation of caffeine can interact with Trp86, and it can be stabilize by Tyr337 in comparison to the smaller Ala328 in the case of human BChE; thus, it can explain the lower binding affinity of caffeine for BChE with reference to AChE. The biological relevance of the findings is discussed. PMID:23698772

  13. Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

    PubMed Central

    Kristensen, David M.; Skalkam, Maria L.; Audouze, Karine; Lesné, Laurianne; Desdoits-Lethimonier, Christele; Frederiksen, Hanne; Brunak, Søren; Skakkebæk, Niels E.; Jégou, Bernard; Hansen, Jacob B.; Junker, Steffen; Leffers, Henrik

    2011-01-01

    Background Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine-disrupting compounds (EDCs) share a high degree of structural similarity with mild analgesics. Objectives and Methods Using cell-based transfection and transduction experiments, mass spectrometry, and organotypic assays together with molecular modeling, we investigated whether inhibition of the PG pathway by known EDCs could be a novel point of endocrine disruption. Results We found that many known EDCs inhibit the PG pathway in a mouse Sertoli cell line and in human primary mast cells. The EDCs also reduced PG synthesis in ex vivo rat testis, and this reduction was correlated with a reduced testosterone production. The inhibition of PG synthesis occurred without involvement of canonical PG receptors or the peroxisome proliferator–activated receptors (PPARs), which have previously been described as targets of EDCs. Instead, our results suggest that the compounds may bind directly into the active site of the cyclooxygenase (COX) enzymes, thereby obstructing the conversion of arachidonic acid to PG precursors without interfering with the expression of the COX enzymes. A common feature of the PG inhibitory EDCs is the presence of aromatic groups that may stabilize binding in the hydrophobic active site of the COX enzymes. Conclusion Our findings suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades. PMID:21081300

  14. Caffeine Inhibits Acetylcholinesterase, But Not Butyrylcholinesterase

    PubMed Central

    Pohanka, Miroslav; Dobes, Petr

    2013-01-01

    Caffeine is an alkaloid with a stimulant effect in the body. It can interfere in transmissions based on acetylcholine, epinephrine, norepinephrine, serotonin, dopamine and glutamate. Clinical studies indicate that it can be involved in the slowing of Alzheimer disease pathology and some other effects. The effects are not well understood. In the present work, we focused on the question whether caffeine can inhibit acetylcholinesterase (AChE) and/or, butyrylcholinesterase (BChE), the two enzymes participating in cholinergic neurotransmission. A standard Ellman test with human AChE and BChE was done for altering concentrations of caffeine. The test was supported by an in silico examination as well. Donepezil and tacrine were used as standards. In compliance with Dixon’s plot, caffeine was proved to be a non-competitive inhibitor of AChE and BChE. However, inhibition of BChE was quite weak, as the inhibition constant, Ki, was 13.9 ± 7.4 mol/L. Inhibition of AChE was more relevant, as Ki was found to be 175 ± 9 ?mol/L. The predicted free energy of binding was ?6.7 kcal/mol. The proposed binding orientation of caffeine can interact with Trp86, and it can be stabilize by Tyr337 in comparison to the smaller Ala328 in the case of human BChE; thus, it can explain the lower binding affinity of caffeine for BChE with reference to AChE. The biological relevance of the findings is discussed. PMID:23698772

  15. Inhibition of Vascularization in Tumor Growth

    NASA Astrophysics Data System (ADS)

    Scalerandi, M.; Sansone, B. Capogrosso

    2002-11-01

    The transition to a vascular phase is a prerequisite for fast tumor growth. During the avascular phase, the neoplasm feeds only from the (relatively few) existing nearby blood vessels. During angiogenesis, the number of capillaries surrounding and infiltrating the tumor increases dramatically. A model which includes physical and biological mechanisms of the interactions between the tumor and vascular growth describes the avascular-vascular transition. Numerical results agree with clinical observations and predict the influence of therapies aiming to inhibit the transition.

  16. Modified atmosphere packaging inhibits browning in fennel

    Microsoft Academic Search

    V. H Escalona; E Aguayo; P Gómez; F Artés

    2004-01-01

    The effects of modified atmosphere packaging (MAP) to inhibit browning of the butt end cut zone of fennel bulbs stored during 14 days at 0°C followed by complementary air storage during 3 days at 15°C were studied. Selected bulbs were placed in 35?m oriented polypropylene bags or in plastic baskets heat-sealed with nonperforated or perforated (control) polypropylene film. Changes in

  17. The inhibition of tyrosinase by pyridinones.

    PubMed Central

    Hider, R C; Lerch, K

    1989-01-01

    3-Hydroxypyridine-4-ones have potential as orally active chelators of iron(III) and therefore may find application in the treatment of thalassaemia. An undesirable feature of these molecules is that they inhibit tyrosinase. We have established that alkyl substitution at position 2 in the aromatic ring minimizes interaction with tyrosinase and does so without appreciably influencing the affinity for iron(III). PMID:2493243

  18. Inhibition of enveloped viruses infectivity by curcumin.

    PubMed

    Chen, Tzu-Yen; Chen, Da-Yuan; Wen, Hsiao-Wei; Ou, Jun-Lin; Chiou, Shyan-Song; Chen, Jo-Mei; Wong, Min-Liang; Hsu, Wei-Li

    2013-01-01

    Curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. Previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (HA) activity. This study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. In all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. In contrast, the nonenveloped enterovirus 71 remained unaffected by curcumin treatment. We evaluated the effects of curcumin on the membrane structure using fluorescent dye (sulforhodamine B; SRB)-containing liposomes that mimic the viral envelope. Curcumin treatment induced the leakage of SRB from these liposomes and the addition of the influenza virus reduced the leakage, indicating that curcumin disrupts the integrity of the membranes of viral envelopes and of liposomes. When testing liposomes of various diameters, we detected higher levels of SRB leakage from the smaller-sized liposomes than from the larger liposomes. Interestingly, the curcumin concentration required to reduce plaque formation was lower for the influenza virus (approximately 100 nm in diameter) than for the pseudorabies virus (approximately 180 nm) and the vaccinia virus (roughly 335 × 200 × 200 nm). These data provide insights on the molecular antiviral mechanisms of curcumin and its potential use as an antiviral agent for enveloped viruses. PMID:23658730

  19. Anandamide inhibits breast tumor-induced angiogenesis

    PubMed Central

    Picardi, P; Ciaglia, E; Proto, MC; Pisanti, S

    2014-01-01

    Breast cancer is one of the most frequently diagnosed malignancies and a leading cause of cancer death in women. Great advances in the treatment of primary tumors have led to a significant increment in the overall survival rates, however recurrence and metastatic disease, the underlying cause of death, are still a medical challenge. Breast cancer is highly dependent on neovascularization to progress. In the last years several anti-angiogenic drugs have been developed and administered to patients in combination with chemotherapeutic drugs. Collected preclinical evidence has proposed the endocannabinoid system as a potential target in cancer. The endocannabinoid anandamide has been reported to affect breast cancer growth at multiple levels, by inhibiting proliferation, migration and invasiveness in vitro and in vivo and by directly inhibiting angiogenesis. Aim of the present work is to investigate if anandamide is able to affect the proangiogenic phenotype of the highly invasive and metastatic breast cancer cells MDA-MB-231. We found that following anandamide treatment, MDAMB-231 cells lose their ability to stimulate endothelial cells proliferation in vitro, due to a significant inhibition of all the pro-angiogenic factors produced by these cells. This finding adds another piece of evidence to the anti-tumor efficacy of anandamide in breast cancer. PMID:25147760

  20. Menaquinone Analogs Inhibit Growth of Bacterial Pathogens

    PubMed Central

    Merriman, Joseph A.; Salgado-Pabón, Wilmara; Mueller, Elizabeth A.; Spaulding, Adam R.; Vu, Bao G.; Chuang-Smith, Olivia N.; Kohler, Petra L.; Kirby, John R.

    2013-01-01

    Gram-positive bacteria cause serious human illnesses through combinations of cell surface and secreted virulence factors. We initiated studies with four of these organisms to develop novel topical antibacterial agents that interfere with growth and exotoxin production, focusing on menaquinone analogs. Menadione, 1,4-naphthoquinone, and coenzymes Q1 to Q3 but not menaquinone, phylloquinone, or coenzyme Q10 inhibited the growth and to a greater extent exotoxin production of Staphylococcus aureus, Bacillus anthracis, Streptococcus pyogenes, and Streptococcus agalactiae at concentrations of 10 to 200 ?g/ml. Coenzyme Q1 reduced the ability of S. aureus to cause toxic shock syndrome in a rabbit model, inhibited the growth of four Gram-negative bacteria, and synergized with another antimicrobial agent, glycerol monolaurate, to inhibit S. aureus growth. The staphylococcal two-component system SrrA/B was shown to be an antibacterial target of coenzyme Q1. We hypothesize that menaquinone analogs both induce toxic reactive oxygen species and affect bacterial plasma membranes and biosynthetic machinery to interfere with two-component systems, respiration, and macromolecular synthesis. These compounds represent a novel class of potential topical therapeutic agents. PMID:23959313

  1. Menaquinone analogs inhibit growth of bacterial pathogens.

    PubMed

    Schlievert, Patrick M; Merriman, Joseph A; Salgado-Pabón, Wilmara; Mueller, Elizabeth A; Spaulding, Adam R; Vu, Bao G; Chuang-Smith, Olivia N; Kohler, Petra L; Kirby, John R

    2013-11-01

    Gram-positive bacteria cause serious human illnesses through combinations of cell surface and secreted virulence factors. We initiated studies with four of these organisms to develop novel topical antibacterial agents that interfere with growth and exotoxin production, focusing on menaquinone analogs. Menadione, 1,4-naphthoquinone, and coenzymes Q1 to Q3 but not menaquinone, phylloquinone, or coenzyme Q10 inhibited the growth and to a greater extent exotoxin production of Staphylococcus aureus, Bacillus anthracis, Streptococcus pyogenes, and Streptococcus agalactiae at concentrations of 10 to 200 ?g/ml. Coenzyme Q1 reduced the ability of S. aureus to cause toxic shock syndrome in a rabbit model, inhibited the growth of four Gram-negative bacteria, and synergized with another antimicrobial agent, glycerol monolaurate, to inhibit S. aureus growth. The staphylococcal two-component system SrrA/B was shown to be an antibacterial target of coenzyme Q1. We hypothesize that menaquinone analogs both induce toxic reactive oxygen species and affect bacterial plasma membranes and biosynthetic machinery to interfere with two-component systems, respiration, and macromolecular synthesis. These compounds represent a novel class of potential topical therapeutic agents. PMID:23959313

  2. Pharmacological Inhibition of Feline Immunodeficiency Virus (FIV)

    PubMed Central

    Mohammadi, Hakimeh; Bienzle, Dorothee

    2012-01-01

    Feline immunodeficiency virus (FIV) is a member of the retroviridae family of viruses and causes an acquired immunodeficiency syndrome (AIDS) in domestic and non-domestic cats worldwide. Genome organization of FIV and clinical characteristics of the disease caused by the virus are similar to those of human immunodeficiency virus (HIV). Both viruses infect T lymphocytes, monocytes and macrophages, and their replication cycle in infected cells is analogous. Due to marked similarity in genomic organization, virus structure, virus replication and disease pathogenesis of FIV and HIV, infection of cats with FIV is a useful tool to study and develop novel drugs and vaccines for HIV. Anti-retroviral drugs studied extensively in HIV infection have targeted different steps of the virus replication cycle: (1) inhibition of virus entry into susceptible cells at the level of attachment to host cell surface receptors and co-receptors; (2) inhibition of fusion of the virus membrane with the cell membrane; (3) blockade of reverse transcription of viral genomic RNA; (4) interruption of nuclear translocation and viral DNA integration into host genomes; (5) prevention of viral transcript processing and nuclear export; and (6) inhibition of virion assembly and maturation. Despite much success of anti-retroviral therapy slowing disease progression in people, similar therapy has not been thoroughly investigated in cats. In this article we review current pharmacological approaches and novel targets for anti-lentiviral therapy, and critically assess potentially suitable applications against FIV infection in cats. PMID:22754645

  3. Resveratrol inhibits protein translation in hepatic cells.

    PubMed

    Villa-Cuesta, Eugenia; Boylan, Joan M; Tatar, Marc; Gruppuso, Philip A

    2011-01-01

    Resveratrol is a plant-derived polyphenol that extends lifespan and healthspan in model organism. Despite extensive investigation, the biological processes mediating resveratrol's effects have yet to be elucidated. Because repression of translation shares many of resveratrol's beneficial effects, we hypothesized that resveratrol was a modulator of protein synthesis. We studied the effect of the drug on the H4-II-E rat hepatoma cell line. Initial studies showed that resveratrol inhibited global protein synthesis. Given the role of the mammalian Target of Rapamycin (mTOR) in regulating protein synthesis, we examined the effect of resveratrol on mTOR signaling. Resveratrol inhibited mTOR self-phosphorylation and the phosphorylation of mTOR targets S6K1 and eIF4E-BP1. It attenuated the formation of the translation initiation complex eIF4F and increased the phosphorylation of eIF2?. The latter event, also a mechanism for translation inhibition, was not recapitulated by mTOR inhibitors. The effects on mTOR signaling were independent of effects on AMP-activated kinase or AKT. We conclude that resveratrol is an inhibitor of global protein synthesis, and that this effect is mediated through modulation of mTOR-dependent and independent signaling. PMID:22242130

  4. Role of calcineurin in inhibiting disadvantageous associations.

    PubMed

    Shaw, J A; Matlovich, N; Rushlow, W; Cain, P; Rajakumar, N

    2012-02-17

    Calcineurin is an important calcium-dependent phosphatase that is evolutionarily conserved in all studied species, and has been implicated in the consolidation and maintenance of new memories. However, recent evidence has extended the role of calcineurin. In contrast to learning tasks that require behavioral acquisition, extinction tasks that require behavioral inhibition have been shown to be reliant on calcineurin. In the present study, using a Morris water maze, we have demonstrated that pharmacological inhibition of calcineurin causes augmentation of spatial learning and perseveration of spatial reversal-learning in a dose-dependent manner. Direct infusions of a specific calcineurin inhibitor, cyclosporine A, into the dorsal hippocampi bilaterally, prior to spatial learning, led to increased learning, whereas similar injections of cyclosporine A following a spatial learning task and prior to a spatial reversal-learning task resulted in perseveration of reversal-learning. Our results indicate that injections of cyclosporin A resulted in decreased calcineurin activity in the dorsal hippocampus and increased difficulty in switching to new task demands, in a dose-dependent manner, despite evidence indicating no deficit in ability to learn new information. Therefore, calcineurin activity contributes to the inhibition of previously learned but unwanted behavioral responses during competitive spatial learning. Involvement of calcineurin in extinction of fear memory has recently been demonstrated. Our results also indicate that calcineurin activity plays a role in memory extinction in spatial memory tasks, and therefore, suggest that calcineurin might be an important molecule in mediating behavioral flexibility in general. PMID:22230044

  5. Inhibition of glycosylphosphatidylinositol anchor formation by mannosamine.

    PubMed

    Pan, Y T; Kamitani, T; Bhuvaneswaran, C; Hallaq, Y; Warren, C D; Yeh, E T; Elbein, A D

    1992-10-15

    Many eucaryotic cell surface proteins are anchored to the plasma membrane via a glycosylphosphatidylinositol (GPI), of which the core region is highly conserved from protozoa to mammalian cells. Previous studies (Lisanti, M. P., Field, M. C., Caras, I. W., Menon, A. K., and Rodiguez-Boulan, E. (1991) EMBO J. 10, 1969-1977) showed that mannosamine blocked the expression of a recombinant GPI-anchored protein in Madin-Darby canine kidney cells and converted this protein to an unpolarized secretory product. In the present study, we examined the effect of mannosamine on the formation of the glycan portion of the GPI anchor precursors. This amino sugar inhibited the incorporation of mannose into the glycan portion, and the inhibition was dose-dependent. Mannosamine was shown to be incorporated into the glycan as mannosamine, probably mostly in the second mannose position and thereby to block the further addition of mannose and other anchor components. The products formed in the presence of this drug were characterized by gel filtration and high resolution TLC both before and after deamination with nitrous acid and dephosphorylation by HF. Galactosamine and trehalosamine were inactive in this system, whereas glucosamine also inhibited mannose incorporation into GPI intermediates. PMID:1400435

  6. Pinocembrin inhibits matrix metalloproteinase expression in chondrocytes.

    PubMed

    Zhang, Dawei; Huang, Bo; Xiong, Chengjie; Yue, Zhou

    2015-01-01

    Osteoarthritis (OA), the most common form of arthritis, affects millions of people worldwide. The degradation of extracellular matrix induced by matrix metalloproteinases (MMPs) is an important cause of cartilage destruction. Pinocembrin (PB) is one of the primary flavonoids abundant in propolis and extracted as a pure compound. The protective effects of PB in OA have not been reported before. In this study, we found that PB inhibits the expression of MMP-1, MMP-3, and MMP-13 at both mRNA levels and protein levels in human chondrocytes. Importantly, the results of luciferase reporter assay indicated that tumor necrosis factor-alpha (TNF-?) induced the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) was inhibited by the treatment with PB. It is also shown that TNF-?-induced p65 nuclear translocation was blocked by the treatment with PB. Mechanistically, PB treatment significantly inhibited TNF-?-induced phosphorylation and degradation of the NF-?B inhibitor I?B? in human chondrocytes. These results suggest a potential protective effect of PB in OA. PMID:25644385

  7. Generic Inhibition of the Selected Movement and Constrained Inhibition of Nonselected Movements during Response Preparation

    PubMed Central

    Labruna, Ludovica; Lebon, Florent; Duque, Julie; Klein, Pierre-Alexandre; Cazares, Christian; Ivry, Richard B.

    2014-01-01

    Previous studies have identified two inhibitory mechanisms that operate during action selection and preparation. One mechanism, competition resolution, is manifest in the inhibition of the nonselected response and attributed to competition between candidate actions. The second mechanism, impulse control, is manifest in the inhibition of the selected response and is presumably invoked to prevent premature response. To identify constraints on the operation of these two inhibitory mechanisms, we manipulated the effectors used for the response alternatives, measuring changes in corticospinal excitability with motor-evoked potentials to TMS. Inhibition of the selected response (impulse control) was independent of the task context, consistent with a model in which this form of inhibition is automatically triggered as part of response preparation. In contrast, inhibition of the nonselected response (competition resolution) was context-dependent. Inhibition of the nonselected response was observed when the response alternatives involved movements of the upper limbs but was absent when one response alternative involved an upper limb and the other involved a lower limb. Interestingly, competition resolution for pairs of upper limbs did not require homologous effectors, observed when a left index finger response was pitted with either a nonhomologous right index finger movement or a right arm movement. These results argue against models in which competition resolution is viewed as a generic or fully flexible process, as well as models based on strong anatomical constraints. Rather, they are consistent with models in which inhibition for action selection is constrained by the similarity between the potential responses, perhaps reflecting an experience-dependent mechanism sensitive to the past history of competitive interactions. PMID:24047388

  8. Chemistry and mechanism of urease inhibition.

    PubMed

    Amtul, Z; Rahman, Atta-Ur; Siddiqui, R A; Choudhary, M I

    2002-07-01

    Studies on enzyme inhibition remain an important area of pharmaceutical research since these studies have led to the discoveries of drugs useful in a variety of physiological conditions. The enzyme inhibitors can interact with enzymes and block their activity towards natural substrates. Urease inhibitors have recently attracted much attention as potential new anti-ulcer drugs. Ironically, urease was the first enzyme crystallized but its mechanism of action is still largely misunderstood. This chapter therefore reviews comprehensive developments in the field of urease inhibitors. Inhibitors of urease can be broadly classified into two categories: (1) active site directed (substrate-like), (2) mechanism-based directed. We present here the examples of selected inhibitors along with their mechanisms of action to characterize their mode of urease inhibition. The observations that urease due to its high substrate (urea) specificity can only bind to a few inhibitors with a similar binding mode as urea is also discussed. Several non-covalent interactions including hydrogen bonds and hydrophobic contacts stabilize the enzyme-inhibitor complex. Regardless of the class of compound, it is reported that only a few functional groups with electronegative atoms such as oxygen, nitrogen and sulfur act either as bidentate (mostly), tridentate (rarely), or as ligand-chelator to form octahedral complexes with two slightly distorted octahedral Ni ions of the enzyme. Bulky groups attached to the pharmacophore were found to decrease the activity of inhibitors, since the lack of a bulky attachment makes it easier for urease inhibitors to enter the substrate-binding pocket as well as avoid unfavorable steric interactions with amino acid residues in its vicinity. This review is intended to provide highlights of the inhibition of urease by hydroxamic acids (HXAs), phosphorodiamidates (PPDs), imidazoles, phosphazene and related compounds. These compounds are compared to previously reported urease inhibitors for the catalytic models proposed for urease activity. The differences in inhibition of urease activities from plants and of bacterial origin by various inhibitors and physiological implications of urease inhibition are discussed. PMID:12132990

  9. Differential effects of cognitive inhibition and intelligence on creativity

    PubMed Central

    Benedek, Mathias; Franz, Fabiola; Heene, Moritz; Neubauer, Aljoscha C.

    2012-01-01

    There are different conceptions about how cognitive inhibition is related to creativity. Creativity has either been associated with effective inhibition, or with disinhibition, or with an adaptive engagement of inhibition. In this study, we examined the relationship of cognitive inhibition, assessed by means of the random motor generation task, with different measures of creativity. We also analyzed whether this relation is mediated by intelligence. We generally found a positive correlation of inhibition and creativity measures. Moreover, latent variable analyses indicate that inhibition may primarily promote the fluency of ideas, whereas intelligence specifically promotes the originality of ideas. These findings support the notion that creative thought involves executive processes and may help to better understand the differential role of inhibition and intelligence in creativity. PMID:22945970

  10. Copper, aluminum, iron and calcium inhibit human acetylcholinesterase in vitro.

    PubMed

    Pohanka, Miroslav

    2014-01-01

    Acetylcholinesterase (AChE) is an important part of cholinergic nerves where it participates in termination of neurotransmission. AChE can be inhibited by e.g. some Alzheimer disease drugs, nerve agents, and secondary metabolites. In this work, metal salts aluminum chloride, calcium chloride, cupric chloride, ferric chloride, potassium chloride, magnesium chloride and sodium chloride were tested for their ability to inhibit AChE. Standard Ellman assay based on human recombinant AChE was done and inhibition was measured using Dixon plot. No inhibition was proved for sodium, potassium and magnesium ions. However, aluminum, cupric, ferric and calcium ions were able to inhibit AChE via noncompetitive mechanism of inhibition. Though the inhibition is much weaker when compared to e.g. drugs with noncompetitive mechanism of action, biological relevance of the findings can be anticipated. PMID:24473150

  11. Inhibition by acrolein of light-induced stomatal opening through inhibition of inward-rectifying potassium channels in Arabidopsis thaliana.

    PubMed

    Islam, Md Moshiul; Ye, Wenxiu; Matsushima, Daiki; Khokon, Md Atiqur Rahman; Munemasa, Shintaro; Nakamura, Yoshimasa; Murata, Yoshiyuki

    2015-01-01

    Acrolein is a reactive ?,?-unsaturated aldehyde derived from lipid peroxides, which are produced in plants under a variety of stress. We investigated effects of acrolein on light-induced stomatal opening using Arabidopsis thaliana. Acrolein inhibited light-induced stomatal opening in a dose-dependent manner. Acrolein at 100??M inhibited plasma membrane inward-rectifying potassium (Kin) channels in guard cells. Acrolein at 100??M inhibited Kin channel KAT1 expressed in a heterologous system using Xenopus leaves oocytes. These results suggest that acrolein inhibits light-induced stomatal opening through inhibition of Kin channels in guard cells. PMID:25144495

  12. A PostSynaptic Inhibition Recurrent Neural Network Structure and Its Application to Pattern Classification

    Microsoft Academic Search

    Su Caihong; Zeng Yongfa; Zhang Zhifei; Wu Jing

    2007-01-01

    The post-synaptic inhibition is an inhibition which is stimulated by the activity of inhibitory interneurons. When the inhibitory interneurons are stimulated by the excitatory neurons, the IPSP arised from postsynaptic membrane will inhibit the activity of post-synaptic neurons. Post-synaptic inhibition includes lateral inhibition, feedback inhibition and feedforward inhibition. In this paper, these three inhibition modalities are in deep analyzed from

  13. Quassinoid Inhibition of AP-1 Function Does Not Correlate with Cytotoxicity or Protein Synthesis Inhibition†

    PubMed Central

    Beutler, John A.; Kang, Moon-Il; Robert, Francis; Clement, Jason A.; Pelletier, Jerry; Colburn, Nancy H.; McKee, Tawnya C.; Goncharova, Ekaterina; McMahon, James B.; Henrich, Curtis J.

    2010-01-01

    Several quassinoids were identified in a high-throughput screening assay as inhibitors of the transcription factor AP-1. Further biological characterization revealed that while their effect was not specific to AP-1, protein synthesis inhibition and cell growth assays were inconsistent with a mechanism of simple protein synthesis inhibition. Numerous plant extracts from the plant family Simaroubaceae were also identified in the same screen; bioassay-guided fractionation of one extract (Ailanthus triphylla) yielded two known quassinoids, ailanthinone (3) and glaucarubinone (4), which were also identified in the pure compound screening procedure. PMID:19199792

  14. Choline kinase inhibition in rheumatoid arthritis

    PubMed Central

    Guma, M; Sanchez-Lopez, E; Lodi, A; Garcia-Carbonell, R; Tiziani, S; Karin, M; Lacal, J C; Firestein, G S

    2014-01-01

    Objectives Little is known about targeting the metabolome in non-cancer conditions. Choline kinase (ChoK?), an essential enzyme for phosphatidylcholine biosynthesis, is required for cell proliferation and has been implicated in cancer invasiveness. Aggressive behaviour of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) led us to evaluate whether this metabolic pathway could play a role in RA FLS function and joint damage. Methods Choline metabolic profile of FLS cells was determined by 1H magnetic resonance spectroscopy (1HMRS) under conditions of ChoK? inhibition. FLS function was evaluated using the ChoK? inhibitor MN58b (IC50=4.2 ?M). For arthritis experiments, mice were injected with K/BxN sera. MN58b (3 mg/kg) was injected daily intraperitoneal beginning on day 0 or day 4 after serum administration. Results The enzyme is expressed in synovial tissue and in cultured RA FLS. Tumour necrosis factor (TNF) and platelet-derived growth factor (PDGF) stimulation increased ChoK? expression and levels of phosphocholine in FLS measured by Western Blot (WB) and metabolomic studies of choline-containing compounds in cultured RA FLS extracts respectively, suggesting activation of this pathway in RA synovial environment. A ChoK? inhibitor also suppressed the behaviour of cultured FLS, including cell migration and resistance to apoptosis, which might contribute to cartilage destruction in RA. In a passive K/BxN arthritis model, pharmacologic ChoK? inhibition significantly decreased arthritis in pretreatment protocols as well as in established disease. Conclusions These data suggest that ChoK? inhibition could be an effective strategy in inflammatory arthritis. It also suggests that targeting the metabolome can be a new treatment strategy in non-cancer conditions. PMID:25274633

  15. Mirk kinase inhibition targets ovarian cancer ascites

    PubMed Central

    Deng, Xiaobing; Hu, Jing; Cunningham, Mary J.; Friedman, Eileen

    2014-01-01

    The Mirk/dyrk1B gene is commonly amplified or upregulated in ovarian cancers, and Mirk is an active kinase in these cancers. Mirk mediates cancer cell survival by decreasing toxic ROS levels through maintaining expression of a series of antioxidant genes, possibly through its transcriptional activator functions. Mirk has the unusual property of being most active in quiescent cancer cells because of marked transcriptional downregulation by Akt/mTOR signaling and by MEK/erk signaling in cycling cells. Metastatic ovarian cancer cells form ascites, non-adherent multicellular aggregates floating within the peritoneal fluid. Most ascites cancer cells are in a reversible quiescent, dormant state, suggesting that Mirk might be expressed in these quiescent cells and thus a therapeutic target. The current studies show that ovarian cancer cell line spheroids that mimic ascites cancer spheroids were largely quiescent in G0/G1, and enriched in Mirk and the quiescence proteins, p130/Rb2 and the CDKI p27. Mirk kinase inhibition in spheroids made from established cell lines and in patient-derived ascites cancer cell spheroids reduced spheroid volume, disrupted spheroid structure to single cells, increased apoptosis, and decreased cell numbers. Earlier studies had shown that the mTOR inhibitor RAD001 increased transcription of the Mirk/dyrk1B gene, so treatments combined RAD001 with the most active Mirk kinase inhibitor. The number of ascites cells from 9 patients was reduced a similar amount by cisplatin, Mirk kinase inhibition or RAD001, but reduced substantially more, about 90%, by concurrent treatment with both the Mirk kinase inhibitor EHT5372 and RAD001. Addition of RAD001 increased the amount of toxic ROS induced by Mirk kinase inhibition. Two ascites samples taken one month apart gave similar drug responses, showing reproducibility of the techniques. Thus Mirk/dyrk1B kinase may be a therapeutic target in ovarian cancer ascites. PMID:25061503

  16. Calreticulin inhibits vitamin D3 signal transduction.

    PubMed Central

    Wheeler, D G; Horsford, J; Michalak, M; White, J H; Hendy, G N

    1995-01-01

    Calreticulin is a calcium binding protein present primarily in the lumen of the endoplasmic reticulum. However, it can also localize to the cytoplasm adjacent to the cell membrane where it binds integrins, and to the nucleus. Recent studies showed that calreticulin inhibits DNA binding and transcriptional activity of glucocorticoid, androgen and retinoic acid receptors. The DNA binding domains of nuclear receptors share a common motif based upon the amino acid sequence KVFFKR which has been implicated in the binding of calreticulin. The vitamin D receptor (VDR) DNA binding domain contains the related motif KgFFrR. Here we show that calreticulin blocks specific DNA binding by the isolated VDR DNA binding domain in DNA mobility shift assays. Importantly, calreticulin blocks specific DNA binding by the full length VDR-RXR heterodimers. By contrast, calreticulin had no effect on specific DNA binding by the transcription factor ATF-a delta which lacks a KVFFKR-like motif in its DNA binding domain. We further showed that overexpression of calreticulin in the rat osteoblast-like cell line (ROS 17/2.8) inhibited the 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] responsive transcriptional activation of a vitamin D-sensitive reporter gene, whereas the response to forskolin stimulation of a control promoter-reporter construct containing a cAMP response element (CRE), but no vitamin D response element (VDRE), was not affected by overexpression of calreticulin. Thus, calreticulin inhibits transcriptional activation by the VDR in vivo. Given the ubiquitous expression of calreticulin and the widespread expression of the VDR the studies described here may point to an important new mechanism whereby VDR mediated gene transcription can be modulated. Images PMID:7667104

  17. GALVANOTROPISM AND "REVERSAL OF INHIBITION" BY STRYCHNINE

    PubMed Central

    Crozier, W. J.

    1927-01-01

    The cathodically galvanotropic orientation of nemerteans, Lineus, and the anodic orientation of the gephyrean Echiurus, are reversed by the action of strychnine under conditions such that the typical "reversal of inhibition" induced by this substance is apparent. Nicotine does not give this result. Since it is necessary to assume that the strychnine effect is due to action upon the central ganglia, and since the galvanotropic effect depends upon action of the current on nerve cell bodies of the central ganglia, it must be assumed that the locus of reversal by strychnine is not perikaryal, but presumably synaptic. PMID:19872331

  18. Hsp90 inhibitor can inhibit UV carcinogenesis.

    PubMed

    Katiyar, Santosh K

    2015-04-01

    Extensive exposure to solar UVR is a well-recognized etiologic factor for cutaneous non-melanoma skin cancer. In this issue of the Journal, Singh et al. show that topical treatment of the skin with 17-[allylamino]-17-demethoxygeldanamycin (17AAG), a heat-shock protein 90 (Hsp90) inhibitor, prevents UVR-induced squamous cell carcinomas (SCCs) in mice. The inhibitory effect of 17AAG on SCC was associated with the inhibition of the UVR-induced (i) hyperplastic response, (ii) Hsp90?-PKC? interaction, and (iii) pStat3 and pAkt expression in mouse skin. PMID:25785948

  19. Inhibition of ?-galactosidases with mono- and disaccharides

    NASA Astrophysics Data System (ADS)

    Pilipenko, O. S.; Atyaksheva, L. F.; Chukhrai, E. S.

    2010-01-01

    It was demonstrated that, in reactions of the hydrolysis of model substrate 2-nitrophenyl-?-D-galactopyranoside (2-NPGP) monosaccharides D-fructose and D-xylose with hydroxyl substituents oppositely directed at the neighboring carbon atoms in the furan ring, as in D-glucose, act as noncompetitive inhibitors of ?-galactosidase from E. coli; for mushroom, ?-galactosidases from P. canescens and A. oryzae D-galactose is a stronger inhibitor. It was also found that the inhibition constant is the highest in the case of the most active enzyme ( E. coli) and is the lowest for the least active one ( P. canescens).

  20. Saw palmetto ethanol extract inhibits adipocyte differentiation.

    PubMed

    Villaverde, Nicole; Galvis, Adriana; Marcano, Adriana; Priestap, Horacio A; Bennett, Bradley C; Barbieri, M Alejandro

    2013-07-01

    The fruits of saw palmetto have been used for the treatment of a variety of urinary and reproductive system problems. In this study we investigated whether the fruit extracts affect in vitro adipogenesis. Saw palmetto ethanol extract inhibited the lipid droplet accumulation by induction media in a dose-dependent manner, and it also attenuated the protein expressions of C-EBP? and PPAR?. Phosphorylation of Erk1/2 and Akt1 were also decreased by saw palmetto ethanol extract. This report suggests that saw palmetto extracts selectively affect the adipocyte differentiation through the modulation of several key factors that play a critical role during adipogenesis. PMID:23179316

  1. Reduction of part-list cuing inhibition 

    E-print Network

    Brown, Jeffrey Michael

    1991-01-01

    in the cued categories but inhibited recall in the non-cued categories. Experiment 2 showed that this inhibitory effect was enhanced as the number of cue items from each category was increased. The results of both of these experiments are predicted... (cued recall) while recalling 8. 56 items on the final test (free recall) . The free recall subjects exhibited little or no reminiscence from test 1 to 2. The present experiments will test if this difference between test 1 and 2 can be increased...

  2. Emergence of clustering: role of inhibition.

    PubMed

    Dwivedi, Sanjiv K; Jalan, Sarika

    2014-09-01

    Though biological and artificial complex systems having inhibitory connections exhibit a high degree of clustering in their interaction pattern, the evolutionary origin of clustering in such systems remains a challenging problem. Using genetic algorithm we demonstrate that inhibition is required in the evolution of clique structure from primary random architecture, in which the fitness function is assigned based on the largest eigenvalue. Further, the distribution of triads over nodes of the network evolved from mixed connections reveals a negative correlation with its degree providing insight into origin of this trend observed in real networks. PMID:25314478

  3. Streptomycin Inhibits Quorum Sensing in Acinetobacter baumannii

    PubMed Central

    Saroj, Sunil D.

    2013-01-01

    Streptomycin at subinhibitory concentrations was found to inhibit quorum sensing in Acinetobacter baumannii. Conditioned medium prepared by growth of A. baumannii in the presence of subinhibitory concentrations of streptomycin exhibited reduced activation of two quorum-sensing-regulated genes, abaI, encoding an autoinducer synthase, and A1S_0112. The reduced expression of AbaI resulted in greatly decreased levels of 3-OH-C12-HSL as confirmed by direct analysis using thin-layer chromatography. The effect on acyl-homoserine lactone (AHL) signal production was specific to streptomycin, as gentamicin and myomycin had no significant effect at subinhibitory levels. PMID:23318804

  4. Streptomycin inhibits quorum sensing in Acinetobacter baumannii.

    PubMed

    Saroj, Sunil D; Rather, Philip N

    2013-04-01

    Streptomycin at subinhibitory concentrations was found to inhibit quorum sensing in Acinetobacter baumannii. Conditioned medium prepared by growth of A. baumannii in the presence of subinhibitory concentrations of streptomycin exhibited reduced activation of two quorum-sensing-regulated genes, abaI, encoding an autoinducer synthase, and A1S_0112. The reduced expression of AbaI resulted in greatly decreased levels of 3-OH-C(12)-HSL as confirmed by direct analysis using thin-layer chromatography. The effect on acyl-homoserine lactone (AHL) signal production was specific to streptomycin, as gentamicin and myomycin had no significant effect at subinhibitory levels. PMID:23318804

  5. Aryl hydrocarbon hydroxylase: induction and inhibition 

    E-print Network

    Andres, Janet Lee

    1982-01-01

    and sacrificed on day 15. Thymus, liver, and spleen were removed and weighed. Studies on the Effects of Cimetidine on AHH and the Toxicit of 3, 3', 4, 4'-TBB To determine the effect of cimetidine on the de novo synthesis of microsomal enzymes, microsomes... Subject: Veterinary Toxicology ARYL HYDROCARBON HYDROXYLASE: INDUCTION AND INHIBITION A Thesis by JANET LEE ANDRES Approved to style and content by: / A ( i m~of=6enssrft tee) n' Member) (Member) (Member) (He d of Departme ) August 19B2 AB...

  6. Inhibition of soil urease activity by aminocresols

    Microsoft Academic Search

    G. A. Rodgers

    1984-01-01

    Summary The effect on soil urease activity of five aminocresols, at concentrations of 5–100 ?g\\/g soil, was examined in the laboratory. Two compounds, 4-amino-o-cresol and 4-amino-m-cresol, significantly inhibited urease activity. The efficacy of 4-amino-o-cresol was compared with that of phenylphosphorodiamidate (PPDA), a known inhibitor, in three U.K. soils. At 50?g\\/g soil 4-amino-o-cresol was as inhibitory as an equivalent concentration of

  7. Requirements for inhibition of localized corrosion

    SciTech Connect

    Gunaltun, Y.M.; Chevrot, T.

    1999-10-01

    In cases of pipeline failures from internal corrosion, localized corrosion (LC) is the principal cause. Inhibition is the most common way to control corrosion in wet gas and oil production lines. Therefore, the inhibitor should be able to control LC in all cases where it may occur. Inhibitor selection philosophy should be based on this requirement. Laboratory and field evaluation of corrosion inhibitors showed that some products were almost 100% efficient in preventing LC if their concentration in the water phase was above a threshold value. The major uncertainty was the inhibitor availability at the pipe surface.

  8. Requirements for inhibition of localized corrosion

    SciTech Connect

    Gunaltun, Y.M. [Total Exploration Production, Paris (France); Chevrot, T. [Total Centre and Recherches, La Havre (France)

    1999-11-01

    Localized corrosion is the principal cause of line failure when corrosion is internal. As the inhibition is the most common way to control corrosion in wet gas and oil production lines, the inhibitor should be able to control localized corrosion in all cases where it may occur. Therefore, inhibitor selection philosophy should be based on this approach. Laboratory and field evaluation of corrosion inhibitors showed that some products are almost 100% efficient in preventing localized corrosion if their concentration in the water phase is above a threshold value. The main uncertainty, which then remains, is the inhibitor availability at the pipe surface.

  9. Na+/K+-ATPase: Activity and inhibition

    NASA Astrophysics Data System (ADS)

    ?olovi?, M.; Krsti?, D.; Krinulovi?, K.; Momi?, T.; Savi?, J.; Vuja?i?, A.; Vasi?, V.

    2009-09-01

    The aim of the study was to give an overview of the mechanism of inhibition of Na+/K+-ATPase activity induced by some specific and non specific inhibitors. For this purpose, the effects of some ouabain like compounds (digoxin, gitoxin), noble metals complexes ([PtCl2DMSO2], [AuCl4]-, [PdCl4]2-, [PdCl(dien)]+, [PdCl(Me4dien)]+), transition metal ions (Cu2+, Zn2+, Fe2+, Co2+), and heavy metal ions (Hg2+, Pb2+, Cd2+) on the activity of Na+/K+-ATPase from rat synaptic plasma membranes (SPM), porcine cerebral cortex and human erythrocytes were discussed.

  10. 3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis

    PubMed Central

    XIAN, SHU-LIN; CAO, WEI; ZHANG, XIAO-DONG; LU, YUN-FEI

    2015-01-01

    Tumor cells primarily depend upon glycolysis in order to gain energy. Therefore, the inhibition of glycolysis may inhibit tumor growth. Our previous study demonstrated that 3-bromopyruvate (3-BrPA) inhibited gastric cancer cell proliferation in vitro. However, the ability of 3-BrPA to suppress tumor growth in vivo, and its underlying mechanism, have yet to be elucidated. The aim of the present study was to investigate the inhibitory effect of 3-BrPA in an animal model of gastric cancer. It was identified that 3-BrPA exhibited strong inhibitory effects upon xenograft tumor growth in nude mice. In addition, the antitumor function of 3-BrPA exhibited a dose-effect association, which was similar to that of the chemotherapeutic agent, 5-fluorouracil. Furthermore, 3-BrPA exhibited low toxicity in the blood, liver and kidneys of the nude mice. The present study hypothesized that the inhibitory effect of 3-BrPA is achieved through the inhibition of hexokinase activity, which leads to the downregulation of B-cell lymphoma 2 (Bcl-2) expression, the upregulation of Bcl-2-associated X protein expression and the subsequent activation of caspase-3. These data suggest that 3-BrPA may be a novel therapy for the treatment of gastric cancer. PMID:25621044

  11. Angiotensin inhibition potentiates the renal responses to neutral endopeptidase inhibition in dogs with congestive heart failure.

    PubMed Central

    Margulies, K B; Perrella, M A; McKinley, L J; Burnett, J C

    1991-01-01

    The renal natriuretic actions of endogenous atrial natriuretic factor are enhanced by neutral endopeptidase inhibition (NEP-I). Recognizing that activation of the renin-angiotensin-aldosterone system in congestive heart failure (CHF) antagonizes the renal actions of atrial natriuretic factor, we hypothesized that angiotensin II antagonism with converting enzyme inhibition would potentiate the renal actions of NEP-I in CHF. To test this hypothesis, the renal responses to a specific NEP-I (SQ 28,603) were assessed in dogs with eight days of experimental CHF produced by rapid ventricular pacing. The renal natriuretic responses to NEP-I in experimental CHF were significant. In the same model of CHF, chronic angiotensin antagonism with converting enzyme inhibition potentiated both renal hemodynamic and excretory responses to NEP-I. The potentiated renal hemodynamic response included significant increases in glomerular filtration rate and filtration fraction. In the CHF group with angiotensin antagonism, an intrarenal infusion of low-dose angiotensin abolished the potentiated renal responses to NEP-I, supporting the concept that intrarenal angiotensin antagonism, rather than improved systemic hemodynamics or potentiation of other peptide systems, mediated the enhanced renal responses to NEP-I in the presence of converting enzyme inhibition. PMID:1658047

  12. Measurement and Reliability of Response Inhibition

    PubMed Central

    Congdon, Eliza; Mumford, Jeanette A.; Cohen, Jessica R.; Galvan, Adriana; Canli, Turhan; Poldrack, Russell A.

    2012-01-01

    Response inhibition plays a critical role in adaptive functioning and can be assessed with the Stop-signal task, which requires participants to suppress prepotent motor responses. Evidence suggests that this ability to inhibit a prepotent motor response (reflected as Stop-signal reaction time (SSRT)) is a quantitative and heritable measure of interindividual variation in brain function. Although attention has been given to the optimal method of SSRT estimation, and initial evidence exists in support of its reliability, there is still variability in how Stop-signal task data are treated across samples. In order to examine this issue, we pooled data across three separate studies and examined the influence of multiple SSRT calculation methods and outlier calling on reliability (using Intra-class correlation). Our results suggest that an approach which uses the average of all available sessions, all trials of each session, and excludes outliers based on predetermined lenient criteria yields reliable SSRT estimates, while not excluding too many participants. Our findings further support the reliability of SSRT, which is commonly used as an index of inhibitory control, and provide support for its continued use as a neurocognitive phenotype. PMID:22363308

  13. Targeting Sphingosine Kinase-1 To Inhibit Melanoma

    PubMed Central

    Madhunapantula, SubbaRao V.; Hengst, Jeremy; Gowda, Raghavendra; Fox, Todd E.; Yun, Jong K; Robertson, Gavin P.

    2012-01-01

    SUMMARY Resistance to therapies develops rapidly for melanoma leading to more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient’s tumors. This study shows that elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity of sphingosine kinase-1 (SPHK1) occur in advanced melanomas. Targeting SPHK1 using siRNA decreased anchorage dependent and independent growth as well as sensitized melanoma cells to apoptosis inducing agents. Pharmacological SPHK1 inhibitors SKI-I but not SKI-II decreased S-1-P content, elevated ceramide levels, caused a G2-M block and induced apoptotic cell death in melanomas. Targeting SPHK1 using siRNA or the pharmacological agent called SKI-I, decreased the levels of pAKT. Furthermore, SKI-I inhibited the expression of CYCLIN D1 protein and increased the activity of caspase-3/7, which in turn led to the degradation of PARP. In animals, SKI-I but not SKI-II retarded melanoma growth by 25-40%. Thus, targeting SPHK1 using siRNAs or SKI-I has therapeutic potential for melanoma treatment either alone or in combination with other targeted agents. PMID:22236408

  14. Understanding biocatalyst inhibition by carboxylic acids

    PubMed Central

    Jarboe, Laura R.; Royce, Liam A.; Liu, Ping

    2013-01-01

    Carboxylic acids are an attractive biorenewable chemical in terms of their flexibility and usage as precursors for a variety of industrial chemicals. It has been demonstrated that such carboxylic acids can be fermentatively produced using engineered microbes, such as Escherichia coli and Saccharomyces cerevisiae. However, like many other attractive biorenewable fuels and chemicals, carboxylic acids become inhibitory to these microbes at concentrations below the desired yield and titer. In fact, their potency as microbial inhibitors is highlighted by the fact that many of these carboxylic acids are routinely used as food preservatives. This review highlights the current knowledge regarding the impact that saturated, straight-chain carboxylic acids, such as hexanoic, octanoic, decanoic, and lauric acids can have on E. coli and S. cerevisiae, with the goal of identifying metabolic engineering strategies to increase robustness. Key effects of these carboxylic acids include damage to the cell membrane and a decrease of the microbial internal pH. Certain changes in cell membrane properties, such as composition, fluidity, integrity, and hydrophobicity, and intracellular pH are often associated with increased tolerance. The availability of appropriate exporters, such as Pdr12, can also increase tolerance. The effect on metabolic processes, such as maintaining appropriate respiratory function, regulation of Lrp activity and inhibition of production of key metabolites such as methionine, are also considered. Understanding the mechanisms of biocatalyst inhibition by these desirable products can aid in the engineering of robust strains with improved industrial performance. PMID:24027566

  15. Inhibition of Siah ubiquitin ligase function

    PubMed Central

    Möller, Andreas; House, Colin M.; Wong, Christina S.F.; Scanlon, Denis B.; Liu, Mira C.P.; Ronai, Ze’ev; Bowtell, David D.L.

    2010-01-01

    Tumor hypoxia induces the up-regulation of Hif-1alpha which in turn induces the expression of genes including VEGF to recruit new blood vessel outgrowth, enabling tumor growth and metastasis. Interference with the Hif-1 pathway and neoangiogenesis is an attractive anti-tumor target. The hydroxylation of Hif-1alpha by PHD proteins during normoxia serves as a recognition motif for its proteasomal degradation. However, under hypoxic conditions, hydroxylation is inhibited and furthermore, PHD proteins are themselves poly-ubiquitylated and degraded by Siah ubiqiuitin ligases. Our data demonstrate for the first time that inhibition of the interaction between Siah and PHD proteins using a peptide derived from a Drosophila protein interferes with the PHD degradation. Furthermore, cells stably expressing the inhibitor display reduced up-regulation of Hif-1alpha protein levels and Hif-1 mediated gene expression under hypoxia. In a syngeneic mouse model of breast cancer, the inhibitor reduced tumor growth and neoangiogenesis and prolonged survival of the mice. In addition, levels of Hif-1alpha and its target Glut-1 are reduced in the inhibitor expressing tumors. These data demonstrate, in a proof-of-principle study, that Siah protein, the most upstream component of the hypoxia pathway yet identified, is a viable drug target for anti-tumor therapies. PMID:18850011

  16. Diacylglycerol Kinase Inhibition and Vascular Function

    PubMed Central

    Choi, Hyehun; Allahdadi, Kyan J.; Tostes, Rita C.A.; Webb, R. Clinton

    2010-01-01

    Diacylglycerol kinases (DGKs), a family of lipid kinases, convert diacylglycerol (DG) to phosphatidic acid (PA). Acting as a second messenger, DG activates protein kinase C (PKC). PA, a signaling lipid, regulates diverse functions involved in physiological responses. Since DGK modulates two lipid second messengers, DG and PA, regulation of DGK could induce related cellular responses. Currently, there are 10 mammalian isoforms of DGK that are categorized into five groups based on their structural features. These diverse isoforms of DGK are considered to activate distinct cellular functions according to extracellular stimuli. Each DGK isoform is thought to play various roles inside the cell, depending on its subcellular localization (nuclear, ER, Golgi complex or cytoplasm). In vascular smooth muscle, vasoconstrictors such as angiotensin II, endothelin-1 and norepinephrine stimulate contraction by increasing inositol trisphosphate (IP3), calcium, DG and PKC activity. Inhibition of DGK could increase DG availability and decrease PA levels, as well as alter intracellular responses, including calcium-mediated and PKC-mediated vascular contraction. The purpose of this review is to demonstrate a role of DGK in vascular function. Selective inhibition of DGK isoforms may represent a novel therapeutic approach in vascular dysfunction. PMID:21547002

  17. Progesterone Signaling Inhibits Cervical Carcinogenesis in Mice

    PubMed Central

    Yoo, Young A; Son, Jieun; Mehta, Fabiola F.; DeMayo, Francesco J.; Lydon, John P.; Chung, Sang-Hyuk

    2014-01-01

    Human papillomavirus is the main cause of cervical cancer, yet other nonviral cofactors are also required for the disease. The uterine cervix is a hormone-responsive tissue, and female hormones have been implicated in cervical carcinogenesis. A transgenic mouse model expressing human papillomavirus oncogenes E6 and/or E7 has proven useful to study a mechanism of hormone actions in the context of this common malignancy. Estrogen and estrogen receptor ? are required for the development of cervical cancer in this mouse model. Estrogen receptor ? is known to up-regulate expression of the progesterone receptor, which, on activation by its ligands, either promotes or inhibits carcinogenesis, depending on the tissue context. Here, we report that progesterone receptor inhibits cervical and vaginal epithelial cell proliferation in a ligand-dependent manner. We also report that synthetic progestin medroxyprogesterone acetate promotes regression of cancers and precancerous lesions in the female lower reproductive tracts (ie, cervix and vagina) in the human papillomavirus transgenic mouse model. Our results provide the first experimental evidence that supports the hypothesis that progesterone signaling is inhibitory for cervical carcinogenesis in vivo. PMID:24012679

  18. Salinomycin, A Polyether Ionophoric Antibiotic, Inhibits Adipogenesis

    PubMed Central

    Szkudlarek-Mikho, Maria; Saunders, Rudel A.; Yap, Sook Fan; Ngeow, Yun Fong; Chin, Khew-Voon

    2012-01-01

    The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor ?. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy. PMID:23123626

  19. Ehrlich tumor inhibition using doxorubicin containing liposomes.

    PubMed

    Elbialy, Nihal Saad; Mady, Mohsen Mahmoud

    2015-04-01

    Ehrlich tumors were grown in female balb mice by subcutaneous injection of Ehrlich ascites carcinoma cells. Mice bearing Ehrlich tumor were injected with saline, DOX in solution or DOX encapsulated within liposomes prepared from DMPC/CHOL/DPPG/PEG-PE (100:100:60:4) in molar ratio. Cytotoxicity assay showed that the IC50 of liposomes containing DOX was greater than that DOX only. Tumor growth inhibition curves in terms of mean tumor size (cm(3)) were presented. All the DOX formulations were effective in preventing tumor growth compared to saline. Treatment with DOX loaded liposomes displayed a pronounced inhibition in tumor growth than treatment with DOX only. Histopathological examination of the entire tumor sections for the various groups revealed marked differences in cellular features accompanied by varying degrees in necrosis percentage ranging from 12% for saline treated mice to 70% for DOX loaded liposome treated mice. The proposed liposomal formulation can efficiently deliver the drug into the tumor cells by endocytosis (or passive diffusion) and lead to a high concentration of DOX in the tumor cells. The study showed that the formulation of liposomal doxorubicin improved the therapeutic index of DOX and had increased anti-tumor activity against Ehrlich tumor models. PMID:25972739

  20. Kaempferol inhibits thrombosis and platelet activation.

    PubMed

    Choi, Jun-Hui; Park, Se-Eun; Kim, Sung-Jun; Kim, Seung

    2015-08-01

    The objectives of the present study were to investigate whether kaempferol affects pro-coagulant proteinase activity, fibrin clot formation, blood clot and thrombin (or collagen/epinephrine)-stimulated platelet activation, thrombosis, and coagulation in ICR (Imprinting Control Region) mice and SD (Sprague-Dawley) rats. Kaempferol significantly inhibited the enzymatic activities of thrombin and FXa by 68 ± 1.6% and 52 ± 2.4%, respectively. Kaempferol also inhibited fibrin polymer formation in turbidity. Microscopic analysis was performed using a fluorescent conjugate. Kaempferol completely attenuated phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38, c-Jun N-terminal kinase (JNK) 1/2, and phosphoinositide 3-kinase (PI3K)/PKB (AKT) in thrombin-stimulated platelets and delayed aggregation time (clotting) by 34.6% in an assay of collagen/epinephrine-stimulated platelet activation. Moreover, kaempferol protected against thrombosis development in 3 animal models, including collagen/epinephrine- and thrombin-induced acute thromboembolism models and an FeCl3-induced carotid arterial thrombus model. The ex vivo anticoagulant effect of kaempferol was further confirmed in ICR mice. This study demonstrated that kaempferol may be clinically useful due to its ability to reduce or prevent thrombotic challenge. PMID:26073152

  1. Apoptosis in caspase-inhibited neurons.

    PubMed Central

    Volbracht, C.; Leist, M.; Kolb, S. A.; Nicotera, P.

    2001-01-01

    BACKGROUND: There is growing evidence of apoptosis in neurodegenerative disease. However, it is still unclear whether the pathological manifestations observed in slow neurodegenerative diseases are due to neuronal loss or whether they are related to independent degenerative events in the axodendritic network. It also remains elusive whether a single, caspase-based executing system involving caspases is responsible for neuronal loss by apoptosis. MATERIALS AND METHODS: Long-term exposure to the microtubule-disassembling agent, colchicine, was used to disrupt the axodendritic network and eventually trigger caspase-3-mediated apoptosis in cultures of cerebellar granule cells. For this model, we investigated the role of Bcl-2 and caspases in neurite degeneration and death of neuronal somata. RESULTS: Early degeneration of the axodendritic network occurred by a Bcl-2 and caspase-independent mechanism. Conversely, apoptosis of the cell body was delayed by Bcl-2 and initially blocked by caspase inhibition. However, when caspase activity was entirely blocked by zVAD-fmk, colchicine-exposed neurons still underwent delayed cell death characterized by cytochrome c release, chromatin condensation to irregularly shaped clumps, DNA-fragmentation, and exposure of phosphatidylserine. Inhibitors of the proteasome reduced these caspase-independent apoptotic-like features of the neuronal soma. CONCLUSION: Our data suggest that Bcl-2-dependent and caspase-mediated death programs account only partially for neurodegenerative changes in injured neurons. Blockage of the caspase execution machinery may only temporarily rescue damaged neurons and classical apoptotic features can still appear in caspase-inhibited neurons. PMID:11474126

  2. [Inhibition of bacteriorhodopsin by formalin and lanthanum].

    PubMed

    Khitrina, L V; Drachev, L A; Kaulen, A D; Chekulaeva, L N

    1982-11-01

    It was shown that the penetrating ions (PCB-) method can be used for quantitative estimation of the proton translocation function. Using this method it was found that the maximal inhibition (up to 5.5-6 times) can be achieved by 1% formalin treatment for 0.5 hrs in 0.5 M phosphate buffer, pH 7.8, 70 degrees. Using three methods, the kinetics of the obtained preparation were compared to those of the previously known inhibitor, La3+. The changes observed were as follows: inhibition of intermediate M412 decay in membrane suspension, decrease in the amplitude of the electric response millisecond phase in the purple membrane--collodium film system and deceleration of the overall photochemical cycle turnover in this system. The latter was registered by the rate of resporation of the electric response amplitude to the second light flash in the presence of uncoupling agents. The possible role of crosslinks during protein treatment with formalin is discussed. PMID:7150667

  3. Diindolilmethane (DIM) selectively inhibits cancer stem cells.

    PubMed

    Semov, Alexandre; Iourtchenco, Ludmila; Liu, Lin Fang; Li, Shengmin; Xu, Yan; Su, Xiaoxue; Muyjnek, Ekaterina; Kiselev, Vsevolod; Alakhov, Valery

    2012-07-20

    Epidemiologic studies repeatedly have shown chemopreventive effects of cruciferous vegetables. Indole-3-carbinol (I3C) and its metabolite diindolylmethane (DIM) were identified in these plants as active ingredients and theirs anti-tumor activities were confirmed in multiple in vitro and in vivo experiments. Here, we demonstrate that DIM is a selective and potent inhibitor of cancer stem cells (CSCs). In several cancer cell lines, DIM inhibited tumor sphere formation at the concentrations 30-300 times lower than concentrations required for growth inhibition of parental cells cultured as adherent culture. We also found that treatment with DIM overcomes chemoresistance of CSCs to cytotoxics, such as paclitaxel, doxorubicin, and SN-38. Pre-treatment of tumor spheres with DIM before implantation to mice significantly retarded the growth of primary tumors compared to tumors formed by untreated tumor spheres. The concentrations of DIM required to suppress CSCs formation are in the close range to those achievable in human plasma after oral dosing of the compound. Therefore, DIM can potentially be used in cancer patients, either alone, or in combinations with existing drugs. PMID:22727906

  4. Calreticulin inhibits commitment to adipocyte differentiation

    PubMed Central

    Szabo, Eva; Qiu, Yuanyuan; Baksh, Shairaz; Michalak, Marek; Opas, Michal

    2008-01-01

    Calreticulin, an endoplasmic reticulum (ER) resident protein, affects many critical cellular functions, including protein folding and calcium homeostasis. Using embryonic stem cells and 3T3-L1 preadipocytes, we show that calreticulin modulates adipogenesis. We find that calreticulin-deficient cells show increased potency for adipogenesis when compared with wild-type or calreticulin-overexpressing cells. In the highly adipogenic crt?/? cells, the ER lumenal calcium concentration was reduced. Increasing the ER lumenal calcium concentration led to a decrease in adipogenesis. In calreticulin-deficient cells, the calmodulin–Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathway was up-regulated, and inhibition of CaMKII reduced adipogenesis. Calreticulin inhibits adipogenesis via a negative feedback mechanism whereby the expression of calreticulin is initially up-regulated by peroxisome proliferator–activated receptor ? (PPAR?). This abundance of calreticulin subsequently negatively regulates the expression of PPAR?, lipoprotein lipase, CCAAT enhancer–binding protein ?, and aP2. Thus, calreticulin appears to function as a Ca2+-dependent molecular switch that regulates commitment to adipocyte differentiation by preventing the expression and transcriptional activation of critical proadipogenic transcription factors. PMID:18606846

  5. Doxycycline inhibits leukemic cell migration via inhibition of matrix metalloproteinases and phosphorylation of focal adhesion kinase.

    PubMed

    Wang, Chunhuai; Xiang, Ru; Zhang, Xiangzhong; Chen, Yunxian

    2015-09-01

    Doxycycline, a tetracycline-based antibiotic, has been reported to attenuate melanoma cell migration through inhibiting the focal adhesion kinase (FAK) signaling pathway. However, it remains to be elucidated whether doxycycline exerts this effect on leukemia cell migration. The present study aimed to examine the role of doxycycline in leukemia cell migration. The invasion capacities of the human leukemia cell lines KG1a (acute myelogenous leukemia) and K562 (chronic myelogenous leukemia) were evaluated using Matrigel® matrix?coated Transwell® chamber assays; leukemic cell lines treated with doxycycline (1 µg/ml) or anti??1?integrin antibodies were added to the upper chamber, while untreated cells were included as controls. Reverse transcription quantitative polymerase chain reaction was performed in order to further understand the influence of doxycycline treatment on the expression of FAK and gelatinases in the KG1a and K562 leukemic cell lines. In addition, FAK protein expression and phosphorylation were determined using western blot analysis in order to investigate the mechanism by which doxycycline inhibited leukemic cell migration. The results revealed that doxycycline treatment significantly attenuated the migration of KG1a and K562 cells, which was demonstrated to be associated with inhibition of the expression and phosphorylation of FAK. In addition, doxycycline treatment inhibited matrix metalloproteinase (MMP)?2 and MMP?9 expression. Furthermore, incubation with blocking anti??1?integrin antibodies had an analogous inhibitory effect on leukemic cell migration to that of doxycycline. In conclusion, the results of the present study suggested that doxycycline attenuated leukemic cell migration through inhibiting the FAK signaling pathway. Therefore, doxycycline may have potential for use as a novel strategy for the treatment of leukemia. PMID:26004127

  6. Ganoderic acid T inhibits tumor invasion in vitro and in vivo through inhibition of MMP expression.

    PubMed

    Chen, Nian-Hong; Liu, Jian-Wen; Zhong, Jian-Jiang

    2010-01-01

    The traditional Chinese medicinal mushroom, Ganoderma lucidum, has been used in Asia for several thousand years for the prevention and treatment of a variety of diseases, including cancer. In previous work, we purified ganoderic acid T (GA-T) from G. lucidum [28]. In the present study, we investigate the functions of GA-T in terms of its effects on invasion in vitro and metastasis in vivo. A trypan blue dye exclusion assay indicates that GA-T inhibits proliferation of HCT-116 cells, a human colon carcinoma cell line. Cell aggregation and adhesion assays show that GA-T promotes homotypic aggregation and simultaneously inhibits the adhesion of HCT-116 cells to the extracellular matrix (ECM) in a dose-dependent manner.Wound healing assays indicate that GA-T also inhibits the migration of HCT-116 cells in a dose-dependent manner, and it suppresses the migration of 95-D cells, a highly metastatic human lung tumor cell line, in a dose- and time-dependent manner. In addition, GA-T inhibits the nuclear translocation of nuclear factor-kappaB (NF-kappaB) and the degradation of inhibitor of kappaB-alpha (IkappaBalpha), which leads to down-regulated expression of matrix metalloproteinase-9 (MMP-9), inducible nitric oxide synthase (iNOS), and urokinase-type plasminogen activator (uPA). Animal and Lewis Lung Carcinoma (LLC) model experiments demonstrate that GA-T suppresses tumor growth and LLC metastasis and down-regulates MMP-2 and MMP-9 mRNA expression in vivo. Taken together, these results demonstrate that GA-T effectively inhibits cancer cell invasion in vitro and metastasis in vivo, and thus it may act as a potential drug for treating cancer. PMID:20360625

  7. Reversal of 2-bromoethanesulfonate inhibition of methanogenesis in Methanosarcina sp.

    PubMed Central

    Smith, M R

    1983-01-01

    2-Bromoethanesulfonate (BES) inhibition of methanogenesis from methanol by resting-cell suspensions or cell extracts of Methanosarcina was reversed by coenzyme M. BES inhibition of methylcoenzyme M methylreductase activity in cell-free extracts was reversed by methylcoenzyme M but not by coenzyme M. Methanol/coenzyme M methyltransferase activity was not inhibited by 10 microM BES. Inhibition of methylreductase by BES and 3-bromopropionate was competitive with methylcoenzyme M, but inhibition by 2-bromoethanol exhibited mixed kinetics. The Ki values for the inhibitors in cell-free extracts were similar to the concentrations which inhibited intact cells. BES-resistant mutants of strain 227 were apparently permeability mutants because in vitro assays showed that mutant and parent strain methylreductases were equally sensitive to BES. PMID:6313605

  8. Molecular mechanisms of DNA repair inhibition by caffeine

    SciTech Connect

    Selby, C.P.; Sancar, A. (Univ. of North Carolina School of Medicine, Chapel Hill (USA))

    1990-05-01

    Caffeine potentiates the mutagenic and lethal effects of genotoxic agents. It is thought that this is due, at least in some organisms, to inhibition of DNA repair. However, direct evidence for inhibition of repair enzymes has been lacking. Using purified Escherichia coli DNA photolyase and (A)BC excinuclease, we show that the drug inhibits photoreactivation and nucleotide excision repair by two different mechanisms. Caffeine inhibits photoreactivation by interfering with the specific binding of photolyase to damaged DNA, and it inhibits nucleotide excision repair by promoting nonspecific binding of the damage-recognition subunit, UvrA, of (A)BC excinuclease. A number of other intercalators, including acriflavin and ethidium bromide, appear to inhibit the excinuclease by a similar mechanism--that is, by trapping the UvrA subunit in nonproductive complexes on undamaged DNA.

  9. Inhibition of fucosyltransferase VII by gallic acid and its derivatives

    Microsoft Academic Search

    Xiaoda Niu; Xuedong Fan; Jing Sun; Pauline Ting; Satwant Narula; Daniel Lundell

    2004-01-01

    Gallic acid (GA) and several gallate derivatives were identified as inhibitors of fucosyltransferase VII (FucT VII). The inhibition by GA and (?)-epigallocatechin gallate (EGCG) is time-dependent and irreversible. GA and EGCG showed inhibition with IC50 of 60 and 700nM, respectively, after pre-incubation with FucT VII in the presence of MnCl2. Absence of MnCl2 results in significantly weaker inhibition. Complexation of

  10. Berry polyphenols inhibit pancreatic lipase activity in vitro

    Microsoft Academic Search

    Gordon J. McDougall; Nimish N. Kulkarni; Derek Stewart

    2009-01-01

    Polyphenol-rich extracts from a range of berries were tested for their ability to inhibit pancreatic lipase activity in vitro. Blackcurrant and rowan extracts had no effect, blueberry caused slight inhibition, whilst lingonberry, Arctic bramble, cloudberry, strawberry and raspberry were considerably more effective. Inhibition by the cloudberry extract showed a saturation effect with an apparent EC50 of around 5?g phenols\\/ml.The inhibitory

  11. White and green tea polyphenols inhibit pancreatic lipase in vitro

    Microsoft Academic Search

    Anais Gondoin; Dominic Grussu; Derek Stewart; Gordon J. McDougall

    2010-01-01

    Green, white and black teas were assayed for inhibition of pancreatic lipase activity in vitro. White tea proved to be more effective than green tea with black tea showing little inhibition even at 200?gGAE\\/ml. The EC50 values for inhibition were 22?g\\/ml for white tea and 35?g\\/ml for green tea; both easily achievable from normal infusions of tea. Liquid chromatography-mass spectroscopy

  12. Targeted inhibition of Src kinase signaling attenuates pancreatic tumorigenesis

    PubMed Central

    Nagaraj, Nagathihalli S.; Smith, J. Joshua; Revetta, Frank; Washington, M. Kay; Merchant, Nipun B.

    2012-01-01

    Elevated Src expression correlates with malignant potential and metastatic disease in many tumors including pancreas cancer. We sought to characterize the molecular effects of Src kinase inhibition with dasatinib (BMS-354825) a novel, multi-targeted kinase inhibitor that targets Src family kinases, in pancreas ductal adenocarcinoma (PDA). We identified sensitive and resistant PDA cell lines to dasatinib treatment and tested the molecular effects of Src inhibition in vitro and in vivo. We show for the first time that cellular localization of Src expression impacts survival in patients with PDA. Pancreas tumors with increased membranous expression of Src result in decreased survival compared with tumors that have increased cytoplasmic Src expression. Src kinase inhibition with dasatinib markedly inhibits cell proliferation, migration, invasion, cell cycle progression and anchorage independent growth and stimulates apoptosis. This is accompanied by decreased phosphorylation of Src, FAK, paxillin, AKT, STAT3, ERK, JNK and MAPK, as well as decreased cyclinD1 expression in a time and concentration-dependent manner. Furthermore, siRNA to Src results in significant decrease in cell proliferation, invasion and migration of pancreas cancer cells. Dasatinib treatment also inhibits in vivo pancreas tumor growth. Mechanisms of resistance to Src inhibition appear to be related to a lack of inhibition of STAT3 and MAPK signaling. These results establish a mechanistic rationale for Src inhibition with dasatinib as a therapeutic target in the treatment of pancreas cancer and identify potential biomarkers of resistance to Src inhibition. PMID:20682659

  13. Inhibition of Mild Steel Corrosion under Hydrodynamic Conditions

    NASA Astrophysics Data System (ADS)

    Musa, Ahmed Y.; Kadhum, Abdul Amir H.; Mohamad, Abu Bakar; Takriff, Mohd Sobri; Daud, Abdul Razak; Kamarudin, Siti Kartom

    2010-07-01

    The inhibition of mild steel corrosion by 4-amino-5-phenyl-4H-1, 2, 4-trizole-3-thiol (APTT) in 2.5 M H2SO4 solution and the effect of hydrodynamic condition on inhibition process were studied. The hydrodynamic condition experiments are simulated by rotating cylinder electrode (RCE). Change of open circuit potential (OCP) with immersion time and potentiodynamic polarization were used to study the effect of hydrodynamic conditions on the inhibition process. Results obtained from changes of open circuit potential (OCP) with immersion time, and potentiodynamic polarization are in good agreement and indicated that the inhibition process was flow velocity dependence.

  14. Arginase inhibition alleviates hypertension in the metabolic syndrome

    PubMed Central

    El-Bassossy, Hany M; El-Fawal, Rania; Fahmy, Ahmed; Watson, Malcolm L

    2013-01-01

    Background and Purpose We have previously shown that arginase inhibition alleviates hypertension associated with in a diabetic animal model. Here, we investigated the protective effect of arginase inhibition on hypertension in metabolic syndrome. Experimental Approach Metabolic syndrome was induced in rats by administration of fructose (10% in drinking water) for 12 weeks to induce vascular dysfunction. Three arginase inhibitors (citrulline, norvaline and ornithine) were administered daily in the last 6 weeks of study before and tail BP was recorded in conscious animals. Concentration response curves for phenylephrine (PE), KCl and ACh in addition to ACh-induced NO generation were obtained in thoracic aorta rings. Serum glucose, insulin, uric acid and lipid profile were determined as well as reactive oxygen species (ROS) and arginase activity. Key Results Arginase activity was elevated in metabolic syndrome while significantly inhibited by citrulline, norvaline or ornithine treatment. Metabolic syndrome was associated with elevations in systolic and diastolic BP, while arginase inhibition significantly reduced elevations in diastolic and systolic BP. Metabolic syndrome increased vasoconstriction responses of aorta to PE and KCl and decreased vasorelaxation to ACh, while arginase inhibition completely prevented impaired responses to ACh. In addition, arginase inhibition prevented impaired NO generation and exaggerated ROS formation in metabolic syndrome. Furthermore, arginase inhibition significantly reduced hyperinsulinaemia and hypertriglyceridaemia without affecting hyperuricaemia or hypercholesterolaemia associated with metabolic syndrome. Conclusions and Implications Arginase inhibition alleviates hypertension in metabolic syndrome directly through endothelial-dependent relaxation/NO signalling protection and indirectly through inhibition of insulin resistance and hypertriglyceridaemia. PMID:23441715

  15. Selective Raf Inhibition in Cancer Therapy

    PubMed Central

    Khazak, Vladimir; Astsaturov, Igor; Serebriiskii, Ilya G; Golemis, Erica A

    2009-01-01

    Over the past 5 years, the Raf kinase family has emerged as a promising target for protein-directed cancer therapy development. The goal of this review is to first provide a concise summary of the data validating Raf proteins as high-interest therapeutic targets. We then outline the mode of action of Raf kinases, emphasizing how Raf activities and protein interactions suggest specific approaches to inhibiting Raf. We then summarize the set of drugs, antisense reagents, and antibodies available or in development for therapeutically targeting Raf or Raf-related proteins, as well as current strategies combining these and other therapeutic agents. Finally, we discuss recent results from systems biology analyses that have the potential to increasingly guide the intelligent selection of combination therapies involving Raf-targeting agents and other therapeutics. PMID:18020980

  16. Tailoring elastase inhibition with synthetic peptides.

    PubMed

    Vasconcelos, Andreia; Azoia, Nuno G; Carvalho, Ana C; Gomes, Andreia C; Güebitz, Georg; Cavaco-Paulo, Artur

    2011-09-01

    Chronic wounds are the result of excessive amounts of tissue destructive proteases such as human neutrophil elastase (HNE). The high levels of this enzyme found on those types of wounds inactivate the endogenous inhibitor barrier thus, the search for new HNE inhibitors is required. This work presents two new HNE inhibitor peptides, which were synthesized based on the reactive-site loop of the Bowman-Birk inhibitor protein. The results obtained indicated that these new peptides are competitive inhibitors for HNE and, the inhibitory activity can be modulated by modifications introduced at the N- and C-terminal of the peptides. Furthermore, these peptides were also able to inhibit elastase from a human wound exudate while showing no cytotoxicity against human skin fibroblasts in vitro, greatly supporting their potential application in chronic wound treatment. PMID:21658384

  17. Acoustic Startle Reflex and Prepulse Inhibition.

    PubMed

    Ouagazzal, Abdel Mottalib; Meziane, Hamid

    2012-01-01

    The completion of genome sequencing in humans and mice has opened new opportunities to study the relationship between gene expression and behavior and for development of novel therapeutic approaches for brain diseases. Recently, several international programs for large-scale production and phenotyping of genetically modified mice have been launched (e.g., EUCOMM, EUMODIC, IMPC), and comprehensive high-throughput behavioral phenotyping strategies have been developed (EUMORPHIA). In this context, startle reflex represents an important research tool for studying the impact of genetic manipulations not only on sensory processes but also on complex brain functions such as cognition, emotions, and movement control. In this unit, step-by-step protocols for measurement of acoustic startle reactivity and prepulse inhibition of startle in mice are described, and supporting experimental data presented. Curr. Protoc. Mouse Biol. 2:25-35 © 2012 by John Wiley & Sons, Inc. PMID:26069003

  18. Inhibition of bleach-induced luminol chemiluminescence.

    PubMed

    Kent, Erina J M; Elliot, Douglas A; Miskelly, Gordon M

    2003-01-01

    The luminol chemiluminescence presumptive test for blood is based on the mild peroxidase activity of hemoglobin in basic peroxide solution. However, this test is subject to interference by strong oxidants, certain transition metal ions, and true peroxidases. This paper reports methods for reducing the interference caused by hypochlorite-containing bleaches. Amines such as 1,2-diaminoethane react rapidly with hypochlorite without interfering significantly with the hemoglobin-catalyzed oxidation. Thus, addition of 0.1 mol/L 1,2-diaminoethane to a standard luminol-peroxide spray lead to almost complete inhibition of hypochlorite-induced chemiluminescence while satisfactory chemiluminescence was still observed from bloodstains. If time allows, an alternative method for reducing interference from hypochlorite bleach is to wait several days until the bloodstains have dried thoroughly, by which time the hypochlorite will have decomposed. PMID:12570200

  19. Inhibition of antibody production by ribonucleases

    PubMed Central

    Mowbray, J. F.; Scholand, J.

    1966-01-01

    The effect on immune responses of pancreatic ribonuclease complexed with other proteins has been studied in mice. The proteins were coupled with bisdiazobenzidine. It was found that an intravenous injection of a complex of bovine albumin and ribonuclease would inhibit the response to sheep cells or typhoid and paratyphoid vaccine (TAB) if given 10–20 hours before the antigen. Complexes of ribonuclease with human ?-globulin and ovalbumin also have similar effects. Polyribonuclease is present in all the preparations and has immunosuppressive activity. Evidence is presented that both polyribonuclease and the complex of ribonuclease with other proteins have immunosuppressive actions. A scheme of injections of ribonuclease complexes which will prevent antibody formation to rat red cells in mice is described. PMID:4162719

  20. Inhibiting homologous recombination for cancer therapy

    PubMed Central

    Chernikova, Sophia B; Game, John C

    2012-01-01

    We review the rationale for seeking inhibitors of homologous recombination (HR) repair for use in cancer therapy. Cells use HR as one way to repair DNA double-strand breaks that arise directly from treatments such as radiotherapy, or indirectly during replication when forks encounter other damage. HR occurs during the S and G2 phases of the cell cycle and is therefore more significant in dividing cancer cells than in non-dividing cells of healthy tissue, giving a potential therapeutic advantage to inhibiting the process. Also, some tumors consist of cells that are defective in other DNA repair pathways, and such cells may be sensitive to HR repair inhibitors because of synthetic lethality, in which blocking two alternative pathways that a cell can use to reach a needed end-point has a much bigger impact than blocking either pathway alone. We review strategies for identifying HR inhibitors and discuss current progress. PMID:22336907

  1. STUDIES ON SERUM PROTEOLYTIC ENZYME INHIBITION

    PubMed Central

    Moll, Frederic C.

    1956-01-01

    Serial studies of the serum levels of trypsin inhibitor have been performed on monkeys following injection of turpentine-falba, total body irradiation, thermal injury, splenectomy, administration of cortisone acetate and egg albumin. Following the injection of turpentine-falba mixture there was a prompt elevation in the trypsin inhibitor power of the serum. A similar response accompanied the administration of cortisone acetate. The response to cortisone was not inhibited by removal of the spleen. Animals premedicated with cortisone acetate for 3 and 4 weeks showed no statistically significant change in the level of the serum inhibitor following injection of the turpentine-falba. Total body irradiation and immunization with egg albumin were accompanied by a very slight rise in the inhibitory power of the serum despite a prompt and extensive drop in the total white blood cell count in the irradiated animals, and development of precipitins in all of the immunized animals. The significance of these findings is discussed. PMID:13295492

  2. Sirtuin Inhibition Adversely Affects Porcine Oocyte Meiosis

    PubMed Central

    Zhang, Liang; Ma, Rujun; Hu, Jin; Ding, Xiaolin; Xu, Yinxue

    2015-01-01

    Sirtuins have been implicated in diverse biological processes, including oxidative stress, energy metabolism, cell migration, and aging. Here, we employed Sirtuin inhibitors, nicotinamide (NAM) and Sirtinol, to investigate their effects on porcine oocyte maturation respectively. The rate of polar body extrusion in porcine oocytes decreased after treatment with NAM and Sirtinol, accompanied with the failure of cumulus cell expansion. We further found that NAM and Sirtinol significantly disrupted oocyte polarity, and inhibited the formation of actin cap and cortical granule-free domain (CGFD). Moreover, the abnormal spindles and misaligned chromosomes were readily detected during porcine oocyte maturation after treatment with NAM and Sirtinol. Together, these results suggest that Sirtuins are involved in cortical polarity and spindle organization in porcine oocytes. PMID:26176547

  3. Inhibition of star formation in Sa galaxies

    SciTech Connect

    Pompea, S.M.; Rieke, G.H. (Steward Observatory, Tucson, AZ (USA))

    1989-07-01

    Only 4 percent of Sas in the Revised Shapley-Ames Catalog with B(T) less than 12 have an infrared luminosity greater than 10 to the 10th solar. This proportion is about one-sixth of the corresponding one for Sbs and Scs. Although the infrared luminosities of most Sa galaxies are dominated by disk emission, the same trend appears in the incidence of nuclear starbursts. IRAS measurements indicate that no more than three Sas out of the entire RSA sample of 166 galaxies have nuclear starbursts that cannot be associated with interactions or active nuclei. Plots of H I fluxes do not strongly correlate with infrared fluxes. Similarly, for at least the infrared selected Sas, the trend of IR flux with CO flux is similar to that of later type spiral galaxies. This would imply that molecular cloud formation is inhibited in Sas, leading to the lack of infrared activity. 38 refs.

  4. Method of inhibiting corrosion in acidizing wells

    SciTech Connect

    Williams, D.A.; Holifield, P.K.; Looney, J.R.; McDougall, L.A.

    1992-02-18

    This patent describes improvement in a method of acidizing a subterranean formation penetrated by a borehole which has metal pipe positioned therein wherein an aqueous acid solution is pumped down the pipe and into the formation. The improvement comprises introducing components of a nonacetylenic corrosion inhibitor directly into the aqueous acid solution to form the corrosion inhibitor in the acid solution at a concentration to inhibit corrosion of the metal, the components consisting essentially of: an antimony compound which provides from 0.04 to 2.0 wt % of antimony ions in the aqueous acid; from 0.2 to 10 wt % of a quaternary ammonium compound capable of forming a complex with the antimony ions; and from 0.1 to 25 wt % of a surfactant capable of water wetting the pipe.

  5. Behavioral inhibition and PTSD symptoms in veterans

    PubMed Central

    Myers, Catherine E.; VanMeenen, Kirsten M.; Servatius, Richard J.

    2012-01-01

    Behavioral inhibition (BI), a temperamental bias to respond to novel stimuli with avoidance behaviors, is a risk factor for posttraumatic stress disorder (PTSD). It is unclear whether BI accounts for additional variance in PTSD symptom severity beyond that accounted for by general anxiety. Here, 109 veterans (mean age 50.4 years, 9.2% female) provided self-assessment of PTSD symptoms, state and trait anxiety, combat exposure, and current (adult) and retrospective (childhood) BI. Adult BI was correlated with anxiety and PTSD symptom severity, especially cluster C (avoidance) symptoms, but not with combat exposure. A regression model including adult BI, state and trait anxiety, and combat exposure was able to correctly classify over 80% of participants according to presence or absence of severe PTSD symptoms. Because avoidance behaviors are a core component of PTSD, self-assessments of BI may be an important tool in understanding PTSD and potentially assessing vulnerability to the disorder. PMID:22397911

  6. Condensation on Aerosol Particles and its Inhibition.

    NASA Astrophysics Data System (ADS)

    Liu, Peter Shen King

    The atmospheric aerosol is of primary importance in the formation of precipitation. Except in the neighbourhood of large sources of pollution most of the atmospheric particles are of natural origin, but human contribution is increasing at such a rate that within a comparatively short time it may equal nature's. Such an increase in the atmospheric particulate load may have significant effects on the distribution and intensity of precipitation. There is a general perception that most of the atmospheric particulate load is soluble in water or has some soluble component and soluble particles condense water more readily than insoluble. In this work a study is made of the solubility of the atmospheric aerosol at various relative humidities. The results confirm that much of the atmospheric aerosol is indeed soluble, but that the soluble proportion is highly variable. This result has significant implications for studies of air pollution in which the respirable fraction of the atmospheric aerosol is deduced from the results of long term dichotomous sampling. Results are also presented of studies in which an attempt was made to inhibit the condensation of water on man-made and adventitious particles with a view to modifying their possible climatic effects. This work has demonstrated that certain agents, notably long chain amines, do indeed have an inhibiting effect on the condensation of water on particles which have been exposed to them, but that the effect of the agents so far tested is not sufficiently great to be of immediate practical importance. It is concluded that further advances must await more precise methods of producing small supersaturations reliably and reproducibly.

  7. Nitric oxide synthases: structure, function and inhibition.

    PubMed Central

    Alderton, W K; Cooper, C E; Knowles, R G

    2001-01-01

    This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family. There is now information on the enzyme structure at all levels from primary (amino acid sequence) to quaternary (dimerization, association with other proteins) structure. The crystal structures of the oxygenase domains of inducible NOS (iNOS) and vascular endothelial NOS (eNOS) allow us to interpret other information in the context of this important part of the enzyme, with its binding sites for iron protoporphyrin IX (haem), biopterin, L-arginine, and the many inhibitors which interact with them. The exact nature of the NOS reaction, its mechanism and its products continue to be sources of controversy. The role of the biopterin cofactor is now becoming clearer, with emerging data implicating one-electron redox cycling as well as the multiple allosteric effects on enzyme activity. Regulation of the NOSs has been described at all levels from gene transcription to covalent modification and allosteric regulation of the enzyme itself. A wide range of NOS inhibitors have been discussed, interacting with the enzyme in diverse ways in terms of site and mechanism of inhibition, time-dependence and selectivity for individual isoforms, although there are many pitfalls and misunderstandings of these aspects. Highly selective inhibitors of iNOS versus eNOS and neuronal NOS have been identified and some of these have potential in the treatment of a range of inflammatory and other conditions in which iNOS has been implicated. PMID:11463332

  8. Allosteric Inhibition of Human Porphobilinogen Synthase*

    PubMed Central

    Lawrence, Sarah H.; Ramirez, Ursula D.; Selwood, Trevor; Stith, Linda; Jaffe, Eileen K.

    2009-01-01

    Porphobilinogen synthase (PBGS) catalyzes the first common step in tetrapyrrole (e.g. heme, chlorophyll) biosynthesis. Human PBGS exists as an equilibrium of high activity octamers, low activity hexamers, and alternate dimer configurations that dictate the stoichiometry and architecture of further assembly. It is posited that small molecules can be found that inhibit human PBGS activity by stabilizing the hexamer. Such molecules, if present in the environment, could potentiate disease states associated with reduced PBGS activity, such as lead poisoning and ALAD porphyria, the latter of which is associated with human PBGS variants whose quaternary structure equilibrium is shifted toward the hexamer (Jaffe, E. K., and Stith, L. (2007) Am. J. Hum. Genet. 80, 329–337). Hexamer-stabilizing inhibitors of human PBGS were identified using in silico prescreening (docking) of ?111,000 structures to a hexamer-specific surface cavity of a human PBGS crystal structure. Seventy-seven compounds were evaluated in vitro; three provided 90–100% conversion of octamer to hexamer in a native PAGE mobility shift assay. Based on chemical purity, two (ML-3A9 and ML-3H2) were subjected to further evaluation of their effect on the quaternary structure equilibrium and enzymatic activity. Naturally occurring ALAD porphyria-associated human PBGS variants are shown to have an increased susceptibility to inhibition by both ML-3A9 and ML-3H2. ML-3H2 is a structural analog of amebicidal drugs, which have porphyria-like side effects. Data support the hypothesis that human PBGS hexamer stabilization may explain these side effects. The current work identifies allosteric ligands of human PBGS and, thus, identifies human PBGS as a medically relevant allosteric enzyme. PMID:19812033

  9. Inhibition of aldose reductase by dietary antioxidant curcumin: mechanism of inhibition, specificity and significance.

    PubMed

    Muthenna, P; Suryanarayana, P; Gunda, Shravan K; Petrash, J Mark; Reddy, G Bhanuprakash

    2009-11-19

    Accumulation of intracellular sorbitol due to increased aldose reductase (ALR2) activity has been implicated in the development of various secondary complications of diabetes. In this study we show that curcumin inhibits ALR2 with an IC(50) of 10 microM in a non-competitive manner, but is a poor inhibitor of closely-related members of the aldo-keto reductase superfamily, particularly aldehyde reductase. Results from molecular docking studies are consistent with the pattern of inhibition of ALR2 by curcumin and its specificity. Moreover, curcumin is able to suppress sorbitol accumulation in human erythrocytes under high glucose conditions, demonstrating an in vivo potential of curcumin to prevent sorbitol accumulation. These results suggest that curcumin holds promise as an agent to prevent or treat diabetic complications. PMID:19850041

  10. Protein synthesis in the hippocampal slice: Transient inhibition by glutamate and lasting inhibition by ischemia

    Microsoft Academic Search

    Bogdan Djuricic; Gabriele Röhn; Wulf Paschen; Konstantin-Alexander Hossmann

    1994-01-01

    Protein synthesis was measured in hippocampal slices which were exposed to glutamate (1 mM or 10 mM) or which were deprived of glucose and oxygen (‘in vitro ischemia’) for 15 min. Glutamate at 1 mM, a concentration estimated to occur duringin vivo ischemia did not affect protein synthesis. Ten mM glutamate inhibited protein synthesis immediately after exposure (50% of control

  11. Carbonic anhydrase inhibition with natural products: novel chemotypes and inhibition mechanisms

    Microsoft Academic Search

    Claudiu T. Supuran

    2011-01-01

    Five genetically distinct classes of carbonic anhydrases (CAs, EC 4.2.1.1) are present in organisms all over the phylogenetic\\u000a tree (?-, ?-, ?-, ?-, and ?-families). These metalloenzymes catalyze CO2 hydration to bicarbonate and protons. Inhibition of ?-CAs from vertebrates, including humans, with sulfonamides was exploited clinically for decades for various classes of diuretics\\u000a and systemically acting antiglaucoma agents, whereas newer

  12. Nafamostat Mesilate Inhibits TNF-?-Induced Vascular Endothelial Cell Dysfunction by Inhibiting Reactive Oxygen Species Production

    PubMed Central

    Kang, Min-Woong; Song, Hee-Jung; Kang, Shin Kwang; Kim, Yonghwan; Jung, Saet-byel; Jee, Sungju; Moon, Jae Young; Suh, Kwang-sun; Lee, Sang Do; Jeon, Byeong Hwa

    2015-01-01

    Nafamostat mesilate (NM) is a serine protease inhibitor with anticoagulant and anti-inflammatory effects. NM has been used in Asia for anticoagulation during extracorporeal circulation in patients undergoing continuous renal replacement therapy and extra corporeal membrane oxygenation. Oxidative stress is an independent risk factor for atherosclerotic vascular disease and is associated with vascular endothelial function. We investigated whether NM could inhibit endothelial dysfunction induced by tumor necrosis factor-? (TNF-?). Human umbilical vein endothelial cells (HUVECs) were treated with TNF-? for 24 h. The effects of NM on monocyte adhesion, vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) protein expression, p38 mitogen-activated protein kinase (MAPK) activation, and intracellular superoxide production were then examined. NM (0.01~100 µg/mL) did not affect HUVEC viability; however, it inhibited the increases in reactive oxygen species (ROS) production and p66shc expression elicited by TNF-? (3 ng/mL), and it dose dependently prevented the TNF-?-induced upregulation of endothelial VCAM-1 and ICAM-1. In addition, it mitigated TNF-?-induced p38 MAPK phosphorylation and the adhesion of U937 monocytes. These data suggest that NM mitigates TNF-?-induced monocyte adhesion and the expression of endothelial cell adhesion molecules, and that the anti-adhesive effect of NM is mediated through the inhibition of p66shc, ROS production, and p38 MAPK activation. PMID:25954127

  13. Cysteinyl Leukotriene Receptor Antagonists Inhibit Tumor Metastasis by Inhibiting Capillary Permeability

    PubMed Central

    Nozaki, Masako; Yoshikawa, Masanobu; Ishitani, Kunihiko; Kobayashi, Hiroyuki; Houkin, Kiyohiro; Imai, Kohzoh; Ito, Yoichiro; Muraki, Takamura

    2012-01-01

    We explored the possibility of the cysteinyl leukotriene receptor antagonists, pranlukast and montelukast, preventing tumor cell migration through both cerebral and peripheral capillaries. To study tumor cell migration through brain capillaries, male Fisher rats were cannulated via the cisterna magna under pentobarbital anesthesia. RCN9 cells labeled with a fluorescent marker PKH67 were intravenously administered following arachidonic acid administration into the subarachnoid space, and specimens of the central nervous system were collected every 30 min for 8 h. Arachidonic acid increased the fluid volume with elevated white blood cell and RCN9 cell counts. When given 2 h before arachidonic acid administration, pranlukast, but not montelukast, reduced the fluid volume and inhibited white blood cell and RCN9 cell extravasation through the brain capillary. In addition, a Lewis lung carcinoma metastasis model in mice was used to study the inhibitory effect of pranlukast and montelukast against cancer cell extravasation through general capillaries. When mice were given food containing either pranlukast or montelukast, immediately after paw amputation, tumor metastasis was prevented by both drugs, and their survival was prolonged. These results show that pranlukast can inhibit tumor cell migration through both the brain and peripheral capillaries, whereas montelukast inhibits tumor cell migration only in the peripheral capillaries. PMID:20375653

  14. Tumor suppressor XAF1 induces apoptosis, inhibits angiogenesis and inhibits tumor growth in hepatocellular carcinoma.

    PubMed

    Zhu, Li Ming; Shi, Dong Mei; Dai, Qiang; Cheng, Xiao Jiao; Yao, Wei Yan; Sun, Ping Hu; Ding, Yanfei; Qiao, Min Min; Wu, Yun Lin; Jiang, Shi Hu; Tu, Shui Ping

    2014-07-30

    X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), a XIAP-binding protein, is a tumor suppressor gene. XAF1 was silent or expressed lowly in most human malignant tumors. However, the role of XAF1 in hepatocellular carcinoma (HCC) remains unknown. In this study, we investigated the effect of XAF1 on tumor growth and angiogenesis in hepatocellular cancer cells. Our results showed that XAF1 expression was lower in HCC cell lines SMMC-7721, Hep G2 and BEL-7404 and liver cancer tissues than that in paired non-cancer liver tissues. Adenovirus-mediated XAF1 expression (Ad5/F35-XAF1) significantly inhibited cell proliferation and induced apoptosis in HCC cells in dose- and time- dependent manners. Infection of Ad5/F35-XAF1 induced cleavage of caspase -3, -8, -9 and PARP in HCC cells. Furthermore, Ad5/F35-XAF1 treatment significantly suppressed tumor growth in a xenograft model of liver cancer cells. Western Blot and immunohistochemistry staining showed that Ad5/F35-XAF1 treatment suppressed expression of vascular endothelial growth factor (VEGF), which is associated with tumor angiogenesis, in cancer cells and xenograft tumor tissues. Moreover, Ad5/F35-XAF1 treatment prolonged the survival of tumor-bearing mice. Our results demonstrate that XAF1 inhibits tumor growth by inducing apoptosis and inhibiting tumor angiogenesis. XAF1 may be a promising target for liver cancer treatment. PMID:24980821

  15. Tumor suppressor XAF1 induces apoptosis, inhibits angiogenesis and inhibits tumor growth in hepatocellular carcinoma

    PubMed Central

    Zhu, Li Ming; Shi, Dong Mei; Dai, Qiang; Cheng, Xiao Jiao; Yao, Wei Yan; Sun, Ping Hu; Ding, Yan Fei; Qiao, Min Min; Wu, Yun Lin; Jiang, Shi Hu; Tu, Shui Ping

    2014-01-01

    X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), a XIAP-binding protein, is a tumor suppressor gene. XAF1 was silent or expressed lowly in most human malignant tumors. However, the role of XAF1 in hepatocellular carcinoma (HCC) remains unknown. In this study, we investigated the effect of XAF1 on tumor growth and angiogenesis in hepatocellular cancer cells. Our results showed that XAF1 expression was lower in HCC cell lines SMMC-7721, Hep G2 and BEL-7404 and liver cancer tissues than that in paired non-cancer liver tissues. Adenovirus-mediated XAF1 expression (Ad5/F35-XAF1) significantly inhibited cell proliferation and induced apoptosis in HCC cells in dose- and time- dependent manners. Infection of Ad5/F35-XAF1 induced cleavage of caspase -3, -8, -9 and PARP in HCC cells. Furthermore, Ad5/F35-XAF1 treatment significantly suppressed tumor growth in a xenograft model of liver cancer cells. Western Blot and immunohistochemistry staining showed that Ad5/F35-XAF1 treatment suppressed expression of vascular endothelial growth factor (VEGF), which is associated with tumor angiogenesis, in cancer cells and xenograft tumor tissues. Moreover, Ad5/F35-XAF1 treatment prolonged the survival of tumor-bearing mice. Our results demonstrate that XAF1 inhibits tumor growth by inducing apoptosis and inhibiting tumor angiogenesis. XAF1 may be a promising target for liver cancer treatment. PMID:24980821

  16. Metformin inhibits gastric cancer via the inhibition of HIF1?/PKM2 signaling

    PubMed Central

    Chen, Guangxia; Feng, Wan; Zhang, Shu; Bian, Kangqi; Yang, Yan; Fang, Cheng; Chen, Min; Yang, Jun; Zou, Xiaoping

    2015-01-01

    Recent evidence suggests that anti-diabetic drug metformin prevents cancer progression, but the mechanism by which metformin inhibits tumor growth remains elusive. In this study, we investigated the anticancer role of metformin in gastric cancer and explored the underlying mechanism. The expression of hypoxia inducible factor 1? (HIF1?) and pyruvate kinase M2 (PKM2) in different stages of gastric cancer tissues was detected by immunohistochemistry. Gastric cancer cell viability was evaluated by CCK-8 assay; apoptosis and cell cycle were analyzed by flow cytometry. The expression of PI3K, Akt, HIF1?, PARP, PKM2 and COX in gastric cancer cells was detected by immunofluorescence and Western blot analysis. We found that HIF1? and PKM2 protein expression levels were higher in advanced gastric cancer tissues than in gastritis tissues. Metformin reduced gastric cancer cell viability, invasion and migration. Metformin induced apoptosis and cell cycle arrest in part through inhibiting PARP expression. Metformin downregulated PI3K, Akt, HIF1?, PARP, PKM2 and COX expression. Moreover, overexpression of HIF1? increased gastric cancer cell viability, invasion and migration. In summary, metformin has profound antitumor effect for gastric cancer by inducing intrinsic apoptosis via the inhibition of HIF1?/PKM2 signaling pathway.

  17. Gambogic acid inhibits angiogenesis through inhibiting PHD2-VHL-HIF-1? pathway.

    PubMed

    Lu, Na; Hui, Hui; Yang, Hao; Zhao, Kai; Chen, Yan; You, Qi-Dong; Guo, Qing-Long

    2013-05-13

    Our previous studies revealed that gambogic acid (GA), the major active ingredient of gamboge, possessed antiangiogenic activities. In this study, we further explored the mechanism of inhibition effects of GA in tumor angiogenesis. The results of luciferase, RT-PCR, and ELISA assays indicated that GA significantly decreased transcription activation, mRNA expression, and secretion of VEGF in hypoxia. We detected that GA had no effect on mRNA level of HIF-1? which targets VEGF gene, but the increase of HIF-1? protein expression in hypoxia was repressed by GA, which can be reversed by proteasomal inhibitor MG132 and siRNA of VHL. But GA exhibited no effect on expression of VHL both in normoxia and hypoxia. HIF prolyl hydroxylases (PHD enzymes) act as oxygen sensors regulating HIF, and hence angiogenesis. Our results showed that GA potentially enhanced level of PHD2, the most important HIF hydroxylase, and showed no effect on PHD1 and PHD3. Transient transfection of siRNA of PHD2 could eliminate GA-induced VEGF secretion increase. Growth of HepG2 xenografts in BALB/cA nude mice was inhibited by GA and angiogenesis was repressed significantly in tumor xenografts by immunohistochemical staining of CD-31, a vascular endothelial marker, accompanied with decrease of HIF-1? and increase of PHD2 expression in tissue extracts. This work provides the demonstration that GA shows anti-angiogenic effects via inhibiting PHD2-VHL-HIF-1? pathway. PMID:23501055

  18. NeuroResource Optogenetic Inhibition of Synaptic Release

    E-print Network

    Tsien, Roger Y.

    in the central nervous system. During synchronized release, calcium influx from voltage-gated calcium channelsNeuron NeuroResource Optogenetic Inhibition of Synaptic Release with Chromophore-Assisted Light that directly inhibits neurotransmitter release. We used a genetically encoded singlet oxy- gen generator, mini

  19. Converting enzyme inhibition and progressive glomerulosclerosis in the rat

    Microsoft Academic Search

    Joke J B Beukers; Annemieke van der Wal; Philip J Hoedemaeker; Jan J Weening

    1987-01-01

    Converting enzyme inhibition and progressive glomerulosclerosis in the rat. The effect of converting enzyme inhibition (CEI) by captopril (CAP, 500 mg\\/liter drinking water) on the development and progression of glomerulosclerosis (GS) was studied in six groups of male unine-phrectomized (UN) Wistar rats. In group A, treated with CAP for four to five weeks after UN, a reduction in systolic blood

  20. Physiological Evidence for Response Inhibition in Choice Reaction Time Tasks

    ERIC Educational Resources Information Center

    Burle, Boris; Vidal, Frank; Tandonnet, Christophe; Hasbroucq, Thierry

    2004-01-01

    Inhibition is a widely used notion proposed to account for data obtained in choice reaction time (RT) tasks. However, this concept is weakly supported by empirical facts. In this paper, we review a series of experiments using Hoffman reflex, transcranial magnetic stimulation and electroencephalography to study inhibition in choice RT tasks. We…

  1. Structural Basis for Enzyme I Inhibition by Ketoglutarate Vincenzo Venditti,

    E-print Network

    Clore, G. Marius

    imbalances can lead to obesity, diabetes, and cancer.1,2 In bacteria, efficient reprogramming of metabolic glucose uptake across the bacterial membrane by inhibition of enzyme I (EI). Autophosphor- ylation of EI-protein interactions is coupled to active transport of sugars across the membrane.9 Inhibition of EI by KG therefore

  2. Metformin inhibits the inflammatory response associated with cellular transformation and

    E-print Network

    , inhibits cel- lular transformation and selectively kills cancer stem cells in breast cancer cell lines stem cell growth Heather A. Hirsch1 , Dimitrios Iliopoulos1 , and Kevin Struhl2 Department Biological-B. Metformin preferentially inhibits nuclear translocation of NF-B and phosphorylation of STAT3 in cancer stem

  3. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs.

    PubMed

    Jacobsen, N W; Halling-Sørensen, B; Birkved, F K

    2008-02-01

    Antiepileptic drugs and epilepsy are often associated with sexual disorder in women such as hyperandrogenism, menstrual disorders and ovarian cysts. In children, until puberty, a hormone imbalance may influence many aspects of development, e.g. growth and sexual maturation. The aromatase complex is the enzyme system that converts androgens to estrogens and consequently an inhibition may induce a hormone imbalance. Twelve antiepileptic drugs, used in mono or polytherapy for the treatment of children, were tested for their ability to inhibit aromatase (CYP19) with commercially available microsomes from transfected insect cells using dibenzylfluorescein as substrate. The drugs inhibiting CYP19 were: lamotrigine, oxcarbazepine, tiagabine, phenobarbital, phenytoin, ethosuximide, and valproate. The inhibitory effects (50% reduction in activity compared to enzymes without inhibitor present) were in the range of 1.4-49.7 mM. Carbamazepine, gabapentin, primidone, topiramate and vigabatrin showed no inhibition. Additionally, binary drug combinations were tested to investigate if combination therapy could potentiate the aromatase inhibition. Additive inhibition was seen in combination experiments with valproate and phenobarbital. When adding carbamazepine to a range of valproate concentrations no additional inhibition was seen. The data for some of the AEDs show that side effects on steroid synthesis in humans due to inhibition of aromatase should be considered. PMID:17959350

  4. Autotoxic inhibition of seed germination by Typha latifolia : an evaluation

    Microsoft Academic Search

    James B. Grace

    1983-01-01

    Seeds of Typha latifolia were exposed to leaf extracts, leaf pieces, and soil water from adult plants of T. latifolia. In liquid culture, only extracts of concentration greater than or equal to 3% (dry weight to volume) inhibited seed germination. Adding soil to the liquid cultures increased the inhibition of seed germination by extracts. The inhibitory effects of extracts were

  5. The Influence of Cue Type on Backward Inhibition

    ERIC Educational Resources Information Center

    Arbuthnott, Katherine D.

    2005-01-01

    Backward inhibition is proposed as a process of lateral inhibition that operates during response selection in task switching, reducing interference caused by the most recently abandoned task set. The effect has been observed across a wide range of contexts but is eliminated by using spatial location to cue tasks (K. D. Arbuthnott & T. S. Woodward,…

  6. Executive functioning in boys with ADHD: primarily an inhibition deficit?

    Microsoft Academic Search

    Anouk Scheres; Jaap Oosterlaan; Hilde Geurts; Sharon Morein-Zamir; Nachson Meiran; Harry Schut; Laurens Vlasveld; Joseph A. Sergeant

    2004-01-01

    This study was aimed at: (1) testing whether boys with Attention Deficit\\/Hyperactivity Disorder (ADHD) demonstrate a deficit in response inhibition and deficits in other executive functions (EF), or alternatively, demonstrate a deficit in only response inhibition; (2) investigating which role associated factors, such as IQ, age, and performance on non-EF tasks play in EF in ADHD; (3) studying the association

  7. Selective Inhibition of WSN Influenza Virus Haemolysis by Pea Lectin

    Microsoft Academic Search

    DAVID L. KRAH; PURNELL W. CHOPPIN

    1988-01-01

    SUMMARY The capacity of lectins to inhibit viral haemolysis of chicken erythrocytes was tested, to evaluate the role of carbohydrate in the fusion reaction. Pretreatment of cells with pea lectin provided a 70 ~ to 85 ~ haemolysis inhibition with WSN influenza virus, but only 109\\/oo to 14~ with PR8 influenza virus. Pea lectin did not detectably bind to virus,

  8. Men in the Triangle: Grief, Inhibition, and Defense

    ERIC Educational Resources Information Center

    Clayton, Robert E.

    2015-01-01

    Inhibition of emotional experience is a widely acknowledged characteristic of many Western-raised men. While this affective inhibition may impact men chronically in many ways, it becomes particularly salient when men are bereaved or otherwise grieving and are unable fully to experience normative emotional responses to loss. This article briefly…

  9. Social Anxiety and Dating Inhibitions: Assessment and Treatment.

    ERIC Educational Resources Information Center

    Arkowitz, Hal

    Recent research on the behavioral assessment and treatment of social anxiety and inhibition is reviewed. Subjects for the studies were college men and women selected on the basis of heterosexual anxiety and inhibition. The first part of the paper is concerned with assessment. The behavioral assessment procedures developed include: (1) direct…

  10. AUXIN-INDUCED SPROUT GROWTH INHIBITION: ROLE OF ENDOGENOUS ETHYLENE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The role of endogenous ethylene in auxin-mediated tuber sprout growth inhibition was determined in potato (Solanum tuberosum L. cv. Russet Burbank) minitubers. Treatment of tubers with biologically active auxins resulted in transient, dose-dependent increase in ethylene production and inhibition of...

  11. Liposomal targeting of glucocorticoids to inhibit tumor angiogenesis

    Microsoft Academic Search

    M. Banciu

    2007-01-01

    Glucocorticoids (GC) have inhibitory actions on solid tumor growth due to suppressive effects on tumor angiogenesis and inflammation. When evaluating the preclinical studies on solid tumor growth inhibition, it appears that GC-induced antitumor effects are achieved by using substantially higher doses than the minimal doses needed to achieve inhibition of inflammatory disease processes. The high doses of GC used in

  12. Mechanisms of cancer inhibition by anti-oxidant nutrients

    Microsoft Academic Search

    G Shklar

    1998-01-01

    The cancer inhibitory properties of anti-oxidant micronutrients have been well established in experimental animal models and cell culture studies. Human studies have also tended to indicate an inhibition of various forms of cancer and the regression of some precancerous lesions. The biological mechanisms for cancer inhibition and regression are now gradually becoming understood, and the anti-oxidant nutrients appear to act

  13. Novobiocin and Coumermycin Inhibit DNA Supercoiling Catalyzed by DNA Gyrase

    Microsoft Academic Search

    Martin Gellert; Mary H. O'Dea; Tateo Itoh; Jun-Ichi Tomizawa

    1976-01-01

    Novobiocin and coumermycin are known to inhibit the replication of DNA in Escherichia coli. We show that these drugs inhibit the supercoiling of DNA catalyzed by E. coli DNA gyrase, a recently discovered enzyme that introduces negative superhelical turns into covalently circular DNA. The activity of DNA gyrase purified from a coumermycin-resistant mutant strain is resistant to both drugs. The

  14. The Affective Consequences of Cognitive Inhibition: Devaluation or Neutralization?

    ERIC Educational Resources Information Center

    Frischen, Alexandra; Ferrey, Anne E.; Burt, Dustin H. R.; Pistchik, Meghan; Fenske, Mark J.

    2012-01-01

    Affective evaluations of previously ignored visual stimuli are more negative than those of novel items or prior targets of attention or response. This has been taken as evidence that inhibition has negative affective consequences. But inhibition could act instead to attenuate or "neutralize" preexisting affective salience, predicting opposite…

  15. Inhibition of Helicobacter pylori by garlic extract ( Allium sativum)

    Microsoft Academic Search

    Luigina Cellini; Emanuela Di Campli; Michele Masulli; Soraya Di Bartolomeo; Nerino Allocati

    1996-01-01

    The antibacterial effect of aqueous garlic extract (AGE) was investigated against Helicobacter pylori. Sixteen clinical isolates and three reference strains of H. pylori were studied. Two different varieties of garlic were used. The concentration of AGE required to inhibit the bacterial growth was between 2–5 mg ml?1. The concentration, for both AGE types, to inhibit 90% (MIC90) of isolates was

  16. Contribution of human uropontin to inhibition of calcium oxalate crystallization

    Microsoft Academic Search

    John R Asplin; Denise Arsenault; Joan H Parks; Fredric L Coe; John R Hoyer

    1998-01-01

    Contribution of human uropontin to inhibition of calcium oxalate crystallization. Uropontin (UP) is known to inhibit the growth and nucleation of calcium oxalate monohydrate (COM) crystals, and it also impedes attachment of calcium oxalate crystals to cultured renal epithelial cells. However, its role in normal defense against renal crystallization, and in pathogenesis of nephrolithiasis is unclear. In this study we

  17. Polygalacturonase-inhibiting proteins in defense against phytopathogenic fungi

    Microsoft Academic Search

    Giulia De Lorenzo; Simone Ferrari

    2002-01-01

    Polygalacturonase-inhibiting proteins (PGIPs) are ubiquitous plant cell wall proteins that are directed against fungal polygalacturonases (PGs), which are important pathogenicity factors. The inhibiting activity of PGIPs directly reduces the aggressive potential of PGs. In addition, it causes PGs to form more long-chain oligogalacturonides that are able to induce defense responses, thereby indirectly contributing to the plant defense. Recent evidence demonstrates

  18. Photonic band-gap inhibition of modulational instabilities.

    PubMed

    Gomila, Damià; Zambrini, Roberta; Oppo, Gian-Luca

    2004-06-25

    Spatial structures as a result of a modulational instability are studied in a nonlinear cavity with a photonic crystal. The interaction of the modulated refractive index with the nonlinearity inhibits the instability via the creation of a photonic band gap. A novel mechanism of light localization due to defects and pattern inhibition is also described. PMID:15245008

  19. Photonic BandGap Inhibition of Modulational Instabilities

    Microsoft Academic Search

    Damià Gomila; Roberta Zambrini; Gian-Luca Oppo

    2004-01-01

    Spatial structures as a result of a modulational instability are studied in a nonlinear cavity with a photonic crystal. The interaction of the modulated refractive index with the nonlinearity inhibits the instability via the creation of a photonic band gap. A novel mechanism of light localization due to defects and pattern inhibition is also described.

  20. Environmentally safe corrosion inhibition of Pb in aqueous solutions

    Microsoft Academic Search

    N. H. Helal; M. M. El-Rabiee; Gh. M. Abd El-Hafez; W. A. Badawy

    2008-01-01

    The corrosion and corrosion inhibition of lead in aqueous solutions with different pHs (2, 7 and 12) were investigated. The corrosion rate was calculated in the absence and presence of the corrosion inhibitor using polarization and impedance techniques. Amino acids have been used as environmentally safe corrosion inhibitors. The inhibition efficiency of the different amino acids at a concentration of

  1. Ligand accumulation counteracts therapeutic inhibition of receptor systems

    E-print Network

    Duffy, Ken

    systems by competitive inhibition is the objective of various protein drugs in development and on the market. A variety of receptor systems also constitute a degradation mechanism for ligand and drug via interplay between ligand kinetics, drug pharmacokinetics, and the drug effect arising from the inhibition

  2. Underlying Personality Characteristics of Behavioral Inhibition in Children

    Microsoft Academic Search

    Peter Muris; Roeland Dietvorst

    2006-01-01

    Behavioral inhibition refers to the tendency of children to be unusually shy and to react with fear and withdrawal in situations that are novel and\\/or unfamiliar, and is generally regarded as a vulnerability factor for developing anxiety disorders. The present study investigated the hypothesis that behavioral inhibition is characterized by a specific constellation of two underlying personality characteristics, namely high

  3. Fermentation of lignocellulosic hydrolysates. I: inhibition and detoxification

    Microsoft Academic Search

    Eva Palmqvist; Bärbel Hahn-Hägerdal

    2000-01-01

    The ethanol yield and productivity obtained during fermentation of lignocellulosic hydrolysates is decreased due to the presence of inhibiting compounds, such as weak acids, furans and phenolic compounds formed or released during hydrolysis. This review describes the effect of various detoxification methods on the fermentability and chemical composition of the hydrolysates. Inhibition of fermentation can be relieved upon treatment with

  4. Pterocarpans and flavanones from Sophora flavescens displaying potent neuraminidase inhibition

    E-print Network

    Lee, Keun Woo

    Pterocarpans and flavanones from Sophora flavescens displaying potent neuraminidase inhibition Pterocarpan Sophora flavescens a b s t r a c t Pterocarpans (1­3) and flavanones (4­10) were isolated from Sophora flavescens and screened for their ability to inhibit neuraminidase (an enzyme crucial

  5. Inhibition and stimulation of yeast growth by acetaldehyde

    Microsoft Academic Search

    G. A. Stanley; N. G. Douglas; E. J. Every; T. Tzanatos; N. B. Pamment

    1993-01-01

    Acetaldehyde at above about 0.3 g\\/l inhibited yeast growth, suggesting that it may contribute to product inhibition in alcohol fermentations when present at high concentrations intracellularly. The toxic effects of acetaldehyde and ethanol were not mutually reinforcing, acetaldehyde appearing to alleviate slightly the effects of ethanol. In support of this, low concentrations of acetaldehyde greatly reduced the lag phase in

  6. Inhibition of Daphnia by Oscillatoria in Lake Washington

    Microsoft Academic Search

    AIDA INFANTE; SALLY E. B. ABELLA

    1985-01-01

    The hypothesis of Edmondson and Litt concerning the inhibition of Daphnia by Oscillatoria in Lake Washington was tested in experiments with cultures. Growth and reproduction of Daphnia pulicaria and Daphnia thorata were reduced by increasing concentrations of Oscillatoria agardhii from 0 to 400 filaments ml-' in the presence of adequate amounts of Cryptomonas as food. Cryptomonas reproduction also was inhibited

  7. Attachment, Behavioral Inhibition, and Anxiety in Preschool Children.

    ERIC Educational Resources Information Center

    Shamir-Essakow, Galia; Ungerer, Judy A.; Rapee, Ronald M.

    2005-01-01

    This study examined the association between insecure attachment, behavioral inhibition, and anxiety in an at risk sample of preschool children. The relationship between maternal anxiety and child anxiety was also assessed. Participants were 104 children aged 3-4 years who were assessed for behavioral inhibition and mother-child attachment (using…

  8. Inhibition of CaMKK2 Stimulates Osteoblast Formation and Inhibits Osteoclast Differentiation

    PubMed Central

    Cary, Rachel L.; Waddell, Seid; Racioppi, Luigi; Long, Fanxin; Novack, Deborah V.; Voor, Michael J.; Sankar, Uma

    2013-01-01

    Bone remodeling, a physiological process characterized by bone formation by osteoblasts (OB) and resorption of pre-existing bone matrix by osteoclasts (OC), is vital for the maintenance of healthy bone tissue in adult humans. Imbalances in this vital process result in pathological conditions including osteoporosis. Owing to its initial asymptomatic nature, osteoporosis is often detected only after the patient has sustained significant bone loss or a fracture. Hence, anabolic therapeutics that stimulates bone accrual is in high clinical demand. Here we identify Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) as a potential target for such therapeutics, as its inhibition enhances OB differentiation and bone growth and suppresses OC differentiation. Mice null for CaMKK2 possess higher trabecular bone mass in their long bones, along with significantly more OBs and fewer multinuclear OCs. Whereas Camkk2?/? MSCs yield significantly higher numbers of OBs, bone marrow cells from Camkk2?/? mice produce fewer multinuclear OCs, in vitro. Acute inhibition of CaMKK2 by its selective, cell-permeable pharmacological inhibitor STO-609 also results in increased OB and diminished OC formation. Further, we find phospho-protein kinase A (PKA) and Ser133 phosphorylated form of cyclic adenosine monophosphate (cAMP) response element binding protein (pCREB) to be markedly elevated in OB progenitors deficient in CaMKK2. On the other hand, genetic ablation of CaMKK2 or its pharmacological inhibition in OC progenitors results in reduced pCREB as well as significantly reduced levels of its transcriptional target, nuclear factor of activated T cells c1 (NFATc1). Moreover, in vivo administration of STO-609 results in increased OBs and diminished OCs, conferring significant protection from ovariectomy (OVX)-induced osteoporosis in adult mice. Overall, our findings reveal a novel function for CaMKK2 in bone remodeling and highlight the potential for its therapeutic inhibition as a valuable bone anabolic strategy that also inhibits OC differentiation in the treatment of osteoporosis. PMID:23408651

  9. Thymoquinone Inhibits Escherichia coli ATP Synthase and Cell Growth

    PubMed Central

    Ahmad, Zulfiqar; Laughlin, Thomas F.; Kady, Ismail O.

    2015-01-01

    We examined the thymoquinone induced inhibition of purified F1 or membrane bound F1FO E. coli ATP synthase. Both purified F1 and membrane bound F1FO were completely inhibited by thymoquinone with no residual ATPase activity. The process of inhibition was fully reversible and identical in both membrane bound F1Fo and purified F1 preparations. Moreover, thymoquinone induced inhibition of ATP synthase expressing wild-type E. coli cell growth and non-inhibition of ATPase gene deleted null control cells demonstrates that ATP synthase is a molecular target for thymoquinone. This also links the beneficial dietary based antimicrobial and anticancer effects of thymoquinone to its inhibitory action on ATP synthase. PMID:25996607

  10. Alpha glucosidase inhibition by stem extract of Tinospora cordifolia.

    PubMed

    Chougale, Ashok D; Ghadyale, Varsha A; Panaskar, Shrimant N; Arvindekar, Akalpita U

    2009-08-01

    Inhibitors of alpha glucosidase have potential use in the treatment of diabetes mellitus. The stem extract of Tinospora cordifolia was evaluated for inhibition of the enzyme. The extract was also found to inhibit the salivary and pancreatic amylase and therefore can effectively reduce an increase in postprandial glucose level. The crude ethyl acetate, dichloromethane (DCM), chloroform and hexane extracts of Tinospora cordifolia were studied. 15 mg of the DCM extract was most effective in that showed 100 % inhibition of the alpha glucosidase whereas salivary amylase was inhibited to the extent of 75 % and pancreatic amylase to 83 %. On giving a maltose load of 2mg / g along with 0.3 mg / g body weight of the DCM Tinospora stem extract a decrease was revealed in the hyperglycemic shoot up in normal and diabetic animals by 50 and 58 % respectively as compared to the controls. The extract was found to inhibit alpha glucosidase in a non-competitive manner. PMID:19555164

  11. Associative learning phenomena in the snail (Helix aspersa): conditioned inhibition.

    PubMed

    Acebes, Félix; Solar, Patricia; Moris, Joaquín; Loy, Ignacio

    2012-03-01

    Two experiments using garden snails (Helix aspersa) showed conditioned inhibition using both retardation and summation tests. Conditioned inhibition is a procedure by which a stimulus becomes a predictor of the absence of a relevant event--the unconditioned stimulus (US). Typically, conditioned inhibition consists of pairings between an initially neutral conditioned stimulus, CS(2), and an effective excitatory conditioned stimulus, CS(1), in the absence of the US. Retardation and summation tests are required in order to confirm that CS(2) has acquired inhibitory properties. Conditioned inhibition has previously been found in invertebrates; however, these demonstrations did not use the retardation and summation tests required for an unambiguous demonstration of inhibition, allowing for alternative explanations. The implications of our results for the fields of comparative cognition and invertebrate physiological models of learning are discussed. PMID:21877176

  12. Mechanism of inhibition of alanine absorption by Na ricinoleate.

    PubMed

    Hajjar, J J; Murphy, D M; Scheig, R L

    1979-05-01

    The mechanism of inhibition of alanine absorption by Na ricinoleate has been examined in the rabbit intestine. This fatty acid in a concentration of 2--5 mM inhibits alanine absorption in vivo and in vitro. The inhibition is more evident in the jejunum than in the ileum. Strips of ileal mucosa treated with Na ricinoleate gain Na. Sodium ricinoleate inhibits alanine influx across rabbit ileum, even in the presence of a sodium gradient across these cells. The results suggest that the main action of Na ricinoleate is on the alanine-transport system at the brush-border membrane. The fatty acid may also inhibit amino acid absorption by increasing intestinal cell Na concentration, which results in a decreased Na gradient across the brush-border membrane. PMID:443374

  13. Effect of overall feedback inhibition in unbranched biosynthetic pathways.

    PubMed Central

    Alves, R; Savageau, M A

    2000-01-01

    We have determined the effects of control by overall feedback inhibition on the systemic behavior of unbranched metabolic pathways with an arbitrary pattern of other feedback inhibitions by using a recently developed numerical generalization of Mathematically Controlled Comparisons, a method for comparing the function of alternative molecular designs. This method allows the rigorous determination of the changes in systemic properties that can be exclusively attributed to overall feedback inhibition. Analytical results show that the unbranched pathway can achieve the same steady-state flux, concentrations, and logarithmic gains with respect to changes in substrate, with or without overall feedback inhibition. The analytical approach also shows that control by overall feedback inhibition amplifies the regulation of flux by the demand for end product while attenuating the sensitivity of the concentrations to the same demand. This approach does not provide a clear answer regarding the effect of overall feedback inhibition on the robustness, stability, and transient time of the pathway. However, the generalized numerical method we have used does clarify the answers to these questions. On average, an unbranched pathway with control by overall feedback inhibition is less sensitive to perturbations in the values of the parameters that define the system. The difference in robustness can range from a few percent to fifty percent or more, depending on the length of the pathway and on the metabolite one considers. On average, overall feedback inhibition decreases the stability margins by a minimal amount (typically less than 5%). Finally, and again on average, stable systems with overall feedback inhibition respond faster to fluctuations in the metabolite concentrations. Taken together, these results show that control by overall feedback inhibition confers several functional advantages upon unbranched pathways. These advantages provide a rationale for the prevalence of this control mechanism in unbranched metabolic pathways in vivo. PMID:11053109

  14. Multiple mechanisms of lung surfactant inhibition.

    PubMed

    Holm, B A; Wang, Z; Notter, R H

    1999-07-01

    We studied the mechanisms by which C16:0 lysophosphatidylcholine (LPC) and albumin inhibit the surface activity of calf lung surfactant extract (CLSE) by using a pulsating bubble apparatus with a specialized hypophase exchange system, plus adsorption and Wilhelmy balance measurements. In the absence of inhibitors, CLSE (1 mg phospholipid/mL) reached minimum surface tension (gamma(min)) < 1 mN/m within 5 min of bubble pulsation at 20 cycles/min at 37 degrees C. Mixtures of CLSE:LPC had impaired surface activity depending on LPC content: gamma(min) was raised to 5 mN/m by 14 wt % LPC, to 15 mN/m by 25-30 wt% LPC, and to >20 mN/m (67 wt % LPC), even at high CLSE concentrations (3 and 6 mg phospholipid/mL). In contrast, inhibition of CLSE by albumin was more easily abolished when surfactant concentration was raised. Mixtures of albumin (3 mg/mL) and CLSE (1 mg phospholipid/mL) had gamma(min) >20 mN/m, but normal values of gamma(min) < 1 mN/m were reached at higher CLSE concentration (3 mg phospholipid/mL) even when albumin concentration was increased 8-fold to 24 mg/mL. In hypophase exchange studies, LPC, but not albumin, was able to penetrate preformed CLSE surface films and raise gamma(min) CLSE surface films with gamma(min) < 1 mN/m were isolated by an initial hypophase exchange with saline, and a second exchange with an LPC-containing hypophase raised gamma(min) to approximately 10 mN/m. CLSE surface films retained the ability to reach gamma(min) < 1 mN/m in analogous hypophase exchange studies with albumin. The ability of LPC to penetrate surface films of CLSE, although albumin could not, was also demonstrated in adsorption experiments in a Teflon dish, where diffusion was minimized by subphase stirring. Wilhelmy balance experiments also demonstrated that LPC could mix and interact with CLSE or dipalmitoyl phosphatidylcholine in solvent-spread surface films. The ability of LPC or other cell membrane lipids to penetrate interfacial films and raise gamma(min) even at high surfactant concentration may increase their inhibitory actions during acute lung injury. PMID:10400140

  15. Inhibition of cellular transformation by berry extracts.

    PubMed

    Xue, H; Aziz, R M; Sun, N; Cassady, J M; Kamendulis, L M; Xu, Y; Stoner, G D; Klaunig, J E

    2001-02-01

    Recent studies have examined and demonstrated the potential cancer chemopreventive activity of freeze-dried berries including strawberries and black raspberries. Although ellagic acid, an abundant component in these berries, has been shown to inhibit carcinogenesis both in vivo and in vitro, several studies have reported that other compounds in the berries may also contribute to the observed inhibitory effect. In the present study, freeze-dried strawberries (Fragara ananassa, FA) or black raspberries (Rubus ursinus, RU) were extracted, partitioned and chromatographed into several fractions (FA-F001, FA-F003, FA-F004, FA-F005, FA-DM, FA-ME from strawberries and RU-F001, RU-F003, RU-F004, RU-F005, RU-DM, RU-ME from black raspberries). These extracts, along with ellagic acid, were analyzed for anti-transformation activity in the Syrian hamster embryo (SHE) cell transformation model. None of the extracts nor ellagic acid by themselves produced an increase in morphological transformation. For assessment of chemopreventive activity, SHE cells were treated with each agent and benzo[a]pyrene (B[a]P) for 7 days. Ellagic acid, FA-ME and RU-ME fractions produced a dose-dependent decrease in transformation compared with B[a]P treatment only, while other fractions failed to induce a significant decrease. Ellagic acid, FA-ME and RU-ME were further examined using a 24 h co-treatment with B[a]P or a 6 day treatment following 24 h with B[a]P. Ellagic acid showed inhibitory ability in both protocols. FA-ME and RU-ME significantly reduced B[a]P-induced transformation only when co-treated with B[a]P for 24 h. These results suggest that a methanol extract from strawberries and black raspberries may display chemopreventive activity. The possible mechanism by which these methanol fractions (FA-ME, RU-ME) inhibited cell transformation appear to involve interference of uptake, activation, detoxification of B[a]P and/or intervention of DNA binding and DNA repair. PMID:11181460

  16. On Inhibition\\/Disinhibition in Developmental Psychopathology: Views From Cognitive and Personality Psychology and a Working Inhibition Taxonomy

    Microsoft Academic Search

    Joel T. Nigg

    2000-01-01

    Disinhibition is a common focus in psychopathology research. However, use of inhibition models often is piecemeal, lacking an overarching taxonomy of inhibitory processes. The author organizes key concepts and models pertaining to different kinds of inhibitory control from the cognitive and temperament\\/personality literatures. Within the rubrics of executive inhibitory processes, motivational inhibitory processes, and automatic attentional inhibition processes, 8 kinds

  17. Method for inhibiting corrosion in aqueous systems

    DOEpatents

    DeMonbrun, James R. (Knoxville, TN); Schmitt, Charles R. (Oak Ridge, TN); Schreyer, James M. (Oak Ridge, TN)

    1980-01-01

    This invention is a method for inhibiting corrosion in aqueous systems containing components composed of aluminum, copper, iron, or alloys thereof. The method comprises (a) incorporating in the aqueous medium 2-10 ppm by weight of tolyltriazole; an effective amount of a biodegradable organic biocide; 500-1000 ppm by weight of sodium metasilicate; 500-2000 ppm by weight of sodium nitrite; and 500-2000 ppm by weight of sodium tetraborate, all of these concentrations being based on the weight of water in the system; and (b) maintaining the pH of the resulting system in the range of 7.5 to 8.0. The method permits longterm operation with very low corrosion rates and bacteria counts. All of the additives to the system are biodegradable, permitting the treated aqueous medium to be discharged to the environment without violating current regulations. The method has special application to solar systems in which an aqueous medium is circulated through aluminum-alloy heat exchangers.

  18. Molecular analysis of carotenoid cyclase inhibition.

    PubMed

    Bouvier, F; d'Harlingue, A; Camara, B

    1997-10-01

    Later steps of carotenoid biosynthesis catalyzed by cyclase enzymes involve the formation of alpha, beta, and kappa-rings. Examination of the primary structure of lycopene beta-cyclase revealed 55% identity with that of antheraxanthin kappa-cyclase. Recombinant lycopene beta-cyclase afforded only beta-carotene, while recombinant antheraxanthin kappa-cyclase catalyzed the formation of beta-carotene from lycopene as well as the conversion of antheraxanthin into the kappa-carotenoid capsanthin. Since the formation of beta- and kappa-rings involves a transient carotenoid carbocation, this suggests that both cyclases initiate and/or neutralize the incipient carbocation by similar mechanisms. Several amine derivatives protonated at physiological pH were used to examine the molecular basis of this phenomenon. The beta-and kappa-cyclases displayed similar inhibition patterns. Affinity or photoaffinity labeling using p-dimethylamino-benzenediazonium fluoroborate, N,N-dimethyl-2-phenylaziridinium, and nicotine irreversibly inactivated both cyclase enzymes. Photoaffinity labeling using [3H]nicotine followed by radiosequence analysis and site-directed mutagenesis revealed the existence of two cyclase domains characterized by the presence of reactive aromatic and carboxylic amino acid residues. We propose that these residues represent the "negative point charges" involved in the coordination of the incipient carotenoid carbocations. PMID:9328284

  19. The mechanism underlying inhibition of saccadic return

    PubMed Central

    Ludwig, Casimir J.H.; Farrell, Simon; Ellis, Lucy A.; Gilchrist, Iain D.

    2009-01-01

    Human observers take longer to re-direct gaze to a previously fixated location. Although there has been some exploration of the characteristics of inhibition of saccadic return (ISR), the exact mechanisms by which ISR operates are currently unknown. In the framework of accumulation models of response times, in which evidence is integrated over time to a response threshold, ISR could reflect a reduction in the rate of accumulation for saccades to return locations or an increase in the effective criterion for response. In two experiments, participants generated sequences of three saccades, in response to a peripheral or a central cue. ISR occurred across these manipulations: saccade latency was consistently increased for movements to the immediately previously fixated location. Latency distributions from individual observers were fit with a Linear Ballistic Accumulator model. ISR was best accounted for as a change in the accumulation rate. We suggest this parameter represents the overall desirability of a particular course of action, the evidence for which may be derived from a variety of sensory and non-sensory sources. PMID:19520369

  20. High outgroup entitativity can inhibit intergroup retribution.

    PubMed

    Newheiser, Anna-Kaisa; Dovidio, John F

    2015-06-01

    Understanding the psychological processes that are involved in the perpetuation and escalation of intergroup conflict remains an important goal for intergroup relations research. In the present research, we examined perceived outgroup entitativity as a potential determinant of intergroup hostility. In intergroup conflict situations, high-entitative outgroups are perceived as particularly deserving of retribution; however, high-entitative outgroups are also perceived as efficacious and capable of retaliating successfully, suggesting that people may inhibit hostility against high-entitative (vs. low-entitative) outgroups that are in a position to retaliate. We tested this prediction in two studies. In Study 1, we manipulated intergroup provocation and outgroup entitativity, and found that higher negative mood predicted greater aggression against a low-entitative provoker outgroup, but failed to predict aggression against a high-entitative provoker outgroup that was plausibly in a position to retaliate. In Study 2, we held provocation constant while manipulating outgroup entitativity and the possibility of retaliation by the outgroup, and found that people acted in a retributive manner against a high-entitative provoker outgroup only when the outgroup was not in a position to retaliate. Implications for intergroup conflict are discussed. PMID:25066604

  1. Chitinase Inhibition Promotes Atherosclerosis in Hyperlipidemic Mice

    PubMed Central

    Kitamoto, Shiro; Egashira, Kensuke; Ichiki, Toshihiro; Han, Xinbing; McCurdy, Sara; Sakuda, Shohei; Sunagawa, Kenji; Boisvert, William A.

    2014-01-01

    Chitinase 1 (CHIT1) is secreted by activated macrophages. Chitinase activity is raised in atherosclerotic patient sera and is present in atherosclerotic plaque. However, the role of CHIT1 in atherosclerosis is unknown. Preliminary studies of atherosclerosis in cynomolgous monkeys revealed CHIT1 to be closely correlated with areas of macrophage infiltration. Thus, we investigated the effects of a chitinase inhibitor, allosamidin, on macrophage function in vitro and on atherosclerotic development in vivo. In RAW264.7 cells, allosamidin elevated monocyte chemoattractant protein 1 and tumor necrosis factor alpha expression, and increased activator protein 1 and nuclear factor-?B transcriptional activity. Although inducible nitric oxide synthase, IL-6, and IL-1? expression were increased, Arg1 expression was decreased by chitinase inhibition, suggesting that suppression of CHIT1 activity polarizes macrophages into a M1 phenotype. Allosamidin decreased scavenger receptor AI, CD36, ABCA1, and ABCG1 expression which led to suppression of cholesterol uptake and apolipoprotein AI-mediated cholesterol efflux in macrophages. These effects were confirmed with CHIT1 siRNA transfection and CHIT1 plasmid transfection experiments in primary macrophages. Apolipoprotein E-deficient hyperlipidemic mice treated for 6 weeks with constant administration of allosamidin and fed an atherogenic diet showed aggravated atherosclerotic lesion formation. These data suggest that CHIT1 exerts protective effects against atherosclerosis by suppressing inflammatory responses and polarizing macrophages toward an M2 phenotype, and promoting lipid uptake and cholesterol efflux in macrophages. PMID:23685110

  2. Stathmin Potentiates Vinflunine and Inhibits Paclitaxel Activity

    PubMed Central

    Malesinski, Soazig; Tsvetkov, Philipp O.; Kruczynski, Anna; Peyrot, Vincent; Devred, François

    2015-01-01

    Cell biology and crystallographic studies have suggested a functional link between stathmin and microtubule targeting agents (MTAs). In a previous study we showed that stathmin increases vinblastine (VLB) binding to tubulin, and that conversely VLB increases stathmin binding to tubulin. This constituted the first biochemical evidence of the direct relationship between stathmin and an antimitotic drug, and revealed a new mechanism of action for VLB. The question remained if the observed interaction was specific for this drug or represented a general phenomenon for all MTAs. In the present study we investigated the binding of recombinant stathmin to purified tubulin in the presence of paclitaxel or another Vinca alkaloid, vinflunine, using Isothermal Titration Calorimetry (ITC). These experiments revealed that stathmin binding to tubulin is increased in the presence of vinflunine, whereas no signal is observed in the presence of paclitaxel. Further investigation using turbidity and co-sedimentation showed that stathmin inhibited paclitaxel microtubule-stabilizing activity. Taken together with the previous study using vinblastine, our results suggest that stathmin can be seen as a modulator of MTA activity and binding to tubulin, providing molecular explanation for multiple previous cellular and in vivo studies showing that stathmin expression level affects MTAs efficiency. PMID:26030092

  3. Morphine directly inhibits nociceptors in inflamed skin.

    PubMed

    Wenk, Heather N; Brederson, Jill-Desiree; Honda, Christopher N

    2006-04-01

    Peripherally delivered opiates attenuate mechanical and thermal hyperalgesia in experimental models of inflammation, suggesting that activation of peripheral opioid receptors decreases the excitability of nociceptors in inflamed tissues. The current study examines the effects of peripheral morphine sulfate on response properties of sensory neurons in healthy and inflamed skin. Afferent units (185) were isolated from tibial nerve of rats using an in vitro glabrous skin-nerve teased-fiber preparation. Of these, 107 units were from normal healthy skin, and 78 were from inflamed skin 18 h after intraplantar injection of complete Freund's adjuvant. As a population, C-fiber units innervating inflamed skin exhibited properties characteristic of sensitization when compared with units innervating healthy control skin. Mechanical thresholds were lowered, responses to noxious mechanical and thermal stimuli were elevated, a greater proportion of units was spontaneously active, and the average rate of spontaneous discharge was higher. Response properties in other conduction velocity groups remained unchanged. Fifty-eight percent of C and C/Adelta nociceptors innervating inflamed skin were opiate-sensitive, and their excitability was attenuated by direct application of morphine to their receptive fields. All morphine-sensitive units were nociceptors from inflamed skin with conduction velocities <1.3 m/s. Morphine effects were concentration-dependent and naloxone-sensitive, indicating that the effects were receptor-mediated. These findings provide direct evidence that morphine acts through peripheral opioid receptors to inhibit the activity of cutaneous nociceptors under conditions of inflammation. PMID:16339007

  4. Rational drug design applied to myeloperoxidase inhibition.

    PubMed

    Van Antwerpen, P; Zouaoui Boudjeltia, K

    2015-06-01

    Rational drug design is a general approach using protein-structure technique in which the discovery of a ligand can be driven either by chance, screening, or rational theory. Myeloperoxidase (MPO) was rapidly identified as a therapeutical target because of its involvement in chronic inflammatory syndromes. In this context, the research of MPO inhibitors was intensified and development of new chemical entities was rationally driven by the research of ligands that enter into the MPO catalytic pocket. Actually, as soon as crystallography data of MPO have become available and its structure was virtually designed, the rational drug design has been applied to this peroxidase. Pharmaceutical industries and academic laboratories apply rational drug design on MPO by either optimizing known inhibitors or searching new molecules by high-throughput virtual screening. By these ways, they were able to find efficient MPO inhibitors and understand their interactions with the enzyme. During this quest of MPO inhibition, it appears that Glu268 is a crucial residue in order to optimize ligand-target interaction. This amino acid should be carefully considered by medicinal chemist when they design inhibitors interfering with MPO activity. PMID:25788127

  5. Olive oil isochromans inhibit human platelet reactivity.

    PubMed

    Togna, Giuseppina I; Togna, Anna Rita; Franconi, Matteo; Marra, Carolina; Guiso, Marcella

    2003-08-01

    The effects of certain polyphenolic compounds in red wine, such as resveratrol and quercetin, have been widely investigated to determine the relationship between dietary phenolic compounds and the decreased risk of cardiovascular diseases. However, the effects of polyphenolic compounds contained in other foods, such as olive oil, have received less attention and little information exists regarding the biological activities of the phenol fraction in olive oil. The aim of this study was to evaluate the antiplatelet activity and antioxidant power of two isochromans [1-(3'-methoxy-4'-hydroxy-phenyl)-6,7-dihydroxy-isochroman (encoded L116) and 1-phenyl-6,7-dihydroxy-isochroman (encoded L137)] recently discovered in olive oil and synthesized in our laboratory from hydroxytyrosol. These compounds were effective free radical scavengers and inhibited platelet aggregation and thromboxane release evoked by agonists that induce reactive oxygen species-mediated platelet activation including sodium arachidonate and collagen, but not ADP. Release of tritiated arachidonic acid from platelets was also impaired by L116 and L137. These results indicate that other Mediterranean diet nutraceuticals also exhibit antioxidant activity that could be beneficial in the prevention of vascular diseases. PMID:12888632

  6. Inhibition of Oxidation in Nuclear Graphite

    SciTech Connect

    Phil Winston; James W. Sterbentz; William E. Windes

    2013-10-01

    Graphite is a fundamental material of high temperature gas cooled nuclear reactors, providing both structure and neutron moderation. Its high thermal conductivity, chemical inertness, thermal heat capacity, and high thermal structural stability under normal and off normal conditions contribute to the inherent safety of these reactor designs. One of the primary safety issues for a high temperature graphite reactor core is the possibility of rapid oxidation of the carbon structure during an off normal design basis event where an oxidizing atmosphere (air ingress) can be introduced to the hot core. Although the current Generation IV high temperature reactor designs attempt to mitigate any damage caused by a postualed air ingress event, the use of graphite components that inhibit oxidation is a logical step to increase the safety of these reactors. Recent experimental studies of graphite containing between 5.5 and 7 wt% boron carbide (B4C) indicate that oxidation is dramatically reduced even at prolonged exposures at temperatures up to 900°C. The proposed addition of B4C to graphite components in the nuclear core would necessarily be enriched in B-11 isotope in order to minimize B-10 neutron absorption and graphite swelling. The enriched boron can be added to the graphite during billet fabrication. Experimental oxidation rate results and potential applications for borated graphite in nuclear reactor components will be discussed.

  7. Collagen hydrolysate inhibits zymosan-induced inflammation.

    PubMed

    Hartog, Anita; Cozijnsen, Miranda; de Vrij, Gerrit; Garssen, Johan

    2013-07-01

    During the past years, evidence accumulated showing that glycine comprises anti-inflammatory activities. These effects occur, at least in part, via the activation of glycine-gated chloride channels (GlyR). Glycine is one of the major structural units of collagen, making up about 30% of the amino acids. This study aims to investigate the anti-inflammatory potential of collagen hydrolysate (CH) using the zymosan-induced ear-skin inflammation mouse model. After oral intake of 12.5, 25 or 50 mg CH the plasma levels of glycine increased in a concentration-dependent manner. CH was able to counteract zymosan-induced ear-skin inflammation locally (ear swelling) as well as systemically (IL-6 production by lipopolysaccharide (LPS)-stimulated whole blood cells). The LPS-stimulated IL-6 production in whole blood correlated positively with the ear swelling response. This correlation was abolished by strychnine (a glycine receptor antagonist), indicating the involvement of GlyR. Collectively, these data show that CH is able to modulate inflammatory responses both locally as well as systemically. This effect might be constituted by inhibiting pro-inflammatory cytokine production via GlyR. PMID:23788175

  8. [Mutual inhibition between positive and negative emotions].

    PubMed

    Shimokawa, A

    1994-02-01

    The purpose of this study is to examine the relationship between positive and negative emotions. In study 1, 62 emotional items were selected in order to measure subjective emotional experiences. In study 2, comics, photos and poems were randomly presented to 1,220 college students to induce emotion. Subjects were asked to rate their momentary emotional intensity on two set of 5-point scales (general emotional intensity scale and 62 specific emotional intensity scale). In analysis 1, positive correlations were suggested between general emotional intensity scale and some of the specific emotional intensity scales which were activated by stimuli. In analysis 2, 10 positive and 10 negative emotional items were extracted from 62 items by factor analysis. In analysis 3, 4 and 5, it became clear that the distribution of frequency of correlations of 10 positive x 10 negative items changed according to the general emotional intensity scale. That is, from low to moderate levels of GEIS, the two kinds of emotion had no or slightly positive correlation, but at high level they became to be negatively correlated. From the facts described above, it is concluded that positive and negative emotions is not always independent, but show mutual inhibition in case of high intensity level of one of each emotions. PMID:8201808

  9. Lentiginosine, a dihydroxyindolizidine alkaloid that inhibits amyloglucosidase.

    PubMed

    Pastuszak, I; Molyneux, R J; James, L F; Elbein, A D

    1990-02-20

    Lentiginosine, a dihydroxyindolizidine alkaloid, was extracted from the leaves of Astragalus lentiginosus with hot methanol and was purified to homogeneity by ion-exchange, thin-layer, and radial chromatography. A second dihydroxyindolizidine, the 2-epimer of lentiginosine, was also purified to apparent homogeneity from these extracts. Gas chromatography of the two isomers (as the TMS derivatives) showed that they were better than 95% pure; lentiginosine eluted at 8.65 min and the 2-epimer at 9.00 min. Both compounds had a molecular ion in their mass spectra of 157, and the NMR spectra demonstrated that both were dihydroxyindolizidines differing in the configuration of the hydroxyl group at carbon 2. Lentiginosine was found to be a reasonably good inhibitor of the fungal alpha-glucosidase, amyloglucosidase (Ki = 1 x 10(-5) M), but it did not inhibit other alpha-glucosidases (i.e., sucrase, maltase, yeast alpha-glucosidase, glucosidase I) nor any other glycosidases. The 2-epimer had no activity against any of the glycosidases tested. PMID:2331469

  10. Inhibition of angiogenesis by S-adenosylmethionine

    SciTech Connect

    Sahin, Mehmet, E-mail: msahin@akdeniz.edu.tr [Health Sciences Research Centre, Faculty of Medicine, Akdeniz University, 07070 Antalya (Turkey)] [Health Sciences Research Centre, Faculty of Medicine, Akdeniz University, 07070 Antalya (Turkey); Sahin, Emel [Department of Central Laboratory, Clinical Biochemistry Unit, Faculty of Medicine, Akdeniz University, 07070 Antalya (Turkey)] [Department of Central Laboratory, Clinical Biochemistry Unit, Faculty of Medicine, Akdeniz University, 07070 Antalya (Turkey); Guemueslue, Saadet [Department of Biochemistry, Faculty of Medicine, Akdeniz University, 07070 Antalya (Turkey)] [Department of Biochemistry, Faculty of Medicine, Akdeniz University, 07070 Antalya (Turkey); Erdogan, Abdullah [Department of Thoracic Surgery, Faculty of Medicine, Akdeniz University, 07070 Antalya (Turkey)] [Department of Thoracic Surgery, Faculty of Medicine, Akdeniz University, 07070 Antalya (Turkey); Gueltekin, Meral [Health Sciences Research Centre, Faculty of Medicine, Akdeniz University, 07070 Antalya (Turkey)] [Health Sciences Research Centre, Faculty of Medicine, Akdeniz University, 07070 Antalya (Turkey)

    2011-04-29

    Highlights: {yields} Effects of S-adenosylmethionine (SAM) were investigated in endothelial cells. {yields} Our results showed that SAM decreased proliferation of endothelial cells. {yields} SAM influentially inhibited the percentage of cell migration. {yields} SAM probably stopped migration as independent from its effects on proliferation. {yields} SAM was shown to suppress in vitro angiogenesis. -- Abstract: Metastasis is a leading cause of mortality and morbidity in cancer. One of the steps in metastasis process is the formation of new blood vessels. Aberrant DNA methylation patterns are common in cancer cells. In recent studies, S-adenosylmethionine (SAM), which is a DNA methylating agent, has been found to have inhibitory effects on some carcinoma cells in vivo and in vitro. In the present study, we have used SAM to investigate whether it is effective against angiogenesis in vitro. Our results have shown that SAM can reduce the formation and organization of capillary-like structures of endothelial cells in tumoral environment. Besides, we have found SAM can block endothelial cell proliferation and the migration of cells towards growth factors-rich media. In conclusion, our study suggests that SAM may be used against angiogenesis as a natural bio-product.

  11. Inhibition of lignifying processes by sulfur dioxide

    SciTech Connect

    Pfanz, H.; Oppmann, B.

    1991-05-01

    Intercellular washing fluids (IWF) from spruce needles (Picea abies L. Karst.) contain peroxidases 1-2% of total IWF protein. These apoplastic enzymes show the ability to polymerize monophenols or phenylpropanes to form lignin precursors in vitro. In the presence of potentially acidic air pollutants like NO{sub 2}, HF(20 mM of salts in solution), and in the presence of Pb-, Cd- (0.5 mM) or Al-salts (8 mM) no inhibitory effect on the polymerization reactions examined was detectable. In contrast, the anions of SO{sub 2} (sulfite and bisulfite) revealed a strong inhibition on the dimerization of ferulic and caffeic acid (Ki ca. 1 mM), and on the dehydration of syringaldazine (Ki ca. 8 {mu}M). Polymerization of coniferyl alcohol, on the other hand, seemed to be enhanced. Maier-Maercker and Koch (1986) demonstrated that the cell walls of guard cells from undamaged spruce needles are properly lignified, whereas those of damaged needles seem to be affected. It is therefore assumed that cell wall lignification, and concomitantly stomatal regulation of coniferous needles are disturbed in regions with high atmospheric SO{sub 2} pollution (e.g. Ore Mountains in CSFR).

  12. Bee venom inhibits growth of human cervical tumors in mice.

    PubMed

    Lee, Hye Lim; Park, Sang Ho; Kim, Tae Myoung; Jung, Yu Yeon; Park, Mi Hee; Oh, Sang Hyun; Yun, Hye Seok; Jun, Hyung Ok; Yoo, Hwan Soo; Han, Sang-Bae; Lee, Ung Soo; Yoon, Joo Hee; Song, Min Jong; Hong, Jin Tae

    2015-03-30

    We studied whether bee venom (BV) inhibits cervical tumor growth through enhancement of death receptor (DR) expressions and inactivation of nuclear factor kappa B (NF-?B) in mice. In vivo study showed that BV (1 mg/kg) inhibited tumor growth. Similar inhibitory effects of BV on cancer growth in primary human cervical cancer cells were also found. BV (1-5 ?g/ml) also inhibited the growth of cancer cells, Ca Ski and C33Aby the induction of apoptotic cell death in a dose dependent manner. Agreed with cancer cell growth inhibition, expression of death receptors; FAS, DR3 and DR6, and DR downstream pro-apoptotic proteins including caspase-3 and Bax was concomitantly increased, but the NF-?B activity and the expression of Bcl-2 were inhibited by treatment with BV in tumor mice, human cancer cell and human tumor samples as well as cultured cancer cells. In addition, deletion of FAS, DR3 and DR6 by small interfering RNA significantly reversed BV-induced cell growth inhibitory effects as well as NF-?B inactivation. These results suggest that BV inhibits cervical tumor growth through enhancement of FAS, DR3 and DR6 expression via inhibition of NF-?B pathway. PMID:25730901

  13. Angiotensin-converting enzyme inhibition delays pulmonary vascular neointimal formation.

    PubMed

    Okada, K; Bernstein, M L; Zhang, W; Schuster, D P; Botney, M D

    1998-09-01

    Primary pulmonary hypertension (PPH) is a disease characterized pathologically by pulmonary artery medial hypertrophy, adventitial thickening, and neointimal proliferation. Increasing recognition of the importance of remodeling to the pathogenesis of PPH suggests new therapeutic possibilities, but it will be necessary to (1) identify essential mediators of remodeling, and (2) demonstrate that inhibiting those mediators suppresses remodeling before new antiremodeling therapies can be considered feasible. The effect of angiotensin-converting enzyme (ACE) inhibition on pulmonary vascular remodeling was studied in a newly developed rat model in which neointimal lesions develop between 3 and 5 wk after monocrotaline injury is coupled with increased pulmonary artery blood flow after contralateral pneumonectomy. Neointimal formation was significantly suppressed at 5 wk by ACE inhibition whether it was started 10 d before or 3 wk after remodeling was initiated, although medial hypertrophy and adventitial thickening still developed. By 11 wk, the extent of neointimal formation in rats treated with ACE inhibition was similar to rats without ACE inhibition at 5 wk. Pulmonary artery pressures and right ventricular weights correlated with the extent of neointimal formation. Northern blot analysis and in situ hybridization demonstrated marked suppression of lung tropoelastin and type I procollagen gene expression in the presence of ACE inhibition. An angiotensin II type I receptor antagonist partially, but not completely, replicated the effects of ACE inhibition. These data suggest that the tissue angiotensin system may be a target for therapeutic efforts to suppress the vascular remodeling that is characteristic of primary pulmonary hypertension. PMID:9731029

  14. Bee venom inhibits growth of human cervical tumors in mice

    PubMed Central

    Kim, Tae Myoung; Jung, Yu Yeon; Park, Mi Hee; Oh, Sang Hyun; Yun, Hye Seok; Jun, Hyung Ok; Yoo, Hwan Soo; Han, Sang-Bae; Lee, Ung Soo; Yoon, Joo Hee; Song, Min Jong; Hong, Jin Tae

    2015-01-01

    We studied whether bee venom (BV) inhibits cervical tumor growth through enhancement of death receptor (DR) expressions and inactivation of nuclear factor kappa B (NF-?B) in mice. In vivo study showed that BV (1 mg/kg) inhibited tumor growth. Similar inhibitory effects of BV on cancer growth in primary human cervical cancer cells were also found. BV (1–5 ?g/ml) also inhibited the growth of cancer cells, Ca Ski and C33Aby the induction of apoptotic cell death in a dose dependent manner. Agreed with cancer cell growth inhibition, expression of death receptors; FAS, DR3 and DR6, and DR downstream pro-apoptotic proteins including caspase-3 and Bax was concomitantly increased, but the NF-?B activity and the expression of Bcl-2 were inhibited by treatment with BV in tumor mice, human cancer cell and human tumor samples as well as cultured cancer cells. In addition, deletion of FAS, DR3 and DR6 by small interfering RNA significantly reversed BV-induced cell growth inhibitory effects as well as NF-?B inactivation. These results suggest that BV inhibits cervical tumor growth through enhancement of FAS, DR3 and DR6 expression via inhibition of NF-?B pathway. PMID:25730901

  15. Procyanidins Inhibit Tumor Angiogenesis by Crosslinking Extracellular Matrix

    PubMed Central

    Zhai, Wan-yin; Jia, Chun-ping; Zhao, Hui; Xu, Yuan-sen

    2011-01-01

    Objective Procyanidins (PC) are widely available natural polyphenols. The present study is designed to investigate if PC can inhibit angiogenesis in lung adenocarcinoma xenografts through crosslinking vascular extracellular matrix (ECM) and preventing proteolysis by matrix metalloproteinases (MMPs). Methods Using the in vitro MMP-2 proteolysis and in vivo subcutaneous implantation models, we investigated if PC crosslinking inhibits MMP-mediated proteolysis. Using a cultured cell detachment assay, an in vitro angiogenesis assay, and a cell proliferation assay, we investigated if PC inhibits MMP-2-mediated endothelial cell detachment, angiogenesis, and cell proliferation, respectively. Using tumor xenografts, we evaluated if PC can inhibit growth of lung adenocarcinoma. Results PC crosslink vascular ECM proteins, protecting them against proteolysis by MMPs in vitro and in vivo, protecting cultured human umbilical vein endothelial cells from detachment by MMP-2, and inhibiting in vitro angiogenesis. However, PC (0.75-100 µg/ml) did not inhibit vascular and tumor cells proliferation. PC injections (30 mg PC/kg bodyweight) in situ had anticancer effects on xenografts of lung adenocarcinoma, most likely by inhibiting angiogenesis during ECM proteolysis by MMPs. Conclusion The results suggest that PC may be important MMP inhibitors that can be used as therapeutic anticancer agents. PMID:23483060

  16. Lactate dehydrogenase activity is inhibited by methylmalonate in vitro.

    PubMed

    Saad, Laura O; Mirandola, Sandra R; Maciel, Evelise N; Castilho, Roger F

    2006-04-01

    Methylmalonic acidemia (MMAemia) is an inherited metabolic disorder of branched amino acid and odd-chain fatty acid metabolism, involving a defect in the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A. Systemic and neurological manifestations in this disease are thought to be associated with the accumulation of methylmalonate (MMA) in tissues and biological fluids with consequent impairment of energy metabolism and oxidative stress. In the present work we studied the effect of MMA and two other inhibitors of mitochondrial respiratory chain complex II (malonate and 3-nitropropionate) on the activity of lactate dehydrogenase (LDH) in tissue homogenates from adult rats. MMA potently inhibited LDH-catalyzed conversion of lactate to pyruvate in liver and brain homogenates as well as in a purified bovine heart LDH preparation. LDH was about one order of magnitude less sensitive to inhibition by MMA when catalyzing the conversion of pyruvate to lactate. Kinetic studies on the inhibition of brain LDH indicated that MMA inhibits this enzyme competitively with lactate as a substrate (K (i)=3.02+/-0.59 mM). Malonate and 3-nitropropionate also strongly inhibited LDH-catalyzed conversion of lactate to pyruvate in brain homogenates, while no inhibition was observed by succinate or propionate, when present in concentrations of up to 25 mM. We propose that inhibition of the lactate/pyruvate conversion by MMA contributes to lactate accumulation in blood, metabolic acidemia and inhibition of gluconeogenesis observed in patients with MMAemia. Moreover, the inhibition of LDH in the central nervous system may also impair the lactate shuttle between astrocytes and neurons, compromising neuronal energy metabolism. PMID:16758363

  17. Inhibition of ongoing responses in patients with Parkinson's disease

    PubMed Central

    Gauggel, S; Rieger, M; Feghoff, T

    2004-01-01

    Objectives: We investigated the involvement of the basal ganglia in inhibiting ongoing responses in patients with Parkinson's disease (PD). Methods: Thirty two patients with PD and 31 orthopaedic controls performed the stop signal task, which allows an estimation of the time it takes to inhibit an ongoing reaction (stop signal reaction time, SSRT). Results: Patients with PD showed significantly longer SSRTs than the controls. This effect seemed to be independent of global cognitive impairment and severity of PD. Furthermore, in the PD patients, there was no significant relation between general slowing and inhibitory efficiency. Conclusions: Our results provide evidence for involvement of the basal ganglia in the inhibition of ongoing responses. PMID:15026491

  18. Inhibition of gravitropism in oat coleoptiles by calcium chelation

    NASA Technical Reports Server (NTRS)

    Roux, S. J.

    1984-01-01

    Some cellular event necessary for gravitropism is inhibited by EGTA without interferring with the overall growth. Calcium relieves this inhibition and demonstrates both that inhibition is reversible and was probably due to a reduction in the ability to free calcium required for one or more at the transduction steps of gravitropism. At the near neutral pH used, EGTA is charged and would not be expected to readily cross the membrane. One of its primary effects, then, is probably the bringing of free calcium in the apoplastic space exterior to the cell membranes.

  19. Antidepressant action of HDAC inhibition in the prefrontal cortex.

    PubMed

    Covington, H E; Maze, I; Vialou, V; Nestler, E J

    2015-07-01

    Previous research has demonstrated antidepressant-like effects in rodents upon intracerebral inhibition of histone deacetylases (HDACs). Such effects have been reported for local HDAC inhibition in the nucleus accumbens, hippocampus, and amygdala. However, the effect of HDAC inhibition within the medial prefrontal cortex, which is integral to depression-related symptoms and their treatment, remains unknown. Here we show that local infusion of the highly selective HDAC inhibitor, MS-275, into the medial prefrontal cortex exerts robust antidepressant-like effects in the chronic social defeat stress paradigm in mice. These findings provide further impetus for the assessment of HDAC inhibitors for the treatment of depression. PMID:25907440

  20. Quantitation of dengue precipitating antibody by inhibition countercurrent immunoelectrophoresis.

    PubMed Central

    Churdboonchart, V; Bhamarapravati, N; Harisdangkul, V; Futrakul, P; Chiengsong, R

    1981-01-01

    The inhibition countercurrent immunoelectrophoresis test was employed to detect dengue virus antibody in patients' sera. Anti-dengue type 2 titers determined by inhibition countercurrent immunoelectrophoresis correlated well with hemagglutination inhibition titers. In secondary cases, more than fourfold increases in precipitating antibodies were observed. The control sera were negative except for sera from a few patients with systemic lupus erythematosus, which showed low titers. Simultaneous detection of dengue virus antigen and antibody in sera collected during the acute phase could confirm at least 90% of cases. This method is recommended as a routine technique to quantitate antibody in sera from suspected cases of dengue hemorrhagic fever. PMID:7240383

  1. RAAS inhibition and mortality in hypertension

    PubMed Central

    Ferrari, Roberto

    2013-01-01

    The renin-angiotensin-aldosterone system (RAAS) regulates the body's hemodynamic equilibrium, circulating volume, and electrolyte balance, and is a key therapeutic target in hypertension, the world's leading cause of premature mortality. Hypertensive disorders are strongly linked with an overactive RAAS, and RAAS inhibitors, like angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), are routinely used to treat high blood pressure (BP). BP reduction is one of the main goals of current European hypertension guidelines. Oral ACE inhibitors, the oldest category of RAAS inhibitor, were commercially released over 30 years ago in the early 1980s, over a decade before the first ARBs became available. The introduction of ACE inhibitors heralded major changes in the way hypertension and cardiovascular disease were treated. Although the decision of the medical community to replace older ACE inhibitors with more modern ARBs in the 1990s was debatable, it did nevertheless allow scientists to learn more about the angiotensin receptors involved in RAAS stimulation. This and much else of value have been discovered since RAAS inhibitors first became available, but some surprising gaps in our knowledge exist. Until recently, the effect of RAAS inhibition on mortality in hypertension was unknown. This question was recently addressed by a meta-analysis of randomized controlled trials in populations who received contemporary antihypertensive medication. The results of this meta-analysis have helped elucidate the long-term consequences of treatment with RAAS inhibitors on mortality in hypertension. This article will consider the differences between RAAS inhibitors in terms of pharmacological and clinical effects and analyze the impact of the main types of RAAS inhibitor, ACE inhibitors and ARBs, on mortality reduction in hypertensive patients with reference to this latest meta-analysis. PMID:24689028

  2. Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1†

    PubMed Central

    Zhang, Pengtao; Yang, Xinye; Zhang, Feiran; Gabelli, Sandra B.; Wang, Renxiao; Zhang, Yihua; Bhat, Shridhar; Chen, Xiaochun; Furlani, Manuel; Amzel, L. Mario; Liu, Jun O.; Ma, Dawei

    2013-01-01

    Cellular protein synthesis is initiated with methionine in eukaryotes with few exceptions. Methionine aminopeptidases (MetAPs) which catalyze the process of N-terminal methionine excision are essential for all organisms. In mammals, type 2 MetAP (MetAP2) is known to be important for angiogenesis, while type 1 MetAP (MetAP1) has been shown to play a pivotal role in cell proliferation. Our previous high-throughput screening of a commercial compound library uncovered a novel class of inhibitors for both human MetAP1 (HsMetAP1) and human MetAP2 (HsMetAP2). This class of inhibitors contains a pyridinylpyrimidine core. To understand the structure-activity relationship (SAR) and to search for analogues of 2 with greater potency and higher HsMetAP1-selectivity, a total of fifty-eight analogues were acquired through either commercial source or by in-house synthesis and their inhibitory activities against HsMetAP1 and HsMetAP2 were determined. Through this systematic medicinal chemistry analysis, we have identified (1) 5-chloro-6-methyl-2-pyridin-2-ylpyrimidine as the minimum element for the inhibition of HsMetAP1; (2) 5?-chloro as the favored substituent on the pyridine ring for the enhanced potency against HsMetAP1; and (3) long C4 side chains as the essentials for higher HsMet AP1-selectivity. At the end of our SAR campaign, 25b, 25c, 26d and 30a–30c are among the most selective and potent inhibitors of purified HsMetAP1 reported to date. In addition, we also performed crystallographic analysis of one representative inhibitor (26d) in complex with N-terminally truncated HsMetAP1. PMID:23507151

  3. Obesity inhibits lymphangiogenesis in prostate tumors.

    PubMed

    Moreira, Ângela; Pereira, Sofia S; Machado, Christiane L; Morais, Tiago; Costa, Madalena; Monteiro, Mariana P

    2014-01-01

    Lymphangiogenesis is the process that leads to new lymphatic vessels formation from preexisting blood vessels in the presence of appropriate inducing signals, which in pathologic conditions such as cancer, may contribute to tumor cells dissemination. The aim of the present study was to study the role of obesity, leptin and insulin in tumor lymphangiogenesis. For that, we have quantified the lymphatic vessels in prostate tumors through their immunohistochemistry staining by Lyve-1 in RM1 prostate tumors induced in different obese mice models (ob/ob, db/db and diet induced obese (DIO) and in normal weight C57BL/6J mice (control). Lymph vessels density was determined by Lyve-1 immunohistochemistry of prostate adenocarcinomas, while the percentage of the Lyve-1 stained area and lymphatic vessels number were obtained using a morphometric computerized tool. Obese ob/ob and DIO mice presented prostate tumors that were significantly larger (p<0.001) than controls, while tumors of db/db mice were significantly smaller (p=0.047). Lyve-1 expression was significantly higher in prostate tumors of DIO mice compared to tumors of db/db mice (p<0.05); furthermore Lyve-1 expression was negatively correlated with the percentage of the epididymal fat and body weight (p<0.01). No significantly correlations were found between Lyve-1 expression and tumor weight and leptin or insulin plasma levels. Our results suggest that obesity may have a protective effect against prostate cancer dissemination by inhibiting lymphangiogenesis through a still unidentified mechanism that appears not to involve leptin or insulin. PMID:24427356

  4. Collagenase inhibition in the healing colon.

    PubMed Central

    Young, H L; Wheeler, M H

    1983-01-01

    A randomized controlled trial was performed to assess the effect of intravenous aprotinin (Trasylol) on the healing of experimental colonic anastomoses in the rabbit following a standard left colonic resection anastomosis. Assessment of tensile strength was by means of both bursting pressure and breaking strength. Those animals subjected to bursting pressure assessment received intravenous aprotinin 80 000 KIU (kallikrein inhibitory units) at the time of anaesthesia, and postoperatively 160 000 KIU per day given in divided doses for three days. Control animals received saline placebo. A further group of animals received a lower loading and maintenance aprotinin dose (40 000 KIU and 60 000 KIU per day respectively) with control animals receiving saline. Breaking strength was employed as the means of assessment. The mean bursting pressures were 47.7 +/- 2.9 mmHg and 37.5 +/- 3.4 mmHg for aprotinin and controls respectively (P less than 0.05). The mean difference in collagen content of the anastomosis compared to the resected specimen was +1.25 +/- 0.50 microgram/mg and -1.02 +/- 0.47 microgram/mg for aprotinin and placebo groups (P less than 0.005). The mean breaking strength in the aprotinin group was 169.6 +/- 74.5 g and 110.0 +/- 65.9 g for the saline group (P less than 0.02). The mean difference in collagen content of the anastomosis compared to the resected specimen was +0.95 +/- 0.69 microgram/mg and -1.5 +/- 0.78 microgram/mg for the aprotinin and saline groups respectively (P less than 0.05). The significant elevation of both bursting pressure and breaking strength assessments, with a significant improvement in the collagen content of the anastomoses, may be the result of collagenase inhibition following the use of intravenous aprotinin in the experimental model. PMID:6186811

  5. Aging Mechanism of Soman Inhibited Acetylcholinesterase

    PubMed Central

    Sirin, Gulseher Sarah; Zhou, Yanzi; Lior-Hoffmann, Lee; Wang, Shenglong; Zhang, Yingkai

    2012-01-01

    Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nervous system that hydrolyses neurotransmitter acetylcholine (ACh) and terminates synaptic signals. The catalytic serine of AChE can be phosphonylated by soman, one of the most potent nerve agents, and subsequently undergo an aging reaction. This phosphonylation and aging process leads to irreversible AChE inhibition, results in accumulation of excess ACh at the synaptic clefts and causes neuromuscular paralysis. By employing Born-Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have characterized the aging mechanism of soman phosphonylated AChE and determined its free energy profile. This aging reaction starts with the scission of the O2-C? bond, which is followed by methyl migration, and results in a tertiary carbenium intermediate. At the transition state, the scissile O2-C? bond is already cleaved with an average O-C distance of 3.2 ± 0.3 Å and the migrating methyl group is shared between C? and C? carbons with C-C distances of 1.9 ± 0.1 and 1.8 ± 0.1 Å, respectively. The negatively charged phosphonate group is stabilized by a salt bridge with the imidazole ring of the catalytic histidine. A major product of aging, 2,3-dimehtyl-2-butanol can be formed swiftly by the reaction of a water molecule. Our characterized mechanism and simulation results provide new detailed insights into this important biochemical process. PMID:22984913

  6. Arginine deiminase inhibits Porphyromonas gingivalis surface attachment

    PubMed Central

    Cugini, Carla; Stephens, Danielle N.; Nguyen, Daniel; Kantarci, Alpdogan

    2013-01-01

    The oral cavity is host to a complex microbial community whose maintenance depends on an array of cell-to-cell interactions and communication networks, with little known regarding the nature of the signals or mechanisms by which they are sensed and transmitted. Determining the signals that control attachment, biofilm development and outgrowth of oral pathogens is fundamental to understanding pathogenic biofilm development. We have previously identified a secreted arginine deiminase (ADI) produced by Streptococcus intermedius that inhibited biofilm development of the commensal pathogen Porphyromonas gingivalis through downregulation of genes encoding the major (fimA) and minor (mfa1) fimbriae, both of which are required for proper biofilm development. Here we report that this inhibitory effect is dependent on enzymic activity. We have successfully cloned, expressed and defined the conditions to ensure that ADI from S. intermedius is enzymically active. Along with the cloning of the wild-type allele, we have created a catalytic mutant (ADIC399S), in which the resulting protein is not able to catalyse the hydrolysis of l-arginine to l-citrulline. P. gingivalis is insensitive to the ADIC399S catalytic mutant, demonstrating that enzymic activity is required for the effects of ADI on biofilm formation. Biofilm formation is absent under l-arginine-deplete conditions, and can be recovered by the addition of the amino acid. Taken together, the results indicate that arginine is an important signal that directs biofilm formation by this anaerobe. Based on our findings, we postulate that ADI functions to reduce arginine levels and, by a yet to be identified mechanism, signals P. gingivalis to alter biofilm development. ADI release from the streptococcal cell and its cross-genera effects are important findings in understanding the nature of inter-bacterial signalling and biofilm-mediated diseases of the oral cavity. PMID:23242802

  7. Arginine deiminase inhibits Porphyromonas gingivalis surface attachment.

    PubMed

    Cugini, Carla; Stephens, Danielle N; Nguyen, Daniel; Kantarci, Alpdogan; Davey, Mary E

    2013-02-01

    The oral cavity is host to a complex microbial community whose maintenance depends on an array of cell-to-cell interactions and communication networks, with little known regarding the nature of the signals or mechanisms by which they are sensed and transmitted. Determining the signals that control attachment, biofilm development and outgrowth of oral pathogens is fundamental to understanding pathogenic biofilm development. We have previously identified a secreted arginine deiminase (ADI) produced by Streptococcus intermedius that inhibited biofilm development of the commensal pathogen Porphyromonas gingivalis through downregulation of genes encoding the major (fimA) and minor (mfa1) fimbriae, both of which are required for proper biofilm development. Here we report that this inhibitory effect is dependent on enzymic activity. We have successfully cloned, expressed and defined the conditions to ensure that ADI from S. intermedius is enzymically active. Along with the cloning of the wild-type allele, we have created a catalytic mutant (ADIC399S), in which the resulting protein is not able to catalyse the hydrolysis of l-arginine to l-citrulline. P. gingivalis is insensitive to the ADIC399S catalytic mutant, demonstrating that enzymic activity is required for the effects of ADI on biofilm formation. Biofilm formation is absent under l-arginine-deplete conditions, and can be recovered by the addition of the amino acid. Taken together, the results indicate that arginine is an important signal that directs biofilm formation by this anaerobe. Based on our findings, we postulate that ADI functions to reduce arginine levels and, by a yet to be identified mechanism, signals P. gingivalis to alter biofilm development. ADI release from the streptococcal cell and its cross-genera effects are important findings in understanding the nature of inter-bacterial signalling and biofilm-mediated diseases of the oral cavity. PMID:23242802

  8. TCDD Inhibits Heart Regeneration in Adult Zebrafish

    PubMed Central

    Hofsteen, Peter; Mehta, Vatsal; Heideman, Warren

    2013-01-01

    Normal adult zebrafish can completely regenerate lost myocardium following partial amputation of the ventricle apex. We report that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly impairs this regeneration. Adult male zebrafish were injected with vehicle (control) or TCDD (70ng/g, ip) 1 day prior to partial amputation of the ventricle apex. Gross observation and histological analysis of the amputated heart at 21 days postamputation revealed that TCDD-exposed fish had not progressed beyond the initial clot formation stage, whereas the vehicle control fish showed substantial recovery and almost complete resolution of the formed clot. In contrast, hearts that were not surgically wounded showed no signs of TCDD toxicity. Striking features in the TCDD-exposed hearts were the absence of the normal sheath of new tissue enveloping the wound and the absence of intense cell proliferation at the site of the wound. In addition, the patterns of collagen deposition at the wound site were different between the TCDD and vehicle groups. Because the receptor for TCDD is the aryl hydrocarbon receptor ligand-activated transcriptional regulator, we examined the effects of TCDD exposure on gene expression in the ventricle using DNA microarrays. Samples were collected just prior to amputation and at 6h and 7 days postamputation. TCDD-pretreated hearts had dysregulated expression of genes involved in heart function, tissue regeneration, cell growth, and extracellular matrix. Because embryonic, but not adult, hearts are major targets for TCDD-induced cardiotoxicity, we speculate that the need for embryonic-like cells in regeneration is connected with the effects of TCDD in inhibiting the response to wounding. PMID:23204111

  9. Control of CA3 output by feedforward inhibition despite developmental changes in the excitation-inhibition balance.

    PubMed

    Torborg, Christine L; Nakashiba, Toshiaki; Tonegawa, Susumu; McBain, Chris J

    2010-11-17

    In somatosensory cortex, the relative balance of excitation and inhibition determines how effectively feedforward inhibition enforces the temporal fidelity of action potentials. Within the CA3 region of the hippocampus, glutamatergic mossy fiber (MF) synapses onto CA3 pyramidal cells (PCs) provide strong monosynaptic excitation that exhibit prominent facilitation during repetitive activity. We demonstrate in the juvenile CA3 that MF-driven polysynaptic IPSCs facilitate to maintain a fixed EPSC-IPSC ratio during short-term plasticity. In contrast, in young adult mice this MF-driven polysynaptic inhibitory input can facilitate or depress in response to short trains of activity. Transgenic mice lacking the feedback inhibitory loop continue to exhibit both facilitating and depressing polysynaptic IPSCs, indicating that this robust inhibition is not caused by the secondary engagement of feedback inhibition. Surprisingly, eliminating MF-driven inhibition onto CA3 pyramidal cells by blockade of GABA(A) receptors did not lead to a loss of temporal precision of the first action potential observed after a stimulus but triggered in many cases a long excitatory plateau potential capable of triggering repetitive action potential firing. These observations indicate that, unlike other regions of the brain, the temporal precision of single MF-driven action potentials is dictated primarily by the kinetics of MF EPSPs, not feedforward inhibition. Instead, feedforward inhibition provides a robust regulation of CA3 PC excitability across development to prevent excessive depolarization by the monosynaptic EPSP and multiple action potential firings. PMID:21084618

  10. Cyclooxygenase inhibitors inhibit antibody response through interference with MAPK/ERK pathways and BLIMP-1 inhibition.

    PubMed

    Purssell, E

    2014-09-01

    Fever is a common symptom of illness in children, and although not harmful in itself, fever and its associated symptoms are often treated with antipyretic drugs. A number of national and other guidelines now recommend against their routine use; a conclusion that was initially supported by a study showing that the prophylactic use of paracetamol might reduce antibody response to some vaccine antigens, although data from booster vaccinations are more equivocal. Although in vivo data on the cause of this inhibition are scarce, in vitro data suggests that the cause may be due to inhibition of the mitogen activated protein kinase/extracellular regulated protein kinase pathways, and a subsequent reduction in the process of plasma cell differentiation at the beginning of the antibody response. This suggests that in high-risk patients these drugs could be avoided in the early part of an infection when plasma-cell differentiation is occurring. More data are needed to define this period; until then existing data support the recommendation against the routine use of these drugs. PMID:25012778

  11. Forensic implications of PCR inhibition--A review.

    PubMed

    Alaeddini, Reza

    2012-05-01

    Polymerase chain reaction (PCR) is currently the method of choice for the identification of human remains in forensic coursework. DNA samples from crime scenes often contain co-purified impurities which inhibit PCR. PCR inhibition is the most common cause of PCR failure when adequate copies of DNA are present. Inhibitors have been routinely reported in forensic investigations of DNA extracted from a variety of templates. Humic compounds, a series of substances produced during decay process have been considered as the materials contaminating DNA in soil, natural waters and recent sediments. Those compounds have been frequently assigned as PCR inhibitors. The current report reviews the characteristics of PCR inhibition, including the proposed mechanisms of inhibition, detection methods and the available technologies to remove or overcome the inhibitory activities. PMID:21917539

  12. Glycinergic inhibition tunes coincidence detection in the auditory brainstem

    PubMed Central

    Myoga, Michael H.; Lehnert, Simon; Leibold, Christian; Felmy, Felix; Grothe, Benedikt

    2014-01-01

    Neurons in the medial superior olive (MSO) detect microsecond differences in the arrival time of sounds between the ears (interaural time differences or ITDs), a crucial binaural cue for sound localization. Synaptic inhibition has been implicated in tuning ITD sensitivity, but the cellular mechanisms underlying its influence on coincidence detection are debated. Here we determine the impact of inhibition on coincidence detection in adult Mongolian gerbil MSO brain slices by testing precise temporal integration of measured synaptic responses using conductance-clamp. We find that inhibition dynamically shifts the peak timing of excitation, depending on its relative arrival time, which in turn modulates the timing of best coincidence detection. Inhibitory control of coincidence detection timing is consistent with the diversity of ITD functions observed in vivo and is robust under physiologically relevant conditions. Our results provide strong evidence that temporal interactions between excitation and inhibition on microsecond timescales are critical for binaural processing. PMID:24804642

  13. Corrosion inhibition mechanisms in polymer systems for compliant coatings technologies

    SciTech Connect

    Granata, R.D.; MacQueen, R.C.; Miron, R.R. [Lehigh Univ., Bethlehem, PA (United States). Zettlemoyer Center for Surface Studies

    1995-12-31

    Corrosion inhibition mechanisms have been reviewed and model systems evaluated for use in barrier-type protective polymeric systems. Emphasis was on compliant, low VOC coatings applications technologies such as powder coatings, UV-cured and electrocoating systems on aluminum. Severe constraints are being imposed on development and use of coatings technologies involving corrosion inhibitors. Barrier-type polymer coatings systems provide excellent protection in many applications. Extending the suitability of these systems to more aggressive corrosion conditions or longer-term uses requires a better understanding of inhibition mechanisms in barrier coatings. Candidate inhibitor systems have been studied using low VOC epoxy polymer and porous polymer films on conversion coated, aluminum alloy 2024. The model defect system was studied using electrochemical impedance methods. Inhibition was observed in short exposure times. The model system is described and inhibition processes discussed relative to known mechanisms.

  14. Prolegomenon to an investigation of inhibition in design

    E-print Network

    Lark, Michael (Michael Andrew), 1965-

    2001-01-01

    This thesis is a preliminary investigation of the phenomenon of inhibition in the design process. My interest stems from observations of the vagaries of my own success as a designer. Sometimes things have gone well, or ...

  15. Functional mechanisms involved in the internal inhibition of taboo words

    PubMed Central

    Kühn, Simone; Hartsuiker, Robert J.; Brass, Marcel

    2012-01-01

    The present study used functional magnetic resonance imaging to investigate brain processes associated with the inhibition of socially undesirable speech. It is tested whether the inhibition of undesirable speech is solely related to brain areas associated with classical stop signal tasks or rather also involves brain areas involved in endogenous self-control. During the experiment, subjects had to do a SLIP task, which was designed to elicit taboo or neutral spoonerisms. Here we show that the internal inhibition of taboo words activates the right inferior frontal gyrus, an area that has previously been associated with externally triggered inhibition. This finding strongly suggests that external social rules become internalized and act as a stop-signal. PMID:21609970

  16. Potent Inhibition of Store Operated Ca2+ Influx and Superoxide

    E-print Network

    Paris-Sud XI, Université de

    and Polymorphonuclear Neutrophils by the Pyrazole Derivative BTP2 Running title: BTP2 inhibits calcium influx calcium entry is a key regulator in the activation of leukocytes. 3,5- bistrifluoromethyl pyrazole (BTP

  17. What about inhibition in the Wisconsin Card Sorting Test?

    PubMed

    Steinmetz, Jean-Paul; Houssemand, Claude

    2011-05-01

    The commercially available Wisconsin Card Sorting Test (WCST) is one of the most commonly used tests for assessing executive functions within clinical settings. Importantly, however, it remains relatively unclear exactly what processes are assessed by the test. Conceptually, increased perseverative errors in sorting cards are usually related to deficient inhibition processes. Empirically, evidence supporting this conclusion is limited. In a sample of 38 healthy adults we addressed the question to what extent inhibition mechanisms assessed by the go/no-go and the stop-signal paradigm are related to WCST performances. Inhibition-related scores were found to predict non-perseverative errors better than perseverative errors. Consequently we conclude that the non-perseverative errors score reflects processes that are partly dependent on inhibition functions. PMID:21547856

  18. Optical inhibition of motor nerve and muscle activity

    E-print Network

    Liske, Holly

    Introduction: There is no therapeutic approach that provides precise and rapidly reversible inhibition of motor nerve and muscle activity for treatment of spastic hypertonia. Methods: We used optogenetics to demonstrate ...

  19. The mechanism of cytochrome C oxidase inhibition by nitric oxide.

    PubMed

    Antunes, Fernando; Cadenas, Enrique

    2007-01-01

    The basic biochemistry of the inhibition of cytochrome oxidase by NO is reviewed. Three possible mechanisms that include the binding of NO to the fully reduced Fe(a3)-Cu(B) site, to the semi-reduced Fe(a3)-Cu(B) site, and to the fully oxidized Fe(a3)-Cu(B) site are confronted with the experimental data. Mathematical models are used to facilitate the analysis and to solve puzzling observations concerning the NO inhibition of cytochrome oxidase. It is concluded that the inhibition of cytochrome oxidase by NO is mixed, having both competitive and uncompetitive components, but under physiological electron flows the competitive component is largely predominant. The physiological and pathological relevance of this inhibition is briefly discussed. PMID:17127353

  20. Angiotensin II inhibits adenylate cyclase from adrenal cortex glomerulosa zone.

    PubMed

    Marie, J; Jard, S

    1983-08-01

    Angiotensin binding and the effects of angiotensin on adenylate cyclase activity were determined on purified membranes from the glomerulosa zone of bovine adrenal cortex. Angiotensin II inhibited adenylate cyclase activity in a dose-dependent manner with an A50-value of 2 nM. The angiotensin effect required the presence of GTP. Angiotensin also inhibited ACTH-stimulated activity. Angiotensin binding was sensitive to the same effectors which influenced angiotensin-induced adenylate cyclase inhibition. In the presence of NaCl 100 mM and magnesium, angiotensin interacted with a single population of binding sites (Kd = 4 nM and maximal binding capacity of 440 fmol/mg protein). These results and published data suggest that the ability to inhibit adenylate cyclase might be a general property of angiotensin receptors. PMID:6873307

  1. Targeting MYCN in neuroblastoma by BET bromodomain inhibition.

    PubMed

    Puissant, Alexandre; Frumm, Stacey M; Alexe, Gabriela; Bassil, Christopher F; Qi, Jun; Chanthery, Yvan H; Nekritz, Erin A; Zeid, Rhamy; Gustafson, William Clay; Greninger, Patricia; Garnett, Matthew J; McDermott, Ultan; Benes, Cyril H; Kung, Andrew L; Weiss, William A; Bradner, James E; Stegmaier, Kimberly

    2013-03-01

    Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis showed downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knockdown phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in 3 in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. PMID:23430699

  2. Inhibiting multiple mode vibration in controlled flexible systems

    NASA Technical Reports Server (NTRS)

    Hyde, James M.; Chang, Kenneth W.; Seering, Warren P.

    1991-01-01

    Viewgraphs on inhibiting multiple mode vibration in controlled flexible systems are presented. Topics covered include: input pre-shaping background; developing multiple-mode shapers; Middeck Active Control Experiment (MACE) test article; and tests and results.

  3. Noninvasive optical inhibition with a red-shifted microbial rhodopsin

    E-print Network

    Miri, Mitra L

    Optogenetic inhibition of the electrical activity of neurons enables the causal assessment of their contributions to brain functions. Red light penetrates deeper into tissue than other visible wavelengths. We present a ...

  4. 46 CFR 153.912 - Certificate of inhibition or stabilization.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...inhibited or stabilized. (2) The name and concentration of the inhibitor or stabilizer. (3) The date the inhibitor or stabilizer was added. (4) The length of time the inhibitor or stabilizer is effective. (5) Any temperature...

  5. 46 CFR 153.912 - Certificate of inhibition or stabilization.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ...inhibited or stabilized. (2) The name and concentration of the inhibitor or stabilizer. (3) The date the inhibitor or stabilizer was added. (4) The length of time the inhibitor or stabilizer is effective. (5) Any temperature...

  6. 46 CFR 153.912 - Certificate of inhibition or stabilization.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...inhibited or stabilized. (2) The name and concentration of the inhibitor or stabilizer. (3) The date the inhibitor or stabilizer was added. (4) The length of time the inhibitor or stabilizer is effective. (5) Any temperature...

  7. 46 CFR 153.912 - Certificate of inhibition or stabilization.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...inhibited or stabilized. (2) The name and concentration of the inhibitor or stabilizer. (3) The date the inhibitor or stabilizer was added. (4) The length of time the inhibitor or stabilizer is effective. (5) Any temperature...

  8. 46 CFR 153.912 - Certificate of inhibition or stabilization.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...inhibited or stabilized. (2) The name and concentration of the inhibitor or stabilizer. (3) The date the inhibitor or stabilizer was added. (4) The length of time the inhibitor or stabilizer is effective. (5) Any temperature...

  9. Behavioural inhibition: is it a risk factor for anxiety?

    PubMed

    Lahat, Ayelet; Hong, Melanie; Fox, Nathan A

    2011-06-01

    Behavioural inhibition is a stable temperamental trait that is identifiable during infancy and toddlerhood and is characterized by fearful reactivity to novelty. Children identified as behaviourally inhibited have been shown to be at increased risk for developing anxiety disorders such as social phobia. The current review addresses the link between behavioural inhibition and the risk for developing anxiety disorders. Research suggests that this risk may be modulated by a number of extrinsic and intrinsic factors. Extrinsic factors include particular parental beliefs, parenting styles, and childrearing contexts. Intrinsic factors include executive function capacities such as attention bias, attention shifting, inhibitory control, and self-monitoring. In the present paper we review the contribution of these factors to the development of anxiety in behaviourally inhibited children. PMID:21923226

  10. Noninvasive optical inhibition with a red-shifted microbial rhodopsin

    PubMed Central

    Chuong, Amy S; Miri, Mitra L; Busskamp, Volker; Matthews, Gillian A C; Acker, Leah C; Sørensen, Andreas T; Young, Andrew; Klapoetke, Nathan C; Henninger, Mike A; Kodandaramaiah, Suhasa B; Ogawa, Masaaki; Ramanlal, Shreshtha B; Bandler, Rachel C; Allen, Brian D; Forest, Craig R; Chow, Brian Y; Han, Xue; Lin, Yingxi; Tye, Kay M; Roska, Botond; Cardin, Jessica A; Boyden, Edward S

    2014-01-01

    Optogenetic inhibition of the electrical activity of neurons enables the causal assessment of their contributions to brain functions. Red light penetrates deeper into tissue than other visible wavelengths. We present a red-shifted cruxhalorhodopsin, Jaws, derived from Haloarcula (Halobacterium) salinarum (strain Shark) and engineered to result in red light–induced photocurrents three times those of earlier silencers. Jaws exhibits robust inhibition of sensory-evoked neural activity in the cortex and results in strong light responses when used in retinas of retinitis pigmentosa model mice. We also demonstrate that Jaws can noninvasively mediate transcranial optical inhibition of neurons deep in the brains of awake mice. The noninvasive optogenetic inhibition opened up by Jaws enables a variety of important neuroscience experiments and offers a powerful general-use chloride pump for basic and applied neuroscience. PMID:24997763

  11. Functional inhibition of UQCRB suppresses angiogenesis in zebrafish

    SciTech Connect

    Cho, Yoon Sun; Jung, Hye Jin [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)] [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Seok, Seung Hyeok [Department of Microbiology and Immunology, Institute for Experimental Animals, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of)] [Department of Microbiology and Immunology, Institute for Experimental Animals, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Payumo, Alexander Y.; Chen, James K. [Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305 (United States)] [Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305 (United States); Kwon, Ho Jeong, E-mail: kwonhj@yonsei.ac.kr [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2013-04-19

    Highlights: ? This is the first functional characterization of UQCRB in vivo model. ? Angiogenesis is inhibited with UQCRB loss of function in zebrafish. ? UQCRB is introduced as a prognostic marker for mitochondria- and angiogenesis-related diseases. -- Abstract: As a subunit of mitochondrial complex III, UQCRB plays an important role in complex III stability, electron transport, and cellular oxygen sensing. Herein, we report UQCRB function regarding angiogenesis in vivo with the zebrafish (Danio rerio). UQCRB knockdown inhibited angiogenesis in zebrafish leading to the suppression of VEGF expression. Moreover, the UQCRB-targeting small molecule terpestacin also inhibited angiogenesis and VEGF levels in zebrafish, supporting the role of UQCRB in angiogenesis. Collectively, UQCRB loss of function by either genetic and pharmacological means inhibited angiogenesis, indicating that UQCRB plays a key role in this process and can be a prognostic marker of angiogenesis- and mitochondria-related diseases.

  12. Functional mechanisms involved in the internal inhibition of taboo words.

    PubMed

    Severens, Els; Kühn, Simone; Hartsuiker, Robert J; Brass, Marcel

    2012-04-01

    The present study used functional magnetic resonance imaging to investigate brain processes associated with the inhibition of socially undesirable speech. It is tested whether the inhibition of undesirable speech is solely related to brain areas associated with classical stop signal tasks or rather also involves brain areas involved in endogenous self-control. During the experiment, subjects had to do a SLIP task, which was designed to elicit taboo or neutral spoonerisms. Here we show that the internal inhibition of taboo words activates the right inferior frontal gyrus, an area that has previously been associated with externally triggered inhibition. This finding strongly suggests that external social rules become internalized and act as a stop-signal. PMID:21609970

  13. Molecular Mechanism of Inhibition of Firefly Luminescence by Local Anesthetics

    Microsoft Academic Search

    Issaku Ueda; Hiroshi Kamaya; Henry Eyring

    1976-01-01

    The kinetics of the action of local anesthetics upon firefly luciferin and luciferase systems is presented. Clinical concentrations of local anesthetics inhibited this ATP-induced luminescence in a dose-dependent manner. From the effects of temperature and pH upon the inhibitory action of the local anesthetics, it is concluded that hydrophobic ligand-enzyme interaction is the predominant cause of the inhibition, but hydrophilic

  14. Novel Antimicrobial Peptides That Inhibit Gram Positive Bacterial Exotoxin Synthesis

    PubMed Central

    Merriman, Joseph A.; Nemeth, Kimberly A.; Schlievert, Patrick M.

    2014-01-01

    Gram-positive bacteria, such as Staphylococcus aureus, cause serious human illnesses through combinations of surface virulence factors and secretion of exotoxins. Our prior studies using the protein synthesis inhibitor clindamycin and signal transduction inhibitors glycerol monolaurate and ?-globin and ?-globin chains of hemoglobin indicate that their abilities to inhibit exotoxin production by S. aureus are separable from abilities to inhibit growth of the organism. Additionally, our previous studies suggest that inhibition of exotoxin production, in absence of ability to kill S. aureus and normal flora lactobacilli, will prevent colonization by pathogenic S. aureus, while not interfering with lactobacilli colonization. These disparate activities may be important in development of novel anti-infective agents that do not alter normal flora. We initiated studies to explore the exotoxin-synthesis-inhibition activity of hemoglobin peptides further to develop potential agents to prevent S. aureus infections. We tested synthesized ?-globin chain peptides, synthetic variants of ?-globin chain peptides, and two human defensins for ability to inhibit exotoxin production without significantly inhibiting S. aureus growth. All of these peptides were weakly or not inhibitory to bacterial growth. However, the peptides were inhibitory to exotoxin production with increasing activity dependent on increasing numbers of positively-charged amino acids. Additionally, the peptides could be immobilized on agarose beads or have amino acid sequences scrambled and still retain exotoxin-synthesis-inhibition. The peptides are not toxic to human vaginal epithelial cells and do not inhibit growth of normal flora L. crispatus. These peptides may interfere with plasma membrane signal transduction in S. aureus due to their positive charges. PMID:24748386

  15. Acetylene inhibition of nitrous oxide reduction by denitrifying bacteria

    Microsoft Academic Search

    T. Yoshinari; R. Knowles

    1976-01-01

    Acetylene (0.1 atm) caused complete or almost complete inhibition of reduction of NâO by whole cell suspensions of Pseudomonas perfectomarinus, P. aeruginosa and Micrococcus denitrificans. Acetylene did not inhibit reduction of NOâ⁻ or NOâ⁻ by these organisms. In the presence of acetylene there was stoichiometric conversion of NOâ⁻ or NOâ⁻ to NâO with negligible subsequent reduction of the latter. In

  16. Synthetic cryptolepine inhibits DNA binding of NF-?B

    Microsoft Academic Search

    Olumayokun A. Olajide; Elke H. Heiss; Daniel Schachner; Colin W. Wright; Angelika M. Vollmar; Verena M. Dirsch

    2007-01-01

    The alkaloid cryptolepine is thought to mediate the anti-inflammatory effects of the climbing shrub, Cryptolepis sanguinoleta. The underlying mechanism of action, however, is largely unknown. In the present study, we show that the synthetic cryptolepine-hydrochloride (2.5–10?M) dose-dependently inhibits lipopolysaccharide (LPS)-induced nitric oxide production in the murine macrophage cell line RAW 264.7. We furthermore demonstrate a strong inhibition of nuclear factor

  17. MIBG inhibits respiration: potential for radio- and hyperthermic sensitization

    Microsoft Academic Search

    John E Biaglow; Yefim Manevich; Dennis Leeper; Britton Chance; Mark W Dewhirst; Walter T Jenkins; Steve W Tuttle; Krzysztof Wroblewski; Jerry D Glickson; Craig Stevens; Sydney M Evans

    1998-01-01

    Introduction: Meta-iodobenzylguanidine (MIBG) in its 131I-labeled form is clinically used as a tumor-targeted radiopharmaceutical in the diagnosis and treatment of adrenergic tumors. This well established drug may have additional clinical applications as a radiosensitizer or hyperthermic agent, i.e., MIBG reportedly inhibits mitochondrial respiration in vitro. The mechanism for MIBG inhibition of cellular oxygen consumption is uncertain. Moreover, MIBG reportedly stimulates

  18. Inhibition of lipid peroxidation by diterpenoid from Podocarpus nagi.

    PubMed

    Haraguchi, H; Ishikawa, H; Sakai, S; Ying, B P; Kubo, I

    1996-06-15

    A diterpenoid, totarol (1), from Podocarpus nagi was evaluated as an antioxidant. This diterpenoid inhibited autoxidation of linoleic acid. Mitochondrial and microsomal lipid peroxidation induced by Fe(III)-ADP/NADH or Fe(III)-ADP/NADPH were also inhibited. Nagilactone E (2), a norditerpene lactone isolated from the same source, had no antioxidative activity. Furthermore, totarol protected red cells against oxidative hemolysis. This diterpene was shown to be effective in protecting biological systems against oxidative stresses. PMID:8698092

  19. Progesterone Inhibits Folic Acid Transport in Human Trophoblasts

    Microsoft Academic Search

    Elisa Keating; Pedro Gonçalves; Clara Lemos; Fernanda Costa; Isabel Campos; Sylvia B. Smith; Christy C. Bridges; Fátima Martel

    2007-01-01

    The aim of this work was to test the putative involvement of members of the ABC superfamily of transporters on folic acid\\u000a (FA) cellular homeostasis in the human placenta. [3H]FA uptake and efflux in BeWo cells were unaffected or hardly affected by multidrug resistance 1 (MDR1) inhibition (with\\u000a verapamil), multidrug resistance protein (MRP) inhibition (with probenecid) or breast cancer resistance

  20. Deferoxamine inhibition of malaria is independent of host iron status

    Microsoft Academic Search

    C. Hershko; T. E. Peto

    1988-01-01

    The mechanism whereby deferoxamine (DF) inhibits the growth of malaria parasites was studied in rats infected with Plasmodium berghei. Peak parasitemia was 32.6% (day 14) in untreated controls and 0.15% (day 7) in rats receiving 0.33 mg\\/g in 8 hourly DF injections, subcutaneously. DF inhibition of parasite growth was achieved without any reduction in transferrin saturation or hemoglobin synthesis and

  1. Iron chelators ICL670 and 311 inhibit HIV1 transcription

    Microsoft Academic Search

    Zufan Debebe; Tatyana Ammosova; Marina Jerebtsova; Joseph Kurantsin-Mills; Xiaomei Niu; Sharroya Charles; Des R. Richardson; Patricio E. Ray; Victor R. Gordeuk; Sergei Nekhai

    2007-01-01

    HIV-1 replication is induced by an excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication by reducing proliferation of infected cells. Treatment of cells with DFO and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2). Our recent studies showed that CDK2 participates in HIV-1 transcription and viral replication

  2. Cytoplasmic Ca 2+ inhibits the ryanodine receptor from cardiac muscle

    Microsoft Academic Search

    D. R. Laver; L. D. Roden; G. P. Ahern; K. R. Eager; P. R. Junankar; A. F. Dulhunty

    1995-01-01

    Ca2+-dependent inhibition of native and isolated ryanodine receptor (RyR) calcium release channels from sheep heart and rabbit skeletal muscle was investigated using the lipid bilayer technique. We found that cytoplasmic Ca2+ inhibited cardiac RyRs with an average Km = 15 mm, skeletal RyRs with Km = 0.7 mm and with Hill coefficients of 2 in both isoforms. This is consistent

  3. Inhibition of tyrosine activity by cultured lichen tissues and bionts.

    PubMed

    Higuchi, M; Miura, Y; Boohene, J; Kinoshita, Y; Yamamoto, Y; Yoshimura, I; Yamada, Y

    1993-06-01

    Axenic, cultured thallus tissues from forty-six species of lichens were evaluated for their inhibitory effect on tyrosinase activity. Methanol extracts of tissues of three lichens, i.e. HYPOGYMNIA PHYSODES, LETHARIA VULPINA, and CETRARIA JUNIPERINA strongly inhibited tyrosinase activity, but extracts from the corresponding natural thalli showed only weak inhibition. The mycobiont of HYPOGYMNIA PHYSODES showed a higher inhibitory action than its photobiont. PMID:17235965

  4. Inhibition of chemical carcinogenesis by Psoralea corylifolia seeds

    Microsoft Academic Search

    P. G Latha; K. R Panikkar

    1999-01-01

    Psoralea corylifolia L. (Fabaceae) seeds are extensively used in Ayurvedic medicine. Topical application of 100 mg\\/kg body weight of the active fraction (AF) of P. corylifolia seeds inhibited the growth and delayed the onset of papilloma formation in mice, initiated with 7,12-dimethyl benz(a) anthracene and promoted using croton oil. The AF at the same dose, when administered orally, inhibited the

  5. Functional Characterization of Citrus Polygalacturonase-inhibiting Protein

    Microsoft Academic Search

    Sarunya NALUMPANG; Yukie GOTOH; Hiroyuki TSUBOI; Kenji GOMI; Hiroyuki YAMAMOTO; Kazuya AKIMITSU

    2002-01-01

      A cDNA encoding a polygalacturonase-inhibiting protein gene (SaiPGIPA) was identified from the citrus cultivar Sainumphung (Citrus sp.), one of the most popular cultivars in northern Thailand. SaiPGIPA was expressed in Escherichia coli cells, and the functional properties of citrus PGIP were analyzed. The PGIP fusion protein inhibited by a maximum of about\\u000a 60% of the endopolygalacturonase activity, and a mixture

  6. Immunostimulatory DNA Inhibits Transforming Growth Factor Expression and Airway Remodeling

    Microsoft Academic Search

    Jae Youn Cho; Marina Miller; Kwang Je Baek; Ji Won Han; Jyothi Nayar; Monica Rodriguez; Sook Young Lee; Kirsti McElwain; Shauna McElwain; Eyal Raz; David H. Broide

    Immunostimulatory sequences of DNA (ISS) inhibit eosinophilic air- way inflammation, Th2 responses, and airway hyperreactivity (AHR) in mouse models of acute ovalbumin (OVA)-induced airway inflam- mation. To determine whether ISS inhibits airway remodeling, we developed a mouse model of airway remodeling in which OVA- sensitized mice were repeatedly exposed to intranasal OVA adminis- tration for 1-6 mo. Mice chronically exposed

  7. Attachment, Behavioral Inhibition, and Anxiety in Preschool Children

    Microsoft Academic Search

    Galia Shamir-Essakow; Judy A. Ungerer; Ronald M. Rapee

    2005-01-01

    This study examined the association between insecure attachment, behavioral inhibition, and anxiety in an at risk sample of preschool children. The relationship between maternal anxiety and child anxiety was also assessed. Participants were 104 children aged 3–4 years who were assessed for behavioral inhibition and mother–child attachment (using the Strange Situation procedure). DSM-IV criteria were used to assess childhood anxiety

  8. Virus inhibition induced by polyvalent nanoparticles of different sizes.

    PubMed

    Vonnemann, Jonathan; Sieben, Christian; Wolff, Christopher; Ludwig, Kai; Böttcher, Christoph; Herrmann, Andreas; Haag, Rainer

    2014-02-21

    The development of antiviral agents is one of the major challenges in medical science. So far, small monovalent molecular drugs that inhibit the late steps in the viral replication cycle, i.e., virus budding, have not worked well which emphasizes the need for alternative approaches. Polyvalently presented viral receptors, however, show potential as good inhibitors of virus-cell binding, which is the first step in the viral infection cycle. By gradually increasing the size of ligand functionalized gold nanoparticles, up to virus-like dimensions, we are now able to quantify the polyvalent enhancement of virus-cell binding inhibition and to identify varying mechanisms of virus inhibition with different efficacies: by employing a new binding assay we found that surface area-normalized polysulfated gold nanoparticles of diameters equal to and larger than the virus diameter (>50 nm) more efficiently inhibit the binding of vesicular stomatitis virus (VSV) to cells than smaller particles. On a per particle basis, larger sized gold nanoparticles were surprisingly shown to inhibit the viral infection up to two orders of magnitude more efficiently than smaller particles, which suggests different mechanisms of virus inhibition. Based on complementary electron microscopic data, we noticed that larger gold nanoparticles act as efficient cross-linkers between virions, whereas smaller gold nanoparticles decorate the surface of individual virus particles. Our systematic study accentuates the need for the design of biodegradable, virus-sized inhibitors capitalizing on polyvalent binding. PMID:24430614

  9. A role of electrical inhibition in sensorimotor integration

    PubMed Central

    Weiss, Shennan A.; Preuss, Thomas; Faber, Donald S.

    2008-01-01

    Although it is accepted that extracellular fields generated by neuronal activity can influence the excitability of neighboring cells, whether this form of neurotransmission has a functional role remains open. In vivo field effects occur in the teleost Mauthner (M)-cell system, where a combination of structural features support the concept of inhibitory electrical synapses. A single spike in one M-cell evoked within as little as 2.2 ms of the onset of an abrupt sound, simulating a predatory strike, initiates a startle-escape behavior [Zottoli SJ (1977) J Exp Biol 66:243–254]. We show that such sounds produce synchronized action potentials in as many as 20 or more interneurons that mediate feed-forward electrical inhibition of the M-cell. The resulting action currents produce an electrical inhibition that coincides with the electrotonic excitatory drive to the M-cell; the amplitude of the peak of the inhibition is ?40% of that of the excitation. When electrical inhibition is neutralized with an extracellular cathodal current pulse, subthreshold auditory stimuli are converted into ones that produce an M-spike. Because the timing of electrical inhibition is often the same as the latency of M-cell firing in freely swimming fish, we conclude that electrical inhibition participates in regulating the threshold of the acoustic startle-escape behavior. Therefore, a field effect is likely to be essential to the normal functioning of the neural network. PMID:19004764

  10. Highly reflective reasoners show no signs of belief inhibition.

    PubMed

    Svedholm-Häkkinen, Annika M

    2015-01-01

    The processes underlying individual differences in reasoning performance are not entirely understood. What do people who do well on reasoning tasks where beliefs and logic conflict do differently from other people? Because abundant evidence shows that even poorer reasoners detect these conflicts, it has been suggested that individual differences in reasoning performance arise from inhibition failures later in the reasoning process. The present paper argues that a minority of highly skilled reasoners may deviate from this general reasoning process from an early stage. Two studies investigated signs of belief inhibition using a lexical access paradigm (Study 1) and a negative priming paradigm (Study 2). Study 1 showed that while other people exhibited signs of belief inhibition following a belief-logic conflict, people with the highest disposition for cognitive reflection did not. In Study 2, this finding was replicated and similar results were also obtained when comparing groups with higher and lower general cognitive ability. Two possible explanations are discussed. The reasoners with a highly reflective cognitive style or high general cognitive ability may have engaged and inhibited belief processing but if so, they may have been exceptionally efficient at recovering from it, wherefore no belief inhibition effects were found. An alternative account is that these reasoners started Type 2 processing directly, without first engaging in and then inhibiting belief-based processing. Under either explanation, the results indicate that individual differences in reasoning may partly arise from differences that occur early in the reasoning process. PMID:25499057

  11. Palmitoylethanolamide inhibits glutamate release in rat cerebrocortical nerve terminals.

    PubMed

    Lin, Tzu-Yu; Lu, Cheng-Wei; Wu, Chia-Chan; Huang, Shu-Kuei; Wang, Su-Jane

    2015-01-01

    The effect of palmitoylethanolamide (PEA), an endogenous fatty acid amide displaying neuroprotective actions, on glutamate release from rat cerebrocortical nerve terminals (synaptosomes) was investigated. PEA inhibited the Ca²?-dependent release of glutamate, which was triggered by exposing synaptosomes to the potassium channel blocker 4-aminopyridine. This release inhibition was concentration dependent, associated with a reduction in cytosolic Ca²? concentration, and not due to a change in synaptosomal membrane potential. The glutamate release-inhibiting effect of PEA was prevented by the Ca(v)2.1 (P/Q-type) channel blocker ?-agatoxin IVA or the protein kinase A inhibitor H89, not affected by the intracellular Ca²? release inhibitors dantrolene and CGP37157, and partially antagonized by the cannabinoid CB1 receptor antagonist AM281. Based on these results, we suggest that PEA exerts its presynaptic inhibition, likely through a reduction in the Ca²? influx mediated by Ca(v)2.1 (P/Q-type) channels, thereby inhibiting the release of glutamate from rat cortical nerve terminals. This release inhibition might be linked to the activation of presynaptic cannabinoid CB1 receptors and the suppression of the protein kinase A pathway. PMID:25768340

  12. Palmitoylethanolamide Inhibits Glutamate Release in Rat Cerebrocortical Nerve Terminals

    PubMed Central

    Lin, Tzu-Yu; Lu, Cheng-Wei; Wu, Chia-Chan; Huang, Shu-Kuei; Wang, Su-Jane

    2015-01-01

    The effect of palmitoylethanolamide (PEA), an endogenous fatty acid amide displaying neuroprotective actions, on glutamate release from rat cerebrocortical nerve terminals (synaptosomes) was investigated. PEA inhibited the Ca2+-dependent release of glutamate, which was triggered by exposing synaptosomes to the potassium channel blocker 4-aminopyridine. This release inhibition was concentration dependent, associated with a reduction in cytosolic Ca2+ concentration, and not due to a change in synaptosomal membrane potential. The glutamate release-inhibiting effect of PEA was prevented by the Cav2.1 (P/Q-type) channel blocker ?-agatoxin IVA or the protein kinase A inhibitor H89, not affected by the intracellular Ca2+ release inhibitors dantrolene and CGP37157, and partially antagonized by the cannabinoid CB1 receptor antagonist AM281. Based on these results, we suggest that PEA exerts its presynaptic inhibition, likely through a reduction in the Ca2+ influx mediated by Cav2.1 (P/Q-type) channels, thereby inhibiting the release of glutamate from rat cortical nerve terminals. This release inhibition might be linked to the activation of presynaptic cannabinoid CB1 receptors and the suppression of the protein kinase A pathway. PMID:25768340

  13. Inhibiting epigenetic enzymes to improve atherogenic macrophage functions.

    PubMed

    Van den Bossche, Jan; Neele, Annette E; Hoeksema, Marten A; de Heij, Femke; Boshuizen, Marieke C S; van der Velden, Saskia; de Boer, Vincent C; Reedquist, Kris A; de Winther, Menno P J

    2014-12-12

    Macrophages determine the outcome of atherosclerosis by propagating inflammatory responses, foam cell formation and eventually necrotic core development. Yet, the pathways that regulate their atherogenic functions remain ill-defined. It is now apparent that chromatin remodeling chromatin modifying enzymes (CME) governs immune responses but it remains unclear to what extent they control atherogenic macrophage functions. We hypothesized that epigenetic mechanisms regulate atherogenic macrophage functions, thereby determining the outcome of atherosclerosis. Therefore, we designed a quantitative semi-high-throughput screening platform and studied whether the inhibition of CME can be applied to improve atherogenic macrophage activities. We found that broad spectrum inhibition of histone deacetylases (HDACs) and histone methyltransferases (HMT) has both pro- and anti-inflammatory effects. The inhibition of HDACs increased histone acetylation and gene expression of the cholesterol efflux regulators ATP-binding cassette transporters ABCA1 and ABCG1, but left foam cell formation unaffected. HDAC inhibition altered macrophage metabolism towards enhanced glycolysis and oxidative phosphorylation and resulted in protection against apoptosis. Finally, we applied inhibitors against specific HDACs and found that HDAC3 inhibition phenocopies the atheroprotective effects of pan-HDAC inhibitors. Based on our data, we propose the inhibition of HDACs, and in particular HDAC3, in macrophages as a novel potential target to treat atherosclerosis. PMID:25446073

  14. “Off with the Old”: Mindfulness Practice Improves Backward Inhibition

    PubMed Central

    Greenberg, Jonathan; Reiner, Keren; Meiran, Nachshon

    2013-01-01

    Mindfulness practice has been linked to reduced depressive rumination and described as involving inhibition of information that has been relevant in the past and is no longer relevant in the present moment. Backward inhibition (BI) is considered to be one of the purest measures of task set inhibition, and impaired BI has been linked to depressive rumination. BI was contrasted with Competitor Rule Suppression (CRS), which is another phenomenon observed in task switching, yet one which involves episodic memory tagging of information that is currently conflicting rather than active inhibition. Although similar at baseline level, a randomly assigned group (n?=?38) who underwent an eight session mindfulness training program exhibited improved BI but not CRS compared to a waiting list group (n?=?38). Findings indicate that mindfulness improves the specific component of task set inhibition, which has previously been linked to reduced rumination. Implications regarding the potential role of task set inhibition in mediating between mindfulness and reduced rumination, as well as the role of mindfulness in “being in the present moment” are discussed. PMID:23335909

  15. The inhibition of lipase and glucosidase activities by acacia polyphenol.

    PubMed

    Ikarashi, Nobutomo; Takeda, Rumi; Ito, Kiyomi; Ochiai, Wataru; Sugiyama, Kiyoshi

    2011-01-01

    Acacia polyphenol (AP) extracted from the bark of the black wattle tree (Acacia mearnsii) is rich in unique catechin-like flavan-3-ols, such as robinetinidol and fisetinidol. In an in vitro study, we measured the inhibitory activity of AP on lipase and glucosidase. In addition, we evaluated the effects of AP on absorption of orally administered olive oil, glucose, maltose, sucrose and starch solution in mice. We found that AP concentration-dependently inhibited the activity of lipase, maltase and sucrase with an IC(50) of 0.95, 0.22 and 0.60?mg?ml(-1), respectively. In ICR mice, olive oil was administered orally immediately after oral administration of AP solution, and plasma triglyceride concentration was measured. We found that AP significantly inhibited the rise in plasma triglyceride concentration after olive oil loading. AP also significantly inhibited the rise in plasma glucose concentration after maltose and sucrose loading, and this effect was more potent against maltose. AP also inhibited the rise in plasma glucose concentration after glucose loading and slightly inhibited it after starch loading. Our results suggest that AP inhibits lipase and glucosidase activities, which leads to a reduction in the intestinal absorption of lipids and carbohydrates. PMID:21660093

  16. Cucurbitacin B inhibits proliferation and induces apoptosis via STAT3 pathway inhibition in A549 lung cancer cells

    PubMed Central

    ZHANG, MENG; BIAN, ZHI-GANG; ZHANG, YI; WANG, JIA-HE; KAN, LIANG; WANG, XIN; NIU, HUI-YAN; HE, PING

    2014-01-01

    Natural products are a great source of cancer chemotherapeutic agents. The present study was conducted to investigate whether cucurbitacin B (CuB), one of the most potent and widely used cucurbitacins, inhibits proliferation and induces apoptosis in the A549 lung cancer cell line. Furthermore, CuB induced apoptosis of A549 cells in a concentration-dependent manner, as determined by fluorescence microscopy, flow cytometry and transmission electron microscopy. The present study also demonstrated that CuB dose-dependently inhibited lung cancer cell proliferation, with cell cycle inhibition and cyclin B1 downregulation. Apoptosis induced by CuB was shown to be associated with cytochrome c release, B-cell lymphoma 2 downregulation and signal transducer and activator of transcription 3 pathway inhibition. CuB may prove to be a useful approach for the chemotherapy of lung cancer. PMID:25242136

  17. Cucurbitacin B inhibits proliferation and induces apoptosis via STAT3 pathway inhibition in A549 lung cancer cells.

    PubMed

    Zhang, Meng; Bian, Zhi-Gang; Zhang, Yi; Wang, Jia-He; Kan, Liang; Wang, Xin; Niu, Hui-Yan; He, Ping

    2014-12-01

    Natural products are a great source of cancer chemotherapeutic agents. The present study was conducted to investigate whether cucurbitacin B (CuB), one of the most potent and widely used cucurbitacins, inhibits proliferation and induces apoptosis in the A549 lung cancer cell line. Furthermore, CuB induced apoptosis of A549 cells in a -concentration-dependent manner, as determined by fluorescence microscopy, flow cytometry and transmission electron microscopy. The present study also demonstrated that CuB dose-dependently inhibited lung cancer cell proliferation, with cell cycle inhibition and cyclin B1 downregulation. Apoptosis induced by CuB was shown to be associated with cytochrome c release, B-cell lymphoma 2 downregulation and signal transducer and activator of transcription 3 pathway inhibition. CuB may prove to be a useful approach for the chemotherapy of lung cancer. PMID:25242136

  18. Inhibition of glycogen phosphorylase (GP) by CP91,149 induces growth inhibition correlating with brain GP expression

    Microsoft Academic Search

    Joachim B Schnier; Kayoko Nishi; Anne Monks; Fredric A Gorin; E. Morton Bradbury

    2003-01-01

    The role of glycogenolysis in normal and cancer cells was investigated by inhibiting glycogen phosphorylase (GP) with the synthetic inhibitor CP-91,149. A549 non-small cell lung carcinoma (NSCLC) cells express solely the brain isozyme of GP, which was inhibited by CP-91,149 with an IC50 of 0.5?M. When treated with CP-91,149, A549 cells accumulated glycogen with associated growth retardation. Treated normal skin

  19. The Effect of Oxidation on Berberine-Mediated CYP1 Inhibition: Oxidation Behavior and Metabolite-Mediated Inhibition.

    PubMed

    Lo, Sheng-Nan; Shen, Chien-Chang; Chang, Chia-Yu; Tsai, Keng-Chang; Huang, Chiung-Chiao; Wu, Tian-Shung; Ueng, Yune-Fang

    2015-07-01

    The protoberberine alkaloid berberine carries methylenedioxy moiety and exerts a variety of pharmacological effects, such as anti-inflammation and lipid-lowering effects. Berberine causes potent CYP1B1 inhibition, whereas CYP1A2 shows resistance to the inhibition. To reveal the influence of oxidative metabolism on CYP1 inhibition by berberine, berberine oxidation and the metabolite-mediated inhibition were determined. After NADPH-fortified preincubation of berberine with P450, the inhibition of CYP1A1 and CYP1B1 variants (CYP1B1.1, CYP1B1.3, and CYP1B1.4) by berberine was not enhanced, and CYP1A2 remained resistant. Demethyleneberberine was identified as the most abundant metabolite of CYP1A1- and CYP1B1-catalyzed oxidations, and thalifendine was generated at a relatively low rate. CYP1A1-catalyzed berberine oxidation had the highest maximal velocity (V max) and exhibited positive cooperativity, suggesting the assistance of substrate binding when the first substrate was present. In contrast, the demethylenation by CYP1B1 showed the property of substrate inhibition. CYP1B1-catalyzed berberine oxidation had low K m values, but it had V max values less than 8% of those of CYP1A1. The dissociation constants generated from the binding spectrum and fluorescence quenching suggested that the low K m values of CYP1B1-catalyzed oxidation might include more than the rate constants describing berberine binding. The natural protoberberine/berberine fmetabolites with methylenedioxy ring-opening (palmatine, jatrorrhizine, and demethyleneberberine) and the demethylation (thalifendine and berberrubine) caused weak CYP1 inhibition. These results demonstrated that berberine was not efficiently oxidized by CYP1B1, and metabolism-dependent irreversible inactivation was minimal. Metabolites of berberine caused a relatively weak inhibition of CYP1. PMID:25953522

  20. Endo- and exopolygalacturonases of Ralstonia solanacearum are inhibited by polygalacturonase-inhibiting protein (PGIP) activity in tomato stem extracts

    Microsoft Academic Search

    Tanja Schacht; Christoph Unger; Andreas Pich; Kerstin Wydra

    2011-01-01

    Polygalacturonases (PGs) of wild-type and non-virulent phenotype conversion mutant (PC) strains of Ralstonia solanacearum were compared by investigating their activities and their inhibition by polygalacturonase-inhibiting proteins (PGIPs) from tomato stems. In cultures of wild-type strain ToUdk2, slimy (s), retarded slimy (rs) and non-slimy (ns) colonies appeared. The conversion of the ‘s’ into the ‘rs’ colony form coincided with the beginning

  1. MEK inhibition, alone or in combination with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and dendritic cells.

    PubMed

    Vella, Laura J; Pasam, Anupama; Dimopoulos, Nektaria; Andrews, Miles; Knights, Ashley; Puaux, Anne-Laure; Louahed, Jamila; Chen, Weisan; Woods, Katherine; Cebon, Jonathan S

    2014-04-01

    Combination therapy with BRAF and MEK inhibition is currently in clinical development for the treatment of BRAF-mutated malignant melanoma. BRAF inhibitors are associated with enhanced antigen-specific T-lymphocyte recognition in vivo. Consequently, BRAF inhibition has been proposed as proimmunogenic and there has been considerable enthusiasm for combining BRAF inhibition with immunotherapy. MEK inhibitors inhibit ERK phosphorylation regardless of BRAF mutational status and have been reported to impair T-lymphocyte and modulate dendritic cell function. In this study, we investigate the effects on isolated T lymphocytes and monocyte-derived dendritic cells (moDC) of a MEK (trametinib) and BRAF (dabrafenib) inhibitor combination currently being evaluated in a randomized controlled clinical trial. The effects of dabrafenib and trametinib, alone and in combination, were studied on isolated normal T lymphocytes and moDCs. Lymphocyte viability, together with functional assays including proliferation, cytokine production, and antigen-specific expansion, were assessed. MoDC phenotype in response to lipopolysaccharide stimulation was evaluated by flow cytometry, as were effects on antigen cross-presentation. Dabrafenib did not have an impact on T lymphocytes or moDCs, whereas trametinib alone or in combination with dabrafenib suppressed T-lymphocyte proliferation, cytokine production, and antigen-specific expansion. However, no significant decrease in CD4(+) or CD8(+) T-lymphocyte viability was observed following kinase inhibition. MoDC cross-presentation was suppressed in association with enhanced maturation following combined inhibition of MEK and BRAF. The results of this study demonstrate that MEK inhibition, alone or in combination with BRAF inhibition, can modulate immune cell function, and further studies in vivo will be required to evaluate the potential clinical impact of these findings. PMID:24764582

  2. Tin compounds inhibit the plasma cell response to metallic tin. Transfer of inhibition by parabiosis.

    PubMed

    Levine, S; Saltzman, A

    1991-02-01

    Injection of metallic tin powder causes intense proliferation of plasma cells in draining lymph nodes of Lewis rats. Pretreatment orally with soluble tin salts prevents this response to subsequently injected metallic tin. In the present work, pretreatment with tin salts by parenteral injection was just as effective as addition to the drinking water. This new approach made the following experiments possible. Poorly soluble tin compounds were found to be inhibitory when injected parenterally. Tin salts injected parenterally into one of two rats joined in parabiotic union prevented the plasma cell response to metallic tin in both parabionts. The transfer of the inhibitory effect via the cross-circulating blood represents significant progress toward understanding the mechanisms involved. The evidence suggests the possibility that tin salts elicit an intermediary substance or process that is responsible for inhibition of the plasma cell response to metallic tin. PMID:1709032

  3. Inhibition of histone H3K79 methylation selectively inhibits proliferation, self-renewal and metastatic potential of breast cancer

    PubMed Central

    Zhang, Li; Deng, Lisheng; Chen, Fengju; Yao, Yuan; Wu, Bulan; Wei, Liping; Mo, Qianxing; Song, Yongcheng

    2014-01-01

    Histone lysine methylation regulates gene expression and cancer initiation. Bioinformatics analysis suggested that DOT1L, a histone H3-lysine79 (H3K79) methyltransferase, plays a potentially important role in breast cancer. DOT1L inhibition selectively inhibited proliferation, self-renewal, metastatic potential of breast cancer cells and induced cell differentiation. In addition, inhibitors of S-adenosylhomocysteine hydrolase (SAHH), such as neplanocin and 3-deazaneplanocin, also inhibited both H3K79 methylation and proliferation of breast cancer cells in vitro and in vivo. The activity of SAHH inhibitors was previously attributed to inhibition of H3K27 methyltransferase EZH2. However, inhibition of EZH2 by a specific inhibitor did not contribute to cell death. SAHH inhibitors had only weak activity against H3K27 methylation and their activity is therefore mainly due to DOT1L/H3K79 methylation inhibition. Overall, we showed that DOT1L is a potential drug target for breast cancer. PMID:25359765

  4. Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells

    PubMed Central

    Gallia, Gary L.; Tyler, Betty M.; Hann, Christine L.; Siu, I-Mei; Giranda, Vincent L.; Vescovi, Angelo L.; Brem, Henry; Riggins, Gregory J.

    2014-01-01

    A commonly activated signaling cascade in many human malignancies including glioblastoma multiforme (GBM) is the Akt pathway. This pathway can be activated via numerous upstream alterations including genomic amplification of EGFR, PTEN deletion, or PIK3CA mutations. In this study, we screened PI3K/Akt small molecule inhibitors in an isogenic cell culture system with an activated Akt pathway secondary to a PIK3CA mutation. One small molecule, A-443654, demonstrated the greatest selective inhibition of cells with the mutant phenotype. Based on these findings, this inhibitor was screened in vitro against a panel of GBM cell lines. All cell lines tested were sensitive to A-443654 with a mean IC50 of approximately 150 nM. An analogue of A-443654, methylated at a region that blocks Akt binding, decreased activity by an average of 36 fold. Caspase assays and dual flow cytometric analysis demonstrated an apoptotic mechanism of cell death. A-443654 was further tested in a rat intracranial model of GBM. Animals treated intracranially with polymers containing A-443654 had significantly extended survival compared to control animals; animals survived 79% and 43% longer than controls when A-443654-containing polymers were implanted simultaneously or in a delayed fashion, respectively. This small molecule also inhibited GBM stem-like cells with similar efficacy compared to traditionally cultured GBM cell lines. These results suggest that local delivery of an Akt small molecule inhibitor is effective against experimental intracranial glioma, with no observed resistance to GBM cells grown in stem cell conditions. PMID:19208828

  5. Sunitinib and SU11652 inhibit acid sphingomyelinase, destabilize lysosomes, and inhibit multidrug resistance.

    PubMed

    Ellegaard, Anne-Marie; Groth-Pedersen, Line; Oorschot, Viola; Klumperman, Judith; Kirkegaard, Thomas; Nylandsted, Jesper; Jäättelä, Marja

    2013-10-01

    Defective apoptosis signaling and multidrug resistance are major barriers for successful cancer treatment. To identify drugs capable of targeting treatment-resistant cancer cells, we screened small-molecule kinase inhibitor libraries for compounds that decrease the viability of apoptosis-resistant human MCF7-Bcl-2 breast cancer cells. SU11652, a multitargeting receptor tyrosine kinase inhibitor, emerged as the most potent compound in the screen. In addition to MCF7-Bcl-2 cells, it effectively killed HeLa cervix carcinoma, U-2-OS osteosarcoma, Du145 prostate carcinoma, and WEHI-S fibrosarcoma cells at low micromolar concentration. SU11652 accumulated rapidly in lysosomes and disturbed their pH regulation and ultrastructure, eventually leading to the leakage of lysosomal proteases into the cytosol. Lysosomal destabilization was preceded by an early inhibition of acid sphingomyelinase, a lysosomal lipase that promotes lysosomal membrane stability. Accordingly, Hsp70, which supports cancer cell survival by increasing lysosomal acid sphingomyelinase activity, conferred partial protection against SU11652-induced cytotoxicity. Remarkably, SU11652 killed multidrug-resistant Du145 prostate cancer cells as effectively as the drug-sensitive parental cells, and subtoxic concentrations of SU11652 effectively inhibited multidrug-resistant phenotype in Du145 prostate cancer cells. Notably, sunitinib, a structurally almost identical and widely used antiangiogenic cancer drug, exhibited similar lysosome-dependent cytotoxic activity, albeit with significantly lower efficacy. The significantly stronger lysosome-targeting activity of SU11652 suggests that it may display better efficacy in cancer treatment than sunitinib, encouraging further evaluation of its anticancer activity in vivo. Furthermore, our data provide a rationale for novel approaches to target drug-resistant cancers by combining classic chemotherapy with sunitinib or SU11652. PMID:23920274

  6. DMSO inhibits human platelet activation through cyclooxygenase-1 inhibition. A novel agent for drug eluting stents?

    SciTech Connect

    Asmis, Lars [Institute for Clinical Hematology, University Hospital Zuerich, Zuerich (Switzerland)] [Institute for Clinical Hematology, University Hospital Zuerich, Zuerich (Switzerland); Tanner, Felix C. [Cardiovascular Research, Physiology Institute, University of Zuerich, Zuerich (Switzerland) [Cardiovascular Research, Physiology Institute, University of Zuerich, Zuerich (Switzerland); Center for Integrative Human Physiology, University of Zuerich, Zuerich (Switzerland); Cardiology, Cardiovascular Center, University Hospital Zuerich, Zuerich (Switzerland); Sudano, Isabella [Cardiology, Cardiovascular Center, University Hospital Zuerich, Zuerich (Switzerland)] [Cardiology, Cardiovascular Center, University Hospital Zuerich, Zuerich (Switzerland); Luescher, Thomas F. [Cardiovascular Research, Physiology Institute, University of Zuerich, Zuerich (Switzerland) [Cardiovascular Research, Physiology Institute, University of Zuerich, Zuerich (Switzerland); Center for Integrative Human Physiology, University of Zuerich, Zuerich (Switzerland); Cardiology, Cardiovascular Center, University Hospital Zuerich, Zuerich (Switzerland); Camici, Giovanni G., E-mail: giovannic@access.uzh.ch [Cardiovascular Research, Physiology Institute, University of Zuerich, Zuerich (Switzerland); Center for Integrative Human Physiology, University of Zuerich, Zuerich (Switzerland)

    2010-01-22

    Background: DMSO is routinely infused together with hematopoietic cells in patients undergoing myeloablative therapy and was recently found to inhibit smooth muscle cells proliferation and arterial thrombus formation in the mouse by preventing tissue factor (TF), a key activator of the coagulation cascade. This study was designed to investigate whether DMSO prevents platelet activation and thus, whether it may represent an interesting agent to be used on drug eluting stents. Methods and results: Human venous blood from healthy volunteers was collected in citrated tubes and platelet activation was studied by cone and platelet analyzer (CPA) and rapid-platelet-function-assay (RPFA). CPA analysis showed that DMSO-treated platelets exhibit a lower adherence in response to shear stress (-15.54 {+-} 0.9427%, n = 5, P < 0.0001 versus control). Additionally, aggregometry studies revealed that DMSO-treated, arachidonate-stimulated platelets had an increased lag phase (18.0% {+-} 4.031, n = 9, P = 0.0004 versus control) as well as a decreased maximal aggregation (-6.388 {+-} 2.212%, n = 6, P = 0.0162 versus control). Inhibitory action of DMSO could be rescued by exogenous thromboxane A2 and was mediated, at least in part, by COX-1 inhibition. Conclusions: Clinically relevant concentrations of DMSO impair platelet activation by a thromboxane A2-dependent, COX-1-mediated effect. This finding may be crucial for the previously reported anti-thrombotic property displayed by DMSO. Our findings support a role for DMSO as a novel drug to prevent not only proliferation, but also thrombotic complications of drug eluting stents.

  7. Global Precipitation Measurement (GPM) Safety Inhibit Timeline Tool

    NASA Technical Reports Server (NTRS)

    Dion, Shirley

    2012-01-01

    The Global Precipitation Measurement (GPM) Observatory is a joint mission under the partnership by National Aeronautics and Space Administration (NASA) and the Japan Aerospace Exploration Agency (JAXA), Japan. The NASA Goddard Space Flight Center (GSFC) has the lead management responsibility for NASA on GPM. The GPM program will measure precipitation on a global basis with sufficient quality, Earth coverage, and sampling to improve prediction of the Earth's climate, weather, and specific components of the global water cycle. As part of the development process, NASA built the spacecraft (built in-house at GSFC) and provided one instrument (GPM Microwave Imager (GMI) developed by Ball Aerospace) JAXA provided the launch vehicle (H2-A by MHI) and provided one instrument (Dual-Frequency Precipitation Radar (DPR) developed by NTSpace). Each instrument developer provided a safety assessment which was incorporated into the NASA GPM Safety Hazard Assessment. Inhibit design was reviewed for hazardous subsystems which included the High Gain Antenna System (HGAS) deployment, solar array deployment, transmitter turn on, propulsion system release, GMI deployment, and DPR radar turn on. The safety inhibits for these listed hazards are controlled by software. GPM developed a "pathfinder" approach for reviewing software that controls the electrical inhibits. This is one of the first GSFC in-house programs that extensively used software controls. The GPM safety team developed a methodology to document software safety as part of the standard hazard report. As part of this process a new tool "safety inhibit time line" was created for management of inhibits and their controls during spacecraft buildup and testing during 1& Tat GSFC and at the Range in Japan. In addition to understanding inhibits and controls during 1& T the tool allows the safety analyst to better communicate with others the changes in inhibit states with each phase of hardware and software testing. The tool was very useful for communicating compliance with safety requirements especially when working with a foreign partner.

  8. Mechanisms of Caffeine-Induced Inhibition of UVB Carcinogenesis

    PubMed Central

    Conney, Allan H.; Lu, Yao-Ping; Lou, You-Rong; Kawasumi, Masaoki; Nghiem, Paul

    2013-01-01

    Sunlight-induced non-melanoma skin cancer is the most prevalent cancer in the United States with more than two million cases per year. Several studies have shown an inhibitory effect of caffeine administration on UVB-induced skin cancer in mice, and these studies are paralleled by epidemiology studies that indicate an inhibitory effect of coffee drinking on non-melanoma skin cancer in humans. Strikingly, decaffeinated coffee consumption had no such inhibitory effect. Mechanism studies indicate that caffeine has a sunscreen effect that inhibits UVB-induced formation of thymine dimers and sunburn lesions in the epidermis of mice. In addition, caffeine administration has a biological effect that enhances UVB-induced apoptosis thereby enhancing the elimination of damaged precancerous cells, and caffeine administration also enhances apoptosis in tumors. Caffeine administration enhances UVB-induced apoptosis by p53-dependent and p53-independent mechanisms. Exploration of the p53-independent effect indicated that caffeine administration enhanced UVB-induced apoptosis by inhibiting the UVB-induced increase in ATR-mediated formation of phospho-Chk1 (Ser345) and abolishing the UVB-induced decrease in cyclin B1 which resulted in caffeine-induced premature and lethal mitosis in mouse skin. In studies with cultured primary human keratinocytes, inhibition of ATR with siRNA against ATR inhibited Chk1 phosphorylation and enhanced UVB-induced apoptosis. Transgenic mice with decreased epidermal ATR function that were irradiated chronically with UVB had 69% fewer tumors at the end of the study compared with irradiated littermate controls with normal ATR function. These results, which indicate that genetic inhibition of ATR (like pharmacologic inhibition of ATR via caffeine) inhibits UVB-induced carcinogenesis support the concept that ATR-mediated phosphorylation of Chk1 is an important target for caffeine’s inhibitory effect on UVB-induced carcinogenesis. PMID:23785666

  9. Inhibition shapes acoustic responsiveness in spherical bushy cells.

    PubMed

    Keine, Christian; Rübsamen, Rudolf

    2015-06-01

    Signal processing in the auditory brainstem is based on an interaction of neuronal excitation and inhibition. To date, we have incomplete knowledge of how the dynamic interplay of both contributes to the processing power and temporal characteristics of signal coding. The spherical bushy cells (SBCs) of the anteroventral cochlear nucleus (AVCN) receive their primary excitatory input through auditory nerve fibers via large, axosomatic synaptic terminals called the endbulbs of Held and by additional, acoustically driven inhibitory inputs. SBCs provide the input to downstream nuclei of the brainstem sound source localization circuitry, such as the medial and lateral superior olive, which rely on temporal precise inputs. In this study, we used juxtacellular recordings in anesthetized Mongolian gerbils to assess the effect of acoustically evoked inhibition on the SBCs input-output function and on temporal precision of SBC spiking. Acoustically evoked inhibition proved to be strong enough to suppress action potentials (APs) of SBCs in a stimulus-dependent manner. Inhibition shows slow onset and offset dynamics and increasing strength at higher sound intensities. In addition, inhibition decreases the rising slope of the EPSP and prolongs the EPSP-to-AP transition time. Both effects can be mimicked by iontophoretic application of glycine. Inhibition also improves phase locking of SBC APs to low-frequency tones by acting as a gain control to suppress poorly timed EPSPs from generating postsynaptic APs to maintain precise SBC spiking across sound intensities. The present data suggest that inhibition substantially contributes to the processing power of second-order neurons in the ascending auditory system. PMID:26041924

  10. Kinetic basis for selective inhibition of cyclo-oxygenases.

    PubMed Central

    Gierse, J K; Koboldt, C M; Walker, M C; Seibert, K; Isakson, P C

    1999-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of prostaglandins by cyclo-oxygenases (COX). The discovery of a second COX isoform (COX-2) associated with inflammation led to agents that selectively inhibit COX-2, e.g. celecoxib. We evaluated the kinetics of inhibition of celecoxib and several NSAIDs. Celecoxib displays classic competitive kinetics on COX-1 (Ki=10-16 microM). An initial competitive interaction with COX-2 can also be discerned with celecoxib (Ki=11-15 microM), followed by a time-dependent interaction leading to potent inhibition, characterized as inactivation (Kinact=0.03-0.5 s-1). Half-maximal inhibition (IC50) using end-point assays reflects the competitive component on COX-1 (IC50=4-19 microM) and the inactivation component on COX-2 (IC50=0.003-0.006 microM). NSAIDs exhibit four distinct modes of COX inhibition based on kinetic behaviour: (1) competitive, e.g. ibuprofen; (2) weak binding, time-dependent, e.g. naproxen, oxicams; (3) tight binding, time-dependent, e.g. indomethacin; (4) covalent, e.g. aspirin. In addition, most NSAIDs display different kinetic behaviour for each isoform. Weakly binding inhibitors show variable behaviour in enzyme assays, with apparent inhibitory activity being markedly influenced by experimental conditions; determination of kinetic constants with this class is unreliable and IC50 values are strongly dependent on assay conditions. Although IC50 determinations are useful for structure/activity analyses, the complex and distinct mechanisms of enzyme inhibition of each COX isoform by the NSAIDs renders comparison of inhibitory activity on COX-1 and COX-2 using IC50 ratios of questionable validity. PMID:10215599

  11. Metformin activates AMP kinase through inhibition of AMP deaminase.

    PubMed

    Ouyang, Jiangyong; Parakhia, Rahulkumar A; Ochs, Raymond S

    2011-01-01

    The mechanism for how metformin activates AMPK (AMP-activated kinase) was investigated in isolated skeletal muscle L6 cells. A widely held notion is that inhibition of the mitochondrial respiratory chain is central to the mechanism. We also considered other proposals for metformin action. As metabolic pathway markers, we focused on glucose transport and fatty acid oxidation. We also confirmed metformin actions on other metabolic processes in L6 cells. Metformin stimulated both glucose transport and fatty acid oxidation. The mitochondrial Complex I inhibitor rotenone also stimulated glucose transport but it inhibited fatty acid oxidation, independently of metformin. The peroxynitrite generator 3-morpholinosydnonimine stimulated glucose transport, but inhibited fatty acid oxidation. Addition of the nitric oxide precursor arginine to cells did not affect glucose transport. These studies differentiate metformin from inhibition of mitochondrial respiration and from active nitrogen species. Knockdown of adenylate kinase also failed to affect metformin stimulation of glucose transport. Hence, any means of increase in ADP appears not to be involved in the metformin mechanism. Knockdown of LKB1, an upstream kinase and AMPK activator, did not affect metformin action. Having ruled out existing proposals, we suggest a new one: metformin might increase AMP through inhibition of AMP deaminase (AMPD). We found that metformin inhibited purified AMP deaminase activity. Furthermore, a known inhibitor of AMPD stimulated glucose uptake and fatty acid oxidation. Both metformin and the AMPD inhibitor suppressed ammonia accumulation by the cells. Knockdown of AMPD obviated metformin stimulation of glucose transport. We conclude that AMPD inhibition is the mechanism of metformin action. PMID:21059655

  12. DASATINIB INHIBITS THE GROWTH OF MOLECULARLY HETEROGENEOUS MYELOID LEUKEMIAS

    PubMed Central

    Guerrouahen, Bella S.; Futami, Muneyoshi; Vaklavas, Christos; Kanerva, Jukka; Whichard, Zakary L.; Nwawka, Kenechi; Blanchard, Elisabeth G.; Lee, Francis Y.; Robinson, Lisa J.; Arceci, Robert; Kornblau, Steven M.; Wieder, Eric; Cayre, Yvon E.; Corey, Seth J.

    2010-01-01

    Purpose Dasatinib is a dual Src/Abl inhibitor, recently approved for Bcr-Abl+ leukemias with resistance or intolerance to prior therapy. Because Src kinases contribute to multiple blood cell functions by triggering a variety of signaling pathways, we hypothesized that their molecular targeting might lead to growth inhibition in acute myeloid leukemia (AML). Experimental Design We studied growth factor-dependent and independent leukemic cell lines, including three cell lines expressing mutants of receptor tyrosine kinases (Flt3 or c-Kit) as well as primary AML blasts for responsiveness to dasatinib. Results Dasatinib resulted in the inhibition of Src family kinases in all cell lines and blast cells at ~10?9 M. It also inhibited mutant Flt3 or Kit tyrosine phosphorylation at ~10?6 M. Mo7e cells expressing the activating mutation (codon 816) of c-Kit were most sensitive to growth inhibition with a GI50 5×10?9 M. Primary AML blast cells exhibited growth inhibition < 10?6 M. Cell lines which showed growth inhibition at ~10?6 M demonstrated a G1 cell cycle arrest and correlated with accumulation of p21 and p27 protein. Addition of rapamycin or cytotoxic agents enhanced the growth inhibition. Dasatinib also caused the apoptosis of Mo7e cells expressing oncogenic Kit. Conclusions While all of the precise targets for dasatinib are not known, this multi-kinase inhibitor causes either growth arrest or apoptosis in molecularly heterogeneous AML. Addition of cytotoxic or targeted agents can enhance its effects. PMID:20145167

  13. Time dependency of craving and response inhibition during nicotine abstinence

    PubMed Central

    Tsaur, Stephen; Strasser, Andrew A.; Souprountchouk, Valentina; Evans, Gretchen C.; Ashare, Rebecca L.

    2015-01-01

    Background Nicotine withdrawal produces increased craving for cigarettes and deficits in response inhibition, and these withdrawal symptoms are predictive of relapse. Although it is well-established that these symptoms emerge early during abstinence, there is mixed evidence regarding whether they occur simultaneously. Given the importance of the early withdrawal period, this study examined craving and response inhibition at 24h and 72h abstinence. Methods Twenty-one non-treatment seeking adult smokers were evaluated at baseline, 24h, and 72h abstinence for craving (Questionnaire on Smoking Urges – Brief) and response inhibition (Stop Signal Task, Stroop Task, Continuous Performance Task). Generalized linear regression models were used for primary outcomes, and Pearson correlations for examining the association between craving and response inhibition. Results Factor 2 craving (anticipated relief of negative affect) increased from baseline to 24h abstinent (p=0.004), which subsided by 72h (p=0.08). Deficits in response inhibition measured by the Stop Signal Task were observed at 72h (p=0.046), but not 24h (p=0.318). No correlation was found between response inhibition and craving at any time point (p-values>0.19), except between the Stroop Task and factor 1 craving at baseline (p=0.025). Conclusions Factor 2 craving peaked at 24h, whereas deficits in response inhibition did not emerge until 72h, indicating that need to target craving and cognitive function during early abstinence may not occur simultaneously. Further characterizing the time course of withdrawal symptoms may guide development of targeted treatments for smoking cessation.

  14. Toll-like receptor 2 agonists inhibit human fibrocyte differentiation

    PubMed Central

    2010-01-01

    Background In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs) are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation. Results When human peripheral blood mononuclear cells (PBMCs) were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fibrocyte differentiation, even though enhanced extracellular tumor necrosis factor (TNF)-? accumulation and/or increased cell surface CD86 or major histocompatibility complex (MHC) class II levels were observed. However, all TLR2 agonists tested inhibited fibrocyte differentiation without any significant effect on cell survival. Adding TLR2 agonists to purified monocytes had no effect on fibrocyte differentiation. However, some TLR2 agonists caused PBMCs to secrete a factor that inhibits the differentiation of purified monocytes into fibrocytes. This factor is not interferon (IFN)-?, IFN-?, interleukin (IL)-12, aggregated immunoglobulin G (IgG) or serum amyloid P (SAP), factors known to inhibit fibrocyte differentiation. TLR2 agonist-treated PBMCs secrete low levels of IL-6, TNF-?, IFN-?, granulocyte colony-stimulating factor and tumor growth factor ?1, but combinations of these factors had no effect on fibrocyte differentiation from purified monocytes. Conclusions Our results indicate that TLR2 agonists indirectly inhibit fibrocyte differentiation and that, for some TLR2 agonists, this inhibition involves other cell types in the PBMC population secreting an unknown factor that inhibits fibrocyte differentiation. Together, these data suggest that the presence of some bacterial signals can inhibit fibrocyte differentiation and may thus slow wound closure. PMID:21106092

  15. Rationalizing cyclooxygenase (COX) inhibition for maximal efficacy and minimal adverse events

    Microsoft Academic Search

    James W Freston

    1999-01-01

    New information indicates that cyclooxygenase-2 (COX-2) is constitutively expressed in several tissues, including brain, lung, pancreas, kidney, and ovary, and plays an important role in renal and gastrointestinal function. Selective COX-2 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin, an effect that inhibits vasodilation without inhibiting platelet aggregation. The

  16. Inhibited and Aggressive Preschool Children at 23 Years of Age: Personality and Social Transitions into Adulthood

    Microsoft Academic Search

    Jens B. Asendorpf; Jaap J. A. Denissen; Marcel A. G. van Aken

    2008-01-01

    In a 19-year longitudinal study, the 15% most inhibited and the 15% most aggressive children at ages 4–6 years were followed up until age 23 years and were compared with controls who were below average in preschool inhibition or aggressiveness. As adults, inhibited boys and girls were judged as inhibited by their parents and showed a delay in establishing a

  17. Comparison of models for subtractive and shunting lateral-inhibition in receptor-neuron fields

    Microsoft Academic Search

    G. G. Furman; Murray Hi

    1965-01-01

    Two types of neuronal lateral inhibition in one-dimensional fields of receptors and neurons are considered. The first type, which has been demonstrated in the eye of Limulus, is called subtractive inhibition (SI): it assumes that neuronal activity depends on the difference between the total excitation and inhibition. The second type is called shunting inhibition (SHI): it assumes that inhibitory influences

  18. DIFFERENTIAL PROFILES OF CHOLINESTERASE INHIBITION AND NEUROBEHAVIORAL EFFECTS IN RATS EXPOSED TO FENAMIPHOS AND PROFENOPHOS.

    EPA Science Inventory

    The relationship between cholinesterase (ChE) inhibition and neurobehavioral changes was examined using two ChE-inhibiting organophosphorus pesticides, fenamiphos and profenophos. Both pesticides inhibit blood ChE, yet brain ChE is relatively spared (little to no inhibition up t...

  19. INHIBITION OF FUNGAL POlYGALACTURONASES BY EXTRACTS OF Eucalyptus grandis WITH DIFFERENT DISEASE SUSCEPTIBILITIES

    E-print Network

    was to determine the inhibition levels of polygalacturonase-inhibiting proteins (PGIPs) associated with a disease production and inhibition by PGIPs was measured by reducing sugar assays. We found that B. dothidea and C to inhibit the endoPGs', An exception was for C. zuluense, where PGIPs from the resistant clone were

  20. In vivo inhibition of RIPK2 kinase alleviates inflammatory disease.

    PubMed

    Tigno-Aranjuez, Justine T; Benderitter, Pascal; Rombouts, Frederik; Deroose, Frederik; Bai, XiaoDong; Mattioli, Benedetta; Cominelli, Fabio; Pizarro, Theresa T; Hoflack, Jan; Abbott, Derek W

    2014-10-24

    The RIPK2 kinase transduces signaling downstream of the intracellular peptidoglycan sensors NOD1 and NOD2 to promote a productive inflammatory response. However, excessive NOD2 signaling has been associated with numerous diseases, including inflammatory bowel disease (IBD), sarcoidosis and inflammatory arthritis, making pharmacologic inhibition of RIPK2 an appealing strategy. In this work, we report the generation, identification, and evaluation of novel RIPK2 specific inhibitors. These compounds potently inhibit the RIPK2 tyrosine kinase activity in in vitro biochemical assays and cellular assays, as well as effectively reduce RIPK2-mediated effects in an in vivo peritonitis model. In conjunction with the development of these inhibitors, we have also defined a panel of genes whose expression is regulated by RIPK2 kinase activity. Such RIPK2 activation markers may serve as a useful tool for predicting settings likely to benefit from RIPK2 inhibition. Using these markers and the FDA-approved RIPK2 inhibitor Gefitinib, we show that pharmacologic RIPK2 inhibition drastically improves disease in a spontaneous model of Crohn Disease-like ileitis. Furthermore, using novel RIPK2-specific inhibitors, we show that cellular recruitment is inhibited in an in vivo peritonitis model. Altogether, the data presented in this work provides a strong rationale for further development and optimization of RIPK2-targeted pharmaceuticals and diagnostics. PMID:25213858